Conditions: Non-squamous Non-small-cell Lung Cancer (NSQ NSCLC)
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 57
Healthy volunteers: no

Brief summary:
Primary Objective:

* Safety run-in part: to assess the tolerability and to determine the recommended doses of tusamitamab ravtansine in combination with pembrolizumab and tusamitamab ravtansine in combination with pembrolizumab and platinum-based chemotherapy with or without pemetrexed to be tested in the expansion part of the study in the NSQ NSCLC population
* Expansion part (including participants treated at the recommended dose for expansion \[RDE\] from the Safety Run-in part): to assess the antitumor activity of several dose levels (DLs; if applicable) of tusamitamab ravtansine in combination with pembrolizumab and of several DLs of tusamitamab ravtansine in combination with pembrolizumab, platinum-based chemotherapy, and pemetrexed in the NSQ NSCLC population

Secondary Objectives:

* To assess the safety and tolerability of several DLs (if applicable) of tusamitamab ravtansine in combination with pembrolizumab and of 1 DL of tusamitamab ravtansine in combination with pembrolizumab and platinum-based chemotherapy, and of several DLs of tusamitamab ravtansine in combination with pembrolizumab, and platinum-based chemotherapy with pemetrexed in the NSQ NSCLC population
* To assess the antitumor activity of several DLs (if applicable) of tusamitamab ravtansine in combination with pembrolizumab and of 1 DL of tusamitamab ravtansine in combination with pembrolizumab and platinum-based chemotherapy, and of several DLs of tusamitamab ravtansine in combination with pembrolizumab, platinum-based chemotherapy, and pemetrexed in the NSQ NSCLC population
* To assess the durability of the response to treatment with several DLs (if applicable) of tusamitamab ravtansine in combination with pembrolizumab and of 1 DL of tusamitamab ravtansine in combination with pembrolizumab and platinum-based chemotherapy, and of several DLs of tusamitamab ravtansine in combination with pembrolizumab and platinum-based chemotherapy, and pemetrexed in the NSQ NSCLC population
* To assess the antitumor activity of tusamitamab ravtansine in combination with pembrolizumab and platinum-based chemotherapy in the NSQ NSCLC population
* To assess the pharmacokinetics (PK) of tusamitamab ravtansine, pembrolizumab, pemetrexed, cisplatin, and carboplatin, each when given in combination as a doublet (tusamitamab ravtansine + pembrolizumab) or a triplet (tusamitamab ravtansine + pembrolizumab + platinum-based chemotherapy) or a quadruplet (tusamitamab ravtansine + pembrolizumab + platinum-based chemotherapy + pemetrexed)
* To assess the immunogenicity of tusamitamab ravtansine in combination with pembrolizumab and tusamitamab ravtansine in combination with pembrolizumab and platinum based chemotherapy with or without pemetrexed

Detailed description:
The expected duration of study intervention for participants may vary, based on disease progression date; median expected duration of study per participant is estimated at 10 months (up to 1 month for screening, a median of 6 months for treatment, a median of 1 month for EOT, and follow-up visit 90 days after the last IMP administration).

Arms:
arm 1: Pembrolizumab dose will be administered intravenously prior to intravenous administration of tusamitamab ravtansine dose every 3 weeks. arm 2: Pembrolizumab dose will be administered intravenously prior to intravenous administration of tusamitamab ravtansine dose every 3 weeks. arm 3: Pembrolizumab dose will be administered intravenously prior to intravenous adminstration of tusamitamab ravtansine dose every 3 weeks. Carboplatin will be infused over 15 to 60 minutes immediately after tusamitamab ravtansine infusion on Day 1 and Q3W for the first 4 cycles. Cisplatin will be infused approximately 30 minutes after tusamitamab ravtansine infusion on Day 1 and Q3W for the first 4 cycles. arm 4: Pembrolizumab dose will be administered intravenously prior to intravenous adminstration of tusamitamab ravtansine dose every 3 weeks. Carboplatin will be infused over 15 to 60 minutes immediately after tusamitamab ravtansine infusion on Day 1 and Q3W for the first 4 cycles. Cisplatin will be infused approximately 30 minutes after tusamitamab ravtansine infusion on Day 1 and Q3W for the first 4 cycles. arm 5: Pembrolizumab dose will be administered intravenously prior to intravenous adminstration of tusamitamab ravtansine dose every 3 weeks. Pemetrexed will be infused over 10 minutes after tusamitamab ravtansine infusion on Day 1 and then Q3W. Carboplatin will be infused over 15 to 60 minutes immediately after pemetrexed infusion on Day 1 and Q3W for the first 4 cycles. Cisplatin will be infused approximately 30 minutes after pemetrexed infusion after pemetrexed infusion on Day 1 and Q3W for the first 4 cycles. arm 6: Pembrolizumab dose will be administered intravenously prior to intravenous adminstration of tusamitamab ravtansine dose every 3 weeks. Pemetrexed will be infused over 10 minutes after tusamitamab ravtansine infusion on Day 1 and then Q3W. Carboplatin will be infused over 15 to 60 minutes immediately after pemetrexed infusion on Day 1 and Q3W for the first 4 cycles. Cisplatin will be infused approximately 30 minutes after pemetrexed infusion after pemetrexed infusion on Day 1 and Q3W for the first 4 cycles.

Interventions: intervention 1: SAR408701 (Tusamitamab ravtansine) intervention 2: Pembrolizumab intervention 3: Cisplatin intervention 4: Carboplatin intervention 5: Pemetrexed
Intervention descriptions: intervention 1: Pharmaceutical form:Concentrate for solution for infusion Route of administration: Intravenous intervention 2: Pharmaceutical form: Concentrate for solution for infusion Route of administration: Intravenous intervention 3: Pharmaceutical form: Lyophilized powder for reconstitution in solution Route of administration: Intravenous intervention 4: Pharmaceutical form: Concentrate for solution for infusion Route of administration: Intravenous intervention 5: Pharmaceutical form: Concentrate for solution for infusion Route of administration: Intravenous

Protocol document:
Prot_000.pdf: 
 
 
 
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Based on Template: Sanofi OneDocument Version 2.0, dated 14-OCT-2019 
Page 1 
I ha  
AMENDED CLINICAL TRIAL PROTOCOL 06  
Protocol title: 
Open-label, Phase 2 study of tusamitamab ravtansine 
(SAR408701) combined with pembrolizumab and 
tusamitamab ravtansine (SAR408701) combined with 
pembrolizumab and platinum-based chemotherapy with or 
without pemetrexed in patients with CEACAM5-positive 
expression advanced/metastatic nonsquamous 
non-small-cell lung cancer (NSQ NSCLC) 
Protocol number: 
ACT16146 
Amendment number: 06 
Compound number 
(INN/Trademark): 
SAR408701 
Tusamitamab ravtansine/Not applicable 
Study phase: 
Phase 2 
Short title: 
Tusamitamab ravtansine (SAR408701) in combination with 
pembrolizumab and tusamitamab ravtansine (SAR408701) 
in combination with pembrolizumab and platinum-based 
chemotherapy with or without pemetrexed in patients with 
NSQ NSCLC (CARMEN-LC05)  
Sponsor name: 
Sanofi aventis recherche & développement 
Legal registered 
address: 
1 avenue Pierre Brossolette, 
91380 Chilly- Mazarin 
FRANCE 
Monitoring Team’s 
Representative Name 
and Contact 
Information 
  
Regulatory agency identifier number(s): 
IND:  
144484 
EudraCT: 
2020-000035-50 
WHO: 
NCT: 
U1111-1233-9798 
NCT04524689 
EUDAMED: 
Not applicable 
Other: 
Not applicable 
Date: 
21-Aug-2023 
Total number of pages: 148 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES  
DOCUMENT HISTORY  
Document 
Country/countries 
impacted by 
amendment 
Date, version 
Amended Clinical Trial Protocol 06 
All 
21 August 2023, version 3 (electronic 10.0) 
Amended Clinical Trial Protocol 05 
All 
04 July 2022, version 1 (electronic 7.0) 
Amended Clinical Trial Protocol 04 
All 
18 August 2021, version 1 (electronic 6.0) 
Amended Clinical Trial Protocol 03  
All 
04 May 2021, version 1 (electronic 4.0) 
Amended Clinical Trial Protocol 02  
All 
25 January 2021, version 1 (electronic 3.0) 
Amended Clinical Trial Protocol 01  
All 
23 November 2020, version 1 (electronic 2.0) 
Original Protocol 
 
