Open-label, Single-arm Trial to Evaluate Antitumor Activity, Safety, and Pharmacokinetics of Tusamitamab Ravtansine (SAR408701) Used in Combination With Ramucirumab or Ramucirumab and Pembrolizumab in Metastatic, Non-squamous, Non Small-cell Lung Cancer (NSQ NSCLC) Patients With CEACAM5-positive Tumors, Previously Treated With Platinum-based Chemotherapy and an Immune Checkpoint Inhibitor
Phase: PHASE2
Conditions: Non-small Cell Lung Cancer Metastatic
Sponsor: Sanofi

NCT04394624

Amended Clinical Trial Protocol 02  
SAR408701-ACT16525 
20-Dec-2022 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
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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 
20 December 2022, version 1 (electronic 2.0) 
Amended Clinical Trial Protocol 01 
All 
12 November 2020, version 1 (electronic 1.0) 
Original Protocol 
 
10 December 2019, version 1 (electronic 1.0) 
 
Amended protocol 02 (20 December 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 because it significantly impacts the design of the study. 
OVERALL RATIONALE FOR THE AMENDMENT  
The purpose of this amendment is to add a new cohort of 6 to 12 patients to assess the safety and 
tolerability of a new combination of tusamitamab ravtansine (SAR408701) with ramucirumab and 
pembrolizumab given every 3 weeks (Q3W) to be further used in future clinical trials.  
Beside this change, further modifications to protocol wording were implemented, as detailed 
below.  
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Title and short tittle 
Modified title to add pembrolizumab 
 
To reflect addition of a new 
cohort 
Title and short title; Throughout the 
document 
Added tusamitamab ravtansine INN name and 
SAR408701 replaced by INN name 
The approved product name 
was added 
List of Figures; 1.2 Schema 
Added Figure 3c 
To reflect addition of a new 
cohort  
1.1 Synopsis; 2.1 Study rationale; 
3 Objectives and endpoints, Table 3; 
9.4.1 Efficacy analyses, Table 16; 
9.4.2 Safety analyses, Table 17 
Added objectives and endpoints specific to new 
cohort with the addition of pembrolizumab 
Added rationale to add pembrolizumab to the 
combination 
To reflect addition of a new 
cohort 
1.1 Synopsis, Intervention groups and 
duration; 4.1 Overall design 
Added details related to triplet cohort with 
pembrolizumab, added 1.3.2 
To reflect addition of a new 
cohort 
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Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis, Study interventions; 
6.1 Study interventions administered 
Added details related to pembrolizumab and 
updated dose regimen of SAR408701 and 
ramucirumab for doublet and triplet cohort 
separately. 
Added Table 8 for triplet cohort 
To reflect addition of a new 
cohort 
1.1 Synopsis, 4.1 Overall design 
Added DLT evaluation period  
Figure 2 and Figure 5 for Decision tree for 
triplet cohort for tusamitamab ravtansine, are 
newly added in Section 1.1 and 4.1, 
respectively 
To reflect addition of a new 
cohort 
1.3.2 Study Flow Chart - Triplet cohort 
Added new flow chart specific to the triplet 
cohort with addition of thyroid function tests and 
changed dosage schedule to Q3W 
To reflect addition of the new 
cohort 
1.3.3.  Pharmacokinetic/Anti-therapeutic 
antibody flow charts 
Added new flow chart for the triplet cohort as 
1.3.3.3 Triplet cohort 
To reflect addition of the new 
cohort 
2.3 Benefit/Risk Assessment 
Added information regarding potential benefit of 
pembrolizumab and combination with 
tusamitamab ravtansine 
To provide new information 
for the triplet cohort  
5.2 Exclusion criteria 
Added pembrolizumab related exclusion criteria 
E38 to E46 
Added “or ≥2.5 mL” was added to E10 
Added “arterial” thrombotic disorder to E08 
To reflect addition of 
pembrolizumab 
For clarity  
For clarity 
5.5 Criteria for temporarily delaying 
Added paragraph to mention Appendix 11  
To comply with new protocol 
template V8 
6.1 Study Intervention administered 
Added possibility to use PO premedication  
For clarity 
6.5.1 Treatments prohibited during study  
Added duration for erythropoietin prohibition for 
triplet cohort  
To reflect addition of the new 
cohort 
1.1 Synopsis; 4.1 Overall design; 
6.6.2 Triplet cohort, Table 10 
Added new section with dose reduction for 
triplet cohort  
Table 2 and Table 6 are newly added in 
Sections 1.1 and 4.1, respectively 
To reflect addition of the new 
cohort 
1.1 Synopsis; 6.6.4 Dose adjustement/dose 
delay, Table 12; 10.4 Appendix 4: 
Recommended supportive care and/or 
dose modification guidelines for 
drug-related adverse events 
Added pembrolizumab and dose modification 
for toxicity for the triplet cohort table 
To reflect addition of the new 
cohort 
7 Discontinuation of study intervention and 
participant discontinuation/withdrawal 
Added cycle duration, study cut-off for primary 
ORR endpoint analysis for the doublet cohort 
and secondary ORR endpoint analysis for the 
triplet cohort 
To reflect addition of the new 
cohort 
8.1 Efficacy assessment 
Specified tumor assessment frequency for the 
triplet cohort to 6 weeks  
To reflect addition of the new 
cohort 
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Section # and Name 
Description of Change 
Brief Rationale 
1.3.1 Study flow chart; 8.2.6.7 Proteinuria 
Removed tests in case of proteinuria 
>500mg/24 hours 
The sentence: If proteinuria >500 mg/24 h: 
blood tests including haptoglobin, LDH, platelet 
count and schizocytes should be performed 
systematically. is removed from footnote k of 
Section 1.3.1 and from Section 8.2.6.7 
Correction of error 
8.2.7 Immune-related adverse reactions  
Added new section with cross reference to 
Section 10.4 Appendix 4, for guidance for 
managing immune-related adverse reactions 
To reflect addition of the new 
cohort 
9.1 Statistical hypotheses 
Add the triplet cohort statistical hypotheses 
To reflect addition of the new 
cohort 
1.1 Synopsis; 4.1 Overall Design. 
9.2 Sample size determination 
Added sample size for triplet cohort  
Added new section 9.2.3 Sample size for the 
triplet cohort 
To reflect addition of the new 
cohort 
9.3 Population for analyses Table 15 
Clarified definition of screened population 
Definition for "DLT-Evaluable and Activity" is 
also updated 
For clarity  
9.4.1 Efficacy analysis Table 16; 
9.4.1.1 Analysis of primary efficacy 
endpoint for the doublet cohort/Secondary 
efficacy endpoint for the triplet cohort 
Added efficacy analysis for the triplet cohort 
To reflect addition of the new 
cohort 
1.1 Synopsis; 3 Objectives and endpoints 
Table 3; 9.4.1 Efficacy analyses Table 16; 
9.4.1.2 Analysis of secondary efficacy 
endpoints for the doublet cohort 
Added disease control rate as a secondary 
endpoint for doublet cohort 
For efficacy analysis 
1.1 Synopsis, 4.1 Overall design; 
9.4.2 Safety analyses Table 17; 
9.4.2.1 Analysis of primary safety endpoint 
Added endpoint for the triplet cohort and DLT 
observation period 
To reflect addition of the new 
cohort 
10.2. Appendix 2: Clinical Laboratory Tests 
- Table 18  
Added thyroid function assessment and 
parameters TSH, T3, FT4 for triplet cohort only   
To reflect addition of the new 
cohort. Monitoring of thyroid 
function as per the 
established safety profile of 
pembrolizumab 
10.3.1 Definition of AE 
Removed symptomatic and/or requiring either 
corrective treatment or consultation in the 
criteria to consider lab abnormality as AE   
To comply with Oncology 
standard 
10.10 Appendix 10: Strong CYP3A 
INHIBITORS 
Updated list of strong CYP3A inhibitors 
To reflect the last version list  
10.11 Appendix 11 
referenced in Sections 5.5, 7.1.2, 8, 9.4.3 
and 10.1.3 
Modified to specify this section is only 
applicable for COVID-19 
To comply with new protocol 
template V8.0   
Appendix 12 (Section 10.12)  
Moving summary of changes for amended 
protocol 1 to this section 
Per Sanofi process 
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Section # and Name 
Description of Change 
Brief Rationale 
10.13 Appendix 13 Abbreviations  
Added Q3W, DCR abbreviations 
To reflect addition of the new 
cohort 
11 References 
Added references 
To reflect addition of the new 
cohort 
Throughout 
Correction of typographical errors and 
standardization of wording  
Cross reference numbers are updated, 
throughout the document. 
For clarity 
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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 .................................................................................................................................. 6 
LIST OF TABLES ......................................................................................................................................... 11 
LIST OF FIGURES ........................................................................................................................................ 11 
1 
PROTOCOL SUMMARY ............................................................................................................... 12 
1.1 
SYNOPSIS ..................................................................................................................................... 12 
1.2 
SCHEMA ........................................................................................................................................ 24 
1.3 
SCHEDULE OF ACTIVITIES (SOA) .............................................................................................. 26 
1.3.1 
Study flow chart - Doublet cohort ................................................................................................... 26 
1.3.2 
Study flow chart - Triplet cohort ..................................................................................................... 29 
1.3.3 
Pharmacokinetic/Anti-therapeutic Antibody Flow Charts ............................................................... 32 
1.3.3.1 
Doublet cohort - Part 1: Safety run-in ............................................................................................ 32 
1.3.3.2 
Doublet cohort - Part 2 ................................................................................................................... 33 
1.3.3.3 
Triplet cohort .................................................................................................................................. 34 
2 
INTRODUCTION ............................................................................................................................ 35 
2.1 
STUDY RATIONALE...................................................................................................................... 35 
2.2 
BACKGROUND ............................................................................................................................. 37 
2.3 
BENEFIT/RISK ASSESSMENT ..................................................................................................... 37 
2.3.1 
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 ......................................................................... 48 
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4.3 
DOSE JUSTIFICATION ................................................................................................................. 49 
4.4 
END OF STUDY DEFINITION ....................................................................................................... 51 
5 
STUDY POPULATION .................................................................................................................. 52 
5.1 
INCLUSION CRITERIA .................................................................................................................. 52 
5.2 
EXCLUSION CRITERIA ................................................................................................................ 53 
5.3 
LIFESTYLE CONSIDERATIONS ................................................................................................... 57 
5.4 
SCREEN FAILURES...................................................................................................................... 57 
5.5 
CRITERIA FOR TEMPORARILY DELAYING PRESCREENING, SCREENING, STUDY 
INTERVENTION, STUDY PROCEDURES.................................................................................... 58 
6 
STUDY INTERVENTIONS ............................................................................................................. 59 
6.1 
STUDY INTERVENTIONS ADMINISTERED ................................................................................ 59 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY....................................................... 61 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ....................................... 62 
6.4 
STUDY INTERVENTION COMPLIANCE ...................................................................................... 62 
6.5 
CONCOMITANT THERAPY .......................................................................................................... 62 
6.5.1 
Treatments prohibited during the study ......................................................................................... 63 
6.6 
DOSE MODIFICATION .................................................................................................................. 63 
6.6.1 
Doublet cohort - Part 1 (Safety Run-In) ......................................................................................... 63 
6.6.2 
Triplet cohort .................................................................................................................................. 64 
6.6.3 
Doublet cohort (Part 1 and Part 2) and triplet cohort: Requirements for retreatment .................... 64 
6.6.4 
Dose adjustment/dose delay .......................................................................................................... 65 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................................... 67 
7.1 
DISCONTINUATION OF STUDY INTERVENTION ...................................................................... 68 
7.1.1 
Definitive discontinuation ............................................................................................................... 68 
7.1.2 
Temporary discontinuation/dosing delays ..................................................................................... 69 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY .................................. 69 
7.3 
LOST TO FOLLOW UP ................................................................................................................. 70 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................... 71 
8.1 
EFFICACY ASSESSMENTS ......................................................................................................... 71 
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8.2 
SAFETY ASSESSMENTS ............................................................................................................. 72 
8.2.1 
Physical examinations ................................................................................................................... 72 
8.2.2 
Specific ocular tests ....................................................................................................................... 73 
8.2.3 
Vital signs ....................................................................................................................................... 73 
8.2.4 
Cardiac assessment....................................................................................................................... 73 
8.2.4.1 
Electrocardiograms ........................................................................................................................ 73 
8.2.4.2 
Echocardiogram or MUGA scan .................................................................................................... 74 
8.2.5 
Clinical safety laboratory assessments .......................................................................................... 74 
8.2.6 
Guidelines for management of adverse events ............................................................................. 74 
8.2.6.1 
Hypersensitivity reactions .............................................................................................................. 74 
8.2.6.2 
Ocular toxicity ................................................................................................................................. 75 
8.2.6.3 
Management of anemia ................................................................................................................. 76 
8.2.6.4 
Management of neutropenia .......................................................................................................... 76 
8.2.6.5 
Liver function tests ......................................................................................................................... 76 
8.2.6.6 
Hypertension .................................................................................................................................. 77 
8.2.6.7 
Proteinuria ...................................................................................................................................... 77 
8.2.6.8 
Bleeding/Hemorrhage .................................................................................................................... 77 
8.2.6.9 
Arterial Thromboembolic Events .................................................................................................... 77 
8.2.6.10 Peripheral neuropathy .................................................................................................................... 77 
8.2.6.11 Colitis (including hemorrhagic) ....................................................................................................... 78 
8.2.7 
Immune-related adverse reactions ................................................................................................ 78 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ........................................................... 78 
8.3.1 
Adverse events, treatment-emergent adverse events, and adverse events of special 
interest ........................................................................................................................................... 78 
8.3.2 
Time period and frequency for collecting AE and SAE information ............................................... 79 
8.3.3 
Method of detecting AEs and SAEs ............................................................................................... 80 
8.3.4 
Follow-up of AEs and SAEs ........................................................................................................... 80 
8.3.5 
Regulatory reporting requirements for SAEs ................................................................................. 80 
8.3.6 
Pregnancy ...................................................................................................................................... 81 
8.3.7 
Disease-related events and/or disease-related outcomes not qualifying as AEs or SAEs ........... 81 
8.3.8 
Guidelines for reporting product complaints .................................................................................. 81 
8.4 
TREATMENT OF OVERDOSE ...................................................................................................... 82 
8.5 
PHARMACOKINETICS .................................................................................................................. 82 
8.5.1 
Non-compartmental analysis ......................................................................................................... 82 
8.5.2 
Population approach ...................................................................................................................... 83 
8.6 
PHARMACODYNAMICS ............................................................................................................... 83 
8.7 
GENETICS ..................................................................................................................................... 83 
8.8 
BIOMARKERS ............................................................................................................................... 83 
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8.9 
IMMUNOGENICITY ASSESSMENTS ........................................................................................... 83 
8.10 
HEALTH ECONOMICS .................................................................................................................. 84 
8.11 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH ................................ 84 
9 
STATISTICAL CONSIDERATIONS .............................................................................................. 86 
9.1 
STATISTICAL HYPOTHESES ....................................................................................................... 86 
9.2 
SAMPLE SIZE DETERMINATION ................................................................................................. 86 
9.2.1 
Sample size for the doublet cohort, safety run-in (Part 1) ............................................................. 86 
9.2.2 
Sample size for the doublet cohort, Part 2 ..................................................................................... 86 
9.2.3 
Sample size for the triplet cohort (safety run-in only) .................................................................... 87 
9.3 
POPULATIONS FOR ANALYSES ................................................................................................. 87 
9.4 
STATISTICAL ANALYSES ............................................................................................................ 88 
9.4.1 
Efficacy analyses ........................................................................................................................... 88 
9.4.1.1 
Analysis of primary efficacy endpoint for the doublet cohort / Secondary efficacy endpoint 
for the triplet cohort ........................................................................................................................ 88 
9.4.1.2 
Analysis of secondary efficacy endpoints for the doublet cohort ................................................... 89 
9.4.2 
Safety analyses .............................................................................................................................. 90 
9.4.2.1 
Analysis of primary safety endpoint ............................................................................................... 91 
9.4.2.2 
Analysis of adverse events ............................................................................................................ 91 
9.4.2.3 
Analysis of deaths .......................................................................................................................... 92 
9.4.2.4 
Analysis of clinical laboratory evaluations ..................................................................................... 92 
9.4.2.5 
Analysis of immunogenicity ............................................................................................................ 92 
9.4.3 
Other analyses ............................................................................................................................... 92 
9.5 
INTERIM ANALYSES .................................................................................................................... 93 
9.6 
DATA MONITORING COMMITTEE (DMC) ................................................................................... 93 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................ 94 
10.1 
APPENDIX 1:  REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ...... 94 
10.1.1 
Regulatory and ethical considerations ........................................................................................... 94 
10.1.2 
Financial disclosure........................................................................................................................ 94 
10.1.3 
Informed consent process .............................................................................................................. 95 
10.1.4 
Data protection ............................................................................................................................... 95 
10.1.5 
Committee Structure ...................................................................................................................... 96 
10.1.6 
Dissemination of clinical study data ............................................................................................... 96 
10.1.7 
Data quality assurance .................................................................................................................. 97 
10.1.8 
Source documents ......................................................................................................................... 97 
10.1.9 
Study and site closure .................................................................................................................... 98 
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10.1.10 Publication policy ........................................................................................................................... 98 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS ......................................................................... 98 
10.3 
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING .............................................. 100 
10.3.1 
Definition of AE ............................................................................................................................ 100 
10.3.2 
Definition of SAE .......................................................................................................................... 101 
10.3.3 
Recording and follow-up of AE and/or SAE ................................................................................. 102 
10.3.4 
Reporting of SAEs........................................................................................................................ 103 
10.4 
APPENDIX 4: RECOMMENDED SUPPORTIVE CARE AND/OR DOSE MODIFICATION 
GUIDELINES FOR DRUG-RELATED ADVERSE EVENTS ....................................................... 105 
10.5 
APPENDIX 5: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION ............................................................................................................................ 111 
10.6 
APPENDIX 6: GENETICS ........................................................................................................... 114 
10.7 
APPENDIX 7: RESPONSE EVALUATION CRITERIA IN SOLID TUMORS VERSION 1.1 ....... 114 
10.8 
APPENDIX 8: COUNTRY-SPECIFIC REQUIREMENTS ............................................................ 121 
10.9 
APPENDIX 9: CYP SUBSTRATES WITH NARROW THERAPEUTIC RANGE (NTR) .............. 121 
10.10 
APPENDIX 10: STRONG CYP3A INHIBITORS .......................................................................... 122 
10.11 
APPENDIX 11: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY ................................. 123 
10.11.1 Remote Prescreening Process .................................................................................................... 123 
10.11.2 Screening procedures: ................................................................................................................. 124 
10.11.3 Study intervention ........................................................................................................................ 124 
10.11.4 Study procedures ......................................................................................................................... 124 
10.11.5 Statistical analyses and deviation ................................................................................................ 125 
10.12 
APPENDIX 12: PROTOCOL AMENDMENT HISTORY .............................................................. 125 
10.13 
APPENDIX 13: ABBREVIATIONS ............................................................................................... 128 
11 
REFERENCES ............................................................................................................................. 131 
 
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LIST OF TABLES  
Table 1 - Dose reduction for the doublet cohort Part 1 (safety run-in) .......................................................... 16 
Table 2 - Dose reduction for the triplet cohort ............................................................................................... 18 
Table 3 - Objectives and endpoints ............................................................................................................... 40 
Table 4 - Dose reduction for the doublet cohort Part 1 (safety run-in) .......................................................... 43 
Table 5 - Dose-limiting toxicities .................................................................................................................... 45 
Table 6 - Dose reduction for the triplet cohort ............................................................................................... 47 
Table 7 - Overview of study interventions administered - Doublet cohort ..................................................... 59 
Table 8 - Overview of study interventions administered - Triplet cohort ....................................................... 59 
Table 9 - Dose reduction for doublet cohort for Part 1 (safety run-in) ........................................................... 64 
Table 10 - Dose reduction for triplet cohort ................................................................................................... 64 
Table 11 - Dose modification for toxicity in doublet cohort ............................................................................ 65 
Table 12 - Dose modification for toxicity in triplet cohort ............................................................................... 66 
Table 13 - List of pharmacokinetic parameters and definitions ..................................................................... 82 
Table 14 - Estimated objective response rate (ORR) depending on number of responders ........................ 87 
Table 15 - Populations for analyses .............................................................................................................. 87 
Table 16 - Efficacy analyses ......................................................................................................................... 88 
Table 17 - Safety analyses ............................................................................................................................ 90 
Table 18 - Protocol-required safety laboratory assessments ........................................................................ 99 
Table 19 - Response criteria ....................................................................................................................... 117 
Table 20 - Response in patients with target disease .................................................................................. 119 
Table 21 - Response in patients with non-target disease only.................................................................... 120 
Table 22 - List of CYP substrates with narrow therapeutic range ............................................................... 121 
Table 23 - List of strong (substrate AUC ratio ≥5) CYP3A inhibitors .......................................................... 122 
 
LIST OF FIGURES  
Figure 1 - Decision tree for the doublet cohort Part 1 for tusamitamab ravtansine ...................................... 17 
Figure 2 - Decision tree for triplet cohort for tusamitamab ravtansine .......................................................... 19 
Figure 3 - 3a-3b-3c - Graphical description of study design ......................................................................... 24 
Figure 4 - Decision tree for the doublet cohort Part 1 for tusamitamab ravtansine ...................................... 44 
Figure 5 - Decision tree for the triplet cohort for tusamitamab ravtansine .................................................... 47 
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1 
PROTOCOL SUMMARY  
1.1 
SYNOPSIS  
Protocol title: 
Open-label, single-arm trial to evaluate antitumor activity, safety, and pharmacokinetics of 
tusamitamab ravtansine (SAR408701) used in combination with ramucirumab or ramucirumab 
and pembrolizumab in metastatic, non-squamous, non-small-cell lung cancer (NSQ NSCLC) 
patients with CEACAM5-positive tumors, previously treated with platinum-based chemotherapy 
and an immune checkpoint inhibitor 
Short title: 
Tusamitamab ravtansine (SAR408701) in combination with ramucirumab or ramucirumab and 
pembrolizumab in pretreated patients with NSQ NSCLC (CARMEN-LC04) 
Rationale:  
Despite recent progress in the treatment of advanced NSCLC, there remains a need for effective 
new treatment at the time of disease progression. New cytotoxic treatments selectively targeted to 
tumor cells have the potential to improve efficacy while managing toxicity. 
One feature that can be used to target some tumor cells is surface expression of carcinoembryonic 
antigen-related cell adhesion molecule 5 (CEACAM5). High levels of CEACAM5 expression are 
observed in several epithelial tumors, including adenocarcinomas of the colon and stomach as 
well as NSQ NSCLC. 
Maytansinoids are antimitotic agents that inhibit microtubule formation to act as very potent 
cytotoxic agents against tumor cell lines in vitro, with IC50 values 100- to 1000-fold more potent 
than conventional tubulin binding compounds, including docetaxel. Tusamitamab ravtansine 
(SAR408701) is an antibody to CEACAM5 conjugated to the cytotoxic maytansinoid agent, 
(DM4). Encouraging preliminary antitumor activity of tusamitamab ravtansine in patients heavily 
pretreated for NSQ NSCLC has been demonstrated in an ongoing study (TED13751). The balance 
of anticipated benefits and the reported risks of tusamitamab ravtansine identified in ongoing 
studies TED13751 and TCD15054 supports its continued clinical development, both as 
monotherapy and in combination regimens with chemotherapy and immunotherapy agents. 
Ramucirumab (Cyramza®), a human IgG1 monoclonal antibody that inhibits vascular endothelial 
growth factor receptor-2 (VEGFR-2), administered 10 mg/kg every 3 weeks (Q3W) in 
combination with docetaxel, is approved for the treatment of patients with metastatic NSCLC.  
Ramucirumab administered 8 mg/kg every 2 weeks (Q2W) also is approved for use as a single 
agent or in combination with paclitaxel for gastric cancer and hepatocellular carcinoma, and in 
combination with folinic acid/fluorouracil/irinotecan (FOLFIRI) for colorectal cancer (CRC).  
The choice of dosing schedule used in this study is supported by preliminary efficacy data from 
studies evaluating tusamitamab ravtansine 100 mg/m2 Q2W and the ramucirumab 8 mg/kg Q2W  
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Immune checkpoint inhibitors (ICIs), administered alone or in combination with other anticancer 
therapies, have shown activity in treating a variety of tumor types, including NSCLC, with a 
manageable safety profile when combined with cytotoxic agents. Pembrolizumab (Keytruda®), a 
humanized IgG4 monoclonal antibody against programmed cell death protein 1 (PD-1), is 
indicated as a single agent as the first-line treatment of patients with NSCLC expressing 
programmed death-ligand 1 protein (PD-L1) (tumor proportion score [TPS] ≥1%) in US as 
determined by an approved test, and in EU if  [TPS] ≥50%, and for the treatment of patients with 
metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved 
test, with disease progression on or after platinum-containing chemotherapy in US  and for the 
treatment of locally advanced or metastatic non-small cell lung carcinoma in adults whose tumors 
express PD-L1 with a ≥1% TPS and who have received at least one prior chemotherapy regimen 
in EU.  
Pembrolizumab is also approved in combination with pemetrexed and platinum chemotherapy, as 
first-line treatment of patients with metastatic NSQ NSCLC, with no EGFR or ALK genomic 
tumor aberrations, and in combination with carboplatin and paclitaxel, as first-line treatment of 
patients with metastatic squamous NSCLC (1). 
Combined ICI and VEGF/VEGF receptor inhibition have shown benefit in multiple tumor types 
through immune modulation. Pembrolizumab and ramucirumab (P+R) were evaluated in patients 
with advanced, ICI-exposed, in a substudy of Lung-MAP1, a master protocol for patients with 
Stage IV previously treated NSCLC. In this randomized, Phase II study from the Lung-MAP 
platform,136 patients were randomized to receive pembrolizumab + ramucirumab or the 
Investigator's choice of standard therapeutic regimens (SOC). Overall survival (OS) was 
significantly improved with P+R compared to SOC: median (95% CI) OS was 14.5 (13.9 to 16.1) 
months for P+R: and 11.6 (9.9 to 13.0) months for SOC (HR: 0.69 [0.51 to 0.92]. P value from the 
standard log-rank test equal to 0.05 and 0 .15 from the weighted log-rank test. Neither 
progression-free survival (PFS) or objective response rate (ORR) differed between the treatment 
arms (2).  
Based on the experience of the first patients treated in ACT16146 for the dosage of tusamitamab 
ravtansine and pembrolizumab and the experience of the doublet cohort, the starting dose for 
tusamitamab ravtansine will be 150 mg/m2, ramucirumab 10 mg/kg and pembrolizumab 200 mg, 
every 3 weeks. 
Preliminary safety data for the tusamitamab ravtansine and pembrolizumab combination from 
Study ACT16146 as of 17 June 2022 indicate the combination was well tolerated. 
The aim of this study is to evaluate the safety, tolerability and antitumor activity (efficacy) of 
tusamitamab ravtansine in combination with ramucirumab alone, and tusamitamab ravtansine 
combined with both ramucirumab and pembrolizumab in participants with CEACAM5-positive 
(CEACAM5 ≥50%) NSQ NSCLC tumors. 
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Objectives and endpoints 
Doublet cohort 
Objectives 
Endpoints 
Primary 
• 
Part 1 (safety run-in):  
To assess the tolerability and to confirm the 
recommended dose of tusamitamab ravtansine in 
combination with ramucirumab in the NSQ NSCLC 
population. 
• 
Part 1  
Incidence of study drug-related dose-limiting 
toxicity (DLT) at Cycle 1 and Cycle 2 (C1D1 to 
C2D14). Anticipated DLT includes, but is not 
limited to,  
corneal toxicity. 
• 
Part 2:  
To assess the antitumor activity of tusamitamab 
ravtansine in combination with ramucirumab in  
the NSQ NSCLC population.  
• 
Part 2:  
Objective response rate (ORR) defined as  
proportion of participants with confirmed complete  
response (CR) or partial response (PR) as best  
overall response (BOR) determined per Response  
Evaluation Criteria in Solid Tumors (RECIST) v1.1.  
Secondary 
• 
To assess the safety and tolerability of tusamitamab 
ravtansine in combination with ramucirumab 
• 
Incidence of treatment emergent adverse events 
(TEAEs) and serious adverse events (SAEs) and 
laboratory abnormalities according to National  
Cancer Institute (NCI) Common Terminology  
Criteria for Adverse Events (CTCAE) V5.0 
• 
To assess the durability of the response to treatment 
with tusamitamab ravtansine in combination with 
ramucirumab  
• 
Duration of response (DOR), defined as the time  
from first documented evidence of CR or PR until 
progressive disease (PD) determined per  
RECIST v1.1 or death from any cause, whichever 
occurs first 
• 
To assess anti-tumor activity of tusamitamab  
ravtansine in combination with ramucirumab on 
progression free survival (PFS) and disease  
control rate (DCR) 
• 
Progression-free survival, defined as the time from  
the first investigational medicinal product (IMP) 
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 
• 
To assess the pharmacokinetic (PK) profiles of 
tusamitamab ravtansine (SAR408701) and  
ramucirumab when given in combination 
• 
Pharmacokinetic parameters of tusamitamab  
ravtansine (SAR408701) and ramucirumab 
• 
To assess the immunogenicity of tusamitamab 
ravtansine (SAR408701) when given in combination  
with ramucirumab 
• 
Incidence of anti-therapeutic antibodies (ATAs)  
against tusamitamab ravtansine (SAR408701) 
Abbreviations: ATA=antitherapeutic antibody; BOR=best overall response; CEA=carcinoembryonic antigen; CR=complete response;  
DLT=dose-limiting toxicity; DCR=disease control rate; DOR=duration of response; IMP=investigational medicinal product; NCI CTCAE= National 
Cancer Institute Common Terminology Criteria for Adverse Events; NSQ NSCLC=non-squamous, non-small-cell lung cancer; PD=progressive 
disease; PFS=progression-free survival; PK=pharmacokinetic; PR=partial response; RECIST=Response Evaluation Criteria in Solid Tumors. 
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Triplet cohort 
Objectives 
Endpoints 
Primary 
• 
To assess the tolerability and to confirm the 
recommended dose of tusamitamab ravtansine in 
combination with ramucirumab and pembrolizumab  
in the NSQ NSCLC population. 
• 
Incidence of study drug-related dose-limiting 
toxicity (DLT) at Cycle 1 (C1D1 to C1D21).  
Anticipated DLT includes, but is not limited to,  
corneal toxicity. 
Secondary 
• 
To assess the safety and tolerability of tusamitamab 
ravtansine in combination with ramucirumab and 
pembrolizumab 
• 
Incidence of treatment emergent adverse events 
(TEAEs) and serious adverse events (SAEs) and 
laboratory abnormalities according to National  
Cancer Institute (NCI) Common Terminology  
Criteria for Adverse Events (CTCAE) V5.0 
• 
To assess the antitumor activity of tusamitamab 
ravtansine in combination with ramucirumab and 
pembrolizumab in the NSQ NSCLC population.  
• 
Objective response rate (ORR) defined as  
proportion of participants with confirmed complete  
response (CR) or partial response (PR) as  
best overall response (BOR) determined per 
Response Evaluation Criteria in Solid Tumors 
(RECIST) v1.1.  
• 
To assess the immunogenicity of tusamitamab 
ravtansine when given in combination with  
ramucirumab and pembrolizumab 
• 
Incidence of anti-therapeutic antibodies (ATAs) 
against tusamitamab ravtansine 
Abbreviations: ATA=antitherapeutic antibody; BOR=best overall response; CR=complete response; DLT=dose-limiting toxicity; 
NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events; NSQ NSCLC=non-squamous, non small-cell lung 
cancer; PK=pharmacokinetic; PR=partial response; RECIST=Response Evaluation Criteria in Solid Tumors. 
Overall design: 
This is a Phase 2, open-label, single-arm, 2 cohorts, multi-center study assessing safety, efficacy 
(antitumor activity), and PK of the combination of tusamitamab ravtansine and ramucirumab 
(Doublet cohort), and tusamitamab ravtansine, ramucirumab, and pembrolizumab (Triplet cohort)  
in patients with metastatic, CEACAM5-positive (defined as CEACAM5 immunohistochemical 
[IHC] intensity ≥2+ in ≥50% of cells) NSQ NSCLC tumors, previously treated with 
platinum-based chemotherapy and an ICI. The prescreening phase will correspond to the period 
for collection of a participant’s tumor sample to allow determination of CEACAM5 status by 
central IHC. Only participants with NSQ NSCLC determined to be CEACAM5-positive by 
central IHC will go through protocol screening procedures during the screening phase.  
The doublet cohort will be in 2 parts: 
Part 1 (Safety Run-In): In Part 1, participants will receive ramucirumab 8 mg/kg followed by 
tusamitamab ravtansine every 2 weeks to assess the tolerability of the combination to be used in 
the subsequent part of the study. The first 3 participants will receive ramucirumab at 8 mg/kg 
followed by tusamitamab ravtansine 100 mg/m2 every 2 weeks. Administration of tusamitamab 
ravtansine will be initiated at least 1 hour after the completion of ramucirumab infusion.  
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As no overlap in the safety profiles for ramucirumab and tusamitamab ravtansine is anticipated, 
the starting dose for tusamitamab ravtansine is selected as the maximum tolerated dose (MTD) 
used in studies evaluating tusamitamab ravtansine as monotherapy. 
A minimum delay of 1 week is required between the initial dose in the first participant treated in a 
DL cohort and dosing the next 2 participants treated at the same DL. 
• If ≤1/3 participants treated at the starting dose experiences a DLT, 3 additional participants 
will be treated to confirm the tolerability of the combination.  
- 
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 DLTs, the dose will be 
de-escalated to DL -1. 
• If ≥2/3 participants treated at the starting dose experience DLTs, the dose will be 
de-escalated to DL minus 1 (DL -1). 
• If ≤1 of the first 3 participants treated at DL -1 experiences a DLT, 3 additional 
participants will be treated at this DL. 
- 
If ≤1/6 participants treated at DL -1 experiences a DLT, DL-1 will be the RP2D. 
- 
If ≥2/6 participants treated at DL -1 experience a DLT, an alternative dosage might 
be considered or the doublet cohort may be stopped. 
• If ≥2/3 participants treated at DL -1 experience a DLT, an alternative dosage might be 
considered or the doublet cohort may be stopped. 
Note: If ≥2/6 or ≥2/3 participants treated at DL -1 experience DLTs, an alternative dosage might 
be considered from a safety viewpoint by the Sponsor after consulting the Study Committee (SC).  
Table 1 shows dose reduction in the case of DLTs occurring in 2 or more of the first 3 participants 
or of 6 participants in a DL cohort in Part 1. Figure 1 shows the decision tree for doses to be 
administered in Part 1.  
Table 1 - Dose reduction for the doublet cohort Part 1 (safety run-in)  
Dose level (DL)  
Tusamitamab ravtansine  
Ramucirumab 
Starting dose 
100 mg/m2 Q2W 
8 mg/kg Q2W 
Minus -1 (DL-1) 
80 mg/m2 Q2W 
8 mg/kg Q2W 
BSA=body surface area; DL=dose level; Q2W=every 2 weeks. 
Infusion of tusamitamab ravtansine will be administered at least 1 hour after the end of ramucirumab infusion. For patients with a BSA 
>2.20 m2, the SAR408701 dose will be calculated based on a BSA of 2.20 m2. 
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Figure 1 - Decision tree for the doublet cohort Part 1 for tusamitamab ravtansine  
 
* Note: In case of 2 or more DLTs at DL -1, the cohort may be stopped or the dosage reconsidered. 
Abbreviations: DL -1=dose level -1 (80 mg/m2); DLT=dose-limiting toxicity; RP2D=recommended dose. 
Part 2: 30 treated participants evaluable for response are planned (the 6 participants from the safety 
run-in treated at the RP2D will be included). 
The triplet cohort will have only 1 part: 
Participants will receive ramucirumab 10 mg/kg, tusamitamab ravtansine followed by 
pembrolizumab 200 mg, every 3 weeks to assess the tolerability of the combination to be used in 
future clinical studies. The first 3 participants will receive ramucirumab at 10 mg/kg, tusamitamab 
ravtansine 150 mg/m2 followed by pembrolizumab 200 mg every 3 weeks. Administration of 
tusamitamab ravtansine will be initiated at least 1 hour after the completion of ramucirumab 
infusion.  
The starting dose for tusamitamab ravtansine is 150 mg/m2 and was defined based on findings 
from first-in-human study TED13751. In this study, the RP2D for tusamitamab ravtansine given 
Q3W was 170 mg/m2. Given that tusamitamab ravtansine exposure PK parameters at Cycle 1 of 
administration as a single agent of 170 mg/m2 Q2W were significantly associated with the 
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occurrence of Grade ≥2 corneal events, it is anticipated that 150 mg/m2 may result in less ocular 
toxicity, and overall will be better tolerated than 170 mg/m2. In addition, this dose corresponds to 
the same dose intensity as with the recommended 100 mg/m² Q2W dose.  
A minimum delay of 1 week is required between the initial dose in the first participant treated in a 
DL cohort and dosing the next 2 participants treated at the same DL. 
• If ≤1/3 participants treated at the starting dose experiences a DLT, 3 additional participants 
will be treated to confirm the tolerability of the combination.  
- 
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 DLTs, the dose will be 
de-escalated to DL -1. 
• If ≥2/3 participants treated at the starting dose experience DLTs, the dose will be 
de-escalated to DL minus 1 (DL -1). 
• If ≤1 of the first 3 participants treated at DL -1 experiences a DLT, 3 additional 
participants will be treated at this DL. 
- 
If ≤1/6 participants treated at DL -1 experiences a DLT, DL-1 will be the RP2D. 
- 
If ≥2/6 participants treated at DL -1 experience a DLT, an alternative dosage might 
be considered or the triplet cohort may be stopped. 
• If ≥2/3 participants treated at DL -1 experience a DLT, an alternative dosage might be 
considered or the triplet cohort may be stopped. 
Note: If ≥2/6 or ≥2/3 participants treated at DL -1 experience DLTs, an alternative dosage might 
be considered from a safety viewpoint by the Sponsor after consulting the Study Committee (SC).  
Table 2 shows dose reduction in the case of DLTs occurring in 2 or more of the first 3 participants 
or of 6 participants in a DL triplet cohort. Figure 2 shows the decision tree for doses to be 
administered.    
Table 2 - Dose reduction for the triplet cohort  
Dose level (DL)  
Tusamitamab 
ravtansine  
ramucirumab 
pembrolizumab 
Starting dose 
150 mg/m2 Q3W 
10 mg/kg Q3W 
200 mg Q3W 
Minus -1 (DL-1) 
120 mg/m2 Q3W 
10 mg/kg Q3W 
200 mg Q3W 
DL=dose level; Q3W=every 3 weeks. 
Infusion of tusamitamab ravtansine will be administered at least 1 hour after the end of ramucirumab infusion. For patients with a BSA 
>2.20 m2, the tusamitamab ravtansine dose will be calculated based on a BSA of 2.20 m2. 
 
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Figure 2 - Decision tree for triplet cohort for tusamitamab ravtansine  
 
* Note: In case of 2 or more DLTs at DL - 1, the cohort may be stopped or the dosage reconsidered. 
Abbreviations: DL -1=dose level -1 (120 mg/m2); DLT=dose-limiting toxicity; RP2D=recommended dose. 
The study cut-off for the secondary ORR endpoint analysis of triplet cohort corresponds to the 
date on which all evaluable treated patients have had at least 2 post baseline tumor assessments, 
experienced confirmed objective response, or have discontinued the study for any reason. This 
study cut-off will occur approximately 4.5 months after the date of the first IMP administration of 
the last participant: 3 months for 2 tumor assessments and 1.5 months if a confirmation of 
response is needed. 
Disclosure Statement: This is a single-arm, 2 cohorts, open-label, treatment study with no 
masking in patients with previously treated metastatic NSQ NSCLC. 
Number of participants: 
In the doublet cohort, approximately 225 participants will be prescreened to achieve up to 
approximately 36 treated participants, based on an estimated CEACAM5 prescreening failure rate 
of 80% and an estimated study screen-failure rate of 20%.   
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In the triplet cohort, approximately 74 participants will be prescreened to achieve up to 
approximately 12 DLT evaluable participants, based on the doublet cohort CEACAM5 
prescreening failure rate of 79% and an estimated study screen-failure rate of 23%. 
Intervention groups and duration: 
The duration of the study for a participant will include:  
• Screening period: up to 28 days. 
• Treatment period: once successfully screened, enrolled participants may receive study 
intervention until disease progression, unacceptable AE, or the participant’s or 
investigator’s decision to stop the treatment. Each cycle of treatment will have a duration 
of 2 weeks in the doublet cohort and 3 weeks in triplet cohort. After discontinuing study 
intervention, participants will return to the study site approximately 30 days after the last 
investigational medicinal product (IMP) administration or before the participant receives 
another anti-cancer therapy, whichever is earlier, for end-of-treatment assessments. 
• Safety follow-up visit: will be performed approximately 90 days after the last dose of 
IMP. If any ongoing related AE/SAE is resolved or stabilized, no further follow-up visit is 
needed. 
The expected duration of study intervention for participants may vary, based on progression date; 
median expected duration of study per participant is estimated as 11 months (up to 1 month for 
screening, a median of 6 months for treatment, and a median of 4 months for end-of-treatment 
assessments and safety follow-up visit). 
Study interventions 
Study interventions include tusamitamab ravtansine, ramucirumab, and pembrolizumab.  To 
prevent hypersensitivity reactions, each administration will be preceded by premedication. Each 
cycle of treatment will have a duration of 2 weeks in the doublet cohort, and 3 weeks in the triplet 
cohort.  
Investigational medicinal products 
Ramucirumab 
Ramucirumab will be administered prior to administration of tusamitamab ravtansine.  
• Formulation: CYRAMZA® (ramucirumab) is a concentrate for solution for infusion 
supplied in 10 mL or 50 mL single-use vial. Each vial contains either 100 mg 
ramucirumab in 10 mL (10 mg/mL) or 500 mg ramucirumab in 50 mL (10 mg/mL). 
• Route of administration: intravenous (IV) infusion. 
• Dose regimen:  
- 
In the doublet cohort, ramucirumab will be administered as an 8 mg/kg IV infusion 
over 1 hour on Day 1 of every 2-week cycle. Each administration will be preceded by 
premedication (as per the approved product label) to prevent hypersensitivity reaction. 
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- 
In the triplet cohort, ramucirumab will be administered as a 10 mg/kg IV infusion over 
1 hour on Day 1 of every 3-week cycle. Each administration will be preceded by 
premedication (as per the approved product label) to prevent hypersensitivity reaction. 
Tusamitamab ravtansine  
tusamitamab ravtansine infusion will start ≥1 hour after the end of ramucirumab infusion.  
• Formulation:  
Tusamitamab ravtansine is supplied as a 25 mL extractable volume of concentrate for 
solution for infusion of 125 mg contained in a 30 mL type I glass vial.  
• Route of administration: IV infusion. 
• Dose regimen:  
- 
In the doublet cohort, tusamitamab ravtansine 100 mg/m2 (or 80 mg/m2, if deemed the 
appropriate dose by the SC) will be administered via IV infusion over 1 hour, 
30 minutes on Day 1, and then every 2 weeks.  
- 
In the triplet cohort, tusamitamab ravtansine 150 mg/m2 (or 120 mg/m2, if deemed the 
appropriate dose by the SC) will be administered via IV infusion over 1 hour, 
30 minutes on Day 1, and then every 3 weeks. 
• For patients with a body surface area (BSA) >2.20 m2, the dose of tusamitamab ravtansine 
will be calculated based on a BSA of 2.20 m2. 
Pembrolizumab 
In the triplet cohort, pembrolizumab will be administered after ramucirumab and tusamitamab 
ravtansine. 
• Formulation: Keytruda® (pembrolizumab) is a concentrate for solution for infusion 
supplied in 100 mg/4 mL (25 mg/mL) solution in single-dose vials. 
• Route of administration: intravenous (IV) infusion. 
• Dose regimen: pembrolizumab will be administered as a 200 mg IV infusion over 
30 minutes on Day 1 and then Q3W. 
Noninvestigational medicinal products:  
Premedication: 
Both tusamitamab ravtansine and ramucirumab have potential risk of infusion-related allergic 
reaction; therefore, premedication with an IV histamine H1 antagonist (diphenhydramine 50 mg 
IV or equivalent; eg, cetirizine, promethazine, dexchlorpheniramine, according to local approval 
and availability) given approximately at least 15 minutes before ramucirumab administration is 
required for all participants.  If a participant previously experienced an infusion-related reaction 
(IRR) following a dose of ramucirumab or tusamitamab ravtansine, premedication for subsequent 
infusions will also include dexamethasone 10 mg IV and acetominophen (paracetamol). All drugs 
used as premedication will be entered on the concomitant premedication page. 
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Statistical considerations: 
• Sample size calculations: 
This study is divided into 2 cohorts:  
Doublet cohort: the cohort is divided in 2 parts: a safety run-in (Part 1) and Part 2. 
In the safety run-in Part, 6 to 12 DLT-evaluable participants will be enrolled in 
order to confirm the RP2D.  In Part 2, the plan is to enroll and treat enough 
participants to attain a total of 30 participants evaluable for activity (ie, having at 
least 1 post-baseline tumor assessment). The 6 participants treated at the RP2D will 
also be evaluable for Part 2. 
Triplet cohort: the cohort will have only 1 part: a safety run-in. 6 to 
12 DLT-evaluable participants will be enrolled in order to confirm the RP2D.    
• Main analysis populations: 
- 
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 analysis of all efficacy parameters. 
- 
DLT-Evaluable population: For the doublet cohort: All participants who received 
2 cycles with at least 80% of the intended dose for both tusamitamab ravtansine and 
ramucirumab at each of the 2 first infusions unless they discontinued the study 
intervention before the end of Cycle 2 due to a DLT. For the triplet cohort: Participants 
who received 1 cycle with at least 80% of the intended dose for each IMP of the 
combination. Participants should have completed Cycle 1 unless they experienced a 
DLT before the end of Cycle 1. 
- 
Activity population (applicable for doublet cohort only): All treated participants 
who have measurable disease at study entry and at least 1 postbaseline evaluable tumor 
assessment. Participants with early clinical progression or early death due to disease 
progression (ie, before first planned tumor assessment) will also be included in this set. 
This population is the secondary population for analysis of efficacy parameters of the 
doublet cohort. 
- 
PK population: All participants from the All-Treated population who actually 
received at least 1 dose or a part of a dose of tusamitamab ravtansine or ramucirumab 
with at least 1 evaluable postbaseline concentration. 
- 
ATA population: All treated participants with at least 1 post-baseline ATA result 
(negative, positive, or inconclusive). 
• Analysis of Primary endpoints for the doublet cohort:  
- 
Objective response rate (ORR) will be summarized using descriptive statistics and 
95% exact confidence intervals (CIs) will be provided using the Clopper-Pearson 
method. 
- 
The DLTs observed during the DLT observation period (Cycle 1 and Cycle 2), will be 
summarized on the DLT-evaluable population, by dose level. In addition, AEs that 
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meet the DLT criteria in subsequent cycles will be summarized on the all-treated 
population. Details will be provided by participant. 
• Analysis of Primary endpoint for the triplet cohort:  
- 
The DLTs observed during the DLT observation period (Cycle 1), 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. 
• Analysis of secondary efficacy endpoints for the doublet cohort: 
- 
Duration of response will be summarized for the subgroup of participants who achieve 
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. 
- 
Progression-free survival will be summarized using Kaplan-Meier methods. The 
median PFS times and associated 95% CI will be provided, along with probabilities of 
being progression-free at different time points. 
- 
Disease control rate (DCR) will be summarized using descriptive statistics and 95% 
exact confidence intervals (CIs) will be provided using the Clopper-Pearson method. 
• Analysis of secondary efficacy endpoints for the triplet cohort: 
- 
ORR will be summarized using descriptive statistics and 95% exact confidence 
intervals (CIs) will be provided using the Clopper-Pearson method. 
• 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, 
adverse events of special interest (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 Committee: No 
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Triplet cohort: 
Figure 3c: 
 
 
 
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1.3 
SCHEDULE OF ACTIVITIES (SOA)  
1.3.1 Study flow chart - Doublet cohort  
Procedure 
Pre-
screeninga Screeningb 
Treatment cycle 1 
Treatment cycle 2 + 
End of treatment 
90 (±7) Days 
(3 month) 
Follow-upd 
Notes* 
Day 
 
Days to first 
infusion 
D1 
14 (±2) days from previous infusion 30 (±5) days from 
last infusion 
 
 
 
 
 
Pre-infusionc 
EOI 
Pre-infusionc 
Every 8 weeks 
(±7 days) 
 
 
 
CEACAM5 expression statusa (archival or fresh tumor 
tissue) – central IHC/ prescreening Informed consent 
X 
 
 
 
 
 
 
 
 
Informed Consent 
 
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
 
≤28 
X 
 
 
 
 
 
Section 5.1,  5.2  
Demography, medical/surgical/disease/smoking historye 
 
≤28 
 
 
 
 
 
 
 
NSCLC characteristicsf 
X 
≤28 
 
 
 
 
 
 
 
Height  
 
≤7 
 
 
 
 
 
 
 
Performance status (ECOG) 
 
≤7 
X 
 
X 
 
X 
X 
Section 8.2.1, 8.2.3 
Physical examination,including vital signs, body weightg 
 
≤7 
X 
 
X 
 
X 
X 
Section 8.2.1  
Hematologyh 
 
≤7 
X 
 
X 
 
X 
 
Section 8.2.5, 10.2 
(Appendix 2) 
Coagulationi 
 
≤7 
X 
 
X 
 
X 
 
Section 10.2 , 
(Appendix 2) 
Clinical blood chemistryj 
 
≤7 
X 
 
X 
 
X 
 
Section 8.2.5, 10.2 
(Appendix 2) 
Urinalysisk 
 
≤7 
X  
 
X 
 
 
 
Section 10.2 , 
(Appendix 2) 
HBsAg & HCV serology and HIV test (only if required at 
country level)  
 
X 
 
 
 
 
 
 
Section 10.8 , 
(Appendix 8) 
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Procedure 
Pre-
screeninga Screeningb 
Treatment cycle 1 
Treatment cycle 2 + 
End of treatment 
90 (±7) Days 
(3 month) 
Follow-upd 
Notes* 
Day 
 
Days to first 
infusion 
D1 
14 (±2) days from previous infusion 30 (±5) days from 
last infusion 
 
 
 
 
 
Pre-infusionc 
EOI 
Pre-infusionc 
Every 8 weeks 
(±7 days) 
 
 
 
Urine or Serum pregnancy testl 
 
≤7 
 
 
X 
 
X 
X 
Section 10.2 
(Appendix 2) 
Section 10.5 
(Appendix 5) 
Left ventricular ejection fraction (MUGA/echocardiogram)m 
 
≤28 
 
  
 
 
 
 
Section 8.2.4.2 
12-lead ECGn 
 
≤7 
X 
X 
X 
 
X 
 
Section 8.2.4.1 
Specific ocular testso 
 
≤28 
 
 
 
 
X 
 
Section 8.2.2 
Tusamitamab ravtansine/Ramucirumab administration 
 
 
X 
 
X 
 
 
 
Section 6.1 
AE assessmentp 
X 
 
Continuously throughout the study period 
Section 8.2, 8.3, 
10.3 (Appendix 3) 
Concomitant medicationq 
 
X 
Continuously throughout the study period 
Section 6.5 
Tumor assessment – RECIST v1.1 - CT/MRI; relevant 
surrogate markersr 
 
≤28 
 
 
 
X 
X 
X 
Section 8.1 
Circulating CEAs 
X 
≤28 
 
 
 
X 
X 
X 
 
IgG 
 
 
X 
 
 
 
 
 
 
Record further anticancer therapy 
 
 
 
 
 
 
 
X 
 
Tusamitamab ravtansine and ramucirumab PK 
 
 
Refer to PK/ATA flowchart, Section 1.3.3 
 
 
Section 8.5 
Tusamitamab ravtansine Immunogenicity 
 
 
Refer to PK/ATA flowchart, Section 1.3.3 
 
 
Section 8.9 
Abbreviations: AE=adverse event; AESI=AE of special interest; ALT (SGPT)=alanine aminotransferase; AST (SGOT)=aspartate aminotransferase; ATA=antitherapeutic antibody; CEA=carcinoembryonic antigen; 
CEACAM5=carcinoembryonic antigen-related cell adhesion molecule 5; CR=complete remission; CT=computed tomography; eCRF=electronic case report form; ECOG=Eastern Cooperative Oncology Group 
(performance status); ECG=electrocardiogram; EOI=end of infusion; HBsAg=hepatitis B virus surface antigen; HCV=hepatitis C virus; HIV=human immunodeficiency virus; IMP=investigational medicinal product; 
LVEF=left ventricular ejection fraction; MRI=magnetic resonance imaging; MUGA=multigated acquisition scan; NSCLC=non-small-cell lung cancer; PD=progressive disease; PK=pharmacokinetic; PR=partial 
response; RBC=red blood cells; RECIST=Response Evaluation Criteria in Solid Tumors; SAE=serious AE; SD=stable disease; WBC=white blood cells. 
a Prescreening:  a prescreening Informed Consent will be signed by the patient for CEACAM5 assay on archival or fresh tumor tissue and circulating CEA assay unless results are available from an assay for 
circulating CEA and from CEACAM5 testing for another study; in this case, an addendum to the informed consent will be sufficient. 
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b Screening: 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. All the tests or procedures on D1 should be done at predose time unless otherwise stated. Assessments must be performed prior to first IMP 
administration: 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, echocardiography, 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 D1 pre-dose: Cycle 1 D1 refers to the day the participant receives the initial dose of IMP. D1 of Cycle 2 and of each subsequent cycle corresponds to D15 of the previous cycle. During treatment, D1 assessment 
can be done on the day of infusion (before infusion) or the day before. C1D1 hematology, blood chemistry, coagulation and urinalysis tests may be omitted if baseline test performed within 7 days are normal. If 
baseline tests are abnormal should be repeated within 2 days of first study intervention. 
d Follow-up visit: SAEs (regardless of relationship with study treatment) and IMP-related AEs ongoing at the end of study treatment, and any new IMP-related AE/SAE/AESI will be followed until resolution or 
stabilization (defined as an event ongoing without any change for at least 3 months).  Date of disease progression and further anticancer treatment will be collected at the follow-up visit. Participants who stopped 
treatment before documented progressive disease (PD; ie, achieving stable disease [SD], or complete or partial response [CR or PR]) should undergo a tumor assessment and an on-site follow-up visit every 
12 weeks (±7 days) after the last tumor assessment until radiological disease progression, death, study cut-off date of the secondary ORR endpoint of the triplet cohort, initiation of further anti-cancer therapy, or 
withdrawal of participant’s consent, whichever comes first. Participants with documented disease progression should attend an on-site follow-up visit 90 days after the last dose of study medication. If every 
ongoing related AE/SAE/AESI is resolved or stabilized, no further follow-up visit is needed.    
e Disease history includes previous antitumor therapy (type, start and end dates, reason for discontinuation and response to the therapy) and smoking history. 
f 
NSCLC characteristics will include histologic types, stage at diagnosis, disease extent at study entry, (collected at screening) and specific mutations including PD-1 expression status (to be collected only at 
prescreening). 
g Physical examination will include: vital signs (temperature, blood pressure, heart rate) and examination of major body systems. Signs and symptoms will be reported in the electronic case report form (eCRF) as 
AEs only if they are still present at the time of first IMP administration 
h Hematology: Hemoglobin, hematocrit, RBC, WBC with differential, platelet counts. These tests will be done before IMP administration at each cycle. If Grade 4 neutropenia, assess absolute neutrophil count (ANC) 
every 2-3 days until ANC ≥0.5 x 109/L. During first 2 cycles, hematology will be performed weekly.  
i 
Coagulation: International normalized ratio (INR), aPTT. 
j 
Clinical blood chemistry: Liver function tests: SGOT (AST), SGPT (ALT), total bilirubin, conjugated bilirubin, AP. Renal function tests: Urea (or BUN) & creatinine. Electrolytes: Sodium, potassium, calcium, glucose, 
Others: LDH, albumin and total proteins. During first cycle, liver function tests will be performed weekly. The liver function tests and renal function tests will be done before IMP administration at each cycle, unless 
clinically appropriate. In case of Grade ≥3 liver function abnormal tests, additional tests will be repeated every 2-3 days until recovery to baseline value.   
k Urinalysis tests on morning spot will be performed by dipstick at baseline, and at every treatment cycle. In case of proteinuria ≥ ++ (dipstick), proteinuria quantification by proteinuria/24 h should be performed.  
l 
Serum pregnancy test: women of childbearing potential must have a negative serum pregnancy test result within 7 days prior to the initial dose of IMP. A pregnancy test (serum/urine) will be repeated every 
4 weeks before IMP administration, and a serum test will be repeated at the End of Treatment evaluation (30±5 days after the last IMP administration), and at the Follow-up visit (90±7 days after last IMP dose).  
m Echocardiogram or MUGA scan: left ventricular ejection fraction (LVEF) will be evaluated during screening period, and whenever clinically indicated. 
n 12-lead ECG is required at baseline (In case the ECG performed less than 7 days before 1st IMP administration is considered as normal, there is no need to repeat it just before the 1st IMP) before starting the and 
after completing the first IMP administration (within 30 minutes after the end of tusamitamab ravtansine infusion).The ECG after the infusion at cycle1 should be performed at any case; before IMP administration at 
each cycle; and at the End of treatment evaluation, 22 to 30 days after last IMP administration.   
o Specific ocular tests will include assessment of ocular/visual symptoms and ocular exams including visual acuity, slit lamp under dilatation, and Schirmer’s test at screening and whenever clinically indicated. 
p AE: For participant who was prescreened and had fresh biopsy, only the Adverse Events related to the fresh biopsy procedure itself should also be reported in eCRF as general requirement of AE/SAE with the 
reporting time frame interval of 1 month for the prescreening period after fresh biopsy. 
q Concomitant medication will be recorded in the eCRF from 28 days prior to the first study intervention administration, before every cycle during the study treatment period, and for up to 30 days after the final dose 
of study intervention. Once the participant has withdrawn from study treatment, concomitant medication should only be recorded if used to treat new or unresolved study treatment-related adverse events. 
r 
Tumor assessment will be made at every 8 weeks interval (±7 days window) during the study treatment period until radiological disease progression; initiation of further anti-cancer therapy; death; or study cut-off 
of the secondary ORR endpoint of the triplet cohort. The scheduled tumor assessment time point will not be modified in case of a cycle delay. 
s CEA samples should be collected before IMP infusion. 
 