26 February 2020, version 1 (electronic 1.0) 
Amended protocol 06 (21 Aug 2023) 
This amendment (Amended protocol 06) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union.  
OVERALL RATIONALE FOR THE AMENDMENT 
The main purpose of this amendment is to recruit additional participants to optimize dose 
selection for tusamitamab ravtansine when combined with pembrolizumab, with or without 
chemotherapy, by testing up to 2 lower tusamitamab ravtansine dose levels (DLs), in addition to 
the recommended dose for the expansion phase of the study (RDE). 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis; 
2.1 Study Rationale 
Updated text to remove specific reference to Part A 
results, and updated the number of the first patients 
treated from 5 patients to 25 patients.  
Preliminary efficacy data are 
presented in a more general 
manner appropriate for 
an ongoing study. 
1.1 Synopsis; 1.2 Schema; 
3 Objectives and endpoints; 
4.1.1 Safety run-in part: DLT 
observation period; 
4.1.2 Expansion Cohorts 
(Parts A & C); 4.3 Justification 
for dose; 6.6.1 Determination of 
recommended doses; 
9.1 Statistical hypotheses; 
9.2 Sample size determination; 
9.5 Interim analyses  
“Recommended Phase 2 dose (RP2D)” replaced with 
“recommended dose for expansion (RDE)” 
The goal of the Safety Run-In 
portion of this Phase 2 study is to 
find an appropriate tusamitamab 
ravtansine dose level for each 
combination regimen in the 
expansion phase of the study.  
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Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
Moved dose-limiting toxicity (DLT) decision tree and 
descriptive text from section describing DLT 
observation procedure in Part A, Part B, and Part C to 
a new synopsis subsection, “DLT observation period” 
following the Part C description; labeled the 
abbreviated sections describing each part under a new 
subheading, “Safety Run-in” 
To simplify presentation of safety 
run-in and DLT procedures for all 
3 parts of the study 
1.1 Synopsis; 3 Objectives and 
endpoints; 8.1 Efficacy 
assessments; 9.4.2 Primary 
endpoint; 9.4.3 Secondary 
endpoints 
Updated primary objective to clarify that the goal of the 
Safety run-in is to determine appropriate tusamitamab 
ravtansine dose levels for evaluation in combination 
regimens in the expansion phase.  
To specify distinct objectives of 
the Safety Run-in and Expansion 
parts  
Added a new primary objective for the Expansion to 
assess antitumor activity of combination treatment 
based on endpoint of objective response rate (ORR; 
proportion of participants with best overall responses of 
complete response [CR] or partial response [PR]). 
Added new secondary objective to assess the antitumor 
activity at several dose levels (DLs) of tusamitamab 
ravtansine in combination regimens as assessed with 
2 endpoints: progression-free survival (PFS) and 
disease control rate (DCR) 
Updated secondary safety objective to reflect multiple 
tusamitamab ravtansine DLs) to be tested in each 
combination regimen. 
New secondary objective and corresponding endpoints 
were added to assess the durability of the response to 
treatment with several tusamitamab ravtansine DLs in 
combination regimens as assessed by duration of 
response (DOR; time from first documented evidence 
of CR or PR until progressive disease [PD]). 
1.1 Synopsis 
Preliminary results of Part A are removed and 
repeated details describing the study population have 
been deleted from the overall design description. 
To make the text more concise. 
1.3.1 Study procedures 
flowchart; 4.1 Overall design 
Specified that PD-L1 status by an approved test will be 
collected “and assessed locally or centrally” and 
circulating CEA will be assessed locally; added 
corresponding footnote “a.” 
To clarify that prescreening tumor 
samples can be assessed either 
locally or centrally. 
1.1 Synopsis; 4.1 Overall 
design; New section 
4.1.2 Expansion cohorts 
(Parts A & C); 9.2 Sample size 
determination 
Specified the subheadings of “Safety run-in” and/or 
“Expansion” for Parts A, B, and C for Synopsis overall 
design, and added new subsection 4.1.2 for Parts A 
and C. 
To clarify the description of study 
design 
1.1 Synopsis; New section 
4.1.2 Expansion cohorts 
(Parts A & C) 
Specified that in Parts A and C, 20 participants would 
be treated at the RDE and at least 20 participants at 1-
2 lower dose levels with early stopping rules,  Updated 
the planned total number of participants for Parts A, B, 
and C. 
To reflect changes to optimize 
tusamitamab ravtansine dose 
selection for each combination 
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Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis; New subsection 
4.1.1 Safety run-in part: DLT 
observation period 
Specified each quadruplet platinum combination for 
Part C as tusamitamab ravtansine, pembrolizumab, 
pemetrexed, and either cisplatin or carboplatin. 
To specify the actual 
combinations of treatments 
administered 
Added explanation that if the quadruplet combination 
investigated in Part C is shown to have an acceptable 
toxicity profile, enrollment to the triplet treatment in 
Part B could be stopped. 
To clarify that triplet treatment 
would be fully evaluated in Part B 
only in the case that the 
quadruplet regimen in Part C was 
not well tolerated. 
1.1 Synopsis; 4.1 Overall 
design; 4.3 Justification of 
dose; 6.1 Study interventions 
administered; 6.6.2 Individual 
dose modifications 
Added text for dose regimen to test lower dose of 
tusamitamab ravtansine 100 mg/m2 Q3W (added lower 
DL in Table 2 and Table 5). 
To clarify decision process to 
optimize dose selection of 
tusamitamab ravtansine when 
combined with pembrolizumab 
with or without chemotherapy. 
1.1 Synopsis; 9.4.1 General 
considerations 
Added cut-off for secondary endpoints including DOR 
and PFS. 
Additional cut-off for these newly 
added secondary endpoints to 
demonstrate antitumor activity 
over longer follow-up times. 
Added statement specifying that study cut-offs will 
occur by parts, and could be grouped if the different 
cut-off dates for the primary endpoint are close. 
Clarification 
1.1 Synopsis; 9.2 Sample size 
determination 
Updated statistical considerations for sample size 
calculations for Part A, Part B, and Part C. 
To optimize the dose selection of 
tusamitamab ravtansine when 
combined with pembrolizumab 
with or without chemotherapy. 
1.1 Synopsis; 9.4.1 General 
considerations 
Specified that ORR, DCR, DOR, and PFS will be 
summarized by part, DL and overall.  
Clarification of planned analyses 
of antitumor activity.  
1.1 Synopsis; 9.2 Sample size 
determination; 9.4.2.2 Objective 
response rate 
Specified Clopper-Pearson method for calculating the 
confidence interval for ORR 
To provide details of planned 
analyses 
1.1 Synopsis; 
9.4.2.2 Secondary endpoints 
Added analysis description for secondary endpoints: 
DOR, PFS, and DCR. 
To describe planned analyses of 
newly added secondary efficacy 
endpoints. 
1.2 Schema 
Updated Figure 2, Figure 3, and Figure 4 with details 
participants numbers and parts details. 
To reflect the new study design 
and population. 
1.1 Synopsis; 1.3.1 Study 
procedure flowcharts; 
4.1.3 Duration of the study; 
8.1 Efficacy assessments 
Added description of timing for tumor assessments for 
a participant who stopped treatment before 
documented progressive disease in text and footnote 
“e” in the SOA. 
To clarify tumor assessment 
procedures. 
1.1 Synopsis; 3 Objective and 
endpoints; 1.3.2.1 PK/ATA flow 
chart for Part A; 
1.3.2.2 PK/ATA flow chart for 
Part B; 1.3.2.3 PK/ATA flow 
chart for Part C; 
8.4 Pharmacokinetics 
Added “SAR408701, DM4, and Me-DM4” in 
parenthesis for PK sample ID in Tusamitamab 
ravtansine. Added footnote “f” for this heading to 
mention that DM4 and Me-DM4 to be collected only for 
patients enrolled from amendment #6. 
DM4 and Me-DM4 will be 
assessed in addition to 
SAR408701 for new participants 
enrolled.  
1.1 Synopsis; 4.1.2 Expansion 
cohorts (Parts A&C) 
Clarified that the expansion phase of Part A was 
dependent on the benefit/risk assessment of the 
participants treated at RDE in Part A and of 
participants treated at a lower dose in Part C 
To make clear that 
implementation of the expansion 
phase is contingent on safety in 
the Safety Run-in 
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Section # and Name 
Description of Change 
Brief Rationale 
1.3.1 Study procedure 
flowcharts 
Added new row for “FFPE sections for RNA and DNA 
analysis” and corresponding footnote “o” and “p”. 
To explore potential sets of 
biomarkers besides target 
expression that could be 
predictive. 
2.1 Study rationale 
Clarified the wordings from “no overlap is expected” to 
“no overlapping toxicities are expected”. 
Clarification. 
3 Objectives and endpoints 
Added new tertiary/exploratory objective to explore 
tumor DNA and RNA as potential prognostic 
biomarkers of  response to treatment 
To explore potential sets of 
biomarkers besides target 
expression that could be 
predictive of response. 
Added new tertiary/exploratory objective to explore 
PK -PD relationship of tusamitamab ravtansine d with 
safety and efficacy endpoints. 
To have additional data for 
understanding of PK-PD 
relationships  
1.1 Synopsis; 4.1 Overall 
design; new subsections 
4.1.1 Safety run-in part: DLT 
observation period; 4.1.2 
Expansion cohorts (Parts A & C)" 
Described design and updated numbers of participants 
in the Safety Run-In Part (DLT observation period); 
details of study design for the expansion cohorts 
(Parts A & C) at the RDE and lower dose level(s) ; and 
added new level 3 headings. 
Clarification of study design. 
4.3 Justification for dose 
Rationale added for decrease to the lower DL 
150 mg/m2 Q3W that would be the recommended for 
the expansion part in all cohorts. Additionally, a lower 
dose of 100 mg/m2 will also be tested. 
Addition of rationale for new DLs. 
5.1 Inclusion criteria 
Added inclusion criterion for life expectancy of at least 
3 months 
To ensure meaningful follow-up of 
safety and efficacy for each 
participant. 
5.2 Exclusion criteria, 
6.5 Concomitant therapy, 
10.8 Appendix 8 Strong CYP3A 
inhibitors 
Removed exclusion criterion for a medical condition 
requiring concomitant administration of a medication 
metabolized by CYP450 with a narrow therapeutic 
window. 
Removed Table of list of CYP substrates with narrow 
therapeutic range from appendix. 
Consistency with Investigator’s 
brochure Edition 9 
6.6.1 Determination of 
recommended doses; Table 4: 
Dose levels (safety run-in part) 
Clarified the phase of the study as “safety run-in 
phase” during DLT observation period. 
To include new DL, 100 mg/m2 
Specified that 100 mg/m2 and 150 mg/m2 doses will be 
tested in expansion cohorts for Parts A and C. 
6.8 Treatment of overdose 
Changed the section number from 8.4 to 6.8 and 
updated the text as per new template. 
To conform to new template 
requirement 
8 Study assessments and 
procedures 
Statement describing contingencies for procedures in 
the case of an emergency and referring to appendix 
detailing these contingencies was added as required 
by new template 
Template update. 
8.1 Efficacy assessments 
Updated text with the details of assessment for 
antitumor activity. 
Updated text with more specific reason for ending the 
assessment. 
To reflect the addition of 
secondary efficacy endpoints 
(DOR, PFS, and DCR). 
New section 8.3.9 Overdose, 
medication errors, misuses or 
abuses of medicinal product 
Section defining overdose, medical error, and misuse 
added as per new template. 
To conform to new template 
requirements 
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Section # and Name 
Description of Change 
Brief Rationale 
8.4 Pharmacokinetics 
Clarified that samples collected for analyses of 
tusamitamab ravtansine concentration may also be 
used to evaluate the relationship of exposure to 
additional safety or efficacy parameters or for testing 
analytical method performance 
To identify additional analyses of 
the relationship of 
pharmacokinetic exposure to 
safety and efficacy  
New subheadings 8.6.1 Plasma 
cfDNA and 8.6.2 Tumor DNA 
and RNA analyses 
New subsections added to describe analyses of RNA 
and DNA in plasma and tumor tissue.  
To clarify DNA and RNA 
assessment procedures 
8.8 Immunogenicity 
assessments 
Added brief description of approach to screening for, 
confirming, and further characterizing treatment 
emergent antitherapeutic antibodies (ATA). 
To explain the strategy for ATA 
management. 
8.10 Use of biological samples 
and data for future research 
Section updated as per new template. 
Template update. 
9.1 Statistical hypothesis 
Updated the text with details of safety run-in and 
expansion for Parts A, B, and C. 
To reflect the addition of efficacy 
primary endpoint and dose 
optimization. 
9.2 Sample size determination 
Added Table 7- Estimated objective response rate 
(ORR) and confidence interval depending on number of 
responders. 
To optimize the dose selection of 
tusamitamab ravtansine when 
combined with pembrolizumab with 
or without chemotherapy. 
9.2 Sample size determination 
Updated text to clarify enrollment based on an interim 
analysis of objective responses in Part A and Part C 
dose expansion 
To clarify estimates of participants 
to be enrolled at each DL based on 
an  interim analysis     
9.4.1 General considerations 
Cut-off for analysis of ORR was restricted to Parts A 
and C, for which ORR is now a primary endpoint. A 
statement was added to explain that the ORR cut-off 
could be defined upon completion of enrollment in 
a given DL. 
To reflect the addition of 
participants with a lower dose 
100 mg/m². 
9.4.3.8 Pharmacokinetic 
variables 
Described planned analyses of PK, population PK, and 
PK-PD analyses. 
To reflect the changes in PK 
analyses 
9.5 Interim analyses 
Added detailsbing  interim analyses of objective 
responses in Part A and Part B.  
To clarify that interim analyses are 
planned in expansion Part A and 
Part C to confirm adequate 
responses in 10 participants 
treated at a lower DL before 
enrolling another 10 participants 
at that DL    
10.1 Appendix 1 Regulatory, 
Ethical, and Study Oversight 
considerations  
Regulatory and ethical considerations, data protection, 
Protection of personal data, and Dissemination of 
clinical study data updated as per new template. 
To comply with new protocol 
template requirements 
10.3 Appendix 3 Adverse 
events: definitions and 
procedures for recording, 
evaluating, follow-up, and 
reporting 
Section updated as per new template. 
To comply with new protocol 
template requirements 
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Section # and Name 
Description of Change 
Brief Rationale 
10.5 Appendix 5 Genetics 
Updated text for RNA sample handling and storage. 
To explore potential sets of 
biomarkers besides target 
expression that could be predictive 
of response and explain handling 
and storage of the samples. 
10.8 Appendix 8 Strong CYP3A 
inhibitors  
In Table 14, vardenafil was replaced with midazolam, 
and information on potent CYP3A Inhibitors was added. 
For consistency with updated 
information for known CYP3A4 
inhibitors 
10.11 Appendix 11: Contingency 
measures for a regional or 
national emergency that is 
declared by a governmental 
agency 
Section updated as per new template. 
To comply with new protocol 
template requirements 
Throughout the document 
Correction of typographical errors and standardization 
of wording. 
For clarification 
 
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TABLE OF CONTENTS 
AMENDED CLINICAL TRIAL PROTOCOL 06 .............................................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................... 2 
TABLE OF CONTENTS .................................................................................................................................. 8 
LIST OF TABLES ......................................................................................................................................... 13 
LIST OF FIGURES ........................................................................................................................................ 13 
1 
PROTOCOL SUMMARY ............................................................................................................... 14 
1.1 
SYNOPSIS ..................................................................................................................................... 14 
1.2 
SCHEMA ........................................................................................................................................ 25 
1.3 
SCHEDULE OF ACTIVITIES (SOA) .............................................................................................. 28 
1.3.1 
Study procedures flowchart ........................................................................................................... 28 
1.3.2 
PK/ATA flowchart ........................................................................................................................... 33 
1.3.2.1 
PK/ATA flow chart for Part A .......................................................................................................... 33 
1.3.2.2 
PK/ATA flow chart for Part B .......................................................................................................... 34 
1.3.2.3 
PK/ATA flow chart for Part C ......................................................................................................... 36 
2 
INTRODUCTION ............................................................................................................................ 38 
2.1 
STUDY RATIONALE...................................................................................................................... 38 
2.2 
BACKGROUND ............................................................................................................................. 40 
2.3 
BENEFIT/RISK ASSESSMENT ..................................................................................................... 41 
2.3.1 
Risk assessment ............................................................................................................................ 41 
2.3.2 
Benefit assessment ........................................................................................................................ 43 
2.3.3 
Overall benefit: risk conclusion ...................................................................................................... 43 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................. 44 
3.1 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 45 
4 
STUDY DESIGN ............................................................................................................................ 46 
4.1 
OVERALL DESIGN ........................................................................................................................ 46 
4.1.1 
Safety run-in part: DLT observation period .................................................................................... 46 
4.1.2 
Expansion cohorts (Parts A & C) ................................................................................................... 48 
4.1.3 
Duration of the study ...................................................................................................................... 48 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ......................................................................... 49 
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4.2.1 
Participant input into design ........................................................................................................... 49 
4.3 
JUSTIFICATION FOR DOSE ........................................................................................................ 50 
4.4 
END OF STUDY DEFINITION ....................................................................................................... 51 
5 
STUDY POPULATION .................................................................................................................. 52 
5.1 
INCLUSION CRITERIA .................................................................................................................. 52 
5.2 
EXCLUSION CRITERIA ................................................................................................................ 54 
5.3 
LIFESTYLE CONSIDERATIONS ................................................................................................... 57 
5.4 
SCREEN FAILURES...................................................................................................................... 57 
5.5 
CRITERIA FOR TEMPORARILY DELAYING ENROLLMENT ...................................................... 57 
6 
STUDY INTERVENTION ............................................................................................................... 58 
6.1 
STUDY INTERVENTIONS ADMINISTERED ................................................................................ 58 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY....................................................... 60 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ....................................... 61 
6.4 
STUDY INTERVENTION COMPLIANCE ...................................................................................... 61 
6.5 
CONCOMITANT THERAPY .......................................................................................................... 62 
6.6 
DOSE MODIFICATION .................................................................................................................. 63 
6.6.1 
Determination of recommended doses .......................................................................................... 63 
6.6.2 
Individual dose modification ........................................................................................................... 65 
6.7 
INTERVENTION AFTER THE END OF THE STUDY ................................................................... 67 
6.8 
TREATMENT OF OVERDOSE ...................................................................................................... 67 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................................... 68 
7.1 
DISCONTINUATION OF STUDY INTERVENTION ...................................................................... 68 
7.1.1 
Permanent discontinuation ............................................................................................................ 68 
7.1.2 
Temporary discontinuation ............................................................................................................. 69 
7.1.2.1 
Rechallenge ................................................................................................................................... 69 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY .................................. 70 
7.3 
LOST TO FOLLOW UP ................................................................................................................. 70 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................... 72 
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8.1 
EFFICACY ASSESSMENTS ......................................................................................................... 72 
8.2 
SAFETY ASSESSMENTS ............................................................................................................. 73 
8.2.1 
Physical examinations ................................................................................................................... 73 
8.2.2 
Performance status ........................................................................................................................ 73 
8.2.3 
Specific ocular test ......................................................................................................................... 73 
8.2.4 
Vital signs ....................................................................................................................................... 74 
8.2.5 
Electrocardiogram .......................................................................................................................... 74 
8.2.6 
Clinical safety laboratory assessments .......................................................................................... 74 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ........................................................... 75 
8.3.1 
Time period and frequency for collecting AE and SAE information ............................................... 75 
8.3.2 
Method of detecting Aes and SAEs ............................................................................................... 76 
8.3.3 
Follow-up of Aes and SAEs ........................................................................................................... 76 
8.3.4 
Regulatory reporting requirements for SAEs ................................................................................. 76 
8.3.5 
Pregnancy ...................................................................................................................................... 76 
8.3.6 
Cardiovascular and death events .................................................................................................. 77 
8.3.7 
Disease-related events and/or disease-related outcomes not qualifying as Aes or SAEs ............ 77 
8.3.8 
Adverse event of special interest ................................................................................................... 77 
8.3.9 
Overdose, medication errors, misuses or abuses of medicinal product ........................................ 78 
8.3.10 
Guidelines for reporting product complaints .................................................................................. 78 
8.3.11 
Guidelines for managing specific adverse events ......................................................................... 78 
8.3.11.1 Hypersensitivity reactions .............................................................................................................. 78 
8.3.11.2 Ocular toxicity ................................................................................................................................. 79 
8.3.11.3 Management of anemia ................................................................................................................. 79 
8.3.11.4 Management of neutropenia .......................................................................................................... 80 
8.3.11.5 Liver function tests ......................................................................................................................... 80 
8.3.11.6 Immune-related adverse reactions ................................................................................................ 80 
8.3.11.7 Peripheral neuropathy .................................................................................................................... 81 
8.3.11.8 Colitis (including hemorrhagic) ....................................................................................................... 81 
8.4 
PHARMACOKINETICS .................................................................................................................. 81 
8.5 
PHARMACODYNAMICS ............................................................................................................... 82 
8.6 
GENETICS ..................................................................................................................................... 82 
8.6.1 
Plasma cfDNA ................................................................................................................................ 82 
8.6.2 
Tumor DNA and RNA analyses ..................................................................................................... 82 
8.7 
BIOMARKERS ............................................................................................................................... 83 
8.8 
IMMUNOGENICITY ASSESSMENTS ........................................................................................... 83 
8.9 
HEALTH ECONOMICS .................................................................................................................. 84 
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8.10 
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 
9.3 
POPULATIONS FOR ANALYSES ................................................................................................. 88 
9.4 
STATISTICAL ANALYSES ............................................................................................................ 88 
9.4.1 
General considerations .................................................................................................................. 89 
9.4.2 
Primary endpoint ............................................................................................................................ 89 
9.4.2.1 
Incidence of DLTs at Cycle 1 ......................................................................................................... 90 
9.4.2.2 
Objective response rate (RECIST) ................................................................................................ 90 
9.4.3 
Secondary endpoints ..................................................................................................................... 90 
9.4.3.1 
Duration of response ...................................................................................................................... 90 
9.4.3.2 
Progression-free survival ............................................................................................................... 91 
9.4.3.3 
Disease control rate ....................................................................................................................... 91 
9.4.3.4 
Adverse events .............................................................................................................................. 91 
9.4.3.5 
Deaths ............................................................................................................................................ 92 
9.4.3.6 
Clinical laboratory evaluations ....................................................................................................... 92 
9.4.3.7 
Immunogenicity .............................................................................................................................. 93 
9.4.3.8 
Pharmacokinetic variables ............................................................................................................. 93 
9.4.4 
Other analyses ............................................................................................................................... 93 
9.5 
INTERIM ANALYSES .................................................................................................................... 93 
9.6 
DATA MONITORING COMMITTEE (DMC) OR OTHER REVIEW BOARD ................................. 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 
Informed consent process .............................................................................................................. 95 
10.1.3 
Data protection ............................................................................................................................... 96 
10.1.4 
Committees structure ..................................................................................................................... 98 
10.1.5 
Dissemination of clinical study data and results ............................................................................ 98 
10.1.6 
Data quality assurance .................................................................................................................. 98 
10.1.7 
Source documents ......................................................................................................................... 99 
10.1.8 
Study and site start and closure ..................................................................................................... 99 
10.1.9 
Publication policy ......................................................................................................................... 100 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS ....................................................................... 100 
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10.3 
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING .............................................. 102 
10.3.1 
Definition of AE ............................................................................................................................ 102 
10.3.2 
Definition of SAE .......................................................................................................................... 103 
10.3.3 
Recording and follow-up of AE and/or SAE ................................................................................. 104 
10.3.4 
Reporting of SAEs........................................................................................................................ 106 
10.4 
APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION ............................................................................................................................ 107 
10.5 
APPENDIX 5: GENETICS ........................................................................................................... 110 
10.6 
APPENDIX 6: RECOMMENDED SUPPORTIVE CARE AND/OR DOSE MODIFICATION 
GUIDELINES FOR DRUG-RELATED ADVERSE EVENTS ....................................................... 111 
10.7 
APPENDIX 7: COUNTRY-SPECIFIC/REGION REQUIREMENTS ............................................. 115 
10.8 
APPENDIX 8: STRONG CYP3A INHIBITORS ............................................................................ 116 
10.9 
APPENDIX 9: RESPONSE EVALUATION CRITERIA IN SOLID TUMORS VERSION 1.1 ....... 117 
10.10 
APPENDIX 10: MASCC CORTICOSTEROID DOSING GUIDELINES (2016 GUIDELINES) .... 124 
10.11 
APPENDIX 11: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY ................................. 124 
10.11.1 Remote prescreening process ..................................................................................................... 125 
10.11.2 Screening procedures .................................................................................................................. 126 
10.11.3 Study intervention ........................................................................................................................ 126 
10.11.4 Study procedures ......................................................................................................................... 126 
10.11.5 Statistical analyses and deviation ................................................................................................ 127 
10.11.6 Informed consent process ............................................................................................................ 127 
10.12 
APPENDIX 12: ABBREVIATIONS ............................................................................................... 127 
10.13 
APPENDIX 13: PROTOCOL AMENDMENT HISTORY .............................................................. 129 
11 
REFERENCES ............................................................................................................................. 147 
 