 
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1.3.2 Study flow chart - Triplet cohort  
Procedure 
Pre-
screeninga Screeningb 
Treatment cycle 1 
Treatment cycle 2 + 
End of treatment 
90 (±7) Days 
(3 month) 
Follow-upd 
Notes* 
Day 
 
Days to first 
infusion 
D1 
21 (±3) days from previous infusion 30 (±5) days from 
last infusion 
 
 
 
 
 
Pre-infusionc 
EOI 
Pre-infusionc 
Every 6 weeks 
(±7 days) 
 
 
 
CEACAM5 expression statusa (archival or fresh tumor 
tissue) – central IHC/ prescreening Informed consent 
X 
 
 
 
 
 
 
 
 
Informed Consent 
 
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
 
≤28 
X 
 
 
 
 
 
Section 5.1,  5.2  
Demography, medical/surgical/disease/smoking historye 
 
≤28 
 
 
 
 
 
 
 
NSCLC characteristicsf 
X 
≤28 
 
 
 
 
 
 
 
Height  
 
≤7 
 
 
 
 
 
 
 
Performance status (ECOG) 
 
≤7 
X 
 
X 
 
X 
X 
Section 8.2.1, 8.2.3 
Physical examination,including vital signs, body weightg 
 
≤7 
X 
 
X 
 
X 
X 
Section 8.2.1  
Hematologyh 
 
≤7 
X 
 
X 
 
X 
 
Section 8.2.5, 10.2 
(Appendix 2) 
Coagulationi 
 
≤7 
X 
 
X 
 
X 
 
Section 10.2 , 
(Appendix 2) 
Clinical blood chemistryj 
 
≤7 
X 
 
X 
 
X 
 
Section 8.2.5, 10.2 
(Appendix 2) 
Thyroid function 
 
≤7 
 
 
X 
 
X 
 
 
Urinalysisk 
 
≤7 
X  
 
X 
 
 
 
Section 10.2 , 
(Appendix 2) 
HBsAg & HCV serology and HIV test (only if required at 
country level)  
 
X 
 
 
 
 
 
 
Section 10.8 , 
(Appendix 8) 
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Procedure 
Pre-
screeninga Screeningb 
Treatment cycle 1 
Treatment cycle 2 + 
End of treatment 
90 (±7) Days 
(3 month) 
Follow-upd 
Notes* 
Day 
 
Days to first 
infusion 
D1 
21 (±3) days from previous infusion 30 (±5) days from 
last infusion 
 
 
 
 
 
Pre-infusionc 
EOI 
Pre-infusionc 
Every 6 weeks 
(±7 days) 
 
 
 
Urine or Serum pregnancy testl 
 
≤7 
 
 
X 
 
X 
X 
Section 10.2 
(Appendix 2) 
Section 10.5 
(Appendix 5) 
Left ventricular ejection fraction (MUGA/echocardiogram)m  
 
≤28 
 
  
 
 
 
 
Section 8.2.4.2 
12-lead ECGn 
 
≤7 
X 
X 
X 
 
X 
 
Section 8.2.4.1 
Specific ocular testso 
 
≤28 
 
 
 
 
X 
 
Section 8.2.2 
Tusamitamab ravtansine/Ramucirumab/Pembrolizumab 
administration 
 
 
X 
 
X 
 
 
 
Section 6.1 
AE assessmentp 
X 
 
Continuously throughout the study period 
Section 8.2, 8.3, 
10.3 (Appendix 3) 
Concomitant medicationq 
 
X 
Continuously throughout the study period 
Section 6.5 
Tumor assessment – RECIST v1.1 - CT/MRI; relevant 
surrogate markersr 
 
≤28 
 
 
 
X 
X 
X 
Section 8.1 
Circulating CEAs 
X 
≤28 
 
 
 
X 
X 
X 
 
IgG 
 
 
X 
 
 
 
 
 
 
Record further anticancer therapy 
 
 
 
 
 
 
 
X 
 
Tusamitamab ravtansine PK 
 
 
Refer to PK/ATA flowchart, Section 1.3.3 
 
 
Section 8.5 
Tusamitamab ravtansine Immunogenicity 
 
 
Refer to PK/ATA flowchart, Section 1.3.3 
 
 
Section 8.9 
Abbreviations: AE=adverse event; AESI=AE of special interest; ALT (SGPT)=alanine aminotransferase; AST (SGOT)=aspartate aminotransferase; ATA=antitherapeutic antibody; CEA=carcinoembryonic antigen; 
CEACAM5=carcinoembryonic antigen-related cell adhesion molecule 5; CR=complete remission; CT=computed tomography; eCRF=electronic case report form; ECOG=Eastern Cooperative Oncology Group 
(performance status); ECG=electrocardiogram; EOI=end of infusion; HBsAg=hepatitis B virus surface antigen; HCV=hepatitis C virus; HIV=human immunodeficiency virus; IMP=investigational medicinal product; 
LVEF=left ventricular ejection fraction; MRI=magnetic resonance imaging; MUGA=multigated acquisition scan; NSCLC=non-small-cell lung cancer; PD=progressive disease; PK=pharmacokinetic; PR=partial 
response; RBC=red blood cells; RECIST=Response Evaluation Criteria in Solid Tumors; SAE=serious AE; SD=stable disease; WBC=white blood cells. 
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a Prescreening:  a prescreening Informed Consent will be signed by the patient for CEACAM5 assay on archival or fresh tumor tissue and circulating CEA assay unless results are available from an assay for 
circulating CEA and from CEACAM5 testing for another study; in this case, an addendum to the informed consent will be sufficient. 
b Screening: 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. All the tests or procedures on D1 should be done at predose time unless otherwise stated. Assessments must be performed prior to first IMP 
administration: 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, echocardiography, 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 D1 pre-dose: Cycle 1 D1 refers to the day the participant receives the initial dose of IMP. D1 of Cycle 2 and of each subsequent cycle corresponds to D22 of the previous cycle. During treatment, D1 assessment 
can be done on the day of infusion (before infusion) or the day before. C1D1 hematology, blood chemistry, coagulation and urinalysis tests may be omitted if baseline test performed within 7 days are normal. If 
baseline tests are abnormal should be repeated within 2 days of first study intervention. 
d Follow-up visit: SAEs (regardless of relationship with study treatment) and IMP-related AEs ongoing at the end of study treatment, and any new IMP-related AE/SAE/AESI will be followed until resolution or 
stabilization (defined as an event ongoing without any change for at least 3 months).  Date of disease progression and further anticancer treatment will be collected at the follow-up visit. Participants with 
documented disease progression should attend an on-site follow-up visit 90 days after the last dose of study medication. If every ongoing related AE/SAE/AESI is resolved or stabilized, no further follow-up visit is 
needed.    
e Disease history includes previous antitumor therapy (type, start and end dates, reason for discontinuation and response to the therapy) and smoking history. 
f 
NSCLC characteristics will include histologic types, stage at diagnosis, disease extent at study entry, (collected at screening) and specific mutations including PD-1 expression status (to be collected only at 
prescreening). 
g Physical examination will include: vital signs (temperature, blood pressure, heart rate) and examination of major body systems. Signs and symptoms will be reported in the electronic case report form (eCRF) as 
AEs only if they are still present at the time of first IMP administration 
h Hematology: Hemoglobin, hematocrit, RBC, WBC with differential, platelet counts. These tests will be done before IMP administration at each cycle. If Grade 4 neutropenia, assess absolute neutrophil count (ANC) 
every 2-3 days until ANC ≥0.5 x 109/L. During first cycle, hematology will be performed weekly.  
i 
Coagulation: International normalized ratio (INR), aPTT. 
j 
Clinical blood chemistry: Liver function tests: SGOT (AST), SGPT (ALT), total bilirubin, conjugated bilirubin, AP. Renal function tests: Urea (or BUN) & creatinine. Electrolytes: Sodium, potassium, calcium, glucose, 
Others: LDH, albumin and total proteins. During first cycle, liver function tests will be performed weekly. The liver function tests and renal function tests will be done before IMP administration at each cycle, unless 
clinically appropriate. In case of Grade ≥3 liver function abnormal tests, additional tests will be repeated every 2-3 days until recovery to baseline value.   
k Urinalysis tests on morning spot will be performed by dipstick at baseline, and at every treatment cycle. In case of proteinuria ≥ ++ (dipstick), proteinuria quantification by proteinuria/24 h should be performed.  
l 
Serum pregnancy test: women of childbearing potential must have a negative serum pregnancy test result within 7 days prior to the initial dose of IMP. A pregnancy test (serum/urine) will be repeated every 
4 weeks before IMP administration, and a serum test will be repeated at the End of Treatment evaluation (30±5 days after the last IMP administration), and at the Follow-up visit (90±7 days after last IMP dose).  
m Echocardiogram or MUGA scan: left ventricular ejection fraction (LVEF) will be evaluated during screening period, and whenever clinically indicated. 
n 12-lead ECG is required at baseline (In case the ECG performed less than 7 days before 1st IMP administration is considered as normal, there is no need to repeat it just before the 1st IMP) before starting and 
after completing the first IMP administration (within 30 minutes after the end of tusamitamab ravtansine infusion); before IMP administration at each cycle; and at the End of treatment evaluation, 22 to 30 days after 
last IMP administration.   
o Specific ocular tests will include assessment of ocular/visual symptoms and ocular exams including visual acuity, slit lamp under dilatation, and Schirmer’s test at screening and whenever clinically indicated. 
p AE: For participant who was prescreened and had fresh biopsy, only the Adverse Events related to the fresh biopsy procedure itself should also be reported in eCRF as general requirement of AE/SAE with the 
reporting time frame interval of 1 month for the prescreening period after fresh biopsy. 
q Concomitant medication will be recorded in the eCRF from 28 days prior to the first study intervention administration, before every cycle during the study treatment period, and for up to 30 days after the final dose 
of study intervention. Once the participant has withdrawn from study treatment, concomitant medication should only be recorded if used to treat new or unresolved study treatment-related adverse events. 
r 
Tumor assessment will be made at every 6 weeks interval (±7 days window) during the study treatment period until radiological disease progression; initiation of further anti-cancer therapy; death; or study cut-off 
of the secondary ORR endpoint of the triplet cohort. The scheduled tumor assessment time point will not be modified in case of a cycle delay. 
s CEA samples should be collected before IMP infusion. 
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2 
INTRODUCTION  
Despite recent progress in the treatment of advanced NSCLC, there remains a need for effective 
new treatment at the time of disease progression. Current therapeutic approaches combining an 
inhibitor of angiogenesis in combination with a systemic cytotoxic agent such as docetaxel entail 
serious hematological and other toxicities; therefore, targeted cytotoxic therapies may offer an 
improvement in safety and tolerability as well as efficacy. 
One feature that can be used to target some tumor cells is surface expression of 
carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5), first described in 1965 
as a tumor-associated antigen in human colon cancer tissue extracts (3). High levels of 
CEACAM5 expression have since been observed in several epithelial tumors, whereas in normal 
adult tissue, its expression is limited to few tissues (4, 5). Immunostaining of CEACAM5 in a 
large panel of human tumor tissue microarray samples has shown the highest prevalence of cell 
surface CEACAM5 expression in adenocarcinomas of the colon and of the stomach and its 
subtypes as well as NSQ NSCLC. 
Maytansinoids are antimitotic agents that inhibit microtubule formation to act as very potent 
cytotoxic agents against tumor cell lines in vitro, with IC50 values 100- to 1000-fold more potent 
than conventional tubulin binding compounds, including docetaxel. Tusamitamab ravtansine is 
an antibody to CEACAM5 conjugated to the cytotoxic maytansinoid agent, (DM4).  
Encouraging preliminary antitumor activity of tusamitamab ravtansine in patients heavily 
pretreated for NSQ NSCLC has been demonstrated in an ongoing study (TED13751). 
2.1 
STUDY RATIONALE  
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, DM4, an inhibitor of 
microtubule assembly. tusamitamab ravtansine is expected to selectively deliver DM4 to cancer 
cells expressing the CEACAM5 antigen, such as colon, stomach and its signet-ring cell subtype 
as well as NSQ NSCLC.  
In the first-in-human monotherapy study (TED13751), the maximum tolerated dosage of 
tusamitamab ravtansine was identified to be 100 mg/m2 every 2 weeks. Dose-limiting toxicities 
were mainly Grade 3 microcystic keratopathy; all were reversible. This dose is also the selected 
started dose for combination studies.  
In the expansion phase of study TED13751, a cohort of patients with heavily pretreated NSQ 
NSCLC tumors testing positive for CEACAM5 (≥2+ in intensity on membranes of ≥50% of the 
tumor cells) have been treated with tusamitamab ravtansine at 100 mg/m2 every 2 weeks. Results 
from the 64 evaluable patients showed encouraging antitumor activity associated with a response 
rate of 20.3% (95% CI, 12.3% to 31.7%) (6).  
Ramucirumab (Cyramza®); a human IgG1 monoclonal antibody that inhibits VEGFR-2 is 
approved in combination with docetaxel for the treatment of patients with metastatic NSCLC.  
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This approval was based on the results of a Phase 3 study (REVEL) a randomized 
placebo-controlled trial of 1,253 patients with metastatic NSCLC previously treated with a 
platinum-based combination therapy. Patients were randomized to receive either ramucirumab in 
combination with docetaxel or placebo in combination with docetaxel. The primary endpoint was 
overall survival (OS). Patients who received ramucirumab in combination with docetaxel had 
improved OS (hazard ratio: 0.86; 95% CI, 0.75 to 0.98). Median OS was 10.5 months on the 
ramucirumab plus docetaxel arm versus 9.1 months on the placebo plus docetaxel arm. Median 
progression free survival was 4.5 months for the ramucirumab arm compared to 3 months in the 
control arm (hazard ratio: 0.76; 95% CI, 0.68 to 0.86). Objective response rate was 22.9% for the 
ramucirumab arm (95% CI, 19.7% to 26.4%) compared to 13.6% in the control arm (7). 
Ramucirumab 10 mg/kg Q3W in combination with docetaxel is approved to treat metastatic 
NSCLC. Additionally, ramucirumab 8 mg/kg administered Q2W is approved to treat other 
advanced cancers: as a single agent or in combination with paclitaxel for gastric or 
gastro-esophageal junction adenocarcinoma, and in combination with a FOLFIRI regimen for 
CRC. The dosing schedule selected for this study is supported by efficacy data from studies with 
tusamitamab ravtansine 100 mg/m2 Q2W (see Investigator’s Brochure for tusamitamab 
ravtansine) and the Q2W dosing schedule for ramucirumab approved for other cancer indications 
(see Cyramza® prescribing information). 
Combined ICI and VEGF/VEGF receptor inhibition have shown benefit in multiple tumor types 
through immune modulation. Pembrolizumab and ramucirumab (P+R) were evaluated in patients 
with advanced, ICI-exposed, in a substudy of Lung-MAP1, a master protocol for patients with 
Stage IV previously treated NSCLC. In this randomized, Phase II study from the Lung-MAP 
platform,136 patients were randomized to receive pembrolizumab + ramucirumab or the 
Investigator's choice of standard therapeutic regimens (SOC). Ramucirumab 10 mg/kg and 
pembrolizumab 200 mg Q3W were used. Overall survival (OS) was significantly improved with 
P+R compared to SOC: median (95% CI) OS was 14.5 (13.9 to 16.1) months for P+R: and 11.6 
(9.9 to 13.0) months for SOC (HR: 0.69 [0.51 to 0.92], P value from the standard log-rank test 
equal to 0.05 and 0 .15 from the weighted log-rank test). Neither progression-free survival (PFS) 
or objective response rate (ORR) differed between the treatment arms (2). 
Addition of pembrolizumab could be a new option for the treatment of advanced NSQ NSCLC 
after platinum and ICI. A new cohort of 6 to 12 patients will be added to this protocol in order to 
assess the safety of this tri-therapy (tusamitamab ravtansine-ramucirumab-pembrolizumab) and 
validate the dose of tusamitamab ravtansine to be used in case of further development of this 
combination in this indication. 
The balance of anticipated benefits and the reported risks of tusamitamab ravtansine identified in 
ongoing studies TED13751 and TCD15054 supports its continued clinical development, both as 
monotherapy and in combination regimens with chemotherapy and immunotherapy agents.  
Given the considerable risks of adverse effects including neutropenia, anemia, and infection 
associated with docetaxel, the combination of tusamitamab ravtansine with ramucirumab may 
represent a treatment regimen with an improved safety profile as compared to the approved 
combination of docetaxel and ramucirumab. 
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The combination of tusamitamab ravtansine with ramucirumab with or without pembrolizumab 
will provide efficacy and safety data in patients with CEACAM5-positive (CEACAM5 ≥50%) 
NSQ NSCLC tumors. 
2.2 
BACKGROUND  
Lung cancer is one of the most commonly diagnosed cancers and is the leading cause of 
cancer-related mortality worldwide (8). Non-small-cell lung cancer (NSCLC) accounts for 85% 
of all lung cancers (9) and comprises several histopathological subtypes, of which 
adenocarcinoma (60%) and squamous-cell carcinoma (15%) are the most common (10). 
The majority of patients with NSCLC presents an advanced stage at the time of diagnosis. These 
patients have a median overall survival (OS) of up to 8 to 12 months (11), and in 2015, a 5 year 
survival rate of approximately 25% (12) About 15% to 20% of patients with NSCLC have 
tumors with key genomic alterations that are amenable to targeted therapy, which include 
epidermal growth factor receptor (EGFR) mutations and ROS receptor tyrosine kinase 1 (ROS1) 
and anaplastic lymphoma kinase (ALK) rearrangements (13). 
Until recently the only available treatment option for advanced or metastatic NSQ NSCLC 
lacking targetable mutations was chemotherapy. Systemic therapy with platinum-based doublet 
regimens, with or without maintenance therapy, is the current first-line treatment for patients 
with advanced NSCLC (14). The standard second-line treatment for NSCLC has been docetaxel 
(15); docetaxel’s activity was found to be enhanced by the addition of ramucirumab (7).    
More recently, immunotherapy has initiated a new paradigm for the treatment of NSCLC. In 
particular, monoclonal antibodies targeting the programmed death-1 receptor (PD-1)/PD ligand 1 
(PD -L1) pathway have emerged as powerful new therapeutic tools in several clinical trials. 
Three drugs targeting the PD-1 pathway (nivolumab, pembrolizumab and atezolizumab) have 
been approved for the treatment of both chemotherapy-naïve and previously treated advanced 
stage NSCLC (16, 17, 18, 19), however only small subset (20% to 30%) of patients responds to 
these treatments. Despite improvement in outcomes with newer lines therapy, including 
anti-PD -1/PD -L1 antibodies, the disease often progresses. Additional therapeutic approaches 
are needed to improve the clinical efficacy and health-related quality of life (HRQOL) in patients 
with advanced/metastatic NSCLC. 
2.3 
BENEFIT/RISK ASSESSMENT  
To date, efficacy and safety data from ongoing studies of tusamitamab ravtansine (TED13751, 
TCD15054, ACT16146, ACT16444, ACT16525, ACT16432 and EFC15858) support continued 
clinical development of tusamitamab ravtansine. Information about the known and expected 
benefits, risks, and reasonably anticipated AEs with tusamitamab ravtansine may be found in the 
Investigator’s Brochure (IB). Based on available safety data, the main anticipated risk to patients 
is corneal toxicity presenting as microcystic keratopathy/keratitis, which is reversible and 
manageable with dose delay and dose reduction in some patients.  Peripheral neuropathy is an 
identified risk.  
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Other potential risks include colitis (including hemorrhagic), cardiotoxicity (myocardial or 
conduction abnormalities), hematologic cytopenia, and hepatotoxicity, as well as systemic acute 
hypersensitivity (including anaphylaxis) and, in patients who received tusamitamab ravtansine in 
peripheral veins, local infusion site reactions to tusamitamab ravtansine (6).  
Ramucirumab, a human IgG1 monoclonal antibody that inhibits VEGFR-2, is approved in 
combination with docetaxel for the treatment of patients with metastatic NSCLC. Given the 
considerable risks of adverse effects including neutropenia, anemia, and infection associated 
with docetaxel, the combination of tusamitamab ravtansine with ramucirumab may represent a 
treatment regimen with an improved safety profile as compared to the approved combination of 
docetaxel and ramucirumab.  More detailed information about the known and expected benefits 
and risks and reasonably expected adverse effects of ramucirumab may be found in the US 
Package Insert or Summary of Product Characteristics for Cyramza®.  
Besides targetable genetic alterations, also the expression of PD-L1, an immune suppressive 
molecule, needs to be considered for therapeutic decision-making. The PD-1 immune checkpoint 
inhibitor (ICI) pembrolizumab has been shown to have higher efficacy as first-line treatment 
compared with platinum-based chemotherapy in patients without the presence of a driver 
oncogene alteration but PD-L1 expression in at least 1% of tumor cells (TPS ≥1%) (1). 
Pembrolizumab, as monotherapy, is approved for the first-line treatment of patients with Stage III 
NSCLC, who are not candidates for surgical resection or definitive chemoradiation, or metastatic 
NSCLC whose tumors express PD-L1 with a TPS ≥50% as determined by an approved test, with 
no EGFR or ALK genomic tumor aberrations. Extension of indication was recently (April 2019) 
given in the US by the FDA to patients for whom TPS is ≥1%. This approval was based on the 
results of a Phase 3, randomized trial of 1274 patients with untreated locally advanced or 
metastatic NSCLC without EGFR or ALK mutations and with PD-L1 TPS ≥1% (1). Patients were 
randomized to receive either pembrolizumab or chemotherapy. The primary endpoint was overall 
survival (OS). Overall survival was significantly longer in the pembrolizumab group than in the 
chemotherapy group in all three TPS populations (TPS ≥50% hazard ratio 0.69, 95% CI 0.56-0.85, 
p=0.0003; TPS ≥20% 0.77, 0.64-0.92, p=0.0020; and TPS ≥1% 0.81, 0.71-0.93, p=0.0018). The 
median survival values by TPS population were 20.0 months (95% CI 15.4-24.9) for pembrolizumab 
versus 12.2 months (10.4-14.2) for chemotherapy, 17.7 months (15.3-22.1) versus 13.0 months 
(11.6-15.3), and 16.7 months (13.9-19.7) versus 12.1 months (11.3-13.3), respectively. In the PD-L1 
TPS ≥50% population, 118 (39%, 95% CI 34-45) of 299 patients in the pembrolizumab group and 
96 (32%, 95% CI 27-38) of 300 patients in the chemotherapy group had an objective response to 
treatment. The values in the TPS ≥20% and ≥1% populations were 138 (33%, 95% CI 29-38) of 
413 versus 117 (29%, 95% CI 25-34) of 405 and 174 (27%, 95% CI 24-31) of 637 versus 169 (27%, 
95% CI 23-30) of 637, respectively (1, 20).  
Pembrolizumab in combination with chemotherapy is approved for the first-line treatment of 
patients with metastatic NSQ NSCLC, with no EGFR or ALK genomic tumor aberrations. This 
approval was based on the results of a Phase 3 double-blind, randomized (in a 2:1 ratio) trial of 
616 patients who had received no previous treatment for metastatic disease to receive pemetrexed 
and a platinum-based drug plus either 200 mg of pembrolizumab or placebo every 3 weeks for 
4 cycles, followed by pembrolizumab or placebo for up to a total of 35 cycles plus pemetrexed 
maintenance therapy (21). Improvement in OS was seen across all PD-L1 categories that were 
evaluated. Median progression-free survival was 8.8 months (95% CI 7.6 to 9.2) in the 
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pembrolizumab-combination group and 4.9 months (95% CI, 4.7 to 5.5) in the 
placebo-combination group (hazard ratio for disease progression or death: 0.52, 95% CI 0.43 to 
0.64, p <0.001). The response rate as assessed by blinded, independent central radiologic review 
was 47.6% (95% CI 42.6 to 52.5) in the pembrolizumab-combination group and 18.9% (95% CI, 
13.8 to 25.0) in the placebo-combination group (p <0.001). 
The combination of tusamitamab ravtansine with an immune-checkpoint inhibitor (ICI) or the 
standard of care (SOC) should improve the outcome, with a better tolerability for triplet 
combination, and without additional toxicity as no overlap is expected.  
Safety data were collected so far with tusamitamab ravtansine and pembrolizumab combination in 
the ACT16146 study. Based on the patients treated as of 17 June 2022, the combination cohorts at 
the suggested dose of tusamitamab ravtansine 150 mg/m2 have all been well tolerated. 
2.3.1 Overall benefit: risk conclusion  
To date, efficacy and safety data from ongoing studies of tusamitamab ravtansine (TED13751 
and TCD15054) support continued clinical development of tusamitamab ravtansine. The 
combination of tusamitamab ravtansine with ramucirumab may represent a treatment regimen 
with an improved safety profile as compared to the combination of docetaxel with ramucirumab 
approved for the treatment of advanced NSCLC. 
Addition of pembrolizumab could be a new option for the treatment of advanced NSQ NSCLC 
after platinum and ICI.  
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3 
OBJECTIVES AND ENDPOINTS  
Table 3 - Objectives and endpoints  
Doublet cohort   
Objectives 
Endpoints 
Primary 
• 
Part 1 (safety run-in):  
To assess the tolerability and to confirm the 
recommended dose of tusamitamab ravtansine in 
combination with ramucirumab in the NSQ NSCLC 
population 
• 
Part 1:  
Incidence of study drug-related dose-limiting toxicity 
(DLT) at Cycle 1 and Cycle 2 (C1D1 to C2D14).  
Anticipated DLT includes, but is not limited to, 
corneal toxicity 
• 
Part 2:  
To assess the antitumor activity of tusamitamab 
ravtansine in combination with ramucirumab in the 
NSQ NSCLC population 
• 
Part 2:  
Objective response rate (ORR) defined as proportion  
of participants with confirmed complete 
response (CR) or partial response (PR) as best  
overall response (BOR) determined per Response 
Evaluation Criteria in Solid Tumors (RECIST) v1.1.  
Secondary 
• 
To assess the safety and tolerability of 
tusamitamab ravtansine in combination with 
ramucirumab 
• 
Incidence of treatment emergent adverse events 
(TEAEs) and serious adverse events (SAEs) and 
laboratory abnormalities according to National 
Cancer Institute (NCI) Common Terminology Criteria 
for Adverse Events (CTCAE) V5.0 
• 
To assess the durability of the response to 
treatment with tusamitamab ravtansine in 
combination with ramucirumab  
• 
Duration of response (DOR), defined as the time 
from first documented evidence of CR or PR until  
progressive disease (PD) determined per  
RECIST v1.1 or death from any cause, whichever 
occurs first 
• 
To assess anti-tumor activity of tusamitamab 
ravtansine in combination with ramucirumab on 
progression free survival (PFS) and disease 
control rate (DCR) 
• 
Progression-free survival, defined as the time from 
the first investigational medicinal product (IMP) 
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 
• 
To assess the pharmacokinetic (PK) profiles of 
tusamitamab ravtansine (SAR408701) and 
ramucirumab when given in combination 
• 
Pharmacokinetic parameters of tusamitamab  
ravtansine (SAR408701) and ramucirumab 
• 
To assess the immunogenicity of tusamitamab 
ravtansine (SAR408701) when given in 
combination with ramucirumab 
• 
Incidence of anti-therapeutic antibodies (ATAs)  
against tusamitamab ravtansine (SAR408701) 
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Objectives 
Endpoints 
Tertiary/Exploratory 
• 
To explore circulating carcinoembryonic  
antigen (CEA) as a potential biomarker for activity  
and to evaluate circulating CEA levels at  
prescreening 
• 
Circulating CEA at prescreening, screening, and  
during the treatment period  
Abbreviations: ATA=antitherapeutic antibody; BOR=best overall response; CEA=carcinoembryonic antigen; CR=complete response;  
DLT=dose-limiting toxicity; DCR=disease control rate; DOR=duration of response; IMP=investigational medicinal product; NCI CTCAE= National 
Cancer Institute Common Terminology Criteria for Adverse Events; NSQ NSCLC=non-squamous, non small-cell lung cancer; PD=progressive 
disease; PFS=progression-free survival; PK=pharmacokinetic; PR=partial response; RECIST=Response Evaluation Criteria in Solid Tumors. 
Triplet cohort  
Objectives 
Endpoints 
Primary 
• 
To assess the tolerability and to confirm the 
recommended dose of tusamitamab ravtansine in 
combination with ramucirumab and 
pembrolizumab in the NSQ NSCLC population 
• 
Incidence of study drug-related dose-limiting toxicity 
(DLT) at Cycle 1 (C1D1 to C1D21).  
Anticipated DLT includes, but is not limited to, corneal 
toxicity. 
Secondary 
• 
To assess the safety and tolerability of 
tusamitamab ravtansine in combination with 
ramucirumab and pembrolizumab 
• 
Incidence of treatment emergent adverse events 
(TEAEs) and serious adverse events (SAEs) and 
laboratory abnormalities according to National Cancer 
Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) V5.0 
• 
To assess the antitumor activity of tusamitamab 
ravtansine in combination with ramucirumab and 
pembrolizumab in the NSQ NSCLC population  
• 
Objective response rate (ORR) defined as proportion 
of participants with confirmed complete response 
(CR) or partial response (PR) as best overall 
response (BOR) determined per Response 
Evaluation Criteria in Solid Tumors (RECIST) v1.1 
• 
To assess the immunogenicity of tusamitamab 
ravtansine (SAR408701) when given in 
combination with ramucirumab and 
pembrolizumab 
• 
Incidence of anti-therapeutic antibodies (ATAs) 
against tusamitamab ravtansine (SAR408701) 
Tertiary/Exploratory 
• 
To explore circulating carcinoembryonic antigen 
(CEA) as a potential biomarker for activity and to 
evaluate circulating CEA levels at prescreening 
• 
Circulating CEA at prescreening, screening, and 
during the treatment period  
Abbreviations: ATA=antitherapeutic antibody; BOR=best overall response; CR=complete response; DLT=dose-limiting toxicity; NCI 
CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events; NSQ NSCLC=non-squamous, non small-cell lung cancer; 
PK=pharmacokinetic; PR=partial response; RECIST=Response Evaluation Criteria in Solid Tumors. 
3.1 
APPROPRIATENESS OF MEASUREMENTS  
Each of the efficacy and safety assessments chosen for use in this study is considered well 
established and relevant in an oncology study setting.  
In addition, suitable steps have been built into each of these assessments to ensure their 
reliability and accuracy and to minimize any risks to participant safety. 
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4 
STUDY DESIGN  
4.1 
OVERALL DESIGN  
This is a Phase 2, open-label, multi-center study assessing safety, efficacy (antitumor activity), 
and PK of the combination of tusamitamab ravtansine and ramucirumab in metastatic 
CEACAM5-positive (defined as CEACAM5 IHC intensity ≥2+ in ≥50% of tumor cells) in 
patients with non-squamous, non–small-cell lung cancer (NSQ NSCLC) participants previously 
treated with platinum-based chemotherapy and an immune checkpoint inhibitor.  
In the prescreening phase, patients with NSQ NSCLC will have tumor tissue tested centrally to 
assess proportions of CEACAM5-positive cells and intensity of expression, with a prospective 
analysis of CEACAM5 expression on most recent archival tumor tissue.  An in vitro diagnostic 
medical device manufactured for Sanofi is provided by a third party. This in vitro diagnostic 
medical device is a qualitative immunohistochemical assay under performance evaluation, called 
CEACAM5 IHC 769 assay. For this analysis, at least 5 × 4 μm slides from FFPE archival tissue 
should be sent to the central laboratory designated by the Sponsor.   
If less material is available, a participant could be eligible only after discussion with the sponsor 
who may confirm that available material is sufficient for key CEACAM5 expression analyses.  
In case of unavailable archival tissue, a fresh biopsy can be considered in participants who have 
reachable lesion that is suitable for biopsy. This prescreening activity can be performed in 
advance, when a participant may be on prior anticancer therapy.  
Once the results for CEACAM5 available, only participants with positive results (defined as 
CEACAM5 expression of ≥2+ in intensity involving at least 50% of the tumor cell population), in 
archival tumor sample (or if not available fresh biopsy sample) will enter in screening phase. 
During the screening phase, all inclusion/exclusion criteria will be checked to confirm the 
participants’ eligibility for treatment part. 
Once the participant is screened, the participant may be determined to be eligible for a treatment 
phase comprising 2 cohorts (doublet cohort and triplet cohort) 
The doublet cohort is a 2-parts study: 
Part 1 (Safety Run-In): In Part 1, participants will be treated with tusamitamab ravtansine and 
ramucirumab to assess the tolerability of the combination to be used in the subsequent part of the 
study.  The first 3 participants will receive ramucirumab at 8 mg/kg followed by tusamitamab 
ravtansine at 100 mg/m2 every 2 weeks (Q2W).  Administration of tusamitamab ravtansine will 
begin at least 1 hour after completion of ramucirumab infusion. 
The DLT observation period is the first 2 cycles (approximately 28 days). A DLT-evaluable 
participant must have completed 2 cycles of treatment or have been discontinued from study 
treatment because of a DLT; DLT non-evaluable participants will be replaced. 
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A minimum delay of 1 week is required between the initial dose in the first participant treated in 
a DL cohort and dosing the next 2 participants treated at the same DL. 
• If ≤1/3 participants treated at the starting dose experiences a DLT, 3 additional participants 
will be treated to confirm the tolerability of the combination.  
- 
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 DLTs, the dose will be 
de-escalated to DL -1. 
• If ≥2/3 participants treated at the starting dose experience DLTs, the dose will be 
de-escalated to DL minus 1 (DL -1). 
• If ≤1 of the first 3 participants treated at DL -1 experiences a DLT, 3 additional 
participants will be treated at this DL. 
- 
If ≤1/6 participants treated at DL -1 experiences a DLT, DL-1 will be the RP2D. 
- 
If ≥2/6 participants treated at DL -1 experience a DLT, an alternative dosage might 
be considered or the doublet cohort may be stopped. 
• If ≥2/3 participants treated at DL -1 experience a DLT, an alternative dosage might be 
considered or the doublet cohort may be stopped. 
Note: if ≥2/6 or ≥2/3 participants treated at DL -1 experience DLTs, an alternative dosage might 
be considered from a safety viewpoint by the Sponsor after consulting with SC.  Dose reduction 
is shown in Table 4.   
Table 4 - Dose reduction for the doublet cohort Part 1 (safety run-in)  
Dose level (DL)  
tusamitamab ravtansine 
Ramucirumab 
Starting dose 
100 mg/m2 Q2W 
8 mg/kg Q2W 
Minus -1 (DL-1) 
80 mg/m2 Q2W 
8 mg/kg Q2W 
DL=dose level; Q2W=every 2 weeks. 
Infusion of tusamitamab ravtansine will be administered at least 1 hour after the end of ramucirumab infusion. For patients with a 
BSA >2.20 m2, the tusamitamab ravtansine dose will be calculated based on a BSA of 2.20 m2. 
 