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LIST OF TABLES  
Table 1 - Objectives and endpoints ............................................................................................................... 44 
Table 2 - Overview of study interventions administered ............................................................................... 58 
Table 3 - Definition of dose-limiting toxicity ................................................................................................... 63 
Table 4 - Dose levels (safety run-in part) ...................................................................................................... 65 
Table 5 - Individual tusamitamab ravtansine dose reduction ........................................................................ 66 
Table 6 - Individual cisplatin/carboplatin and pemetrexed dose reduction ................................................... 67 
Table 7 - 
.................................................................................................................................................... 88 
Table 8 - Populations for analyses ................................................................................................................ 88 
Table 9 - Protocol-required laboratory assessments .................................................................................. 101 
Table 10 - Recommended dose modification or discontinuation for tusamitamab ravtansine.................... 111 
Table 11 - Recommended dose modification or discontinuation for pembrolizumab ................................. 114 
Table 12 - Recommended dose modification for cisplatin/carboplatin and pemetrexed hematological 
toxicity .......................................................................................................................................................... 115 
Table 13 - Recommended dose modification for cisplatin/carboplatin and pemetrexed nonhematological 
toxicity .......................................................................................................................................................... 115 
Table 14 - List of strong CYP3A inhibitors .................................................................................................. 116 
Table 15 - Response criteria ....................................................................................................................... 120 
Table 16 - Response in patients with target disease .................................................................................. 122 
Table 17 - Response in patients with non-target disease only.................................................................... 123 
Table 18 - Recommended corticosteroid (dexamethasone) dosing ........................................................... 124 
 
LIST OF FIGURES  
Figure 1 - Decision tree for tusamitamab ravtansine dose in Part A, Part B, and Part C ............................. 18 
Figure 2 - Graphical study design for Part A ................................................................................................. 25 
Figure 3 - Graphical study design for Part B (Safety run-in only) ................................................................. 26 
Figure 4 - Graphical study design for Part C ................................................................................................. 27 
 
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1 
PROTOCOL SUMMARY  
1.1 
SYNOPSIS  
Protocol title: Open-label, Phase 2 study of tusamitamab ravtansine (SAR408701) combined 
with pembrolizumab and tusamitamab ravtansine (SAR408701) combined with 
pembrolizumab and platinum-based chemotherapy with or without pemetrexed in 
patients with CEACAM5-positive expression advanced/metastatic nonsquamous 
non-small-cell lung cancer (NSQ NSCLC)  
Short title: 
Tusamitamab ravtansine (SAR408701) in combination with pembrolizumab and 
tusamitamab ravtansine (SAR408701) in combination with pembrolizumab and 
platinum-based chemotherapy with or without pemetrexed in patients with NSQ 
NSCLC (CARMEN-LC05) 
Rationale: 
Most patients with NSCLC present with an advanced cancer stage at the time of diagnosis. 
Despite recent progress in the treatment of advanced/metastatic NSCLC, there remains a need for 
effective new treatment at the time of disease progression.  
Tusamitamab ravtansine is an antibody conjugate to the cytotoxic maytansinoid agent DM4. In 
an ongoing Phase 1 study (TED13751), tusamitamab ravtansine has demonstrated meaningful 
preliminary antitumor activity in patients heavily pretreated for NSQ NSCLC with high 
CEACAM5 expression. 
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 combination with platinum-based 
chemotherapy with no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase 
(ALK) genomic tumor aberrations, and in Stage III when patients are not candidates for surgical 
resection or definitive chemoradiation, or metastatic (1). 
The combination of tusamitamab ravtansine with an immune-checkpoint inhibitor (ICI) or the 
standard of care should improve outcome with a better tolerability for doublet or triplet 
combinations, and without additional toxicity for quadruplet combination as no overlap is 
expected.  
Encouraging preliminary efficacy data of ongoing ACT16146 study have been observed in the 
first 25 patients treated in the study. The results observed in TED13751 where tusamitamab 
ravtansine was administered as monotherapy at 100 mg/m² Q2W in patients with CEACAM5 
expression ≥1% and these preliminary efficacy data from Part A where tusamitamab ravtansine is 
administered in combination with pembrolizumab in patients with CEACAM5 expression 
≥50% support a decrease in threshold of CEACAM5 expression from 50% to 1%. 
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The objective of this study is to evaluate the safety and antitumor activity (efficacy) of 
tusamitamab ravtansine in combination with pembrolizumab and tusamitamab ravtansine in 
combination with pembrolizumab and platinum-based chemotherapy (Investigator’s choice of 
cisplatin or carboplatin) and tusamitamab ravtansine in combination with the standard of care for 
first-line treatment, pembrolizumab, platinum-based chemotherapy, and pemetrexed in NSQ 
NSCLC participants with CEACAM5 high or moderate expression in tumors (high expression is 
defined as CEACAM5 immunohistochemistry [IHC] intensity ≥2+ in ≥50% of tumor cells and 
moderate expression is defined as intensity ≥2+ in ≥1% and <50% of tumor cells). 
Objectives and endpoints 
Objectives 
Endpoints 
Primary 
• 
Safety run-in part: to assess the tolerability and to 
determine the recommended doses of tusamitamab 
ravtansine in combination with pembrolizumab and 
tusamitamab ravtansine in combination with 
pembrolizumab and platinum-based chemotherapy 
with or without pemetrexed to be tested in the 
expansion part of the study in the NSQ NSCLC 
population 
• 
Incidence of study drug-related dose-limiting toxicity 
(DLTs) at Cycle 1 (C1D1 to C1D21), including but 
not limited to corneal toxicity 
• 
Expansion part (including participants treated at the 
recommended dose for expansion [RDE] from the 
Safety Run-in part): to assess the antitumor activity 
of several dose levels (DLs; if applicable) of 
tusamitamab ravtansine in combination with 
pembrolizumab and of several DLs of tusamitamab 
ravtansine in combination with pembrolizumab, 
platinum-based chemotherapy, and pemetrexed in 
the NSQ NSCLC population  
• 
Objective response rate defined as proportion of 
participants who have a confirmed complete 
response (CR) or partial response (PR) as best 
overall response per Response Evaluation Criteria 
in Solid Tumors (RECIST) v1.1 (2) 
Secondary 
• 
To assess the safety and tolerability of several DLs 
(if applicable) of tusamitamab ravtansine in 
combination with pembrolizumab and of 1 DL of 
tusamitamab ravtansine in combination with 
pembrolizumab and platinum-based chemotherapy, 
and of several DLs of tusamitamab ravtansine in 
combination with pembrolizumab and platinum-
based chemotherapy with pemetrexed in the 
NSQ NSCLC population  
• 
Incidence of treatment-emergent adverse events 
(TEAEs), serious adverse events (SAEs), and 
laboratory abnormalities according to the National 
Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE) V5.0 
• 
To assess the antitumor activity of several DLs (if 
applicable) of tusamitamab ravtansine in 
combination with pembrolizumab and of 1 DL of 
tusamitamab ravtansine in combination with 
pembrolizumab and platinum-based chemotherapy, 
and of several DLs of tusamitamab ravtansine in 
combination with pembrolizumab, platinum-based 
chemotherapy, and pemetrexed in the NSQ NSCLC 
population 
• 
Progression-free survival (PFS), 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 (not for Part B). 
• 
Disease control rate (DCR), defined as the 
percentage of participants who have achieved 
confirmed CR, confirmed PR, or stable disease 
(SD) as best overall response (BOR) per 
RECIST v1.1 
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Objectives 
Endpoints 
• 
To assess the durability of the response to 
treatment with several DLs (if applicable) of 
tusamitamab ravtansine in combination with 
pembrolizumab and of 1 DL of tusamitamab 
ravtansine in combination with pembrolizumab and 
platinum-based chemotherapy, and of several DLs 
of tusamitamab ravtansine in combination with 
pembrolizumab, platinum-based chemotherapy, and 
pemetrexed in the NSQ NSCLC population 
• 
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 the antitumor activity of tusamitamab 
ravtansine in combination with pembrolizumab and 
platinum-based chemotherapy in the NSQ NSCLC 
population 
• 
Objective response rate, defined as proportion of 
participants who have a confirmed CR or PR as per 
BOR per RECIST v1.1 (2) 
• 
To assess the pharmacokinetics (PK) of 
tusamitamab ravtansine, pembrolizumab, 
pemetrexed, cisplatin, and carboplatin, each when 
given in combination as a doublet (tusamitamab 
ravtansine + pembrolizumab) or a triplet 
(tusamitamab ravtansine + pembrolizumab + 
platinum-based chemotherapy) or a quadruplet 
(tusamitamab ravtansine + pembrolizumab + 
platinum-based chemotherapy + pemetrexed) 
• 
Pharmacokinetic concentrations of tusamitamab 
ravtansine (SAR408701, DM4, Me-DM4), 
pembrolizumab, pemetrexed, cisplatin, and 
carboplatin. 
• 
To assess the immunogenicity of tusamitamab 
ravtansine in combination with pembrolizumab and 
tusamitamab ravtansine in combination with 
pembrolizumab and platinum-based chemotherapy 
with or without pemetrexed 
• 
Incidence of antitherapeutic antibodies (ATAs) 
against tusamitamab ravtansine 
Overall design: 
This is a Phase 2, open-label, multicenter study.  
CEACAM5 expression will be assessed by IHC during the prescreening phase and participants 
with NSQ NSCL CEACAM5 high expression (≥50%) or moderate expression (≥1% and <50%) 
tumors will go through protocol screening procedures. They will be enrolled in Part A, Part B or 
Part C per Investigator’s choice. 
SAFETY RUN-IN 
PART A:  
The tolerability and safety of the tusamitamab ravtansine and pembrolizumab combination will be 
assessed.  
The first 3 participants will receive, Q3W, a 200 mg pembrolizumab infusion followed by 
a tusamitamab ravtansine infusion at the starting dose of 150 mg/m².  
The tolerability of the doublet combination will be assessed in approximately 6 to 18 participants 
to determine the recommended dose for expansion (RDE). 
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PART B: 
The tolerability and safety of the pembrolizumab, tusamitamab ravtansine, and platinum-based 
chemotherapy combinations will be assessed. Participants can be assigned to either cisplatin or 
carboplatin, per Investigator choice.  
Participants will receive Q3W pembrolizumab 200 mg + tusamitamab ravtansine (150 mg/m², 
170 mg/m², or 120 mg/m²) + cisplatin 75 mg/m² or carboplatin AUC 5, all on Day 1 for the 
first 4 cycles, followed by Q3W pembrolizumab 200 mg + tusamitamab ravtansine (150 mg/m², 
170 mg/m², or 120 mg/m²) on Day 1 of subsequent cycles. 
The tolerability of each triplet platinum combination will be assessed in approximately 6 to 
18 participants to determine the RDE in each triplet platinum combination arm (carboplatin or 
cisplatin).  
If the quadruplet combination investigated in Part C has an acceptable toxicity profile, and as the 
triplet combination was explored in Part B only in case the quadruplet would not be well 
tolerated, enrollment in Part B will be stopped as soon as the Safety Run-In for Part C ends. 
PART C: 
The tolerability and safety of the tusamitamab ravtansine, pembrolizumab, platinum-based 
chemotherapy, and pemetrexed combinations will be assessed. Participants can be assigned to 
either cisplatin or carboplatin, per Investigator choice.  
Participants will receive Q3W pembrolizumab 200 mg + tusamitamab ravtansine (150 mg/m², 
170 mg/m², or 120 mg/m²) + pemetrexed 500 mg/m² (with vitamin supplementation) + cisplatin 
75 mg/m² or carboplatin AUC 5, all on Day 1 for the first 4 cycles, followed by Q3W 
pembrolizumab 200 mg + tusamitamab ravtansine (150 mg/m², 170 mg/m², or 120 mg/m²) + 
pemetrexed 500 mg/m2 (with vitamin supplementation) on Day 1 of subsequent cycles. 
The tolerability of each quadruplet platinum combination (ie, tusamitamab ravtansine, 
pembrolizumab, pemetrexed, and either cisplatin or carboplatin) will be assessed in approximately 
6 to 18 participants to determine the RDE.  
Dose-limiting toxicity observation period:   
The DLT observation period is the first cycle (21 days). Depending on the DLTs observed, up to 
3 dose levels (DLs) of tusamitamab ravtansine can be tested: 150 mg/m², 170 mg/m², and 
120 mg/m².  
For each DL of the combination arm (starting dose, DL plus 1 [DL +1], and DL minus 1 [DL -1] 
if applicable), a minimum of 1 week is mandatory between the first dose of the first participant 
treated at this DL and the first dose of the next participant treated at the same DL. Once 
3 participants have been treated at this DL and are DLT-evaluable, the tolerability of the 
combination is assessed according to the following algorithm as illustrated in Figure 1. 
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Figure 1 - Decision tree for tusamitamab ravtansine dose in Part A, Part B, and Part C  
 
DL: dose level; DLT: dose-limiting toxicity; RDE: recommended dose for expansion 
Note: In case of 2 or more DLTs at DL -1, the study part may be stopped or the dosage reconsidered. 
The RDE dose is based on DLTs as well as the totality of the data, including overall safety, efficacy, and PK-PD modeling. 
EXPANSION (PARTS A & C) 
The Expansion Phase will determine the recommended dose for Phase 3 studies for Parts A and C 
based on safety, efficacy, and PK-PD modeling of at least 2 DLs of tusamitamab ravtansine, as 
detailed below.  
• In Part A, at least 20 participants will be treated at the RDE (150 mg/m2 and at least 
20 participants will be treated at a lower DL (100 mg/m2). An optional 10 participants may 
be treated at an additional DL after these cohorts are completed.  
- 
If fewer than 3 of 10 participants at 100 mg/m2 have a confirmed objective response, 
early stopping rules will be applied, such that enrollment at this DL will be stopped, 
and at least 20 participants will then be treated at an intermediate DL (120 mg/m2). If 
the 100 mg/m2 DL is not stopped early, enrollment will continue at this DL to treat at 
least 20 participants. 
• In Part C, at least 20 participants will be treated at the RDE (150 mg/m2) and at least 
20 participants will be treated at a lower DL (100 mg/m2). An optional 10 participants may 
be treated at an additional DL after these cohorts are completed.  
If fewer than 4 of 10 participants at 100 mg/m2 have a confirmed objective response, early 
stopping rules will be applied, such that enrollment at this DL will be stopped, and at least 
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20 participants will then be treated at an intermediate DL (120 mg/m2). If the 100 mg/m2 
DL is not stopped early, enrollment will continue at this DL to treat at least 
20 participants. 
• Enrollment of a participant into Part C or A will be based on the Investigator’s choice. 
For each part, expansion cohorts will be opened for enrollment after completion of the Safety 
Run-in for the considered part. Opening of each cohort and enrollment of participants in each 
cohort will be defined by the Sponsor based on discussions with the Study Committee. 
Disclosure Statement: This is a parallel group treatment with 5 arms and no masking. 
Number of participants: 
In Part A, the actual sample size could vary depending on DLTs observed. It is anticipated that 
6 to 62 participants will be treated with tusamitamab ravtansine + pembrolizumab: up to 12 DLT-
evaluable participants at a DL other than RDE in the safety run-in; at least 20 participants at the 
RDE (including 6 participants at the RDE from the safety run-in); 20 to 30 participants at lower 
DL(s), and optional 10 patients at an additional DL. 
In Part B, the actual sample size could vary depending on DLTs observed. It is anticipated that in 
each triplet combination arm, 6 to 18 participants will be treated with tusamitamab ravtansine + 
pembrolizumab + cisplatin or carboplatin: up to 12 DLT-evaluable participants in each triplet 
combination arm treated at a DL other than the RDE, and 6 DLT-evaluable participants in each 
triplet combination arm treated at the RDE.  
In Part C, the actual sample size could vary depending on DLTs observed. It is anticipated that 
overall, 12 to 74 participants will be treated with tusamitamab ravtansine + pembrolizumab + 
pemetrexed + cisplatin or carboplatin: up to 12 DLT-evaluable participants in each quadruplet 
combination arm treated at a DL other than the RDE; at least 20 participants at the RDE 
(including participants at the RDE from the safety run-in); at least 20 participants at the RDE 
(including 6 participants at the RDE from the safety run-in); 20 to 30 participants at lower DL(s), and 
optional 10 patients at an additional DL. 
Study periods and duration: 
The duration of the study for a participant, irrespective of the study part, will include: 
• Screening period: up to 28 days.  
• Treatment period: once successfully screened, enrolled participants may receive study 
intervention 4 cycles of cisplatin or carboplatin (Part B and C), and pemetrexed (Part C), and 
tusamitamab ravtansine and pembrolizumab until confirmed disease progression, 
unacceptable toxicity, new anticancer therapy initiation, death, or the participant’s or 
investigator’s decision to stop the treatment. Each cycle of treatment will last for 3 weeks. 
After discontinuing study intervention, participants will return to the study site approximately 
30 days (±5 days) after the last IMP administration or before the participant receives another 
anticancer therapy, whichever is earlier, for end of treatment (EOT) assessments. 
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• Safety follow-up visit: will be performed 90 days (±7 days) after the last IMP 
administration.  
• Tumor assessments will be performed at baseline, every 6 weeks for the first 24 weeks 
from C1D1, then every 9 weeks until radiological disease progression, death, the data cut-
off date for the secondary endpoints, initiation of further anticancer therapy, or withdrawal 
of participant’s consent, whichever comes first. Participants who stopped treatment before 
documented progressive disease (PD) should also undergo tumor assessments. 
The cut-off date for each interim analysis on the primary endpoint (ORR) in Part A and Part C 
corresponds to the date on which the first 10 participants treated at the lower DL (100 mg/m2) 
have had at least 2 postbaseline tumor assessments, experienced confirmed objective response, or 
have discontinued the study for any reason.  
The study cut-off for the primary endpoint (ORR) corresponds to the date on which all-treated 
participants have had at least 2 postbaseline tumor assessments, experienced confirmed objective 
response, or have discontinued the study for any reason. This study cut-off will occur by part 
(Parts A & C) unless the respective cut-off dates are close together, and will be approximately 
4.5 months (3 months for 2 tumor assessments, and 1.5 months if a confirmation of response is 
needed) after the date of the first IMP administration of the last participant in each part.  
The cut-off for the secondary endpoints including DOR and PFS will be approximately 6 months 
after the cut-off date for the primary endpoint. 
After the study cut-off date for the secondary endpoints, participants with observed clinical 
benefit who are still receiving study treatment can continue study treatment until confirmed 
progressive disease, unacceptable toxicity, new anticancer therapy initiation, death, or the 
participant’s or Investigator’s decision to stop the treatment, and will continue to undergo all 
assessments as per the study flow chart.  
Study interventions 
Investigational medicinal products 
Study interventions include pembrolizumab, tusamitamab ravtansine, cisplatin, carboplatin and 
pemetrexed. 
Pembrolizumab 
Pembrolizumab will be administered prior to administration of 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. 
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Tusamitamab ravtansine (SAR408701) 
Tusamitamab ravtansine infusion will start after the end of pembrolizumab 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:  
- 
Tusamitamab ravtansine 150 mg/m2 (or 170 mg/m2, or 120 mg/m², depending on the 
safety run-in DLTs and the Study Committee decision) or a lower dose (100 mg/m2 or 
other, if applicable) will be administered via IV infusion over 1 hour 30 minutes on 
Day 1, and then Q3W. To prevent hypersensitivity reactions, premedication will be 
given before each administration (see below).  
- 
For participants with a body surface area (BSA) >2.20 m², the dose will be calculated 
based on a BSA of 2.20 m². 
Pemetrexed 
• Formulation: Refer to labeling for formulation of pemetrexed for injection. 
• Route of administration: IV infusion.  
• Dose regimen: Pemetrexed 500 mg/m2 should be infused over 10 minutes after 
tusamitamab ravtansine infusion on Day 1 and then Q3W. All subjects should receive the 
appropriate supplementation of vitamin B12 and folic acid and corticosteroid prophylaxis.  
Cisplatin 
• Formulation: Refer to labeling for formulation of cisplatin for injection. 
• Route of administration: IV infusion.  
• Dose regimen: Cisplatin 75 mg/m² should be infused approximately 30 minutes after 
tusamitamab ravtansine (Part B) or pemetrexed (Part C) infusion on Day 1 and then Q3W 
for the first 4 cycles. Infusion of cisplatin should be immediately preceded and followed 
by hydration procedures and should be administered according to local practice and labels. 
Carboplatin 
• Formulation: Refer to labeling for formulation of carboplatin for injection. 
• Route of administration: IV infusion. 
• Dose regimen: Carboplatin AUC 5 mg/mL/min will be administered as an IV infusion 
over 15 to 60 minutes as per local practice and labels immediately after tusamitamab 
ravtansine (Part B) or pemetrexed (Part C) infusion on Day 1 and Q3W for the 
first 4 cycles. The carboplatin dose should not exceed 750 mg, and should be calculated 
using the Calvert formula and CrCl should be calculated by Cockcroft-Gault equation. 
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Non-investigational medicinal products: 
Premedication for tusamitamab ravtansine: 
Premedication with Histamine H1 antagonist (oral diphenhydramine 50 mg or equivalent 
[eg, dexchlorpheniramine] given approximately 15 minutes to 1 hour before tusamitamab 
ravtansine administration depending on the administration form IV or oral [15 minutes prior for 
IV and 1 hour prior for oral) is required for all participants before administration of tusamitamab 
ravtansine. If a participant has experienced an infusion reaction in a previous tusamitamab 
ravtansine administration, premedication will also include dexamethasone 10 mg IV for future 
infusions. In case participant does not experience any hypersensitivity reactions after 4 cycles, the 
premedication can be discontinued at the discretion of the investigator. 
Duration of study intervention 
The expected duration of study intervention for participants may vary, based on disease 
progression date; median expected duration of study per participant is estimated at 10 months 
(up to 1 month for screening, a median of 6 months for treatment, a median of 1 month for EOT, 
and follow-up visit 90 days after the last IMP administration). 
Statistical considerations 
Sample size calculations: 
• Part A: 
Assuming a prescreening failure rate of 80% (as per the initial protocol) and a study 
screening failure rate of 20%, approximately 38 to 388 participants would be prescreened 
to achieve 6 to approximately 62 participants (up to 12 DLT-evaluable participants at 
a DL other than the RDE in the Safety Run-In, at least 20 participants treated with the 
RDE [including participants at the RDE from the Safety Run-In], and a total of 20 to 
30 participants treated at a lower DL (100 mg/m2) or at an intermediate DL (120 mg/m2). 
Assuming a prescreening failure rate of 45%, the number of participants could 
significantly be decreased (approximately 141 participants need to be prescreened to 
achieve 62 participants). 
• Part B: 
Assuming a prescreening failure rate of 80% (as per the initial protocol), and a study 
screening failure rate of 20%, approximately 75 to 225 participants would be prescreened 
to achieve 12 to 36 DLT-evaluable participants in Part B. Assuming a prescreening failure 
rate of 45%, the number of participants to be prescreened could significantly be decreased 
(approximately 82 participants need to be prescreened to achieve 36 participants).  
• Part C: 
Assuming a prescreening failure rate of 45% and a study screening failure rate of 20%, 
approximately 28 to 169 participants will be prescreened to achieve 12 to approximately 
74 participants in Part C (up to 12 DLT-evaluable participants in each quadruplet 
combination arm treated at DL other than the RDE); overall regardless of the quadruplet 
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platinum combination arm, at least 20 participants treated with the RDE [including 
participants at the RDE from the Safety Run-In], and a total of 20 to 30 participants 
treated at a lower DL (100 mg/m2) or at an intermediate DL (120 mg/m2). 
Main analysis populations: 
• All-treated population:  
All participants assigned to study intervention and who have actually received at least 
1 dose of study intervention. 
• DLT-evaluable population: 
Participants who received 1 cycle with at least 80% of the intended dose for each IMP of 
the combination during the safety run-in of Part A, Part B or Part C. Participants should 
have completed Cycle 1 unless they experienced a DLT before the end of Cycle 1. 
• PK population:  
All treated participants with at least 1 available concentration result postbaseline 
(whichever the cycle and even if dosing is incomplete) with adequate documentation of 
date and time of dosing and date and time of sampling. 
• ATA population:  
All treated participants with at least 1 ATA result (negative, positive, or inconclusive) 
postbaseline.  
Analysis of primary endpoint: 
• The DLTs observed during the DLT observation period (Cycle 1) will be summarized on 
the DLT-evaluable population, by DL. 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. 
• Objective response rate (ORR) will be summarized on the all-treated population by part, 
DL and overall using descriptive statistics and 95% exact confidence intervals (CIs) will 
be provided using the Clopper-Pearson method.  
Analysis of secondary efficacy endpoint: 
The secondary endpoints will be summarized by part, DL and overall. 
• ORR (Part B) will be analyzed similarly as for Parts A & C. 
• 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.  
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• 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 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 premature discontinuation, 
TEAEs leading to permanent discontinuation, 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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1.2 
SCHEMA  
Figure 2 - Graphical study design for Part A  
 