The decision tree for doses in Part 1 is summarized in Figure 4.   
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Figure 4 - Decision tree for the doublet cohort Part 1 for tusamitamab ravtansine  
 
*Note: In case of 2 or more DLTs at DL -1, the cohort may be stopped or the dosage reconsidered. 
Abbreviations: DL -1=dose level -1 (80 mg/m2); DLT=dose-limiting toxicity; RP2D=recommended dose. 
 
Following the identification of the RP2D, Part 2 of the study will be initiated. 
Dose limiting toxicity definition 
All AEs specified in Table 5 occurring during the first 2 cycles of treatment, unless due to disease 
progression or to a cause obviously unrelated to IMP, will be considered DLTs. 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 NCI CTCAE version 5.0 will be used to assess the severity of AEs. 
Causal relationships are to be determined by the Investigator. The DLTs will be confirmed by the 
SC. 
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Table 5 - 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 
Non-hematological abnormalities 
Elevated urine protein ≥3 g/24 h 
Grade 4 non-hematologic AE 
Grade ≥3 keratopathy 
Grade 4 or refractory hypertension 
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. 
Part 2: It is planned that 30 treated patients will be evaluable for response (the 6 patients from the 
safety run-in treated at the recommended dose will be included).  During the treatment period, 
participants will have tumor assessments every 8 weeks.  
After the EOT visit, the Follow-up (FU) visit will be performed at 90 (±7) days after the last 
infusion.  During the FU visit, the participants will be monitored for all ongoing related AEs and 
all SAEs and AESIs, regardless of relationship until resolution or stabilization (ie, an event 
ongoing without any change for at least 3 months).  All new related AEs, SAEs, or AESIs will be 
followed until resolution or stabilization.  If ongoing IMP-related AEs and all SAEs/AESIs are 
resolved or stabilized, no further safety follow-up visit will be needed; if not resolved or 
stabilized, an on-site follow-up visit will be performed every 12 weeks (±7 days) until resolution 
or stabilization. 
For the doublet cohort, a participant who stopped treatment for a reason other than PD, follow-up 
visits will be performed every 12 weeks (±7 days) after the last tumor assessment until 
documented radiological disease progression, start of a new anticancer therapy, death, study cut-off 
date of the secondary ORR endpoint of the triplet cohort, or withdrawal of participant’s consent 
(whichever comes first). 
The study cut-off for the primary ORR endpoint analysis corresponds to the date on which all 
evaluable treated patients have had at least 2 postbaseline tumor assessments, experienced 
confirmed objective response, or have discontinued the study for any reason; the study cut-off can 
be up to approximately 6 months (4 months for 2 assessments, with an additional 2 months if 
confirmation of a response is needed) from the date the last participant’s first administration. 
After the study cut-off date for the primary ORR analysis, if clinical benefit is observed, a patient 
still receiving study treatment can continue study treatment until PD, unacceptable toxicity, or 
withdrawal of participant’s consent, and will continue to undergo all assessments as per the study 
flow chart.  
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Triplet cohort: 
Participants will be treated with tusamitamab ravtansine and ramucirumab and pembrolizumab to 
assess the tolerability of the combination to be used in the subsequent studies.  The first 
3 participants will receive ramucirumab at 10 mg/kg followed by tusamitamab ravtansine at 
150 mg/m2 and pembrolizumab at 200 mg every 3 weeks (Q3W).  Administration of tusamitamab 
ravtansine will begin at least 1 hour after completion of ramucirumab infusion. 
DLT definition is reported in Table 5. 
The DLT observation period is the first cycle (approximately 21 days). A DLT-evaluable 
participant must have completed 1 cycle of treatment or have been discontinued from study 
treatment because of a DLT. DLT non-evaluable 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 the next 2 participants treated at the same DL. 
• If ≤1/3 participants treated at the starting dose experiences a DLT, 3 additional participants 
will be treated to confirm the tolerability of the combination.  
- 
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 DLTs, the dose will be 
de-escalated to DL -1. 
• If ≥2/3 participants treated at the starting dose experience DLTs, the dose will be 
de-escalated to DL minus 1 (DL -1). 
• If ≤1 of the first 3 participants treated at DL -1 experiences a DLT, 3 additional 
participants will be treated at this DL. 
- 
If ≤1/6 participants treated at DL -1 experiences a DLT, DL-1 will be the RP2D. 
- 
If ≥2/6 participants treated at DL -1 experience a DLT, an alternative dosage might 
be considered or the triplet cohort may be stopped. 
• If ≥2/3 participants treated at DL -1 experience a DLT, an alternative dosage might be 
considered or the triplet cohort may be stopped. 
Note: if ≥2/6 or ≥2/3 participants treated at DL -1 experience DLTs, an alternative dosage might 
be considered from a safety viewpoint by the Sponsor after consulting with SC.  Dose reduction 
is shown in Table 6. 
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Table 6 - Dose reduction for the triplet cohort   
Dose level (DL)  
tusamitamab 
ravtansine 
ramucirumab 
pembrolizumab 
Starting dose 
150 mg/m2 Q3W 
10 mg/kg Q3W 
200 mg Q3W 
Minus -1 (DL-1) 
120 mg/m2 Q3W 
10 mg/kg Q3W 
200 mg Q3W 
DL=dose level; Q3W=every 3 weeks. 
Infusion of tusamitamab ravtansine will be administered at least 1 hour after the end of ramucirumab infusion. For patients with a 
BSA >2.20 m2, the tusamitamab ravtansine dose will be calculated based on a BSA of 2.20 m2. 
 
The decision tree for doses for triplet cohort is summarized in Figure 5.  
Figure 5 - Decision tree for the triplet cohort for tusamitamab ravtansine  
 
*Note: In case of 2 or more DLTs at DL -1, the cohort may be stopped or the dosage reconsidered. 
Abbreviations: DL -1=dose level -1 (120 mg/m2); DLT=dose-limiting toxicity; RP2D=recommended dose. 
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The study cut-off for the secondary ORR endpoint analysis of triplet cohort corresponds to the 
date on which all evaluable treated patients have had at least 2 post baseline tumor assessments, 
experienced confirmed objective response, or have discontinued the study for any reason. This 
study cut-off will occur approximately 4.5 months after the date of the first IMP administration of 
the last participant: 3 months for 2 tumor assessments and 1.5 months if a confirmation of 
response is needed. 
Disclosure Statement: 
This is an open-label, single-arm, 2 cohorts study in patients with previously treated metastatic 
NSQ NSCLC.  
Number of participants: 
In the doublet cohort, approximately 225 participants will be prescreened (CEACAM5 
prescreening failure rate is 80% and study screen failure rate is 20%) to achieve up to 
approximately 36 treated participants.  
In the triplet cohort, approximately 74 participants will be prescreened to achieve up to 
approximately 12 DLT evaluable participants, based on the doublet cohort CEACAM5 
prescreening failure rate of 79% and an estimated study screen-failure rate of 23%. 
Intervention groups and duration: 
The duration of the study for a participant will include a period for screening of up to 28 days. 
Once successfully screened, enrolled participants may receive study intervention until disease 
progression, unacceptable AE, or the participant’s or investigator's decision to stop the treatment. 
Each cycle of treatment will have a duration of 2 weeks in the doublet cohort and 3 weeks in 
triplet cohortAfter discontinuing study intervention, participants will return to the study site 
approximately 30 (±5) days after the last IMP administration or before the participant receives 
another anticancer therapy, whichever is earlier, for end-of-treatment assessments; additionally, a 
final safety follow-up visit will be scheduled 90 days after the last dose of IMP.  The expected 
duration of study intervention for participants may vary, based on progression date; median 
expected duration of study per participant is estimated as 11 months (1 month for screening, a 
median of 6 months for treatment, and a median of 4 months for end-of-treatment follow-up). 
The total estimated duration of enrollment will be approximately 12 months. 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN  
Based on histology, therapy and prognosis, lung cancer is divided into two major classes: 
small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC). NSCLC accounts 
80% of lung cancer and it includes 2 major subtypes: non-squamous carcinoma (including 
adenocarcinoma, large-cell carcinoma and other subtypes) and squamous cell (epidermoid) 
carcinoma.  Adenocarcinoma is the most common subtype of NSQ-NSCLC (17). 
The past decade has dramatically changed the approach on diagnosis and treatment of lung 
cancer with the concept of personalized medicine, which led discovery of several therapeutic 
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options that are only approved for treatment of patients with specific histopathologic 
characteristics (22).  
Accurate pathologic assessment with tumor mutation profiling and staging are essential for 
treatment decisions. In general, systemic therapy is recommended for patients with metastatic 
(Stage IV) disease, especially in disseminated metastasis.  Appropriate systemic therapy choice 
depends on the histologic type, whether there are genetic alterations that can be targeted for 
therapy, and the performance status of the patient.   
In the advanced setting, platinum-based chemotherapy has been considered the gold standard, 
with evidence of improved survival and symptom control, and superior quality of life compared 
to best supportive care.  After improvement of biomarker testing for genetic alterations in tumor 
cells, the number of available targeted therapies has been increasing, and targeted therapy has 
been shown to decrease tumor burden, decrease symptom and dramatically improve the quality 
of life for patient with specific genetic alteration.  
Doublet chemotherapy regimens are recommended as first line chemotherapy for NSQ NSCLC 
patients whose tumor has negative ALK and ROS1 re-arrangement or sensitizing EGFR mutations 
and with PD-L1 expression <50% or unknown.  Based on genetic profiling, targeted therapies 
maybe considered as first line before or as second line therapy after platinum-based 
chemotherapy.  
Immune-checkpoint inhibitors are recommended as subsequent therapy for all patients, based on 
reported improvement in survival, longer response duration, and a better safety profile compared 
to chemotherapy. Current data suggest that patients with EGFR mutations or ALK rearrangement 
have low response rates to PD-1 or PD-L1 inhibitors when compared to patients without these 
alterations; therefore checkpoint inhibitors are not considered as recommended subsequent 
treatment in patients with these alterations. 
Since ramucirumab has shown activity in combination with docetaxel in the REVEL study (7), it 
is anticipated that ramucirumab combined with tusamitamab ravtansine should also show 
antitumor activity in advanced NSQ NSCLC. Due to the different mechanisms of action of 
tusamitamab ravtansine and ramucirumab, their combination should have better efficacy than 
either agent alone, and based on lack of anticipated PK interaction, should have similar safety 
profiles to those with either monotherapy.  Because tusamitamab ravtansine’s safety profile differs 
from that of docetaxel, it is expected that the safety of a ramucirumab/tusamitamab ravtansine 
combination will be improved compared to the combination of ramucirumab with docetaxel 
currently approved to treat advanced NSCLC. 
4.3 
DOSE JUSTIFICATION  
In the dose-escalation phase of 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 patients with heavily 
pretreated, CEACAM5-positive, NSQ NSCLC ongoing in TED13751 are receiving tusamitamab 
ravtansine at the recommended dose of 100 mg/m2 every 2 weeks.  Results from the 64 treated and 
evaluable patients from this cohort showed encouraging antitumor activity in the subset with NSQ 
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NSCLC tumors that were ≥50% positive for CEACAM5 expression (6).  This antitumor activity 
was associated with a response rate of 20.3% (95% CI, 12.3% to 31.7%) per RECIST v1.1 in the 
response-evaluable population. 
As no overlap in the safety profiles for ramucirumab and for tusamitamab ravtansine is 
anticipated, the starting dose tested in the Part 1 of the study for tusamitamab ravtansine will be 
the MTD used in monotherapy, 100 mg/m2 every 2 weeks. In the event of a safety concern, the 
dose will be decreased to 80 mg/m2 every 2 weeks. Should a safety concern still exist despite a 
decrease in the dose, the study will be definitively stopped. 
A fixed dose of ramucirumab will be administered.  The dosage chosen for ramucirumab of 
8 mg/kg Q2W has been approved as monotherapy for the treatment of pretreated hepatocellular 
carcinoma; as monotherapy or in combination with paclitaxel for the treatment of heavily 
pretreated advanced or metastatic gastric or gastroesophageal-junction adenocarcinoma; and in 
combination with FOLFIRI for the treatment of CRC.  Therefore, extensive postmarketing clinical 
experience as well as registrational trials for these indications demonstrate both acceptable safety 
and tolerability of the 8 mg/kg Q2W regimen in heavily pretreated patients with advanced cancers, 
as well as potent antitumor activity.  Because nonclinical studies do not predict an effect of 
tusamitamab ravtansine on ramucirumab metabolism or exposures, it is not anticipated that any 
adjustment to ramucirumab dosing will be required for the combination. 
Combining ICI and VEGF/VEGF receptor inhibition have shown benefit in multiple tumor types 
through immune modulation. Pembrolizumab 200 mg iv and ramucirumab10mg/kg every 
3 weeks (P+R) were evaluated in patients with advanced, ICI-exposed, in a substudy of 
Lung-MAP1, a master protocol for patients with Stage IV previously treated NSCLC. In this 
randomized, Phase II study from the Lung-MAP platform,136 patients were randomized to 
receive pembrolizumab + ramucirumab or the Investigator's choice of standard therapeutic 
regimens (SOC). Overall survival (OS) was significantly improved with P+R compared to SOC: 
median (95% CI) OS was 14.5 (13.9 to 16.1) months for P+R: and 11.6 (9.9 to 13.0) months for 
SOC (HR: 0.69 [0.51 to 0.92], P value from the standard log-rank test equal to 0.05 and 0 .15 
from the weighted log-rank test). Neither progression-free survival (PFS) or objective response 
rate (ORR) differed between the treatment arms (2). 
As of August 2022, a total of 20 patients were treated in the ACT16146 study. Preliminary 
encouraging signs of activity with the 3 regimens - tusamitamab ravtansine (SAR408701) 
combined with pembrolizumab and platinum-based chemotherapy with or without pemetrexed, 
have been observed. The combination of tusamitamab ravtansine with pembrolizumab, with or 
without chemotherapy, is feasible and well tolerated without new safety signal observed. Given 
the development of a dose limiting toxicity with 170 mg/m2 and the association between 
exposure and development of ocular toxicity observed in first-in-human (FIH) study, as well as a 
lack of discernable difference in efficacy between 150 and 170 mg/m2, 150 mg/m2 has been 
chosen as the recommended dose for tusamitamab ravtansine in subsequent studies when 
combined with pembrolizumab with or without chemotherapy. 
The starting dose for tusamitamab ravtansine is 150 mg/m2 and was defined based on findings 
from first-in-human study TED13751. In this study, the RP2D for tusamitamab ravtansine given 
Q3W was 170 mg/m2. Given that tusamitamab ravtansine exposure PK parameters at Cycle 1 of 
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administration as a single agent of 170 mg/m2 Q2W were significantly associated with the 
occurrence of Grade ≥2 corneal events, it is anticipated that 150 mg/m2 may result in less ocular 
toxicity, and overall will be better tolerated than 170 mg/m2. In addition, this dose corresponds to 
the same dose intensity as with the recommended 100 mg/m² Q2W dose.  
Based on the experience of the first patients treated in ACT16146 for the dosage of tusamitamab 
ravtansine and pembrolizumab and the experience of the doublet cohort, the starting dose for 
tusamitamab ravtansine will be 150 mg/m2, ramucirumab 10 mg/kg and pembrolizumab 200 mg, 
every 3 weeks. 
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 End of Treatment 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 for the 
last participant in the trial globally.   
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5 
 STUDY POPULATION  
Prospective approval of protocol deviations from 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 the following criteria apply: 
Age 
I 01. Participants must be ≥18 years of age (or country’s legal age of majority, if >18 years), at 
the time of signing the informed consent.  
Type of participant and disease characteristics 
I 02. Histologically or cytologically proven diagnosis of NSQ NSCLC. 
I 03. Metastatic disease progression fulfilling both of the following 2 criteria:  
a) Having progressive disease during or after platinum-based chemotherapy (at least 
2 cycles). Maintenance therapy following platinum-based chemotherapy is not 
considered as a separate regimen. Adjuvant/neoadjuvant treatment for a patient who 
had a relapse with metastatic disease during or within 6 months of completing 
treatment will be considered as first-line treatment.  
AND 
b) Having progressive disease during or after 1 immune checkpoint inhibitor 
(anti-PD1/PD-L1); this could be given as monotherapy or in combination with 
platinum-based chemotherapy (whatever the order). 
I 04. For a tumor genotype with a sensitizing EGFR mutation or BRAF mutation or ALK/ROS 
alteration, demonstrated disease progression while receiving approved treatment for that 
genotype in addition to platinum-based chemotherapy and immune checkpoint inhibitor.  
I 05. Expression of CEACAM5 as demonstrated prospectively by a centrally assessed 
immunohistochemical (IHC) assay of ≥2+ in intensity involving at least 50% of the tumor 
cell population in archival tumor sample (or if not available fresh biopsy sample).  At 
least 5 slides of formalin-fixed, paraffin embedded (FFPE) tumor tissue sectioned at a 
thickness of 4 µm are required.  If less material is available, the patient 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 06. At least one measurable lesion by RECIST v1.1 as determined by local site Investigator 
radiology assessment. An irradiated lesion can be considered measurable only if 
progression has been demonstrated on the irradiated lesion. 
I 07. Eastern Cooperative Oncology Group (ECOG) performance status 0-1. 
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Sex 
I 08. All (male or 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 
A male participant must agree to use contraception (see Appendix 5, Section 10.5) 
during the intervention period and for at least 4 months after the last dose of study 
intervention. 
b) Female participants 
A female participant is eligible to participate if she is not pregnant (see Appendix 5, 
Section 10.5), not breastfeeding, and at least 1 of the following conditions applies: 
- 
Not a woman of child-bearing potential (WOCBP) as defined in Appendix 5 
(Section 10.5). 
OR 
- 
A WOCBP who agrees to follow the contraceptive guidance in Appendix 5 
(Section 10.5) during the intervention period and for at least 7 months after the 
last dose of study intervention. 
Informed Consent 
I 09. Capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the informed consent form (ICF) and in this 
protocol. 
5.2 
EXCLUSION CRITERIA  
Participants are excluded from the study if any of the following criteria applies: 
Medical conditions 
E 01. Untreated brain metastases and history of leptomeningeal disease. Patients with 
previously treated brain metastases may participate provided they are stable (ie, without 
evidence of progression by imaging for at least 4 weeks prior to the first administration of 
study intervention, and any neurologic symptoms have returned to baseline); there is no 
evidence of new or enlarging brain metastases; and the patient does not require any 
systemic corticosteroids to manage brain metastases within 3 weeks prior to the first dose 
of study intervention. 
E 02. Significant concomitant illness, including any severe medical condition that, in the 
opinion of the investigator or Sponsor, would impair the patient’s participation in the 
study or interpretation of the results. 
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E 03. History within the last 3 years of an invasive malignancy other than that treated in this 
study, with the exception of resected/ablated basal or squamous-cell carcinoma of the 
skin or carcinoma in situ of the cervix, or other local tumors considered cured by local 
treatment. 
E 04. History of known acquired immunodeficiency syndrome (AIDS)-related illnesses or 
known human immunodeficiency virus (HIV) disease requiring antiretroviral treatment; 
or active infection with hepatitis A, B (defined as either positive HBs antigen or positive 
hepatitis B viral DNA test above the lower limit of detection of the assay), or C (defined 
as known positive result for antibodies to hepatitis C and known quantitative hepatitis C 
virus [HCV] RNA results greater than the lower limit of detection of the assay).   
E 05. 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. 
E 06. Unresolved corneal disorder or any previous corneal disorder considered by an 
ophthalmologist to predict higher risk of drug-induced keratopathy. The use of contact 
lenses is not permitted. Patients using contact lenses who are not willing to stop wearing 
them for the duration of the study intervention are excluded. 
E 07. Radiographic evidence of major airway or blood vessel invasion or intratumor cavitation, 
regardless of tumor histology. 
E 08. History of uncontrolled hereditary or acquired arterial thrombotic disorder or history of 
aneurism. 
E 09. Major surgery within 28 days prior to Day 1/first IMP infusion, or subcutaneous venous 
access device placement within 7 days prior to Day1. Postoperative bleeding 
complications or wound complications from a surgical procedure performed in the last 
2 months. 
E 10. History of gross hemoptysis (defined as bright red blood or ≥1/2 teaspoon or ≥2.5 mL) 
within 2 months before the first administration of study intervention. 
E 11. Clinically relevant congestive heart failure (CHF; NYHA II-IV, or LVEF less than 50%) 
or symptomatic or poorly controlled cardiac arrhythmia. 
E 12. Any arterial thrombotic event, including myocardial infarction, unstable angina, 
cerebrovascular accident, or transient ischemic attack, within 6 months before the first 
administration of study intervention. 
E 13. Uncontrolled arterial hypertension (systolic ≥150 mmHg or diastolic ≥90 mmHg) despite 
standard medical management.  A participant with systolic pressure >150 mmHg or 
diastolic pressure >90 mmHg is ineligible for the study. 
E 14. Serious or nonhealing wound, skin ulcer, or bone fracture within 28 days before the first 
administration of study intervention. 
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E 15. Gastrointestinal (GI) perforation and/or fistulae within 6 months prior to first 
administration of study intervention. 
E 16. Significant bleeding disorders, vasculitis, or Grade 3-4 gastrointestinal (GI) bleeding 
within 3 months before the first administration of study intervention.  
E 17. Bowel obstruction, history or presence of inflammatory enteropathy or extensive 
intestinal resection Crohn's disease, ulcerative colitis, or chronic diarrhea. 
E 18. Medical condition requiring concomitant administration of a medication with a narrow 
therapeutic window and metabolized by CYP450 (See Appendix 9, Section 10.9); and for 
which a dose reduction cannot be considered. 
E 19. Medical conditions requiring concomitant administration of a strong CYP3A inhibitor 
(see Appendix 10; Section 10.10), unless it can be discontinued at least 2 weeks before 
first administration of study intervention. 
Prior/concomitant therapy 
E 20. Concurrent treatment with any other anticancer therapy. 
E 21. More than 1line previous chemotherapy in metastatic setting. 
E 22. Prior treatment with ramucirumab or docetaxel. 
E 23. Prior therapy targeting CEACAM5. 
E 24. Prior maytansinoid treatment (DM1 or DM4 antibody-drug conjugate). 
E 25. Washout period before the first administration of study intervention of less than 3 weeks 
or less than 5 times the half-life, whichever is shorter, for prior antitumor therapy 
(chemotherapy, targeted agents, immunotherapy and radiotherapy, or any investigational 
treatment). 
E 26. Contraindication to use of corticosteroid premedication. 
E 27. Current therapeutic anticoagulation with warfarin, low-molecular-weight heparin, or 
similar agents. Patients receiving prophylactic, low-dose anticoagulation therapy are 
eligible provided that the coagulation parameters defined in the inclusion criteria 
(INR ≤1.5 or PT ≤1.5 × ULN, and PTT/aPTT ≤1.5 × ULN) are met. 
Prior/concurrent clinical study experience 
E 28. Previous enrollment in this study, current participation in any other clinical study 
involving an investigational study treatment, or any other type of medical research. 
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Diagnostic assessments 
E 29. Poor organ function as defined by any one of the following prior to IMP administration: 
a) 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. 
b) Total bilirubin >1.0 × ULN. 
aspartate aminotransferase (AST), alanine aminotransferase (ALT) >2.5 × ULN  
or  
AST, ALT >5 x ULN in case of documented liver metastasis  
or  
AST, ALT >1.5 × ULN concomitant with alkaline phosphatase (ALP) >2.5 × ULN. 
ALP >5 × ULN with normal ALT/AST, for patients with bone metastases. 
c) Neutrophils <1.5 × 109/L 
or  
platelet count <100 × 109/L 
or  
hemoglobin <9 g/dL (blood infusion-free for at least 2 weeks). 
E 30. Urine dipstick or routine analysis indicating proteinuria of 2+ or higher, unless a 24 hour 
urine collection demonstrates <1000 mg of protein. 
Other exclusions 
E 31. Individuals accommodated in an institution because of regulatory or legal order; prisoners 
or subjects who are legally institutionalized. 
E 32. Any country-related specific regulation that would prevent the subject from entering the 
study - see Appendix 8: Country-specific requirements (Section 10.8). 
E 33. 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 34. Participants are dependent on the Sponsor or Investigator (in conjunction with 
Section 1.61 of the ICH-GCP Ordinance E6). 
E 35. Participants are employees of the clinical study site or other individuals directly involved 
in the conduct of the study, or immediate family members of such individuals. 
E 36. Any specific situation during study implementation/course that may rise ethics 
considerations. 
E 37. 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.   
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Triplet cohort exclusions 
E 38. History of active autoimmune disease that has required systemic treatment in the past 
2 years. 
E 39. History of allogeneic tissue/solid organ transplantation. 
E 40. Active infection requiring IV systemic therapy within 2 weeks prior to first study 
intervention administration or active tuberculosis. 
E 41. Interstitial lung disease or history of pneumonitis that has required oral or IV steroids. 
E 42. Symptomatic herpes zoster within 3 months prior to screening. 
E 43. Significant allergies to humanized monoclonal antibodies. 
E 44. Any radiation therapy to lung >30 Gy within 6 months of first study intervention 
administration. 
E 45. Has received or will receive a live vaccine within 30 days prior to the first study 
intervention administration. 
E 46. Thyroid-stimulating hormone (TSH) out of normal limits. If TSH is not within normal 
limits at baseline, the subject may still be eligible if T3 and free T4 are within the normal 
limits 
5.3 
LIFESTYLE CONSIDERATIONS  
Not applicable. 
5.4 
SCREEN FAILURES  
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently 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. 
For an individual who does 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 new participant number different from that assigned for the initial screening, and all 
the screening procedures will be repeated and entered in the screening visit pages. Participants 
who screen failed and then rescreen need to re-sign a new ICF. In the case that the participant is 
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a temporary screen failure (ie, requirement of a prolongation of the screening period), there is no 
need to have participant sign a new ICF if the participant finally participates in the trial. 
However, if the reason for the temporary screen failure is a reason that might have altered the 
participant’s initial given agreement to participate, the Investigator should ask the participant to 
confirm willingness to continue or repeat some screening procedures and to participate in the 
trial. This oral agreement should be documented in the participant’s chart. All the tests repeated 
outside of the protocol-specified window for the screening period should be repeated and entered 
to the additional pages. 
5.5 
CRITERIA FOR TEMPORARILY DELAYING PRESCREENING, SCREENING, STUDY 
INTERVENTION, STUDY PROCEDURES  
During a regional or national emergency declared by a governmental agency, if the site is unable 
to adequately follow protocol mandated procedures, contingency measures are proposed in 
Appendix 11 (Section 10.11: Contingency measures for a regional or national emergency that is 
declared by a governmental agency) should be considered for prescreening, screening, study 
intervention, and study procedures. 
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6 
STUDY INTERVENTIONS  
6.1 
STUDY INTERVENTIONS ADMINISTERED  
A study intervention is defined as any investigational intervention, marketed product, placebo, or 
medical device intended to be administered to a study participant according to the study protocol. 
Study drugs to be administered for doublet cohort are detailed in Table 7. 
Table 7 - Overview of study interventions administered - Doublet cohort  
Enter Arm Name (single arm) 
tusamitamab ravtansine 
ramucirumab 
Type 
Drug/Biologic 
Biologic 
Dose formulation 
Concentrated solution for IV 
Concentrated solution for IV 
Unit dose strength(s) 
5 mg/mL 
10 mg/mL 
Dosage level(s) 
100 (80) mg/m2 every 2 weeks 
8 mg/kg every 2 weeks 
Route of administration 
IV infusion 
IV infusion 
IMP (single-arm) 
IMP 
IMP 
Packaging and labeling 
Supplied in a 30 mL glass vial with a 
plastic flip-off cap, containing 
125 mg/25 mL tusamitamab 
ravtansine, and labelled with a 
multilingual booklet 
Supplied in a single-dose vial 
(100 mg/10 mL or 500 mg/50 mL) 
individually packaged in a carton. 
[Current/Former name(s) or alias(es)] 
None 
Cyramza 
Study drugs to be administered for triplet cohort are detailed in Table 8.  
Table 8 - Overview of study interventions administered - Triplet cohort  
Enter Arm Name  
(single arm) 
tusamitamab 
ravtansine 
ramucirumab 
pembrolizumab 
Type 
Drug/Biologic 
Biologic 
Biologic 
Dose formulation 
Concentrated solution for 
IV 
Concentrated solution for 
IV 
Concentrate for solution 
for infusion 
Unit dose strength(s) 
5 mg/mL 
10 mg/mL 
25 mg/mL 
Dosage level(s) 
150 (120) mg/m2 every 
3 weeks 
10 mg/kg every 3 weeks 
200 mg every 3 weeks 
Route of administration 
IV infusion 
IV infusion 
IV infusion  
IMP (single-arm) 
IMP 
IMP 
IMP 
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Enter Arm Name  
(single arm) 
tusamitamab 
ravtansine 
ramucirumab 
pembrolizumab 
Packaging and labeling 
Supplied in a 30 mL glass 
vial with a plastic flip-off 
cap, containing 
125 mg/25 mL 
tusamitamab ravtansine, 
and labelled with a 
multilingual booklet 
Supplied in a single-dose 
vial (100 mg/10 mL or 
500 mg/50 mL) individually 
packaged in a carton. 
Supplied in single-dose 
vials containing 
100 mg/4 mL 
pembrolizumab labelled 
with a multilingual booklet. 
1 vial per treatment box 
[Current/Former name(s) or 
alias(es)] 
None 
Cyramza 
Keytruda 
Study medication infusion: 
Infusion via a central line is preferred, 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.   
On Day 1 of each treatment cycle, the patient’s BSA will be determined using the current weight 
and baseline height; dose may not be adjusted if body weight change is ≤5%. 
Investigational medicinal products: 
Ramucirumab: Ramucirumab should be administered prior to tusamitamab ravtansine infusion. 
Using a controlled infusion pump, ramucirumab will be administered by IV infusion over 1 hour 
on D1 of each cycle. If the first infusion is tolerated, all subsequent ramucirumab infusions may 
be administered over 30 minutes.  In case of IRR, Grade 1 or 2, the infusion rate of ramucirumab 
will be reduced by 50%.   
Tusamitamab ravtansine: Infusion of tusamitamab ravtansine should be initiated at least 1 hour 
after the end of ramucirumab infusion.  Using a controlled infusion pump, tusamitamab 
ravtansine will be administered by IV infusion over 1 hour 30 minutes.  For patients with a BSA 
>2.20 m2, the calculated dose of tusamitamab ravtansine will be based on a BSA of 2.20 m2. 
After first study intervention of tusamitamab ravtansine, patients should be observed for acute 
reactions at site up to 4 hours depending on any sign of drug-induced allergic reaction. Detailed 
instructions for dilution and administration of the IMP is provided in Pharmacy Manual. 
Pembrolizumab: Pembrolizumab will be administered after administration of tusamitamab 
ravtansine in the triplet cohort only. Using a controlled infusion pump, pembrolizumab will be 
administered as a 200 mg IV infusion over 30 minutes on Day 1 and then Q3W. 
Noninvestigational medicinal products: 
Premedication: 
Both tusamitamab ravtansine and ramucirumab have potential risk of IRR; thus, premedication 
with an IV histamine-1 receptor antagonist (diphenhydramine 50 mg IV or equivalent; eg, 
cetirizine, promethazine, dexchlorpheniramine, according to local approval and availability) will 
be given approximately at least 15 minutes before ramucirumab administration. In case of IV 
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forms unavailability, a per os administration should be considered in an appropriate timeframe. If 
a participant previously experienced an IRR following a dose of ramucirumab or tusamitamab 
ravtansine, premedication will also include corticosteroids equivalent to 10 mg IV 
dexamethasone, and acetaminophen/paracetamol for future infusions.  All drugs used as 
premedication will be entered on the concomitant premedication page. 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY  
1. The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention and only authorized 
site staff may supply or administer study intervention. All study intervention must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the Investigator and 
authorized site staff. 
3. The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records). 
Partially-used and used study treatments will be destroyed at the study site according to the 
standard practices of the site after an accurate accountability has been performed and signed by 
the Investigator (or the pharmacist). A detailed treatment log form of the destroyed study 
treatment will be established with the Investigator (or the pharmacist) and countersigned by the 
Investigator and the Monitoring Team. The Investigator must not destroy the unused IMP unless 
Sanofi provides written authorization.  
Further guidance and information for the final disposition of used and unused study interventions 
are provided in the pharmacy manual and/or monitoring plan. 
Any quality issue noticed with the receipt or use of an IMP/non-IMP (NIMP; eg, deficiency in 
condition, appearance, pertaining documentation, labeling, expiration date) must be promptly 
reported to the Sponsor. Some deficiencies may be recorded through a complaint procedure 
(Section 8.3.8). 
A potential defect in the quality of IMP/NIMP may be subject to initiation of a recall procedure 
by the Sponsor. In this case, the Investigator will be responsible for promptly addressing any 
request made by the Sponsor, in order to recall the IMP/NIMP and eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP/NIMP to a third party (except for DTP 
shipment, for which a courier company has been approved by the Sponsor), allow the 
IMP/NIMP to be used other than as directed by this clinical trial protocol, or dispose of 
IMP/NIMP in any other manner. 
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6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING  
Not applicable. 
6.4 
STUDY INTERVENTION COMPLIANCE  
Administration of the IMP will be supervised by the Investigator or Sub-investigator. The person 
responsible for drug dispensing is required to maintain adequate records of the IMPs. These 
records (eg, drug movement form) include the date the IMPs are received from the Sponsor, 
dispensed to the participant and destroyed or returned to the Sponsor. The packaging batch 
number (IP number) and the treatment number on the vial must be recorded on the drug 
accountability form. The person responsible for drug administration to the participant will record 
precisely the date and the time of the drug administration to the participant. Deviation(s) from the 
prescribed dosage regimen should be recorded in the electronic case report form (eCRF).  
6.5 
CONCOMITANT THERAPY  
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment or receives 
during the study must be recorded along with: 
• Reason for use 
• Dates of administration including start and end dates 
• Route of administration 
Concomitant medications should be kept to a minimum during the study. However, if these are 
considered necessary for the patient's welfare and are unlikely to interfere with the IMP, they may 
be given at the discretion of the investigator and recorded in the e-CRF. Concomitant medication 
will be recorded in the eCRF from 28 days prior to the first study intervention administration, 
before every cycle during the study treatment period, and for up to 30 days after the final dose of 
study intervention. Once the participant has withdrawn from study treatment, concomitant 
medication should only be recorded if used to treat new or unresolved study treatment-related 
adverse events. 
Concomitant treatment 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 intent). If palliative 
radiotherapy is being considered, the Sponsor should be contacted for approval prior to 
initiating treatment, and prior to resuming therapy on the study.  
The irradiated area should be as small as possible and should involve no more than 20% of 
the bone-marrow in any given 3-week period. In all such cases, the possibility of tumor 
progression should be ruled out by physical and radiological assessments of the tumor. 
The irradiated area cannot be used as a parameter for response assessment. If the only 
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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. 
• Prior to elective surgery, omit ramucirumab for 28 days.  Resume ramucirumab no sooner 
than 28 days after surgery and the wound is fully healed. 
• Any background therapy taken by the participant for concomitant illnesses other than 
cancer (eg, hormone-replacement therapy, statin, antihypertensive medication) is allowed. 
• Supportive treatment as medically indicated for the patient's well-being may be prescribed 
at the Investigator's discretion. Every medication or treatment taken by the patient during 
the trial and the reason for its administration must be recorded on the eCRF. 
6.5.1 Treatments prohibited during the study  
The following treatments are not permitted during this study: 
• Concurrent treatment with other investigational drugs. 
• Concurrent treatment with any other anticancer therapy not specified in the protocol, 
including immunotherapy, hormonal therapy, targeted therapy or biological therapies. 
• The primary prophylactic use of granulocyte colony-stimulating factor (G-CSF) is not 
allowed during the Cycle 1 and Cycle 2 for the Part 1 of the study. Secondary prophylaxis 
or therapeutic administration is allowed as detailed in Section 6.6. 
• Use of prophylactic erythropoietin during the first 2 cycles for the doublet cohort and 
during the first cycle for the triplet cohort. 
• Patients treated or intended to be treated with drugs identified as CYP450 substrates with 
narrow therapeutic range (NTR) should be carefully monitored (see Appendix 9,  
Section 10.9). 
• Concomitant use of strong CYP3A inhibitors should be avoided from 2 weeks before 
tusamitamab ravtansine administration up to the last tusamitamab ravtansine 
administration (see Appendix 10, Section 10.10). 
• The use of contact lenses will not be permitted during the study treatment period. 
Ramucirumab and pembrolizumab are not considered as a concomitant therapy and should be 
recorded as IMPs.  
6.6 
DOSE MODIFICATION  
6.6.1 Doublet cohort - Part 1 (Safety Run-In)  
If ≥2 of the first 3 patients or of the 6 patients treated at the initial DL present with DLTs, the SC 
may decide to decrease the dose of tusamitamab ravtansine to DL -1 (80 mg/m2 in combination 
with 8 mg/kg ramucirumab). The tolerability of the reduced DL will be assessed in at least 
6 participants.  Dose reduction in the case of 2 or more DLTs for the cohort is shown in Table 9.   
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Table 9 - Dose reduction for doublet cohort for Part 1 (safety run-in)  
Dose level (DL)  
tusamitamab ravtansine 
Ramucirumab 
Starting dose 
100 mg/m2 Q2W 
8 mg/kg Q2W 
Minus -1 (DL-1) 
80 mg/m2 Q2W 
8 mg/kg Q2W 
BSA=body surface area; DL=dose level; Q2W=every 2 weeks. 
Infusion of tusamitamab ravtansine will be administered at least 1 hour after the end of ramucirumab infusion. For patients with a 
BSA >2.20 m2, the tusamitamab ravtansine dose will be calculated based on a BSA of 2.20 m2. 
6.6.2 Triplet cohort  
If ≥2 of the first 3 patients or of the 6 patients treated at the initial DL present with DLTs, the SC 
may decide to decrease the dose of tusamitamab ravtansine to DL -1 (120 mg/m2 in combination 
with 10 mg/kg ramucirumab). The tolerability of the reduced DL will be assessed in at least 
6 participants.  Dose reduction in the case of 2 or more DLTs for the cohort is shown in Table 10.  
Table 10 - Dose reduction for triplet cohort  
Dose level (DL)  
tusamitamab 
ravtansine 
ramucirumab 
pembrolizumab 
Starting dose 
150 mg/m2 Q3W 
10 mg/kg Q3W 
200 mg Q3W 
Minus -1 (DL-1) 
120 mg/m2 Q3W 
10 mg/kg Q3W 
200 mg Q3W 
DL=dose level; Q3W=every 3 weeks. 
Infusion of tusamitamab ravtansine will be administered at least 1 hour after the end of ramucirumab infusion. For patients with a 
BSA >2.20 m2, the tusamitamab ravtansine dose will be calculated based on a BSA of 2.20 m2. 
6.6.3 Doublet cohort (Part 1 and Part 2) and triplet cohort: Requirements for retreatment  
For the retreatment of patients on Day 1 of each subsequent cycle, the following conditions should 
be met:  
• Neutrophils count ≥1.5 × 109/L.  
• Platelets ≥100 × 109/L.  
• Total bilirubin ≤1.5 × ULN. 
• AST, ALT ≤2.5 × ULN or ≤5 × ULN in case of documented liver metastasis. 
• No IMP-related toxicity Grade >1 (except for alopecia) or baseline severity. 
• Urine protein: 
- 
<2+ on dipstick or urinalysis for C1D1, 
- 
≤2+ on dipstick or urinalysis for subsequent infusions, 
OR 
- 
<2 g on 24 hours urine collection. 
• Hypertension is controlled, every attempt should be made to control blood pressure  
(<140 mmHg systolic and <90 mmHg diastolic). 
• Wound healing: any wound is fully healed. 
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6.6.4 Dose adjustment/dose delay  
Dose adjustment and/or cycle delay are permitted in case of adverse reaction. In case of toxicity, 
cycle delays and dose modifications should be implemented according to Appendix 4 
(Section 10.4). Every effort will be made to administer the full dose regimen and maximize dose 
intensity.  
Dose adjustments will be made according to the worst grade of adverse reaction observed within a 
cycle. If a participant experiences several adverse reactions and there are conflicting 
recommendations, the most conservative dose adjustment recommended should be followed.  
Administration of the study treatment will be discontinued in the event of a TEAE that persists 
despite appropriate dose modifications or any other AE that, in the opinion of the Investigator, 
warrants discontinuation.  
Pembrolizumab, ramucirumab or tusamitamab ravtansine can be discontinued prematurely. The 
patient will remain on study treatment until the last IMP can be discontinued until disease 
progression, unacceptable AE, or the participant’s or investigator’s decision to stop the treatment. 
The reason for premature discontinuation will be captured in the appropriate eCRF page. 
Dose modifications different from those stated in the protocol should be made only 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 G-CSF should be administered according to the current 
American Society of Clinical Oncology (ASCO) guidelines (23). In case of neutropenia or febrile 
neutropenia, prophylactic G-CSF should be started and in case of second episode beside 
prophylactic G-CSF, then dose should be reduced.  
The acceptable treatment window for tusamitamab ravtansine and ramucirumab and 
pembrolizumab administration is ±2 days for a Q2W (doublet cohort) and ±3 days for a Q3W 
administration (triplet cohort). 
See Appendix 4 in Section 10.4 for further guidance in dose modification or discontinuation.  
Approved product label should be followed for patient receiving ramucirumab treatment for 
supportive care and dose modification requirement due to not listed adverse events. During the 
conduct of the study, second dose reduction may be needed, and need to be decided case by case 
discussion with the sponsor.  
In case a dose reduction is necessary, the study intervention will be administered as shown in 
Table 11 and Table 12:  
Table 11 - Dose modification for toxicity in doublet cohort  
Drug name 
Starting dose 
1st dose reduction 
2nd dose reduction 
tusamitamab ravtansine 
100 mg/m2 Q2W 
80 mg/m2 Q2W 
(not permitted) 
ramucirumab  
8 mg/kg Q2W 
6 mg/kg Q2W 
5 mg/kg Q2W 
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Table 12 - Dose modification for toxicity in triplet cohort  
Drug name 
Starting dose 
1st dose reduction 
2nd dose reduction 
tusamitamab ravtansine 
150 mg/m2 Q3W 
120 mg/m2 Q3W 
(not permitted) 
ramucirumab 
pembrolizumab  
10 mg/kg Q3W 
200 mg Q3W 
8 mg/kg Q3W 
(not permitted) 
6 mg/kg Q3W 
(not permitted) 
Any patient who requires a tusamitamab ravtansine or ramucirumab dose reduction will continue 
to receive a reduced dose until discontinuation from tusamitamab 
ravtansine/ramucirumab/pembrolizumab or discontinuation from the study. 
Any patient who has had 1 tusamitamab ravtansine dose reduction or 2 ramucirumab dose 
reductions and who experiences an event that would cause an additional dose reduction must be 
discontinued from tusamitamab ravtansine/ramucirumab. 
If 1 of the 3 drugs (tusamitamab ravtansine or ramucirumab or pembrolizumab) is prematurely 
permanently discontinued, the other drug(s) can be continued until disease progression. 
Retreatment of a patient requiring a dose delay of more than 1 month will need to be justified by 
an individual case risk-benefit assessment. 
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7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL  
The duration of the study for a participant will include: 
• Screening period: up to 28 days. 
• Treatment period: once successfully screened, enrolled participants may receive study 
intervention until disease progression, unacceptable AE, or the participant’s or 
investigator’s decision to stop the treatment. Each cycle of treatment will have duration of 
2 weeks in doublet cohort and 3 weeks in triplet cohort. 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 assessments. 
• Safety follow-up visit: will be performed at 90 days after the last infusion. If ongoing 
related AE and all SAEs and AESI are resolved or stabilized, no further follow-up visit is 
needed. 
For the doublet cohort, a participant who stops treatment before documented PD (achieving SD, 
CR or PR) should undergo a tumor assessment and an on-site follow-up visit every 12 weeks 
(±7 days) after the last tumor assessment until radiological disease progression, start of new 
anti-cancer therapy, death, the study cut-off date of the secondary ORR endpoint analysis of 
triplet cohort, or withdrawal of participant’s consent, whichever comes first. After PD or a start of 
new anti-cancer therapy, a participant will be followed until any ongoing related AE/SAE is 
resolved or stabilized. 
The study cut-off for the primary ORR endpoint analysis of doublet cohort corresponds to the date 
on which all evaluable treated patients have had at least 2 post baseline tumor assessments, 
experienced confirmed objective response, or have discontinued the study for any reason and 
which can be up to approximately 6 months (4 months for 2 treatment assessment, and 2 months if 
response confirmation is needed) from the date the last participant first administration.  
The study cut-off for the secondary ORR endpoint analysis of triplet cohort corresponds to the 
date on which all evaluable treated patients have had at least 2 post baseline tumor assessments, 
experienced confirmed objective response, or have discontinued the study for any reason. This 
study cut-off will occur approximately 4.5 months after the date of the first IMP administration of 
the last participant: 3 months for 2 tumor assessments and 1.5 months if a confirmation of 
response is needed.  
After the study cut-off dates for the primary ORR analysis of doublet cohort and for the secondary 
ORR analysis of triplet cohort, patients who are still receiving study treatment can continue study 
treatment, if clinical benefit is observed, until PD, unacceptable toxicity, or withdrawal of 
participant’s consent, 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; 
median expected duration of study per participant is estimated as 11 months (up to 1 month for 
screening, a median of 6 months for treatment, and a median of 4 months for end-of-treatment 
assessments and safety follow-up visit). 
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Study Team will add details on the specific changes to follow-up for patients with ongoing 