 
 
C: cycle; D: study day; CEACAM5: carcinoembryonic antigen-related cell adhesion molecule 5; DL: dose level; EOT: end of treatment; ICF: informed consent form; IMP: investigational medicinal product; 
NSQ NSCLC: nonsquamous non-small-cell lung cancer; RDE: recommend dose for expansion. 
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Figure 3 - Graphical study design for Part B (Safety run-in only)  
 
C: cycle; CEACAM5: carcinoembryonic antigen-related cell adhesion molecule 5; D: study day; EOT: end of treatment; ICF: informed consent form; IMP: investigational medicinal product; NSQ NSCLC: nonsquamous, 
non-small-cell lung cancer  
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Figure 4 - Graphical study design for Part C  
 
 
C: cycle; CEACAM5: carcinoembryonic antigen-related cell adhesion molecule 5; D: study day; EOT: end of treatment; ICF: informed consent form; IMP: investigational medicinal product; NSQ NSCLC: nonsquamous, 
non-small-cell lung cancer; RDE: recommended dose for expansion.  
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1.3 
SCHEDULE OF ACTIVITIES (SOA)  
1.3.1 Study procedures flowchart  
 
Procedure 
Pre- 
screeninga 
Screeningb 
Treatment 
Cycle 1 
Treatment Cycle 2 
and subsequent 
End of 
treatment 
Follow-up 
visite 
 
Notes 
Day 
 
Days prior 
to initial 
infusion 
D1 Pre-
infusionc 
D1 Pre-
infusionc 
(±3 days) 
Every 
6 weeks 
(±7 days)  
D30 after 
last 
infusion 
(±5 days) 
90 days 
(±7 days) 
 
CEACAM5 expression statusa 
(archival or fresh tumor tissue) 
assessed by central IHC after 
prescreening informed consent. 
X 
 
 
 
 
 
 
 
PD-L1 expressiona 
(local assessment) 
X 
 
 
 
 
 
 
 
Informed consent 
 
Xb 
 
 
 
 
 
 
IRT contact 
X 
X 
X 
X 
 
X 
X 
 
Inclusion/exclusion criteria 
 
≤28 
X 
 
 
 
 
 
Age 
X 
 
 
 
 
 
 
 
Demography and 
medical/surgical/disease 
history/smoking history 
 
≤28 
 
 
 
 
 
 
NSCLC characteristics 
 
≤28 
 
 
 
 
 
Includes histologic types, stage at 
diagnosis, disease extent at study 
entry 
Height 
 
≤7 
 
 
 
 
 
 
ECOG, Body Weight 
 
≤7 
X 
X 
 
X 
 
 
Physical examinationf, signs and 
symptoms 
 
≤7 
X 
X 
 
X 
X 
 
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Procedure 
Pre- 
screeninga 
Screeningb 
Treatment 
Cycle 1 
Treatment Cycle 2 
and subsequent 
End of 
treatment 
Follow-up 
visite 
 
Notes 
Day 
 
Days prior 
to initial 
infusion 
D1 Pre-
infusionc 
D1 Pre-
infusionc 
(±3 days) 
Every 
6 weeks 
(±7 days)  
D30 after 
last 
infusion 
(±5 days) 
90 days 
(±7 days) 
 
Hematologyg 
 
≤7 
X (+weekly 
in C1) 
X (+weekly in 
C2) 
 
X 
 
 
Coagulation (INR) 
 
≤7 
X 
X 
 
X 
 
 
Blood chemistry: liver function testsh 
 
≤7 
X (+weekly 
in C1) 
X (+weekly in 
C2) 
 
X 
 
 
Blood chemistry: other testsh 
 
≤7 
X 
X 
 
X 
 
 
Thyroid function 
 
≤7 
 
X 
 
X 
 
 
HBsAg & HCV serology; 
HIV test (only if required at country 
level)  
 
X 
 
 
 
 
 
 
WOCBP: Urine or Serum pregnancy 
testi 
 
≤7 
 
X 
 
X 
 
Mandatory serum test at 
screening and EOT, serum or 
urine test during study treatment 
period.  
12-lead ECG 
 
≤7 
 
X 
 
X 
 
 
Specific ocular testsj 
 
≤28 
 
 
 
X 
 
 
Assessment of ocular/visual 
symptoms 
 
 
X 
X 
 
 
 
On the same day or within 2 days 
before each study intervention 
IMP administrationd 
 
 
X 
X 
 
 
 
 
AE assessment 
Xk 
X 
Continuously throughout the study period 
 
Concomitant medication 
 
X 
Continuously throughout the study period 
 
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Procedure 
Pre- 
screeninga 
Screeningb 
Treatment 
Cycle 1 
Treatment Cycle 2 
and subsequent 
End of 
treatment 
Follow-up 
visite 
 
Notes 
Day 
 
Days prior 
to initial 
infusion 
D1 Pre-
infusionc 
D1 Pre-
infusionc 
(±3 days) 
Every 
6 weeks 
(±7 days)  
D30 after 
last 
infusion 
(±5 days) 
90 days 
(±7 days) 
 
Tumor assessment - RECIST v1.1 - 
CT/MRI and surrogate markers when 
relevant (see Section 10.9 for 
details) 
 
≤28 
 
 
X 
X 
 
Baseline; every 6 weeks for the 
first 24 weeks; then every 
9 weekse 
Circulating CEAn 
X 
≤28 
 
 
X 
X 
 
 
FFPE sections for RNA and DNA 
analysis  
(archival or fresh tumor tissue)o 
 
X 
Xp 
 
 
 