treatment after final study cut-off date. 
7.1 
DISCONTINUATION OF STUDY INTERVENTION  
7.1.1 Definitive discontinuation  
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention. If study intervention is permanently discontinued, the participant will remain in the 
study to be evaluated for safety and disease progression status when applicable. See Section 1.3 
for data to be collected at the time of discontinuation of study intervention. All efforts should be 
made to document the reasons for discontinuation, and these should be recorded in the eCRF.  
Ramucirumab or tusamitamab ravtansine or pembrolizumab can be discontinued prematurely. The 
patient will remain on study treatment until the last IMP is discontinued. The reason for premature 
discontinuation will be captured in the appropriate eCRF page.  
Study intervention should be discontinued in any of the following cases:  
1. Unacceptable AE.  
2. Disease progression.  
3. Poor compliance to the study protocol.  
4. Other such as concurrent illness, that prevents further administration of study intervention.  
See the Schedule of Activities (SOA; Section 1.3) for data to be collected at the time of 
intervention discontinuation and follow-up and for any further evaluations that need to be 
completed. 
Handling of participants after definitive intervention discontinuation 
Participants will be followed-up according to the study procedures specified in this protocol up to 
the scheduled date of study completion, or up to recovery or stabilization of any AE to be 
followed-up as specified in this protocol, whichever comes last. 
If possible, and after the definitive discontinuation of intervention, the participants will be 
assessed using the procedure normally planned for the last dosing day with the IMP including 
PK/antigenicity sample, if appropriate. 
All cases of definitive intervention discontinuation must be recorded by the Investigator in the 
appropriate pages of the e-CRF when considered as confirmed. 
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7.1.2 Temporary discontinuation/dosing delays  
See Section 6.6.4. Temporary intervention discontinuation (ie, prolonged cycle delay) may be 
considered by the Investigator because of suspected AEs or disruption of the clinical trial due to a 
regional or national emergency declared by a governmental agency (Appendix 11 
[Section 10.11]). 
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 early discontinuation visit should be 
conducted. See the SOA (Section 1.3) 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. 
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 
e-CRF and in the participant’s medical records. In the medical record, at least the date of the 
withdrawal and the reason should be documented. 
In addition, a participant may withdraw his/her consent to stop participating in the study. 
Withdrawal of consent for intervention should be distinguished from withdrawal of consent for 
follow-up visits and from withdrawal of consent for non-participant contact follow-up, eg, medical 
record checks.  
The site should document any case of withdrawal of consent. The patient should withdraw 
consent, preferably, in writing.  If the patient or the patient’s representative refuses or is physically 
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unavailable, the site should document and sign the reason for the patient’s failure to withdraw 
consent in writing. 
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 (Section 1.3). Protocol 
waivers or exemptions are not allowed. For a regional or national emergency declared by a 
governmental agency, contingency measures are included in Appendix 11 (Section 10.11). 
• Adherence to the study design requirements, including those specified in the SOA, is 
essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The Investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.  
• Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SOA. 
• In patients who failed prescreening, limited information will be collected as detailed 
in Section 1.3. 
During the screening period, demography, medical/surgical and disease history will be evaluated. 
Demography includes age, gender, race, and ethnicity. Medical/surgical history includes relevant 
history of previous pathologies and surgeries. Disease history includes the histologic types, stage 
at diagnosis and disease extent at study entry, specific mutations including PD1 expression status 
and previous antitumor therapy (type, start and end dates, reason for discontinuation and response 
to the therapy) and smoking history.  
8.1 
EFFICACY ASSESSMENTS  
The assessment of antitumor activity of tusamitamab ravtansine combined with ramucirumab in 
doublet cohort is the primary efficacy objective. 
All participants treated must have at least one measurable lesion as per RECIST v1.1 for inclusion 
based on tumor assessment defined in the SOA, Section 1.3. 
For the doublet cohort: Tumor assessment will be made every 8 weeks (±7 days window), and a 
scheduled assessment time point will not be modified in case of a cycle delay. 
Thoracic-abdominal-pelvic CT-scan or MRI and any other examinations as clinically indicated 
will be performed to assess disease status at baseline; then every 8 weeks during the study 
treatment period until radiological disease progression, initiation of further anticancer therapy, 
death, or study cut-off of the secondary ORR endpoint of the triplet cohort, whichever comes first; 
and at the end of study treatment, except if already done at last cycle. 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 patients without imaging 
performed within past 4 weeks, and every 12 weeks (±7 days) after the last tumor assessment until 
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disease progression or initiation of a new anticancer treatment, death, or the study cut-off date of 
the secondary ORR endpoint of the triplet cohort, whichever comes first.  
For the triplet cohort: Tumor assessment will be made every 6 weeks (±7 days window), and a 
scheduled assessment time point will not be modified in case of a cycle delay. 
Thoracic-abdominal-pelvic CT-scan or MRI and any other examinations as clinically indicated 
will be performed to assess disease status at baseline; then every 6 weeks during the study 
treatment period until IMP discontinuation; and at the end of study treatment, except if already 
done at last cycle. 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 patients without imaging performed within past 4 weeks. 
For both cohorts: Brain CT-scan or MRI should be performed at baseline and followed only for 
patients with brain lesions at baseline.  Imaging assessments during the on-treatment period are to 
be scheduled using the Cycle 1, Day 1 date as the reference date for all time points and are not to 
be scheduled based on the date of the previous imaging time point. Delay of an imaging 
assessment to conform to treatment delay is not permitted. The same tumor assessment technique 
must be used throughout the study for a given lesion/participant. 
For the doublet cohort, secondary efficacy endpoints will include DOR,  PFS, and DCR. 
The RECIST v1.1 criteria will be followed for assessment of tumor response; see Appendix 7 for 
details (Section 10.7). 
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, temperature, blood pressure, 
heart rate (see vital signs in Section 8.2.3), and assessments of the major body systems, 
including cardiovascular and central nervous systems. Weight will also be measured and 
recorded before premedication and IMP administration at all treatment visits, and at the 
End of treatment and follow-up visits.  Height will be recorded only at Screening.  
• ECOG performance status should be assessed before each IMP administration and at the 
follow-up visit. 
• Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
• Any new finding or worsening of previous finding should be reported as a new AE. 
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8.2.2 Specific ocular tests  
Specific complete ocular tests at baseline will include: assessment of ocular/visual symptoms and 
ocular exams including visual acuity, slit lamp under dilatation, and Schirmer’s test. 
Standard specific ocular tests include:  
• Assessment of ocular/visual symptoms, (ie, blurred vision, photophobia, dry eye, etc) at 
each visit before each study intervention. Start and end dates of symptoms will be 
collected. 
• Visual acuity at screening and whenever clinically indicated. 
• Slit lamp under dilatation at screening and whenever clinically indicated. 
• Schirmer’s test at screening and whenever clinically indicated. 
In participants with any ocular/visual symptom (eg, blurred vision, photophobia), complete ocular 
tests will be repeated at the time of the occurrence of the ocular toxicity, if any regardless of the 
grade.  Thereafter, visual acuity, slit lamp examination under dilatation, and Schirmer’s test will 
be repeated once weekly (if not recommended to have less frequent assessment by 
ophthalmologist based on lesion characteristics) until resolution to Grade 1. In case of recurrent 
ocular toxicity observed in subsequent cycles, visual acuity and slit lamp examination under 
dilatation, and Schirmer’s test will be performed at the time of the event onset, then weekly until 
resolution to Grade 1. 
8.2.3 Vital signs  
• Temperature, blood pressure, heart rate will be assessed during each physical examination 
(Section 8.2.1). 
• For blood pressure assessments, 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). 
8.2.4 Cardiac assessment  
8.2.4.1 Electrocardiograms  
• A single 12-lead ECG is required at baseline screening; before starting and after 
completing the first IMP administration (within 30 minutes after the end of the infusion); 
before IMP administration at each cycle; and at the end of treatment evaluation (between 
Day 22 and Day 30 after the last IMP administration).  This test can be performed on the 
same day before the study intervention administration, or on the day before. An ECG is to 
be repeated as clinically indicated. 
• A single 12-lead ECG will be obtained using an ECG machine that automatically 
calculates the heart rate and measures PR, QRS, and QT intervals.  
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• ECGs will be interpreted by a qualified physician at the site as soon after the time of ECG 
collection as possible, and ideally while the patient is still present, should additional ECGs 
be performed or for immediate patient management should any clinically relevant findings 
be identified. 
8.2.4.2 Echocardiogram or MUGA scan  
An echocardiogram or multigated acquisition (MUGA) scan to evaluate left ventricular ejection 
fraction (LVEF) will be evaluated during screening period, and whenever clinically indicated. 
8.2.5 Clinical safety laboratory assessments  
See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed and to the 
SOA (Section 1.3) for the timing and frequency.  In general, these tests will be done at each cycle; 
during the first 2 cycles, hematology and liver function tests will be assessed weekly.  
If Grade 4 neutropenia occurs, assess ANC every 2 to 3 days until ANC ≥0.5 × 109/L.  
In case of Grade ≥3 abnormal liver function tests, additional tests will be done every 2 to 3 days 
until recovery to the baseline value. Additional tests will be performed when clinically 
appropriate. This test can be performed before the study intervention administration on the same 
day or the day before. 
The Investigator must review the laboratory reports and must document this review in the source 
documents. 
8.2.6 Guidelines for management of adverse events  
Management of the AE related to tusamitamab ravtansine and ramucirumab and pembrolizumab is 
summarized in Appendix 4 (Section 10.4); for specific AE related to ramucirumab or 
pembrolizumab intake, please refer to the current prescribing information leaflet; the most relevant 
reported events are summarized in this section as reminder. 
8.2.6.1 Hypersensitivity reactions  
Premedication treatments provided for treatment of hypersensitivity reactions are detailed 
in Section 6.1. 
In case of event of hypersensitivity reactions, please refer to the recommended dose modification 
or discontinuation table in Appendix 4 (Section 10.4). 
As with other monoclonal antibodies, IRRs may occur during or following ramucirumab or 
tusamitamab ravtansine or pembrolizumab administration. Patients should be closely monitored 
for signs and symptoms indicative of an IRR from the initiation of the infusion in an area where 
resuscitation equipment and other agents (such as epinephrine and corticosteroids) are readily 
available.  
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A 1-hour observation period following the ramucirumab infusion is mandatory for the first 
2 infusions. If the patient shows no evidence of an IRR with the first 2 infusions of ramucirumab, 
no observation period is required for subsequent infusions. In the event an IRR occurs thereafter, 
the 1-hour observation should be reinstituted. Symptoms of IRRs include rigors/tremors, back 
pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and 
paresthesia. In severe cases, symptoms include bronchospasm, supraventricular tachycardia, and 
hypotension. If the patient experiences a Grade 2 IRR, interrupt the infusion and treat the patient 
with anti-allergic medication. If symptoms resolve, resume the infusion at a reduced rate (50%). 
8.2.6.2 Ocular toxicity  
It is recommended that topical artificial tears (and/or hyaluronic ophthalmic gel) are used regularly 
in all patients treated with tusamitamab ravtansine during the study treatment period. 
The patient should be asked about ocular/visual symptoms at each visit, and ocular evaluation 
including visual acuity, slit lamp examination under dilatation, and Schirmer’s test should be 
carried on according to Study Procedures (Section 1.3). Ocular evaluation will be performed at 
baseline (during the screening period), as required during the treatment (ie, on occurrence of 
ocular symptoms such as blurred vision, photophobia, pain), at the EOT visit, and when relevant 
at follow-up visit(s). The outcome of the examination should be available before infusion of the 
next cycle. If ocular symptoms are present, then a formal ocular examination should be 
performed. In patients with any ocular/visual symptom(s) (eg, blurred vision, photophobia), the 
ocular evaluation should be repeated once weekly, unless less frequent assessment is 
recommended by an ophthalmologist, until resolution to Grade 1. Subsequently, the participant 
should be followed with ocular exam (slit lamp and visual acuity) at each cycle until total 
resolution of the event. 
Photographs of the cornea are recommended to be taken at the site, if possible, when ocular 
findings are first documented, and to follow progression when relevant. Tonometry and additional 
ocular assessment can be performed at discretion of an ophthalmologist when applicable. 
8.2.6.2.1 Keratopathy/keratitis management  
Reversible non-inflammatory, microcystic keratopathy was identified as the DLT during the dose 
escalation process in TED13751 study with tusamitamab ravtansine. At slit-lamp examination, it 
presents as lesions consisting of 100s to 1000s microcysts and/or deposits that are initially 
observed at the periphery of the cornea, the limbus being preserved. The lesions have a centripetal 
distribution and evolve towards the center of the corneal upon resolution, following the natural 
keratinocyte regeneration process.  
For standardization of AE verbatim, keratopathy should be preferred term unless otherwise 
specified by an ophthalmologist due to inflammatory findings on eye exams leading to diagnosis 
of keratitis.  
The potential ocular/visual toxicity symptoms could include, but are not limited to, blurred vision, 
dry eye, and photophobia. Curative treatment may be used as recommended by an 
ophthalmologist.  
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No primary prophylaxis other than prevention of dry eye with artificial tears and/or hyaluronic 
ophthalmic gel is recommended; the use of contact lenses is not permitted during the treatment 
period. Corticosteroid-containing ocular drugs are recommended for the management of 
keratopathy/keratitis in the case that ocular symptoms occur, and treatment will be performed 
based on discretion of ophthalmologist. Dose modification and recommendations are further 
described in Appendix 4 (Section 10.4). 
After resuming study treatment, a patient who had Grade ≥2 keratopathy/keratitis should be 
followed with standard ocular exams (ie, slit lamp examination under dilatation and visual acuity) 
every 2 cycles, even if symptoms are no longer reported. If no event recurs during the next 
4 cycles, then regular follow-up (ie, symptom assessment at each visit with standard ocular exam 
in case of any ocular sign/symptom) is applied.  
8.2.6.3  Management of anemia  
Close surveillance of any signs and symptoms is required: a routine blood hematology workup, 
including red blood cell (RBC) counts, hemoglobin, hematocrit, WBC with differential, and 
platelet counts will be done weekly during the first 2 cycles, and thereafter each treatment cycle 
before IMP administration. Patients should not start Cycle 1 treatment if hemoglobin is <9.0 g/dL. 
To be eligible for the study and to receive the first study treatment, the participant must have been 
transfusion-free for 2 weeks. During the treatment period, erythrocyte transfusion can be given, 
upon Investigator decision. Erythropoietin can be given at the discretion of the Investigator, 
except during Screening and the first 2 cycles. Cycle delays or modifications should be compliant 
with Appendix 4 (Section 10.4). 
8.2.6.4 Management of neutropenia  
In patients who experienced either Grade 3 or 4 febrile neutropenia or Grade 4 decreased 
neutrophil count (<500 cells/mm3) for more than 1 week during study intervention, prophylactic 
G-CSF should be implemented per ASCO guidelines (23) to ensure dose intensity (Appendix 4 
in Section 10.4).  Doses of tusamitamab ravtansine should be reduced in case of recurrent events 
even after prophylactic G-CSF use. 
If the patient continues to experience these reactions at a lowered dose, the treatment should be 
discontinued (Section 7). 
8.2.6.5 Liver function tests  
Hepatic enzyme increase has been reported with tusamitamab ravtansine administration as 
monotherapy or ramucirumab. Patients should be carefully followed and in case of Grade ≥3 
abnormal liver function tests, additional liver function tests will be done every 2 to 3 days until 
recovery to baseline value. Tusamitamab ravtansine should be permanently discontinued in case of 
drug-induced Grade 4 liver enzyme increase. For stopping rules for ramucirumab administration, 
the current product leaflet should be followed. 
Grade ≥3 (ie, >5 × ULN) increased liver enzyme events should be reported as AESIs. 
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8.2.6.6 Hypertension  
An increased incidence of severe hypertension (CTCAE Grade 3) has been reported in patients 
receiving ramucirumab as compared with placebo. In most cases, hypertension was controlled 
using standard antihypertensive treatment. Preexisting hypertension should be controlled before 
starting ramucirumab treatment. Monitoring of blood pressure is required during ramucirumab 
therapy. Every attempt should be made to control blood pressure to systolic <140 mmHg and 
diastolic <90 mmHg prior to starting treatment with ramucirumab. Routine clinical and laboratory 
monitoring is required in patients who again develop hypertension or experience a deterioration in 
previous hypertension. 
Withhold ramucirumab for severe hypertension until medically controlled. Permanently 
discontinue ramucirumab for medically significant hypertension that cannot be controlled with 
antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy. 
8.2.6.7 Proteinuria  
Proteinuria is an adverse effect for all therapies targeting the vascular endothelial growth factor 
(VEGF)/VEGFR-2 pathway, including ramucirumab. Proteinuria has been associated with 
ramucirumab in clinical studies; the majority of events were Grade 1 or 2.  
Monitor proteinuria by urine dipstick and/or urinary protein creatinine ratio. If the result of the 
urine dipstick is 2+ or greater, perform a 24 hours urine collection for protein measurement.  
Withhold ramucirumab for urine protein levels of 2 or more grams collected over 24 hours. 
Reinitiate ramucirumab at a reduced dose once the urine protein level returns to less than 2 grams 
over 24 hours. Permanently discontinue ramucirumab for urine protein levels greater than 3 grams 
over 24 hours, or in the setting of nephrotic syndrome. 
8.2.6.8 Bleeding/Hemorrhage  
Ramucirumab is an antiangiogenic therapy and has the potential to increase the risk of severe 
bleeding. Permanently discontinue ramucirumab in patients who experience severe (Grade 3 or 
Grade 4) bleeding. 
8.2.6.9 Arterial Thromboembolic Events  
Serious, sometimes fatal, arterial thromboembolic events (ATEs), including myocardial infarction, 
cardiac arrest, cerebrovascular accident, and cerebral ischemia, occurred across clinical trials. 
Permanently discontinue ramucirumab in patients who experience an ATE. 
8.2.6.10 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. 
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There is no further recommendation beyond routine guidance on prevention and treatment of 
peripheral neuropathy.  Cycle delays or modifications should be compliant with Appendix 4 
(Section 10.4). 
8.2.6.11 Colitis (including hemorrhagic)   
In study TED13751 evaluating tusamitamab ravtansine in patients with several cancer types, a 
limited number of participants developed colitis. Based on clinical observations, patients with 
known underlying colitis or gastrointestinal tract conditions are noted to be at highest risk for such 
events. The monitoring of patients for GI toxicities will rely on careful evaluation by routine 
history, physical examination, and standard laboratory examination. Close surveillance of any 
signs and symptoms is required, with additional routine hematology workup (hemoglobin, 
hematocrit, and WBC with differential and platelet counts) whenever indicated. As 1 case of 
Grade 4 erosive colitis has been reported, it is recommended to conduct close surveillance of any 
diarrhea event, with further exams when clinically indicated. Treatment is per patient condition, 
based on Investigator discretion. 
8.2.7 Immune-related adverse reactions  
Immune-related adverse reactions are provided in Appendix 4 (Section 10.4).   
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS  
8.3.1 Adverse events, treatment-emergent adverse events, and adverse events of special 
interest  
The safety profile of the IMP will be based on incidence, severity (as graded by the 
NCI CTCAE V5.0), and cumulative nature of TEAEs. TEAEs are defined as AEs that develop, 
worsen or become serious during the on-treatment period. For this study, the on-treatment period 
will be defined as the period from the time of first dose of IMP to at least Day 30 of the last 
tusamitamab ravtansine administration. Each patient will be assessed preferably by the same 
physician for AEs and according to the NCI CTCAE V5.0 classification. 
An AESI is an AE (serious or nonserious) of scientific and medical concern specific to the 
Sponsor’s product or program, for which ongoing monitoring and immediate notification by the 
Investigator to the Sponsor is required. Such events may require further investigation in order to 
characterize and understand them. Adverse events of special interest may be added, modified or 
removed during a study by protocol amendment. 
• Pregnancy of a female subject entered in a study as well as pregnancy occurring in a 
female partner of a male subject entered in a study with IMP/NIMP;  
- 
Pregnancy occurring in a female participant entered in the clinical trial or in a female 
partner of a male participant entered in the clinical trial. It will be qualified as an SAE 
only if it fulfills one of the seriousness criteria (see Appendix 3 [Section 10.3]).  
- 
In the event of pregnancy in a female participant, IMP should be discontinued.  
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- 
Follow-up of the pregnancy in a female participant or in a female partner of a male 
participant is mandatory until the outcome has been determined (See Appendix 5 
[Section 10.5]). 
• Grade ≥3 keratopathy 
• Bundle branch blocks or any conduction defects. 
• Grade ≥3 liver enzyme increased (symptomatic or asymptomatic) 
• Symptomatic overdose (serious or nonserious) with IMP/NIMP 
- 
An overdose (accidental or intentional) with the IMP/NIMP is an event suspected by 
the Investigator or spontaneously notified by the participant and defined as at least 
30% above the intended administered dose at each cycle expressed in unit per body 
surface or unit per weight. 
• All protocol-defined DLT (Section 4.1). 
The definitions of an AE or SAE can be found in Appendix 3 (Section 10.3). 
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). 
8.3.2 Time period and frequency for collecting AE and SAE information  
All SAEs will be collected from the signing of the screening ICF at the time points specified in the 
SOA (Section 1.3) and until at least 30 days after the last study intervention administration. 
All AEs will be collected from the signing of the screening ICF at the time points specified in the 
SOA (Section 1.3) and until at least 30 days after the last study intervention administration. 
For participant who was prescreened and had fresh biopsy, only the Adverse Events related to the 
fresh biopsy procedure itself should also be reported in eCRF as general requirement of AE/SAE 
with the reporting time frame interval of 1 month for prescreening period after fresh biopsy. All 
SAEs and AESI will be recorded and reported to the Sponsor or designee immediately and under 
no circumstance should this exceed 24 hours, as indicated in Appendix 3 (Section 10.3). The 
Investigator will submit any updated SAE data to the Sponsor within 24 hours of it being 
available. 
Investigators are not obligated to actively seek AE or SAE after the conclusion of 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. 
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During the follow-up period, SAEs (regardless of relationship to IMP) ongoing at the end of study 
treatment and IMP-related AEs ongoing at the end of study treatment, as well as new IMP-related 
AE/SAEs, will be followed until resolution or stabilization. 
8.3.3 Method of detecting AEs and SAEs  
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3 (Section 10.3). 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.  
8.3.4 Follow-up of AEs and SAEs  
After the initial AE/AESI/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. At the pre-specified study end-date, all SAEs, and 
nonserious AESIs (as defined in Section 8.3.1), will be followed until resolution, stabilization, the 
event is otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). 
Further information on follow-up procedures is given in Appendix 3 (Section 10.3). 
8.3.5 Regulatory reporting requirements for SAEs  
• Prompt notification by the Investigator to the Sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
study intervention under clinical investigation are met.  
• The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and Investigators. 
• Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy and 
forwarded to Investigators as necessary. 
• Adverse events that are considered expected will be specified in the reference safety 
information (IB for tusamitamab ravtansine and SPC for ramucirumab). 
• An Investigator who receives an Investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will review 
and then file it along with the Investigator’s Brochure and will notify the IRB/IEC, if 
appropriate according to local requirements. 
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8.3.6 Pregnancy  
• Details of all pregnancies in female participants and, if indicated, female partners of male 
participants will be collected after the start of study intervention and until one year after 
the birth.  
• If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 3 
(Section 10.3).  
• Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
8.3.7 Disease-related events and/or disease-related outcomes not qualifying as AEs or 
SAEs  
The following disease related events (DREs) are common in participants with cancer and can be 
serious/life threatening:  
• Progression of underlying disease, as it is the study endpoint.  
• Death due to progression of underlying disease, if it occurs after 30 days after the last IMP 
administration.  All death that occurs within 30 days of the last study intervention should 
be reported as a SAE.  
Because these events are typically associated with the disease under study, they will not be 
reported according to the standard process for expedited reporting of SAEs even though the event 
may meet the definition of a SAE. These events will be recorded on the corresponding page in the 
participant’s eCRF within the appropriate time frame.  
In case of progression of the underlying disease, with no radiologic documentation, symptoms 
leading to disease progression should be reported as an AE. 
8.3.8 Guidelines for reporting product complaints  
Any defect in the IMP/NIMP must be reported as soon as possible by the Investigator to the 
monitoring team that will complete a product complaint 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. 
Guidance and information (contact and complaint form) are provided in the pharmacy manual 
and/or monitoring plan. 
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8.4 
TREATMENT OF OVERDOSE  
There is no specific antidote for treatment of overdose. In the event of an overdose, the 
Investigator should:  
1. Contact the Medical Monitor immediately. 
2. Closely monitor the participant for any AE/SAE and laboratory abnormalities. 
3. Document the quantity of the excess dose as well as the duration of the overdose in the 
eCRF.  
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant. 
8.5 
PHARMACOKINETICS  
Blood samples will be collected for the measurement of tusamitamab ravtansine and ramucirumab 
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 in a separate laboratory manual.  These samples will be tested by the 
Sponsor’s designee. 
8.5.1 Non-compartmental analysis  
Pharmacokinetic parameters of tusamitamab ravtansine will be calculated using 
non-compartmental methods from concentrations assayed in Part 1 (safety run-in).  The 
parameters will include, but may not be limited to, those listed in Table 13: 
Table 13 - List of pharmacokinetic parameters and definitions  
Parameters 
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 quantification after infusion 
tlast 
Time of Clast 
Ctrough 
Concentration observed just before treatment administration during repeated dosing 
AUC0-14d 
Area under the plasma concentration versus time curve calculated using the trapezoidal method from 
time 0 to 14 days. 
Ramucirumab Ctrough values for Part 1 and Part 2 will be reported. 
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8.5.2 Population approach  
Data from plasma concentrations of tusamitamab ravtansine will be used for population PK 
analysis by non-linear 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). 
8.6 
PHARMACODYNAMICS  
Approximately 3 mL venous blood samples for measurement of circulating CEA will be collected 
at prescreening, at baseline, and during the treatment period as close as possible to tumor 
assessments. 
For CEA sample collection scheduled on the day of a treatment visit, samples should be drawn 
prior to initiation of ramucirumab infusion and tusamitamab ravtansine infusion. 
8.7 
GENETICS  
Genetics are not evaluated in this study. 
8.8 
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. 
• Blood samples will be collected for IgG measurement to explore the impact of IgG level 
on PK of tusamitamab ravtansine. 
The level of IgG in blood drawn pre-infusion on Day 1 of Cycle 1 will be determined by a central 
laboratory. For this test, 2 mL of blood, corresponding to 1 mL of serum, will be collected. 
Instructions for the collection and handling of biological samples will be provided by the Sponsor 
in a separate laboratory manual.  Samples may be stored for a maximum of 15 years (or according 
to local regulations) following the last participant’s last visit for the study at a facility selected by 
the Sponsor to enable further analysis of biomarker responses to tusamitamab ravtansine. 
8.9 
IMMUNOGENICITY ASSESSMENTS   
Blood samples will be collected for assessing the presence of ATA against tusamitamab 
ravtansine in plasma from all participants as described in the PK/ATA flowcharts (see 
Section 1.3.3).  These samples will be tested by the Sponsor’s designee. 
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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. 
8.10 
HEALTH ECONOMICS  
Not applicable. 
8.11 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH  
Future research may help further the understanding of disease subtypes, disease biology, related 
conditions, drug response, and toxicity, and can help identify new drug targets or biomarkers that 
predict a patient’s response to treatment. Therefore, when participants provide written consent 
(Appendix 1, Section 10.1.3), data and biological samples will be stored and used for future 
research unless prohibited by local laws or IRBs/IECs (in such a case, consent for future use of 
samples will not be included in the local ICF).  
For participants who consent to the storage and use of their data and remaining and/or extra 
clinical samples, data and samples may be used after the study ends 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.  
In the event future research is proposed to be conducted for other purposes, the study participants 
will be informed of those intended purposes, and will be given means to object to participation in 
those research projects.  
Data and samples will be used in compliance with the information provided to participants in the 
ICF Part 2 (future research).  
All study participant data and samples will be coded such that no participant direct identifiers will 
be linked to them. 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 
(Section 10.1.4). 
Samples will be stored for a maximum of 15 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 a case, samples will be destroyed and related coded 
data will be anonymized unless otherwise required by applicable laws.  
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Study participants’ coded data will be stored for future research for up to 25 years after the end of 
the study. If data are still considered of important scientific value after this period, coded data 
already available will be anonymized unless otherwise required by applicable laws (the same will 
apply to the data of a study participant who has requested the destruction of his/her samples).  
Participants’ coded data sets 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  
9.1 
STATISTICAL HYPOTHESES  
The doublet cohort contains 2 parts: 
Part 1 (safety run-in) aims to establish the recommended dose (RD) of tusamitamab ravtansine in 
combination with ramucirumab according to DLTs observed. 
Part 2 is designed to obtain preliminary efficacy, safety, and PK data on tusamitamab ravtansine 
administered in combination with ramucirumab to participants with NSQ NSCLC.  As the second 
part is not intended to explicitly test a hypothesis, calculations of power and Type I error were not 
considered in the study design.   
The triplet cohort (safety run-in only) is designed to assess the tolerability and to confirm the 
recommended dose of tusamitamab ravtansine in combination with ramucirumab and 
pembrolizumab in the NSQ NSCLC population. 
9.2 
SAMPLE SIZE DETERMINATION  
In the doublet cohort, assuming a prescreening failure rate of 80% and a study screening failure 
rate of 20%, approximately 225 participants will be prescreened to achieve a total of up to 
approximately 36 treated participants, including Part 1 (safety run-in) and Part 2. 
In the triplet cohort, assuming a prescreening failure rate of 79% and a study screening failure rate 
of 23% based on the doublet cohort, approximately 74 participants will be prescreened to achieve 
a total of up to approximately 12 DLT evaluable participants. 
9.2.1 Sample size for the doublet cohort, safety run-in (Part 1)  
The actual sample size is expected to vary depending on DLTs observed.  It is anticipated that 
around 6 to 12 DLT-evaluable participants will be enrolled in the safety run-in part of the cohort. 
9.2.2 Sample size for the doublet cohort, Part 2  
The initial plan is to treat a total of 30 participants evaluable (at least one post-baseline tumor 
assessment) for activity.  The 6 participants treated at the recommended dose level in the safety 
run-in part will also be evaluable for this second part of the cohort.  
Estimated ORR and 95% exact CI by numbers of responders from a sample size of 30 participants 
evaluable for activity are summarized in Table 14. 
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Table 14 - Estimated objective response rate (ORR) depending on number of responders  
Number of Responders 
(N=30) 
Objective Response Rate in % 
(95% Clopper-Pearson CI) 
6 
20.00% (7.71% - 38.57%) 
8 
26.67% (12.28% - 45.89%) 
9 
30.00% (14.73% - 49.40%) 
11 
36.67% (19.93% - 56.14%) 
12 
40.00% (22.66% - 59.40%) 
CI=confidence interval. 
9.2.3 Sample size for the triplet cohort (safety run-in only)  
The actual sample size is expected to vary depending on DLTs observed.  It is anticipated that 
around 6 to 12 DLT evaluable participants will be enrolled in the safety run-in of the triplet 
cohort. 
9.3 
POPULATIONS FOR ANALYSES  
For purposes of analysis, the following populations are defined (Table 15): 
Table 15 - Populations for analyses  
Population 
Description 
Pre-screened 
All participants who signed the prescreening informed consent for CEACAM5 assay 
assessment of their biopsy. 
Screened 
All participants who signed informed consent for study participation 
All-treated 
All registered participants exposed to the study treatment, regardless of the amount 
of treatment administered. This population is the primary population for analysis of 
all efficacy parameters. 
DLT-Evaluable 
For the doublet cohort: Participants who received 2 cycles with at least 80% of the 
intended dose for both tusamitamab ravtansine and ramucirumab at each of the two 
first infusions unless they discontinued the study intervention before the end of 
Cycle 2 due to a DLT. 
For the triplet cohort: Participants who received 1 cycle with at least 80% of the 
intended dose for each IMP of the combination. Participants should have completed 
Cycle 1 unless they experienced a DLT before the end of Cycle 1. 
Activity (applicable for doublet cohort 
only) 
All treated participants who have measurable disease at study entry and at least 
1 post-baseline evaluable tumor assessment. Participants with an early clinical 
progression or an early death due to disease progression (ie, before first planned 
tumor assessment) will also be included in this set. This population is the secondary 
population for analysis of efficacy parameters of the doublet cohort. 
PK 
All participants from the all-treated population who have actually received at least 
1 dose or a part of a dose of tasumitamab ravtansine (SAR408701) or ramucirumab 
with at least 1 evaluable post-baseline concentration. 
ATA 
All treated participants with at least 1 post-baseline ATA result (negative, positive, 
or inconclusive). 
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9.4 
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. 
The statistical analyses of the doublet and triplet cohorts will be presented separately. 
9.4.1 Efficacy analyses  
All efficacy analyses will be performed on the all-treated population (primary population for 
analysis of all efficacy parameters). In addition, the primary endpoint (ORR) for the doublet 
cohort will be analyzed on the Activity population (secondary population).  All efficacy analyses 
will be summarized only for the subgroup of participants treated at the recommended dose (ie, 
excluding participants treated at the starting dose if this differs from the RP2D). 
Objective response rate, as well as PFS, DOR, and DCR will be derived using the local 
radiologist’s/Investigator’s assessment.  A summary of efficacy analyses is provided in Table 16.   
Table 16 - Efficacy analyses  
Endpoint 
Statistical Analysis Methods 
Primary for doublet cohort / Secondary for triplet 
cohort 
• 
ORR 
Descriptive statistics and 95% CIs using the Clopper-Pearson method.  
Secondary for doublet cohort 
• 
DOR 
Kaplan-Meier method for descriptive statistics. Median DOR and 95% CI 
will be provided. 
• 
PFS 
Kaplan-Meier method for probabilities of being event free at different 
time points. Median PFS and 95% CI will be provided. 
• 
DCR 
Descriptive statistics and 95% CIs using the Clopper-Pearson method. 
Tertiary/exploratory  
Circulating CEA at prescreening, screening, and 
during the treatment period 
Will be described in the SAP. 
ORR=objective response rate; DCR=disease control rate; DOR=duration of response; PFS=progression free survival; CI=confidence interval. 
9.4.1.1 Analysis of primary efficacy endpoint for the doublet cohort / Secondary efficacy 
endpoint for the triplet cohort  
The ORR will be estimated by dividing the number of participants with confirmed objective 
response (CR or PR as BOR), derived 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 the first administration of IMP 
until disease progression, death, or initiation of post-treatment anticancer therapy, whichever 
occurs first. 
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ORR will be summarized for the all-treated population with descriptive statistics. In addition, 
two-sided 95% CIs will be computed using the Clopper-Pearson method. 
ORR will also be summarized on the activity population as a supplementary analysis for the 
doublet cohort. 
9.4.1.2 Analysis of secondary efficacy endpoints for the doublet cohort  
The 3 secondary efficacy endpoints are DOR, PFS, and DCR for the doublet cohort. 
9.4.1.2.1 Duration of response  
Duration of response will be summarized only for the subgroup of participants who have achieved 
confirmed objective response in the all-treated population.  
The definition of DOR is the time from the date of first initial occurrence of the confirmed CR or 
PR to the date of first documentation of objective PD according to RECIST v1.1 before the 
initiation of any post-treatment anti-cancer therapy or death due to any cause. 
In the absence of disease progression or death, DOR will be censored at the date of the last valid 
tumor assessment performed before the date of initiation of new anti-cancer therapy. Duration of 
response will be summarized with descriptive statistics using Kaplan-Meier methods. The median 
DOR and associated 95% CI will be provided. 
9.4.1.2.2 Progression-free survival  
Progression-free survival is defined as the time from the date of first administration of IMP to the 
date of the first documentation of objective PD according to RECIST v1.1 or death due to any 
cause, whichever occurs first.  
The analysis of PFS will be based on the following censoring rules: 
• If progression or death is not observed 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 date of initiation of a further anti-cancer therapy. 
• 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 administration of IMP 
(Day 1). 
Progression-free survival will be summarized using Kaplan-Meier methods. The median PFS 
times and associated 95% CI will be provided, along with probabilities of being progression-free 
at different time points. 
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9.4.1.2.3 Disease control rate  
The disease control rate will be estimated by dividing the number of participants with confirmed 
objective response or stable disease (CR or PR or SD 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. 
DCR will also be summarized on the activity population as a supplementary analysis. 
9.4.2 Safety analyses  
All safety analyses will be performed on the all-treated population for the Part 1 (safety run-in 
part) and Part 2 of the doublet cohort, and for the triplet cohort, by dose level and overall. 
Summary of Safety data will be performed by participant. For each safety parameter, a baseline 
value will be defined as the last value or measurement taken up to the first administration of the 
IMP.  
A summary of safety analyses is provided in Table 17.  
Table 17 - Safety analyses  
Endpoint 
Statistical Analysis Methods 
Primary 
For the doublet cohort: Incidence of study drug-related 
dose-limiting toxicity (DLTs) at Cycle 1 and Cycle 2 
For the triplet cohort: Incidence of study drug-related DLTs at 
Cycle 1 
 