 
 
Plasma for tumor cfDNA and whole 
blood for germline DNA 
 
 
X 
 
 
 
 
Additionally, plasma for tumor 
cfDNA isolation will be collected 
at pre-infusion of Cycle 5 Day 1. 
If the participant discontinues the 
treatment before Cycle 5, the 
sample can be taken at the end 
of treatment 
Optional: whole blood for circulating 
tumoral cells (CTC)l 
 
 
X 
 
 
 
 
 
IgGm 
 
 
X 
 
 
 
 
 
Further anticancer therapy 
 
 
 
 
 
 
X 
 
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Procedure 
Pre- 
screeninga 
Screeningb 
Treatment 
Cycle 1 
Treatment Cycle 2 
and subsequent 
End of 
treatment 
Follow-up 
visite 
 
Notes 
Day 
 
Days prior 
to initial 
infusion 
D1 Pre-
infusionc 
D1 Pre-
infusionc 
(±3 days) 
Every 
6 weeks 
(±7 days)  
D30 after 
last 
infusion 
(±5 days) 
90 days 
(±7 days) 
 
Tusamitamab ravtansine, 
pembrolizumab PK (Part A); 
tusamitamab ravtansine, 
pembrolizumab, carboplatin or 
cisplatin PK (Part B); tusamitamab 
ravtansine, pembrolizumab, 
pemetrexed, carboplatin or cisplatin 
PK (Part C) 
 
 
See PK/ATA Flowchart in Section 1.3.2 
 
 
 
Tusamitamab ravtansine 
Immunogenicity 
 
 
See PK/ATA Flowchart in Section 1.3.2 
 
 
a Prescreening: a prescreening informed consent will be signed by the patient before CEACAM5 assay on archival or fresh tumor tissue. Patients who have additional tumor tissue samples available during the 
prescreening phase may be re-assessed for CEACAM5 expression level and the most recent tissue sample assessed for CEACAM5 expression will be used to determine eligibility of patients for screening. 
Participants will require local or central assessment of tumor PD-L1 expression. Circulating CEA will be performed locally if possible. 
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. Routine baseline tests performed prior to ICF signature do not need to be repeated as long as they are within the screening defined timeframe. 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-positive 
expression as assessed centrally. Baseline evaluation should be completed within 1 week prior to initiation of therapy, except for tumor assessment, circulating CEA, and ocular tests that may be performed within 
4 weeks prior to the first IMP administration. Results of these tests should be reviewed by the Investigator prior to initiation of therapy. 
c D1 predose: 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 and coagulation tests may be omitted if baseline test performed within 7 days are normal. If baseline tests 
are abnormal, they should be repeated within 2 days of first study intervention. 
d Treatment: participants should receive study intervention until confirmed disease progression, unacceptable toxicity, new anticancer therapy initiation, death, or the participant’s or investigator’s decision to stop 
the treatment. 
e Follow-up visit: at the follow-up visit, SAEs/AESIs (regardless of relationship with study treatment) and IMP-related AEs ongoing at the end of study treatment, and any new IMP-related AE/SAE/AESI will be 
followed until resolution or stabilization (stabilization is defined as an event ongoing without any change for at least 3 months). Date of disease progression (PD) and further anticancer treatment will be collected at 
the follow-up visit. Tumor assessments are performed at baseline, every 6 weeks for the first 24 weeks from C1D1, and thereafter every 9 weeks until radiological disease progression, death, study cut-off date of 
the secondary endpoints, initiation of further anticancer therapy, or withdrawal of participant’s consent, whichever comes first. A participant who stops treatment before documented progressive disease should 
undergo tumor assessments as for those who continued treatment up to PD.    
f 
Physical examination will include: vital signs (temperature, blood pressure, pulse rate) and examination of major body systems including cardiovascular, central nervous system, respiratory system, 
hepatomegaly, splenomegaly, lymphadenopathy. Signs and symptoms will be reported in the eCRF as AEs only if they are still present at the time of first IMP administration. 
g Hematology: Hemoglobin, hematocrit, WBC with differential, platelet counts. If Grade 4 neutropenia, assess ANC every 2-3 days until ANC ≥0.5 x 109/L. 
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h 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, phosphate, 
chloride, Others: Glucose, LDH, albumin and total proteins. The liver function tests and renal function tests will be done before IMP administration at each cycle. In case of Grade ≥3 liver function abnormal tests, 
additional tests will be repeated every 2-3 days until recovery to baseline value.  
i 
Serum pregnancy test: WOCBP must have a negative serum pregnancy test result within 7 days prior to the initial dose of IMP. A pregnancy test (urine or serum as required by local regulations) will be repeated 
every 3 weeks before each IMP administration and at the end of treatment evaluation. 
j 
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, EOT and whenever clinically 
indicated. 
k AEs/SAEs during the prescreening period: only AEs/SAEs related to the fresh biopsy procedure (if applicable) and occurring within 1 month after the fresh biopsy will be recorded in the eCRF. 
l 
A sample for CTC analysis will be taken in a maximum of 10 participants during the course of the study. 
m Sampling for IgG may be stopped during the course of the study, upon notification from the Sponsor 
n For CEA sample collection scheduled on the day of a treatment visit, samples should be drawn prior to initiation of any IMP infusion 
o At least 3  10 μm slides (best) or 6  3–5 μm slides (or equivalent to the same total amount of material) from FFPE tissue (from same sample as the one used for CEACAM5 expression status if possible) is 
requested at screening or C1D1, if enough material is available. An additional 5 µm section is requested for hematoxyline-eosine staining. 
p  If FFPE sections for RNA and DNA analysis not performed at Screening, then back-up could be at C1D1. 
AE: adverse event; AESI: adverse event of special interest; ALT: alanine aminotransferase; ANC: absolute neutrophil count; AP: alkaline phosphatase; AST: aspartate aminotransferase; ATA: antitherapeutic antibody; 
BUN: blood urea nitrogen; C: Cycle; CEA: carcinoembryonic antigen; CEACAM5: carcinoembryonic antigen-related cell adhesion molecule 5; cfDNA: circulating free deoxyribonucleic acid; CT: computed tomography; 
D: Day; DNA: deoxyribonucleic acid; ECG: electrocardiogram; eCRF: electronic caser report form; EOT: end of treatment; FFPE: formalin-fixed, paraffin embedded; HBsAg: hepatitis B surface antigen; HCV: hepatitis 
C virus; HIV: human immunodeficiency virus; IHC: immunohistochemistry; IMP: investigational medicinal product; INR: international normalized ratio; IRT: interactive response technology; LDH: lactate 
dehydrogenase; MRI: magnetic resonance imaging; NSCLC: non-small-cell lung cancer; PD-1: programmed cell death protein 1; PD-L1: programmed death-ligand 1; PK: pharmacokinetic; PS: performance status; 
RECIST: response evaluation criteria in solid tumors; SAE: serious adverse event; SGOT: serum glutamic-oxaloacetic transaminase; SGPT: serum glutamic-pyruvic transaminase; TA: tumor assessment; VS: vital 
signs; WBC: white blood cell; WOCBP: woman of childbearing potential. 
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1.3.2 PK/ATA flowchart  
1.3.2.1 PK/ATA flow chart for Part A  
 
Cycle 
C1 
C2 
C3 
C4 
C5  
and beyondb, c, d 
EOT 
Day 
D1 
D4 
D1 
D1 
D1 
D1 
D30 ±5 days 
after last IMP 
Pembrolizumab 
IV infusion 
X--- 
 
 
X 
X 
X 
 
X 
 
Sample RNT (hours) 
Ref. Pembrolizumab SOI 
SOI 
 
 
SOI 
 
SOI 
 
SOI 
 
Sample time window 
(-24 h, SOI) 
 
 
(-24 h, SOI) 
 
(-24 h, SOI) 
 
(-24 h, SOI) 
 
PK sample ID 
S00a 
 
 
S00a 
 
S00a 
 
S00a, b 
 
Tusamitamab ravtansine 
IV infusion 
X--- 
---X 
 
X 
X 
X 
 
X 
 
Sample RNT (hours) 
Ref. tusamitamab ravtansine 
SOI 
SOI 
EOI 
72h 
SOI 
SOI 
SOI 
EOI+1 h 
SOI 
 
Sample time window 
(-24 h, SOI) 
±10 min 
±24 h 
(-24 h, SOI) 
(-24 h, SOI) 
(-24 h, SOI) 
±10 min 
(-24 h, SOI) 
 
PK sample ID  
(SAR408701, DM4 and Me-DM4f) 
P00a 
P01e 
P02 
P00a 
P00a 
P00a 
P01 
P00a, c 
 
ATA sample ID 
AB00a 
 
 
AB00a 
AB00a 
AB00a 
 
AB00a, d 
ABF00 
Note: Sampling for PK and ATA may be reduced or stopped during the course of the study, upon notification from the Sponsor. 
a Samples collected strictly before start of infusion (SOI), tusamitamab ravtansine and pembrolizumab predose samples can be collected at the same time before pembrolizumab administration. 
b Pembrolizumab PK samples will be collected at SOI at Cycle 8 only. 
c Tusamitamab ravtansine PK samples will be collected at SOI each cycle at Cycles 5, 6, 7, and 8; thereafter, only at Cycle 13. 
d Tusamitamab ravtansine ATA samples will be collected at SOI at Cycle 6, Cycle 8 and thereafter every 5 cycles (ie, C8, C13, C18…). 
e Actual EOI sample should be taken when the pump beeps (end of infusion) before flush. 
f 
DM4 and Me-DM4 to be collected only for participants enrolled from amendment #6 
ATA: antitherapeutic antibody; C: Cycle; D: Day; EOI: end of infusion; EOT: end of treatment; IMP: investigational medicinal product; IV: intravenous; P: plasma; PK: pharmacokinetics; RNT: relative nominal time; 
S: serum; SOI: start of infusion. 
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1.3.2.2 PK/ATA flow chart for Part B  
 
Cycle 
C1 
C2 
C3 
C4 
C5 and 
beyondb, c, d 
EOT 
Day 
D1 
D4 
D1 
D1 
D1 
D1 
D30 ±5 days 
after last IMP
Pembrolizumab 
IV infusion 
X--- 
 
 
 
 
X 
X 
X 
 
X 
 
Sample RNT (hours) 
Ref. Pembrolizumab SOI 
SOI 
 
 
 
 
SOI 
 
SOI 
 
SOI 
 
Sample time window 
(-24 h, 
SOI) 
 
 
 
 
(-24 h, 
SOI) 
 
(-24 h, 
SOI) 
 
(-24 h, SOI) 
 
PK sample ID 
S00a 
 
 
 
 
S00a 
 
S00a 
 
S00a, b 
 
Tusamitamab ravtansine 
IV infusion 
X--- 
---X 
 
 
 