Descriptive statistics 
Secondary 
Incidence of TEAEs and SAEs and laboratory abnormalities 
according to NCI CTCAE V5.  
 
Descriptive statistics 
 
Incidence 
of 
ATAs 
against 
tusamitamab 
ravtansine 
(SAR408701) 
Will be described in the SAP 
Exploratory 
No exploratory endpoint is defined for safety analyses. 
ATA=anti-therapeutic antibodies; TEAE=treatment emergent adverse event; SAE=serious adverse event; SAP=statistical analysis plan. 
The observation period will be divided into 4 segments: 
• The prescreening period is defined as the time from when the participants give prescreening 
informed consent or provide an addendum to informed consent (for participants who 
already have available CEACAM5 expression result) 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. 
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• 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. 
9.4.2.1 Analysis of primary safety endpoint  
Dose-limiting toxicities observed during the DLT observation period (Cycle 1 and Cycle 2 for the 
doublet cohort; Cycle 1 for the triplet cohort) 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 patient. 
9.4.2.2 Analysis of 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 system organ class (SOC)/ preferred term (PT) according 
to the latest available version of the MedDRA dictionary. 
• 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.  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.  Pre-screening, 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 TEAEs Grade ≥3 
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• Serious treatment-related TEAEs 
• AESI 
Number and percentage of participants experiencing TEAEs by primary SOC and PT will be 
summarized by NCI-CTCAE V5.0 grade (all grades and Grade ≥3) for the 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.  
9.4.2.3 Analysis of deaths  
The following deaths summaries will be generated: 
• Number and percentage of patients 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 number (%) of participants. 
9.4.2.4 Analysis of clinical laboratory evaluations  
Clinical laboratory values will be analyzed after conversion into standard international units. 
International units will be used in all listings and tables. 
Hematology and 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.  
When the NCI-CTCAE V5.0 grading scale is not applicable, the number of participants with 
laboratory abnormality out-of-normal laboratory range value will be displayed. 
9.4.2.5 Analysis of immunogenicity  
Immunogenicity analyses and the potential impact on PK, safety and efficacy will be described in 
the SAP, and will be performed on the ATA population. 
9.4.3 Other analyses  
Analyses of PK and pharmacodynamics and exploratory biomarker analyses will be described in 
the statistical analysis plan, to be finalized before database lock.  
The population PK methodology will be described in a separate report provided by the 
Pharmacokinetics, Dynamics, and Metabolism (PKDM) Modeling and Simulation group. 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Appendix 11 (Section 10.11). 
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9.5 
INTERIM ANALYSES  
No interim analysis is planned. 
9.6 
DATA MONITORING COMMITTEE (DMC)  
Not applicable. 
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10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS  
10.1 
APPENDIX 1:  REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS  
10.1.1 Regulatory and ethical considerations  
• This study will be conducted in accordance with the protocol and with the following: 
- 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and the applicable amendments and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical Guidelines 
- 
Applicable ICH Good Clinical Practice (GCP) Guidelines 
- 
Applicable laws and regulations 
• The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the Investigator and 
reviewed and approved by the IRB/IEC before the study is initiated.  
• Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.  
• The Investigator will be responsible for the following: 
- 
Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC 
- 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
- 
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 
for clinical studies (if applicable), and all other applicable local regulations 
10.1.2 Financial disclosure  
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate, financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
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10.1.3 Informed consent process  
• The Investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding 
the study.  
• Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representative will be required to sign a statement of informed consent 
that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Health 
Insurance Portability and Accountability Act (HIPAA) requirements, where applicable, 
and the IRB/IEC or study center.  
• The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF. 
• Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study.  
• A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative.  
• A participant who requires prolongation of the screening period (temporary screen failure) 
is not required to sign another ICF. However, if the reason for the temporary screen failure 
is a reason that might have altered the participant’s initial given agreement to participate, 
the Investigator should ask the participant to confirm willingness to continue or repeat 
some screening procedures and to participate in the trial. This oral agreement should be 
documented in the participant’s chart. Participants who screen failed and then rescreen 
need to re-sign a new screening ICF. 
• A participant who has CEACAM5 results available from a prior study must sign an 
addendum to the informed consent; no additional prescreening informed consent will be 
required. 
•  For a regional or national emergency declared by a governmental agency, contingency 
measures are included in Appendix 11 (Section 10.11). 
10.1.4 Data protection  
All personal data collected related to participants, Investigators, or any person involved in the 
study, which may be included in the Sponsor’s databases, shall be treated in compliance with all 
applicable laws and regulations including the GDPR (Global Data Protection Regulation).  
Data collected must be adequate, relevant and not excessive, in relation to the purposes for which 
they are collected. Each category of data must be properly justified and in line with the study 
objective. 
Participant race and ethnicity will be collected in this study because these data are required by 
several regulatory agencies (eg, on African-American population for the FDA or on Japanese 
population for the Pharmaceuticals and Medical Devices Agency in Japan). 
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• Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred. 
• The participant must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with local data protection law. The level of disclosure must also 
be explained to the participant. 
• The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
• When archiving or processing personal data pertaining to the Investigator and/or to the 
participants, the Sponsor shall take all appropriate measures to safeguard and prevent 
access to this data by any unauthorized third party. 
10.1.5 Committee Structure  
Study committee 
The SC includes the Investigators or designees and Sponsor team members and, when appropriate, 
ad hoc experts.  Decisions to continue the enrollment at a dose level 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 the study (run-in) in the doublet cohort and 
during the triplet cohort DLT evaluation period; and may meet ad hoc for specific discussions.  
Meeting minutes will be documented. 
10.1.6 Dissemination of clinical study data  
Sanofi shares information about clinical trials and results on publicly accessible websites, based 
on company commitments, international and local legal and regulatory requirements, and other 
clinical trial disclosure commitments established by pharmaceutical industry associations.  These 
websites include clinicaltrials.gov, 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 
clinicalstudydatarequest.com. 
Individual participant data and supporting clinical documents are available for request at 
clinicalstudydatarequest.com. While making information available we continue to protect the 
privacy of participants in our clinical trials. Details on data sharing criteria and process for 
requesting access can be found at this web address: clinicalstudydatarequest.com. 
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10.1.7 Data quality assurance  
• All participant data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the Sponsor or designee electronically (eg, laboratory data). The 
Investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.  
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.  
• The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in separate study documents. 
• The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
• The Sponsor assumes accountability for actions delegated to other individuals 
(eg, Contract Research Organizations). 
• Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements.  
• Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator for 25 years after the signature of the final study report 
unless local regulations or institutional policies require a longer retention period. No 
records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.  
10.1.8 Source documents  
• Every data point recorded in the eCRF must have a source document. The 
Investigator/delegated site staff will report all the original data in the participant’s medical 
chart or in a study-specific source document created by him/her. If such a document is 
used, the template should be reviewed by the CRA. A list of source documents and their 
locations will be filed in the Investigator Study File. 
• Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the Investigator’s site. 
• Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The Investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 
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10.1.9 Study and site closure  
The Sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination. 
Reasons for study termination by the Sponsor, as well as reasons for the early closure of a study 
site by the Sponsor or Investigator may include, but are not limited to: 
• For study termination: 
- 
Information on the product leads to doubt as to the benefit/risk ratio 
- 
Discontinuation of further study intervention development 
• For site termination: 
- 
Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor’s procedures, or GCP guidelines 
- 
Inadequate or no recruitment (evaluated after a reasonable amount of time) of 
participants by the Investigator 
- 
Total number of participants included earlier than expected 
10.1.10 Publication policy  
• The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor 
before submission. This allows the Sponsor to protect proprietary information and to 
provide comments.  
• The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data. In 
this case, a coordinating Investigator will be designated by mutual agreement. 
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS  
• The tests detailed in Table 18 will be performed by the local laboratory. 
• Protocol-specific requirements for inclusion or exclusion of participants are detailed 
in Section 5 of the protocol. 
• Additional tests may be performed at any time during the study as determined necessary by 
the Investigator or required by local regulations. 
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• Pregnancy testing will be performed in all WOCBP at baseline, at End of treatment visit, 
and the 3 month follow-up, as detailed in the SOA (Section 1.3). Women of child-bearing 
potential must have a negative serum pregnancy test result within 7 days prior to the initial 
intervention; at the End of treatment evaluation (30 ±5 days after the last IMP 
administration); and at the Follow-up (90 ±7 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 (ie, every 2 cycles/every other cycle). 
Table 18 - Protocol-required safety laboratory assessments  
Laboratory assessments 
Parameters 
Hematology 
 
 
Platelet count 
 
Red blood cell (RBC) count 
 
Hemoglobin 
 
Hematocrit 
 
White blood cell (WBC) count with differential: 
 
Neutrophils 
 
Lymphocytes 
 
Monocytes 
 
Eosinophils 
 
Basophils 
Clinical blood chemistrya 
 
 
Urea/blood urea nitrogen (BUN) 
 
Creatinine 
 
Glucose     
 
Potassium 
 
Sodium 
 
Calcium 
 
Aspartate aminotransferase (AST)/ Serum glutamic-oxaloacetic transaminase (SGOT) 
 
Alanine aminotransferase (ALT)/ Serum glutamic-pyruvic transaminase (SGPT) 
 
Alkaline phosphatase 
 
Total and conjugated bilirubin 
 
Total protein 
 
Albumin 
 
LDH 
 
Coagulation parameters (INR, aPTT)  
 
Thyroid function (triplet cohort 
only) 
Thyroid-stimulating hormone (TSH) 
Total tri-iodothyronine (T3)  
Free thyroxine (FT4) 
Serum/urine pregnancyb 
 
NOTES : 
a Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or monitoring event are given 
in Section 8.2.6.5. All events of Grade 4 AST/ALT increase must be reported as an SAE. Investigators must document their review of each 
laboratory safety report. 
b Only for WOCBP. 
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10.3 
APPENDIX 3: ADVERSE EVENTS: 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. 
Events meeting the AE definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the Investigator (ie, not related to progression of underlying 
disease), eg:  
- 
Leading to IMP discontinuation or modification of dosing, and/or  
- 
Fulfilling a seriousness criterion, and/or  
- 
Defined as an AESI. 
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study intervention administration even though 
it may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. 
• “Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy assessments. 
However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will 
be reported as AE or SAE if they fulfil the definition of an AE or SAE.  
• The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfil the definition of an AE or SAE. Also, “lack of 
efficacy” or “failure of expected pharmacological action” also constitutes an AE or SAE. 
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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  
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (eg, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
A SAE is defined as any untoward medical occurrence that, at any dose: 
a) Results in death 
b) Is life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe. 
c) Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
d) Results in persistent disability/incapacity 
- 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
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- 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
e) Is a congenital anomaly/birth defect 
f) Other situations: 
- 
Medical or scientific judgment should be exercised in deciding whether SAE reporting 
is appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
participant or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These events should usually be considered 
serious. 
- 
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency or 
drug abuse. 
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 in the eCRF. 
• It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to the Monitoring Team in lieu of completion of the Sanofi/AE/SAE eCRF page.  
• There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. 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 
Monitoring Team. 
• The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported during the 
study and assign it to 1 of the following NCI CTCAE v.5.0 categories: Mild; Moderate; Severe. 
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as described 
in the definition of an SAE, NOT when it is rated as severe. 
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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 Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment. 
• For each AE/SAE, the Investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• There may be situations in which an SAE has occurred, and the Investigator has minimal 
information to include in the initial report to Sanofi. However, it is very important that 
the Investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Monitoring Team. 
• The Investigator may change his/her opinion of causality in light of follow-up information 
and send a SAE follow-up report with the updated causality assessment. 
• The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
Follow-up of AEs and SAEs 
• The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the Monitoring 
Team to elucidate the nature and/or causality of the AE or SAE as fully as possible. This 
may include additional laboratory tests or investigations, histopathological examinations, 
or consultation with other health care professionals. 
• New or updated information will be recorded in the originally completed CRF. 
• The Investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information. 
10.3.4 Reporting of SAEs  
SAE reporting to Sanofi via an electronic data collection tool 
• The primary mechanism for reporting an SAE to the Monitoring Team will be the 
electronic data collection tool. 
• If the electronic system is unavailable, then the site will use the paper SAE data collection 
tool (see next section) in order to report the event within 24 hours. 
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• The site will enter the SAE data into the electronic system as soon as it becomes available. 
• After the study is completed at a given site, the electronic data collection tool will be taken 
off-line to prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken 
off-line, then the site can report this information on a paper SAE form (see next section) or 
to the Monitoring Team by telephone. 
• Contacts for SAE reporting can be found in the Investigator Study File. 
SAE reporting to Sanofi via paper CRF 
• Facsimile transmission of the SAE paper CRF is the preferred method to transmit this 
information to the Monitoring Team. 
• In rare circumstances and in the absence of facsimile equipment, notification by telephone 
is acceptable with a copy of the SAE data collection tool sent by overnight mail or courier 
service. 
• Initial notification via telephone does not replace the need for the Investigator to complete 
and sign the SAE CRF pages within the designated reporting time frames. 
• Contacts for SAE reporting can be found in the Investigator Study File. 
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10.4 
APPENDIX 4: RECOMMENDED SUPPORTIVE CARE AND/OR DOSE MODIFICATION GUIDELINES FOR DRUG-RELATED ADVERSE EVENTS  
Event 
Symptoms severity (Nadir)  
(NCI CTCAE v5) 
Management of IMP dosing 
(ramucirumab)) 
Management of IMP dosing 
(tusamitamab ravtansine) 
Supportive care guidelines 
Infusion-related reaction  
Grade 1-2 
Mild-moderate 
Eg, Grade ≤2 nausea, headache, 
tachycardia, hypotension, rash, 
shortness of breath. 
Interrupt ramucirumab infusion and 
start appropriate treatment.   
 
Reduce infusion rate by 50% 
Interrupt tusamitamab ravtansine infusion. 
tusamitamab ravtansine may be resumed 
only after patient recovery, at half the 
previous infusion ratea. 
Give diphenhydramine 50 mg IV and/or 
dexamethasone 10 mg IV. ramucirumab 
label should be followed 
Dexamethasone can be added as 
premedication for upcoming cycles for 
tusamitamab ravtansine 
 
Grade 3-4 
Severe 
Eg, symptomatic bronchospasm, 
urticaria lesions covering >30% BSA, 
hypotension, angioedema. 
Interrupt ramucirumab infusion and 
prematurely definitively discontinue 
ramucirumab 
Interrupt tusamitamab ravtansine infusion 
and prematurely discontinue tusamitamab 
ravtansine and consider infusion delay. 
Give diphenhydramine 50 mg IV and/or 
dexamethasone 10 mg IV and/or 
epinephrine and any required treatment per 
investigator judgement. 
Ocular toxicity:  
Keratopathy/keratitisb associated with 
tusamitamab ravtansine 
Grade 1 - Asymptomatic 
Corneal lesions only observed on 
routine ocular examination and not 
requiring topical treatment. 
Administer ramucirumab at same 
dose, and same day as tusamitamab 
ravtansine 
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). 
Standard ocular examination is planned as 
recommended by the ophthalmologist. 
 
Grade 2 
Symptomatic or requiring topical 
treatment (curative) or limiting 
instrumental activity of daily life. 
Moderate decrease in visual acuity 
(best corrected visual acuity 20/40 and 
better or 3 lines or less decreased 
vision from known baseline) 
Administer ramucirumab as planned, 
and re-introduce tusamitamab 
ravtansine when recovery to Grade 1 
1st episode: Omit tusamitamab ravtansine 
until resolution to Grade 1 (asymptomatic) 
and restart tusamitamab ravtansine at the 
same dose. 
2nd episode:  Omit SAR until resolution to 
Grade 1 (asymptomatic) and tusamitamab 
ravtansine dose reduction. 
3rd episode: depending on benefit risk, 
premature definitive discontinuation of 
tusamitamab ravtansine may be envisaged 
 
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 2 cycles, even 
asymptomatic during next 4 cycles. If no 
recurrence, standard process with follow-up 
with ocular symptom is resumed,  
Management of study drug upon recurrence 
to be discussed according to Grade of the 
event at recurrence, clinical benefit from 
study drug and recommendation from the 
ophthalmologist. 
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Event 
Symptoms severity (Nadir)  
(NCI CTCAE v5) 
Management of IMP dosing 
(ramucirumab)) 
Management of IMP dosing 
(tusamitamab ravtansine) 
Supportive care guidelines 
 
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 selfcare activity of daily life 
Administer ramucirumab as planned, 
and re-introduce tusamitamab 
ravtansine when recovery to Grade 1 
1st episode: Omit tusamitamab ravtansine 
until resolution (asymptomatic) and restart 
tusamitamab ravtansine with dose reduction. 
2nd episode: definitive discontinuation of 
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 2 cycles, even 
asymptomatic during next four cycles. If no 
recurrence, standard process with follow-up 
with ocular symptom is resumed   
Management of study drug upon recurrence 
to be discussed according to Grade of the 
event at recurrence, clinical benefit from 
study drug and recommendation from the 
ophthalmologist 
 
Grade 4 
Perforation or best corrected visual 
acuity of 20/200 or worse in the 
affected eye. 
Administer ramucirumab as planned,  Definitive discontinuation of tusamitamab 
ravtansine. 
 
Complete the corneal examination as 
recommended by ophthalmologist. Repeat 
the standard ocular examination weeklyc 
until resolutiond. 
Start curative treatment per ophthalmologist 
recommendation.  
Conduction disorder associated with 
tusamitamab ravtansine 
Grade 1 
Mild symptoms 
Administer ramucirumab as planned,  tusamitamab ravtansine administration to be 
continued upon decision by the Investigator 
and Sponsor, depending on the nature of the 
conduction disorder. 
ECG performed once weekly until event 
resolution. 
Additional evaluations such as LVEF and 
Holter monitoring should be performed 
when relevant. 
 
Grade ≥2 
Administer ramucirumab as planned,  Definitive discontinuation of tusamitamab 
ravtansine. 
 
ECG to be repeated twice weekly until event 
resolution. 
Prompt cardiology consultation 
Additional evaluations such LVEF and 
Holter monitoring should be performed 
when relevant. 
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Event 
Symptoms severity (Nadir)  
(NCI CTCAE v5) 
Management of IMP dosing 
(ramucirumab)) 
Management of IMP dosing 
(tusamitamab ravtansine) 
Supportive care guidelines 
Peripheral neuropathy 
Grade 1:  
Asymptomatic 
Administer ramucirumab as planned, 
Administer tusamitamab ravtansine as 
planned, 
Patient who has ongoing Grade 1 
neuropathy has high risk of worsening of 
his/her symptoms and should be closely 
followed.  
 
Grade 2:   
Moderate symptoms; limiting 
instrumental Activities of Daily Living 
Delay cycle until recovery to 
≤ Grade 1; at next cycle, administer 
ramucirumab as planned, 
Delay cycle until recovery to ≤ Grade 1 and 
dose reduction if no improvement with dose 
delay 
Grade 3:  
Severe symptoms; limiting self care 
Activities of Daily Living 
Administer ramucirumab as planned, 
 Definitive discontinuation of tusamitamab 
ravtansine 
Grade 4: 
Life-threatening consequences; urgent 
intervention indicated 
Administer ramucirumab as planned, 
 Definitive discontinuation of tusamitamab 
ravtansine 
Neutrophil count decreased 
Grade 1 
<LLN - 1500/mm3 ; <LLN - 1.5 × 109/L 
No change in IMPs administration. 
No change in IMPs administration  
No intervention. 
 
Grade 2 
<1500 - 1000/mm3; <1.5 - 1.0 × 109/L 
Delay the cycle until recovery of 
absolute neutrophil count >1500/mm3. 
Restart at the same dose. 
Delay the cycle until recovery of absolute 
neutrophil count >1500/mm3. 
Restart at the same dose. 
No intervention. 
 
Grade 3 
<1000 - 500/mm3; <1.0 - 0.5 × 109/L 
Or 
Grade 4 
<500/mm3; <0.5 × 109/L 
Delay the cycle until recovery of 
absolute neutrophil count >1500/mm3. 
Restart when absolute neutrophil 
count >1500/mm3 at the same dose. 
Prophylactic G-CSF should be 
considered in all subsequent cycles 
Delay the cycle. 
Restart the treatment when absolute 
neutrophil count >1500/mm3 at the same 
dose prophylactic G-CSF can be considered 
in all subsequent cycles  
Follow ASCO guidelines on usage G-CSF 
and antibiotherapy (20, 23). Repeat test 
every 3 days.  
 
 
Grade 4 >7days 
<500/mm3; <0.5 × 109/L 
Delay the cycle until absolute 
neutrophil count >1500/mm3. 
1st episode administer next cycle with 
ramucirumab at the same dose and 
administer growth factors 
2nd episode: administer ramucirumab 
as the same dose 
3rd episode: definitive discontinuation 
of IMPs 
 Delay the cycle until absolute neutrophil 
count >1500/mm3. 
1st episode administer tusamitamab 
ravtansine next cycle at the same dose and 
administer growth factors 
2nd episode: administer tusamitamab 
ravtansine at reduced dose 
3rd episode: definitive discontinuation 
 
Follow ASCO guidelines onG-CSF usage 
and antibiotherapy. Repeat test every 
3 days.  
 
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Event 
Symptoms severity (Nadir)  
(NCI CTCAE v5) 
Management of IMP dosing 
(ramucirumab)) 
Management of IMP dosing 
(tusamitamab ravtansine) 
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 absolute neutrophil 
count >1500/mm3. 
1st episode administer next cycle at 
the same dose and administer G-CSF 
2nd episode: administer ramucirumab 
at reduce dose 
3rd episode: definitive discontinuation  
Delay cycle until absolute neutrophil count 
>1500/mm3. 
1st episode administer next cycle at the 
same dose and administer G-CSF 
2nd episode: administer tusamitamab 
ravtansine at reduce dose 
3rd episode: definitive discontinuation  
To ensure relative dose intensity, G-CSF is 
recommended as secondary prophylaxis in 
all patients with Grade 3 febrile neutropenia  
ASCO guideline is recommended for 
supportive treatment if there are no defined 
clinical standards (23) 
 
Grade 4 
Life-threatening consequences 
Administration changes to be decided 
at the Investigator’s discretion per 
product label 
Administration changes to be decided at the 
Investigator’s discretion. 
1st episode: administer next cycle at reduced 
dose and administer G-CSF 
2nd episode: definitive discontinuation 
 
Hypertension 
Grade 3 
Severe hypertension 
Withhold ramucirumab until controlled 
with medical management, and restart 
at same dose 
Administer tusamitamab ravtansine as 
planned 
 
Grade 4 
Severe hypertension that cannot be 
controlled with antihypertensive 
therapy 
Definitively discontinue ramucirumab 
Administer tusamitamab ravtansine as 
planned 
 
Proteinuria 
First occurrence of increased urine 
protein levels greater than or equal to 
2 g per 24 hours 
Omit ramucirumab until urine protein 
level is ≤2 g per 24 hours; then 
resume ramucirumab at a reduced 
dose (in doublet cohort, 8 mg at 
1st episode, then 5 mg if 2nd episode 
and in triplet cohort,8 mg at 1st 
episode, then 6 mg if 2d episode) 
Administer tusamitamab ravtansine as 
planned 
 
Reoccurrence of urine protein level 
greater than 2 g per 24 hours following 
initial dose reduction 
Omit ramucirumab until protein level 
is ≤2 g per 24 hours; then resume 
ramucirumab at a reduced dose:(6 mg 
or 5 mg) 
Administer tusamitamab ravtansine as 
planned 
 
Urine protein level greater than 3 g per 
24 hours or in the setting of nephrotic 
syndrome 
Definitvely discontinue ramucirumab 
Consider benefit/risk for the patient to 
continue or delay tusamitamab ravtansine 
infusion 
 
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Event 
Symptoms severity (Nadir)  
(NCI CTCAE v5) 
Management of IMP dosing 
(ramucirumab)) 
Management of IMP dosing 
(tusamitamab ravtansine) 
Supportive care guidelines 
Hemorrhage 
Grade 3 or 4 
Definitively discontinue ramucirumab 
Permanently discontinue tusamitamab 
ravtansine 
 
Gastrointestinal Perforation 
All Grades 
Permanently discontinue 
ramucirumab 
Consider benefit/risk for the patient to 
continue or delay tusamitamab ravtansine 
infusion 
 
Arterial Thromboembolic Events 
All Grades 
Definitively discontinue ramucirumab 
Administer tusamitamab ravtansine as 
planned 
 
Wound Healing Complications 
All Grades 
Definitively discontinue ramucirumab 
for wound healing complications 
requiring medical intervention 
Consider benefit/risk for the patient to 
continue or delay tusamitamab ravtansine 
infusion 
 
a tusamitamab ravtansine is stable at least 7.5 hours in the infusion bag at room temperature. If necessary, a new infusion should be prepared with the remaining dose to be administered. 
b The NCI CTCAE V5.0 grading is to be applied to keratopathy. 
c Standard ocular examination per protocol includes visual acuity, slit lamp examination, Schirmer’s test, and enquiring for ocular/visual symptoms. 
d When possible at the site, photographs should be done when findings are first documented and to follow progression when relevant. Any additional relevant ocular examination can be done if indicated. 
Abbreviations: ASCO = American Society of Clinical Oncology, ASOCT = Anterior segment optical coherence, BSA = Body surface area, ECG = Electrocardiogram, G-CSF = Granulocyte colony-stimulating factor, 
Hb = Hemoglobin, IMP = Investigational medicinal product, IV = Intravenous; LLN = Lower limit of normal, LVEF = Left ventricular ejection fraction, NCI CTCAE = National Cancer Institute Common Terminology 
Criteria for Adverse Events, RBC = Red blood cell. 
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Event 
Symptoms severity 
(NCI CTCAE v5.0) 
Management of IMP dosing 
(pembrolizumab)  
Infusion-related reactions 
Grades 1 or 2 
Interrupt or slow the rate of infusion 
Grades 3 or 4 
Permanently discontinue 
Immune-mediated pneumonitis 
Grade 2 
Withhold  
Grades 3 or 4 or recurrent Grade 2 
Permanently discontinue 
Immune-mediated colitis 
Grades 2 or 3 
Withhold  
Grade 4 or recurrent Grade 3 
Permanently discontinue 
Immune-mediated hepatitis 
AST or ALT greater than 3 but no more than 5 times the ULN or total 
bilirubin greater than 1.5 but no more than 3 times the ULN 
Withhold  
Immune-mediated endocrinopathies 
Grades 3 or 4 
Withhold until clinically stable 
Immune-mediated nephritis 
Grade 2 
Withhold  
Grades 3 or 4 
Permanently discontinue 
Immune-mediated skin adverse reactions 
Grade 3 or suspected Stevens-Johnson Syndrome (SJS) or toxic epidermal 
necrolysis (TEN) 
Withhold  
Grade 4 or confirmed SJS or TEN 
Permanently discontinue 
Other immune-mediated adverse reactions 
Grades 2 or 3 based on the severity and type of reaction 
Withhold 
Grade 3 based on the severity and type of reaction or Grade 4 
Permanently discontinue 
Recurrent immune-mediated adverse reactions 
Recurrent Grade 2 pneumonitis 
Recurrent Grades 3 or 4 
Permanently discontinue 
Inability to taper corticosteroid 
Requirement for 10 mg per day or greater prednisone or equivalent for 
more than 12 weeks after last dose of pembrolizumab 
Permanently discontinue 
Persistent Grade 2 or 3 adverse reaction (excluding 
endocrinopathy) 
Grades 2 or 3 adverse reactions lasting 12 weeks or longer after last 
pembrolizumab 
Permanently discontinue 
General instructions: 
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks. 
2. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and corticosteroid has been tapered.  
3. For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment should be initiated if irAEs cannot be controlled by corticosteroids. 
For additional guidelines, please refer to ASCO Guidelines published in 2021 (24).
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10.5 
APPENDIX 5: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION  
DEFINITIONS: 
Woman of childbearing potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention, additional evaluation should be considered. 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
- 
Documented hysterectomy 
- 
Documented bilateral salpingectomy 
- 
Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than 
the above, (eg, mullerian agenesis, androgen insensitivity), Investigator discretion 
should be applied to determining study entry. 
Note:  Documentation can come from the site personnel’s: review of the participant’s medical 
records, medical examination, or medical history interview. 
3. Postmenopausal female 
- 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
- 
A high follicle stimulating hormone (FSH) level in the postmenopausal range may be 
used to confirm a postmenopausal state in women not using hormonal contraception or 
hormonal replacement therapy (HRT). However, in the absence of 12 months of 
amenorrhea, confirmation with more than one FSH measurement is required. 
- 
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-estrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
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CONTRACEPTION GUIDANCE: 
CONTRACEPTIVESaALLOWED DURING THE STUDY INCLUDE: 
Highly Effective Methodsb That Have Low User Dependency Failure rate of <1% per year when used 
consistently and correctly. 
• Implantable progestogen-only hormone contraception associated with inhibition of ovulationb 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS)b 
• Bilateral tubal occlusion 
• Vasectomized partner 
(Vasectomized partner is a highly effective contraceptive method provided that the partner is the sole 
sexual partner of the woman of childbearing potential and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used. Spermatogenesis cycle is 
approximately 90 days.) 
Highly Effective Methodsb That Are User Dependent Failure rate of <1% per year when used 
consistently and correctly. 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of 
ovulationc 
- 
oral 
- 
intravaginal 
- 
transdermal 
- 
injectable 
Progestogen-only hormone contraception associated with inhibition of ovulationc 
- 
oral 
- 
injectable 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual 
lifestyle of the participant. 
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ACCEPTABLE METHODSd 
• Progestogen-only oral hormonal contraception where inhibition of ovulation is not the primary mode 
of action 
• Male or female condom with or without spermicidee 
• Cervical cap, diaphragm, or sponge with spermicide 
• A combination of male condom with either cervical cap, diaphragm, or sponge with spermicide 
(double-barrier methods)c 
a Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive methods for those 
participating in clinical studies. 
b Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those when used consistently and 
correctly. 
c If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable contraceptive methods are limited to 
those which inhibit ovulation as the primary mode of action. 
d Considered effective, but not highly effective - failure rate of ≥1% per year.  Periodic abstinence (calendar, symptothermal, post-ovulation 
methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea method (LAM) are not acceptable methods of 
contraception.  
e Male condom and female condom should not be used together (due to risk of failure with friction). 
COLLECTION OF PREGNANCY INFORMATION: 
Male participants with partners who become pregnant 
• The Investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This 
applies only to male participants who receive study intervention. 
• After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. The 
female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to the Sponsor. 
Generally, the follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date but may last up to one year. Any termination of the pregnancy will be 
reported regardless of fetal status (presence or absence of anomalies) or indication for 
the procedure. 
Female participants who become pregnant 
• The Investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. Information will be recorded on the 
appropriate form and submitted to the Sponsor within [24 hours] of learning of a 
participant's pregnancy. The participant will be followed to determine the outcome of 
the pregnancy. The Investigator will collect follow-up information on the participant and 
the neonate and the information will be forwarded to the Sponsor. Generally, follow-up 
will not be required for longer than 6 to 8 weeks beyond the estimated delivery date but 
may last up to one year. Any termination of pregnancy will be reported, regardless of 
fetal status (presence or absence of anomalies) or indication for the procedure. 
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• Any pregnancy complication or elective termination of a pregnancy will be reported as 
an AE or SAE. A spontaneous abortion (occurring at <22 weeks gestational age) or still 
birth (occurring at >22 weeks gestational age) is always considered to be an SAE and 
will be reported as such. Any post-study pregnancy related SAE considered reasonably 
related to the study intervention by the Investigator will be reported to the Sponsor as 
described in Section 8.3.5. While the Investigator is not obligated to actively seek this 
information in former study participants, he or she may learn of an SAE through 
spontaneous reporting. 
• Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention. 
10.6 
APPENDIX 6: GENETICS  
Not applicable. 
10.7 
APPENDIX 7: RESPONSE EVALUATION CRITERIA IN SOLID TUMORS VERSION 1.1  
Details provided in bibliographic reference 25. 
Measurability of tumor at baseline 
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as 
follows. 
Measurable lesions must be accurately measured in at least 1 dimension (longest diameter in the 
plane of the measurement to be recorded) with a minimum size of: 
• 10 mm by CT scan (CT scan slice thickness no greater than 5 mm). 
• 10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable). 
• 20 mm by chest X-ray. 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node 
must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended 
to be no greater than 5 mm). At baseline and in follow-up, only the short axis will be measured 
and followed. 
Non-measurable lesions are all other lesions, including small lesions (longest diameter <10 mm or 
pathological lymph nodes with ≥10 to <15 mm short axis), as well as non-measurable lesions. 
Lesions considered non-measurable include: leptomeningeal disease, ascites, pleural or pericardial 
effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses/abdominal organomegaly identified by physical exam that is not measurable by 
reproducible imaging techniques. 
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Special considerations regarding lesion measurability: 
• Bone lesions: 
1. Bone scan, positron emission tomography scan or plain films are not considered adequate 
imaging techniques to measure bone lesions. However, these techniques can be used to 
confirm the presence or disappearance of bone lesions. 
2. Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross sectional imaging techniques such as CT or MRI can be 
considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above. 
3. Blastic bone lesions are non-measurable. 
• Cystic lesions: 
4. Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, 
by definition, simple cysts. 
5. “Cystic lesions” thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if 
non-cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
• Lesions with prior local treatment: 
6. Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion. 
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. 
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• CT, MRI: CT is the best currently available and reproducible method to measure lesions 
selected for response assessment. Measurability of lesions on CT scan is based on the 
assumption that CT slice thickness is 5 mm or less. When CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion should be twice the slice 
thickness. 
• Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement. If new lesions are identified by ultrasound in the course of 
the study, confirmation by CT or MRI is advised. 
• Endoscopy, laparoscopy: The utilization of these techniques for objective tumor 
evaluation is not advised. 
• Tumor markers: Tumor markers alone cannot be used to assess objective tumor 
response. 
• Cytology, histology: These techniques can be used to differentiate between PR and CR in 
rare cases if required by protocol. 
Baseline documentation of “target” and “non-target” lesions 
When more than 1 measurable lesion is present at baseline all lesions up to a maximum of 
5 lesions total (and a maximum of 2 lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline. 
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, and should lend themselves to reproducible repeated 
measurements. 
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 categorization criteria are summarized in Table 19.   
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Table 19 - Response criteria  
Response criteria 
Evaluation of target lesions 
CR 
Disappearance of all target lesions. Any pathological lymph nodes (whether target or 
non-target) must have reduction in short axis to <10 mm. 
PR 
At least a 30% decrease in the sum of diameters of target lesions, taking as reference the 
baseline sum diameters. 
PD 
At least a 20% increase in the sum of diameters of target lesions, taking as reference the 
smallest sum on study (this includes the baseline sum if that is the smallest on study). In 
addition to the relative increase of 20%, the sum must also demonstrate an absolute increase 
of at least 5 mm. (Note: the appearance of 1 or more new lesions is also considered 
progression). 
SD 
Neither sufficient shrinkage from the baseline study to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum diameters while on study. 
Abbreviations: CR=complete response; PD=progressive disease; PR=partial response; SD=stable disease. 
Special notes on the assessment of target lesions 
Lymph nodes identified as target lesions should always have the actual short axis measurement 
recorded and should be measured in the same anatomical plane as the baseline examination, even 
if the nodes regress to below 10 mm on study. This means that when lymph nodes are included as 
target lesions, the “sum” of lesions may not be zero even if CR criteria are met, since a normal 
lymph node is defined as having a short axis of <10 mm. For PR, SD and PD, the actual short axis 
measurement of the nodes is to be included in the sum of target lesions. 
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”. 
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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. 
• 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. 
• PD: Unequivocal progression of existing non-target lesions. (Note: the appearance of 1 or 
more new lesions is also considered progression). 
The concept of progression of non-target disease requires additional explanation as follows: 
When the participant also has measurable disease; in this setting, to achieve “unequivocal 
progression” on the basis of the non-target disease, there must be an overall level of substantial 
worsening in non-target disease such that, even in presence of SD or PR in target disease, the 
overall tumor burden has increased sufficiently to merit discontinuation of therapy. A modest 
“increase” in the size of 1 or more non-target lesions is usually not sufficient to qualify for 
unequivocal progression status. 
When the participant has only non-measurable disease; to achieve “unequivocal progression” on 
the basis of the non-target disease, there must be an overall level of substantial worsening such 
that the overall tumor burden has increased sufficiently to merit discontinuation of therapy. A 
modest “increase” in the size of 1 or more non-target lesions is usually not sufficient to qualify for 
unequivocal progression status. Because worsening in non-target disease cannot be easily 
quantified (by definition: if all lesions are truly non-measurable) a useful test that can be applied 
when assessing patients for unequivocal progression is to consider if the increase in overall 
disease burden based on the change in non-measurable disease is comparable in magnitude to the 
increase that would be required to declare PD for measurable disease: ie, an increase in tumor 
burden representing an additional 73% increase in “volume” (which is equivalent to a 
20% increase diameter in a measurable lesion). Examples include an increase in a pleural effusion 
from “trace” to “large”, an increase in lymphangitic disease from localized to widespread, or may 
be described in protocols as “sufficient to require a change in therapy”. If “unequivocal 
progression” is seen, the patient should be considered to have had overall PD at that point. 
New lesions 
The appearance of new malignant lesions denotes disease progression. The finding of a new 
lesion should be unequivocal: ie, not attributable to differences in scanning technique, change in 
imaging modality or findings thought to represent something other than tumor (for example, some 
“new” bone lesions may be simply healing or flare of preexisting lesions). This is particularly 
important when the participant’s baseline lesions show PR or CR. For example, necrosis of a liver 
lesion may be reported on a CT scan report as a “new” cystic lesion, which it is not. 
A lesion identified on a follow-up study in an anatomical location that was not scanned at baseline 
is considered a new lesion and will indicate disease progression. An example of this is the patient 
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who has visceral disease at baseline and while on study has a CT or MRI brain ordered which 
reveals metastases. The participant’s brain metastases are considered to be constitute PD even if 
he/she did not have brain imaging at baseline. 
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents new disease. If repeat scans confirm that there is a 
new lesion, then progression should be declared using the date of the initial scan. 
While fluorodeoxyglucose-positron emission tomography (FDG-PET) response assessments need 
additional study, it is sometimes reasonable to incorporate the use of FDG-PET scanning to 
complement CT scanning in assessment of progression (particularly possible “new” disease). New 
lesions on the basis of FDG-PET imaging can be identified according to the following algorithm: 
A) Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
B) No FDG-PET at baseline and a positive FDG-PET at follow-up: 
If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed by 
CT, this is PD. 
If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan). If the positive FDG-PET at follow-up corresponds to a preexisting site of 
disease on CT that is not progressing on the basis of the anatomic images, this is not PD. 
Evaluation of best overall response 
Time point response: At each protocol specified time point, a response assessment should occur.   
Table 20 provides a summary of the overall response status calculation at each time point for 
patients who have measurable disease at baseline. 
Table 20 - Response in patients with target disease  
Target lesions 
Non-target lesions 
New lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
Inevaluable 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Abbreviations: CR=complete response; PD=progressive disease; PR=partial response; SD=stable disease.  
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When patients have non-measurable (therefore non-target) disease only, Table 21 is to be used. 
Table 21 - Response in patients with non-target disease only  
Non-target lesions 
New lesions 
Overall response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD 
Not all evaluated 
No 
Inevaluable  
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
Abbreviations: CR=complete response; PD=progressive disease; PR=partial response; SD=stable disease. 
Missing assessments and inevaluable designation: When no imaging/measurement is done at all at 
a particular time point, the patient is not evaluable (NE) at that time point. 
If only a subset of lesion measurements are made at an assessment, usually the case is also 
considered NE at that time point, unless a convincing argument can be made that the contribution 
of the individual missing lesion(s) would not change the assigned time point response. This would 
be most likely to happen in the case of PD. 
Special notes on response assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to “normal” 
size (<10 mm), they may still have a measurement reported on scans. This measurement should be 
recorded even though the nodes are normal in order not to overstate progression should it be based 
on increase in size of the nodes. As noted earlier, this means that patients with CR may not have a 
total sum of “zero” on the CRF. 
In trials where confirmation of response is required, repeated “NE” time point assessments may 
complicate best response determination. The analysis plan for the trial must address how missing 
data/assessments will be addressed in determination of response and progression. For example, in 
most trials it is reasonable to consider a patient with time point responses of PR-NE-PR as a 
confirmed response. 
Patients with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be reported as “symptomatic 
deterioration”. Every effort should be made to document objective progression even after 
discontinuation of treatment. Symptomatic deterioration is not a descriptor of an objective 
response: it is a reason for stopping study therapy. 
The objective response status of such patients is to be determined by evaluation of target and 
non-target disease. For equivocal findings of progression (eg, very small and uncertain new 
lesions; cystic changes or necrosis in existing lesions), treatment may continue until the next 
scheduled assessment. If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected. 
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Duration of response 
The DOR 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 (SD) 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 tumours: Revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228-47 (25).  
10.8 
APPENDIX 8: COUNTRY-SPECIFIC REQUIREMENTS  
Serology for HBsAg and HCV and HIV test at screening will be performed only if required at the 
country level. 
10.9 
APPENDIX 9: CYP SUBSTRATES WITH NARROW THERAPEUTIC RANGE (NTR)  
Table 22 - List of CYP substrates with narrow therapeutic range   
Narrow Therapeutic Range (NTR) Substrates of CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6 
and CYP3A in vivo 
CYP enzyme 
NTR Substratesa 
CYP1A2 
Theophylline, tizanidine 
CYP2C8 
Paclitaxel 
CYP2C9 
Warfarin, phenytoin 
CYP2C19 
S-mephenytoin 
CYP2D6 
Thioridazine 
CYP3A 
Alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, quinidine, sirolimus, 
tacrolimus, cisapride, astemizole, terfenadine, pimozide 
a CYP Substrates with a Narrow Therapeutic Range - drugs with an exposure-response relationship that indicates that 
relatively small increases in their exposure levels by co-administered CYP inhibitors may lead to safety concerns. 
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10.10 APPENDIX 10: STRONG CYP3A INHIBITORS  
Table 23 - List of strong (substrate AUC ratio ≥5) CYP3A inhibitors  
CYP3A inhibitors 
Precipitant Therapeutic Class 
Victim (oral, unless 
otherwise specified) 
AUC 
Ratio 
VIEKIRA PAK 
Antivirals 
Tacrolimus 
55.76 
Telaprevir 
Antivirals 
Midazolam 
13.50 
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 
12.80 
Posaconazole 
Antifungals 
Midazolam 
6.23 
Telithromycin 
Antibiotics 
Midazolam 
6.20 
Conivaptan 
Vasopressin AntagonistsDiuretics 
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 
10.40 
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), updated in 
July 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: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY  
For European countries contingency measures are currently only applicable for COVID-19 
pandemic. 
For a regional or national emergency declared by a governmental agency, contingency procedures 
may be implemented for the duration of the emergency. The participant or legally authorized 
representative should be informed verbally prior to initiating any change that is to be implemented 
for the duration of the emergency (eg, study visit delays, use of back-up sites for safety laboratory 
or tumor assessment). 
As the situation may evolve differently by country, by region, or by site, each site should define 
its business continuity plan, and inform the Sponsor of its plan as early as possible. Some 
guidance to be considered in formulating a contingency plan during a regional or national 
emergency is provided in this section.  
10.11.1 Remote Prescreening Process  
If there is no other way to conduct prescreening procedures during a regional or national 
emergency declared by a governmental agency (eg, due to a COVID-19 pandemic), the site may 
consider implementing for only those participants who have enough archival samples a remote 
prescreening ICF process compliant with country/site requirements.  
The process should be compliant with accepted principals of patients’ rights and global, national, 
and local regulatory requirements. 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 
circulating CEA and CEACAM5 expression).  The Investigator/delegate should respond to 
any question raised by a participant, and this correspondence should be documented in 
detail in the participant’s source file. 
• If a participant agrees to participate in the prescreening phase, the participant should print 
out, sign, and date 2 copies of the ICF. A scan of a signed ICF should be sent via secured 
email (if available), and 1 of the signed original ICFs to be filed in the Investigator Study 
File should be sent via postal mail.  
• The Investigator/delegate should review each received signed ICF (or a printout of an 
electronically submitted, scanned copy), sign and date it, and archive it in the Investigator 
Study File.  It is mandatory for the Investigator to ensure the collection of the original 
signed ICF sent by mail; the signed original should be attached to any previously filed 
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signed printout of an electronically submitted signed ICF. After properly documenting this 
consent process, the site may proceed to collect a blood sample for local measurement of 
circulating CEA and prepare and send the slides for CEACAM5 assessment. 
10.11.2 Screening procedures:  
The Investigator/site should assess the site’s capacity to conduct study procedures throughout the 
study for each participant before starting any screening procedure. If the site cannot guarantee an 
accurate follow-up in the context of the trial, alternative treatment outside the clinical trial should 
be proposed. This assessment, per the Investigator’s medical judgement and depending on the 
country/ site status, should be communicated to the participant. The participant should satisfy all 
eligibility criteria before enrolling to the study; no protocol waiver is acceptable. Remote 
signature of main study ICF is not acceptable in any circumstance.  
10.11.3 Study intervention  
During a regional or national emergency declared by a governmental agency, all contingency 
plans should be implemented to ensure compliance to study treatment, based on a case-by-case 
benefit–risk assessment. Administration (or, in case of temporary interruption, re-initiation) of the 
IMP can occur only once the Investigator has determined, according to his/her best judgement, 
that the contribution of the IMP(s) to the occurrence of the epidemic event (eg, COVID-19) was 
unlikely. 
During a regional or national emergency due to pandemic (eg, COVID-19), the Investigator’s 
choice, based on a benefit–risk assessment, to initiate prophylactic G-CSF treatment at Cycle 1 for 
a participant in Part 2 should be considered acceptable.  The Investigator’s decision to initiate 
G-CSF should be detailed in the source data and reported on eCRF.   
Any further safety measure (eg, interim laboratory assessment such as neutrophil count 
monitoring; regular contact with site staff) to follow the safety of patients during the regional or 
national emergency period can be considered.  
10.11.4 Study procedures  
Depending on site status, if needed, Cycle 1 and Cycle 2 weekly safety laboratory assessment 
(hematology [differential WBC] and liver function tests [AST, ALT, total and direct bilirubin, 
ALP]) can be arranged to be performed either at a laboratory certified to perform these tests that is 
close to patient home, or via sampling at patient’s home.  
All efforts should be made to ensure that measurements of key parameters for efficacy endpoints 
can be performed at the site.  If the Investigator is unable to guarantee that the protocol-required 
efficacy assessments can be conducted, no participant should be screened until the site confirms 
its 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 
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assessment by a regional or national emergency situation (eg, COVID-19 outbreak). The 
Investigator should ensure that the back-up site conducts the RECIST assessment in same manner 
as that used for baseline tumor assessments.  
In the case that the primary tumor assessment site is incapacitated, ongoing patients would then be 
referred to the back-up site for tumor assessment. The Investigator/delegate should ensure the 
information on baseline assessment methods is shared with the back-up site’s radiologist to ensure 
same method is followed for scans to be sent to IRC. 
10.11.5 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. 
10.12 APPENDIX 12: PROTOCOL AMENDMENT HISTORY  
The “Protocol Amendment Summary of Changes Table” for the current amendment is located 
directly before the Table of Contents (TOC). 
Amended protocol 01: (12 November 2020) 
This amended protocol 01 (amendment 01) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union because it significantly impacts the design of the study. 
Overall Rationale for the Amendment 
The purposes of this amendment are to clarify inclusion criteria/exclusion criteria (IC3, IC5, 
EC21, EC11); to update the safety guidelines; to introduce DLT as an adverse event of special 
interest (AESI); to introduce and clarify agreements regarding the future use of samples and data; 
and to add information concerning contingency measures in the case of an emergency such as a 
pandemic.  
Beside this change, further modifications to protocol wording were implemented, as detailed 
below. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis; Objectives and endpoints; 
Section 3 Objectives and endpoints, 
Table 2; 9.4.1 Efficacy analyses, Table 11 
Modified tertiary/exploratory objective to include 
evaluation of circulating CEA at prescreening, 
and modified endpoint to include assessments 
of CEA at prescreening and screening, as well 
as during treatment 
To reflect addition of new 
CEA assessment at 
prescreening 
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Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis, Intervention groups and 
duration; 1.3.1 Study Flowchart, footnote d; 
4.1 Overall design; 7 Discontinuation of 
Study Intervention and Participant 
Discontinuation/Withdrawal; 8.1 Efficacy 
assessments  
Add ±7 day window at follow-up visits specified 
after the last tumor assessment 
For clarity 
1.1 Synopsis, Study interventions; 
6.1 Study interventions administered: IMP 
and Non-IMP 
Moved heading for non-IMP medications to 
before premedication; changed to 
Noninvestigational medicinal products 
For clarity 
1.1 Synopsis: Main analysis populations 
and Section 9.3 Populations for analyses  
Clarified definition of Activity population 
For clarity 
1.3.1 Study Flow Chart; 
8.6 Pharmacodynamics 
Added assessment of circulating CEA at 
prescreening 
To reflect new prescreening 
assessment  
1.3.1 Study Flow Chart, footnote a; 
10.11 Appendix 11: Contingency measures 
for a regional or national emergency that is 
declared by a governmental agency  
Modified statement regarding prescreening 
informed consent to reflect new requirement of 
circulating CEA assay results at prescreening 
To reflect new prescreening 
Informed Consent form (ICF) 
requirement  
1.3.1 Study Flow Chart;  
8.8 Biomarkers  
Added preinfusion IgG sample at Cycle 1 
To explore the impact of IgG 
on PK parameters 
1.3.1 Study Flow Chart  
Collection of NSCLC charactaristics added for 
prescreening; footnote f updated to specify that 
only PD-1 status is collected prescreening 
For clarity 
1.3.1 Study Flow Chart   
Footnote a updated to clarify that prescreening 
informed consent is not required for participants 
with known CEACAM5 status 
For clarity 
1.3.1 Study Flow Chart, footnote n; 
8.2.4.1 Electrocardiograms  
Specified timing window of 30 min after end of 
first IMP infusion at Cycle 1 for postinfusion 
ECG  
For clarity 
2.3 Benefit/Risk Assessment 
Information regarding potential risks of 
tusamitamab ravtansine modified; added 
description of ramucirumab mechanism of 
action 
To provide up-to-date 
information regarding 
potential risks to participants 
4.1 Overall design 
Clarified requirements for safety follow-up visits 
For clarity 
4.1 Overall design;  
5.1 Inclusion Criterion I05 
Reduced required number of tumor tissue 
slides for prescreening CEACAM status from 7 
to 5. 
To reflect actual analysis 
processing requirement 
5.1 Inclusion criteria, I03 
Modified criterion and clarified wording to 
specify that both sub criteria a and b should be 
met at study entry 
For clarity 
5.2 Exclusion criteria, E11 
Added LVEF<50% as criterion for clinically 
relevant congestive heart failure 
For clarity 
5.2 Exclusion criteria, E21 
Corrected to exclude >1 line of prior 
chemotherapy in metastatic setting 
For clarity 
5.4 Screen failures. 
Added requirements for re-screening and 
emergency contingencies 
To reflect and define 
operational process 
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Section # and Name 
Description of Change 
Brief Rationale 
6.6.1 Part 1 (Safety run-in) 
Added footnote for Table 6 Dose Reduction for 
Phase 1 part (safety run-in) to clarify how to 
proceed to treat patients initially at starting 
dose DL in the Part 1  
For clarity 
8 Study assessments and procedures 
Removed references to histology, smoking 
status, medical history, and demography from 
statement regarding information to be collected 
from prescreening failures  
To reflect operational 
process, as these data are 
not collected from 
prescreening failures 
8.2.6.2 Ocular toxicity  
Specified periodic ocular exams to follow 
participants presenting with ocular toxicity  
For clarity of safety 
management guidelines 
8.2.6.10 Peripheral neuropathy  
new section with guidance for managing 
peripheral neuropathy 
For clarity of safety 
management guidelines 
8.2.6.11 Colitis (including hemorrhagic) 
New section for managing GI toxicity 
For clarity of safety 
management guidelines 
8.3.1 Adverse events, treatment-emergent 
adverse events, and adverse events of 
special interest 
Protocol-defined DLT added as AESI 
For safety analysis 
8.11 Use of biological samples and data for 
future research 
New section to describe consent to store 
samples for future studies  
To comply with Sanofi policy 
and procedures 
9.4.2 Safety analyses  
Reworded definition of prescreening period 
For clarity 
10.1.3 Informed consent process  
Added details regarding ICF and process 
To comply with Sanofi policy 
and procedures 
10.4 Appendix 4: Recommended 
supportive care and/or dose modification 
guidelines for drug-related adverse events  
Added clarifications for Grade 2, Grade 3, and 
Grad 4 ocular toxicity; added peripheral 
neuropathy (Grades 1-4); Neutrophil count 
decreased Grade 4; Grade 4 febrile 
neutropenia. 
For clarity 
10.4 Appendix 4: Recommended 
supportive care and/or dose modification 
guidelines for drug-related adverse events 
Changed “Prematurely/Permanently” 
discontinue to “Definitively” discontinue for 
Hypertension, Hemorrhage, Proteinuria, Arterial 
thromboembolic events, and Wound healing 
complications 
Consistency of terminology 
and clarity 
10.5 Appendix 5: Contraceptive guidance 
and collection of pregnancy information  
Deleted redundant wording for reporting of 
pregnancy 
For clarity 
New Appendix 11 (Section 10.11) 
referenced in Sections 4.1, 6, 7.1.2, 8, 
9.4.3, and10.1.3 
Addition of contingency measures to be 
implemented in the case of a regional or 
national emergency 
To permit adaptation of study 
procedures in an emergency  
New Appendix 12 (Section 10.12) to 
precede Abbreviations (now Appendix 13 
[Section 10.13]);  
Addition of Document History Appendix 
Per Sanofi process 
Throughout 
Correction of typographical errors and 
standardization of wording  
For clarity 
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10.13 APPENDIX 13: ABBREVIATIONS  
 
ADC: 
antibody-drug conjugate 
AESI: 
adverse event of special interest 
AIDS: 
acquired immunodeficiency syndrome 
ALK: 
anaplastic lymphoma kinase (gene) 
ALP: 
alkaline phosphatase 
ALT: 
alanine aminotransferase (SGPT) 
ANC 
absolute neutrophil count 
ASCO: 
American Society of Clinical Oncology 
AST: 
aspartate aminotransferase (SGOT) 
ATA: 
antitherapeutic antibody 
ATE: 
arterial thromboembolic event 
BOR: 
best overall response 
BSA: 
body surface area 
CEA: 
carcinoembryonic antigen 
CEACAM5: 
carcinoembryonic antigen-related cell adhesion molecule 5 
CHF: 
congestive heart failure 
CI: 
confidence interval 
CONSORT: 
Consolidated Standards of Reporting Trials 
CR: 
complete response 
CRC: 
colorectal cancer 
CTCAE: 
Common Terminology Criteria for Adverse Events 
CYP: 
cytochrome P450 
DL: 
dose level 
DLT: 
dose-limiting toxicity 
DOR: 
duration of response 
DCR 
disease control rate 
ECG: 
electrocardiogram 
ECOG: 
Eastern Cooperative Oncology Group 
eCRF: 
electronic case report form 
eGFR: 
estimated glomerular filtration rate 
EGFR: 
epidermal growth factor receptor (gene)  
EOI: 
end of infusion 
FDG-PET: 
fluorodeoxyglucose-positron emission tomography 
FFPE: 
formalin-fixed, paraffin-embedded 
FOLFIRI: 
folinic acid/fluorouracil/irinotecan  
GI: 
gastrointestinal  
G-CSF: 
granulocyte colony-stimulating factor 
HBsAg: 
hepatitis B virus surface antigen 
HCV: 
hepatitis C virus 
HRQOL: 
health-related quality of life 
HIV: 
human immunodeficiency virus 
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IB: 
Investigator's Brochure 
ICI: 
immune chekpoint inhibitors 
ICF: 
informed consent form 
IEC: 
independent ethics committee 
IHC: 
immunohistochemical 
IMP: 
investigational medicinal product 
IRB: 
institutional review board 
IRR: 
infusion-related reaction 
IV: 
intravenous 
LVEF: 
left ventricular ejection fraction 
MDRD: 
Modification of Diet in Renal Disease  
MTD: 
maximum tolerated dosee 
MRI: 
magnetic resonance imaging 
MUGA: 
multigated acquisition scan 
NCI: 
National Cancer Institute 
NE: 
not evaluable 
NIMP: 
non-investigational medicinal product 
NSCLC: 
non-small-cell lung cancer 
NSQ NSCLC: 
non-squamous, non-small-cell lung cancer 
NTR: 
narrow therapeutic range  
ORR: 
objective response rate 
PD: 
progressive disease 
PD-L1: 
programmed death ligand 1 
PD-1: 
programmed death-1  
PFS: 
progression-free survival 
PK: 
pharmacokinetic 
PR: 
partial response 
PT: 
preferred term 
Q2W: 
every 2 weeks 
Q3W 
every 3 weeks 
RBC: 
red blood cells 
RD: 
recommended dose 
RECIST: 
Response Evaluation Criteria in Solid Tumors 
ROS1 
ROS receptor tyrosine kinase 1 (gene) 
RP2D: 
recommended Phase 2 dose 
SAE: 
serious adverse event 
SAP: 
statistical analysis plan 
SC: 
Study Committee 
SD: 
stable disease 
SOA: 
schedule of assessements 
SOC: 
system organ class 
TEAE: 
treatment-emergent adverse event 
ULN: 
upper limit of normal  
VEGF: 
vascular endothelial growth factor  
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VEGFR-2: 
vascular endothelial growth factor receptor-2 
WBC 
white blood cells 
WOCBP: 
woman of child-bearing potential 
 
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11 
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