X 
X 
X 
 
X 
 
Sample RNT (hours) 
Ref. tusamitamab ravtansine SOI 
SOI 
EOI 
 
 
72h 
SOI 
SOI 
SOI 
EOI+1 
h 
SOI 
 
Sample time window 
(-24 h, 
SOI) 
±10 min 
 
 
±24 h 
(-24 h, 
SOI) 
(-24 h, 
SOI) 
(-24 h, 
SOI) 
±10 min 
(-24 h, SOI) 
 
PK sample ID 
(SAR408701, DM4 and Me-DM4f) 
P00a 
P01e 
 
 
P02 
P00a 
P00a 
P00a 
P01 
P00a, c 
 
ATA sample ID 
AB00a 
 
 
 
 
AB00a 
AB00a 
AB00a 
 
AB00a, d 
ABF00 
Cisplatin/Carboplatin 
IV infusion 
X--- 
---X 
 
 
 
 
 
 
 
 
 
Sample RNT (hours) 
Ref. cisplatin/carboplatin SOI 
SOI 
EOI 
EOI+1H 
Cisplatin: 
EOI+3H  
Carboplatin: 
EOI+4H 
 
 
 
 
 
 
 
Sample time window 
(-24 h, 
SOI) 
Within 5 min 
before EOI 
±10 min 
±15 min 
 
 
 
 
 
 
 
PK sample ID 
P00a 
P01 
P02 
P03 
 
 
 
 
 
 
 
Note: Sampling for PK and ATA may be reduced or stopped during the course of the study upon notification from the Sponsor. 
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a Samples collected strictly before start of infusion (SOI), tusamitamab ravtansine, pembrolizumab and cisplatin or carboplatin predose samples can be collected at the same time before pembrolizumab 
administration. 
b Pembrolizumab PK samples will be collected at SOI at Cycle 8 only. 
c Tusamitamab ravtansine PK samples will be collected at SOI each cycle at Cycles 5, 6, 7, and 8; thereafter, only at Cycle 13. 
d Tusamitamab ravtansine ATA samples will be collected at SOI at Cycle 6, Cycle 8 and thereafter every 5 cycles (ie, C8, C13, C18). 
e Actual EOI sample should be taken when the pump beeps (end of infusion) before flush. 
f 
DM4 and Me-DM4 to be collected only for patients enrolled from amendment #6 
ATA: antitherapeutic antibody; C: Cycle; D: Day; EOI: end of infusion; EOT: end of treatment; IMP: investigational medicinal product; IV: intravenous; P: plasma; PK: pharmacokinetics; RNT: relative nominal time; 
S: serum; SOI: start of infusion. 
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1.3.2.3 PK/ATA flow chart for Part C  
 
Cycle 
C1 
C2 
C3 
C4 
C5 and 
beyondb, c, d 
EOT 
Day 
D1 
D2 
D4 
D1 
D1 
D1 
D1 
D30 
±5 days 
after 
last IMP 
Pembrolizumab 
IV infusion 
X--- 
 
 
 
 
 
 
X 
X 
X 
 
X 
 
Sample RNT (hours) 
Ref. Pembrolizumab SOI 
SOI 
 
 
 
 
 
 
SOI 
 
SOI 
 
SOI 
 
Sample time window 
(-24 h, 
SOI) 
 
 
 
 
 
 
(-24 h, 
SOI) 
 
(-24 h, 
SOI) 
 
(-24 h, SOI) 
 
PK sample ID 
S00a 
 
 
 
 
 
 
S00a 
 
S00a 
 
S00a, b 
 
Tusamitamab ravtansine 
IV infusion 
X--- 
---X 
 
 
 
 
 
X 
X 
X 
 
X 
 
Sample RNT (hours) 
Ref. tusamitamab ravtansine SOI 
SOI 
EOI 
 
 
 
 
72h 
SOI 
SOI 
SOI EOI+1 h 
SOI 
 
Sample time window 
(-24 h, 
SOI) 
±10 min 
 
 
 
 
±24 h 
(-24 h, 
SOI) 
(-24 h, 
SOI) 
(-24 h, 
SOI) 
±10 min 
(-24 h, SOI) 
 
PK sample ID (SAR408701, DM4 
and Me-DM4f) 
P00a 
P01e 
 
 
 
 
P02 
P00a 
P00a 
P00a 
P01 
P00a, c 
 
ATA sample ID 
AB00a 
 
 
 
 
 
 
AB00a 
AB00a 
AB00a 
 
AB00a, d 
ABF00 
Pemetrexed 
IV infusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Sample RNT (hours) 
Ref. pemetrexed SOI 
SOI 
30 min 
2h 
4h 
8h 
24h 
 
 
 
 
 
 
 
Sample time window 
(-24 h, 
SOI) 
±10 min ±15 min 
±30 min 
±1 h 30 ±5 h 
 
 
 
 
 
 
 
PK sample ID 
P00a 
P01 
P02 
P03 
P04 
P05 
 
 
 
 
 
 
 
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Cycle 
C1 
C2 
C3 
C4 
C5 and 
beyondb, c, d 
EOT 
Day 
D1 
D2 
D4 
D1 
D1 
D1 
D1 
D30 
±5 days 
after 
last IMP 
Cisplatin/Carboplatin 
IV infusion 
X--- 
---X 
 
 
 
 
 
 
 
 
 
 
 
Sample RNT (hours) 
Ref. cisplatin/ 
carboplatin SOI 
SOI 
EOI 
EOI+1H Cisplatin: 
EOI+3H  
Carboplatin: 
EOI+4H 
 
 
 
 
 
 
 
 
 
Sample time window 
(-24 h, 
SOI) 
Within 
5 min 
before 
EOI 
±10 min 
±15 min 
 
 
 
 
 
 
 
 
 
PK sample ID 
P00a 
P01 
P02 
P03 
 
 
 
 
 
 
 
 
 
Note: Sampling for PK and ATA may be reduced or stopped during the course of the study upon notification from the Sponsor. 
a Samples collected strictly before start of infusion (SOI), tusamitamab ravtansine, pembrolizumab, pemetrexed and cisplatin or carboplatin predose samples can be collected at the same time before pembrolizumab 
administration. 
b Pembrolizumab PK samples will be collected at SOI at Cycle 8 only. 
c Tusamitamab ravtansine PK samples will be collected at SOI each cycle at Cycles 5, 6, 7, and 8; thereafter, only at Cycle 13. 
d Tusamitamab ravtansine ATA samples will be collected at SOI at Cycle 6, Cycle 8 and thereafter every 5 cycles (ie, C8, C13, C18…). 
e Actual EOI sample should be taken when the pump beeps (end of infusion) before flush. 
f 
DM4 and Me-DM4 to be collected only for patients enrolled from amendment #6 
ATA: antitherapeutic antibody; C: Cycle; D: Day; EOI: end of infusion; EOT: end of treatment; IMP: investigational medicinal product; IV: intravenous; P: plasma; PK: pharmacokinetics; RNT: relative nominal time; 
S: serum; SOI: start of infusion. 
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2 
INTRODUCTION  
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, a tumor-associated carcinoembryonic antigen, 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. 
Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) was 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. 
2.1 
STUDY RATIONALE  
The management of patients with metastatic NSCLC underwent significant transformation in the 
last 10-15 years with the development of precision medicine based on molecular characterization. 
Molecular analysis revealed distinct targetable driver mutations in about 10% to 20% of patients 
with metastatic NSCLC. In Asia, the prevalence is even 30% to 40%.  
Tusamitamab ravtansine ADC has shown a significant level of activity and a favorable safety 
profile in heavily pretreated NSQ metastatic NSCLC patients. Study TED13751 included a cohort 
of patients with heavily pretreated, NSQ NSCLC tumors treated with tusamitamab ravtansine 
100 mg/m² Q2W. In the 64 treated patients with ≥50% CEACAM5 expression, tusamitamab 
ravtansine showed encouraging antitumor activity associated with an overall response rate of 
20.3% per RECIST1.1 (95% CI: 12.27%-31.71%), warranting further development of 
tusamitamab ravtansine to treat this patient population. In the 28 treated patients with NSQ 
NSCLC CEACAM5 expression ≥1% and <50%, the overall response rate was 7.1% per 
RECIST◦1.1 (95% CI: 1.98%-22.65%). 
Besides these 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 (June 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 
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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 3 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).  
Pembrolizumab in combination with chemotherapy is also 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 (6). Improvement in OS was seen across all PD-L1 categories that were 
evaluated. Median PFS was 8.8 months (95% CI 7.6 to 9.2) in the 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 should improve the outcome, with a better tolerability for doublet or triplet 
combinations, and without additional toxicity for the quadruplet combination, as no overlapping 
toxicities are expected.  
Encouraging preliminary efficacy data, from ongoing ACT16146 study, have been observed in the 
first 25 patients treated in the study. The results observed in TED13751 where tusamitamab 
ravtansine was administered as monotherapy at 100 mg/m² Q2W in patients with CEACAM5 
expression ≥1% and these preliminary efficacy data from Part A where tusamitamab ravtansine is 
administered in combination with pembrolizumab in patients with CEACAM5 expression 
≥50% open the door to a decrease in threshold of CEACAM5 expression from 50% to 1%. 
The objective of this study is to evaluate the safety and antitumor activity efficacy of tusamitamab 
ravtansine in combination with pembrolizumab, tusamitamab ravtansine in combination with 
pembrolizumab and platinum-based chemotherapy (Investigator’s choice of cisplatin or 
carboplatin) and tusamitamab ravtansine in combination with the standard of care for first-line 
treatment pembrolizumab, platinum-based chemotherapy (Investigator’s choice of cisplatin or 
carboplatin) and pemetrexed in untreated advanced/metastatic NSQ NSCLC participants with 
CEACAM5 high or moderate expression (high expression is defined as CEACAM5 
immunohistochemistry [IHC] intensity ≥2+ in ≥50% of tumor cells and moderate expression is 
defined as intensity ≥2+ in ≥1% and <50% of tumor cells) in tumors. 
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2.2 
BACKGROUND  
Lung cancer is one of the most commonly diagnosed cancers and is the leading cause of cancer-
related mortality worldwide (7). Non-small cell lung cancer (NSCLC) accounts for approximately 
85% of all lung cancers and comprises several histopathological subtypes, the most common of 
which are adenocarcinoma (40% to 60%) and squamous cell carcinoma (10% to 15%) (8). 
The majority of NSCLC patients presents with an advanced stage of disease at the time of 
diagnosis. These patients have a median OS of up to 8 to 12 months, and a 5 year survival rate of 
approximately 18% (8). Between 10% and 20% of patients with NSCLC have tumors with key 
genomic alterations that are amenable to targeted therapy, which include EGFR mutations and 
ROS1 and ALK rearrangements. 
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 (9).  
More recently, immunotherapy has initiated a new paradigm for the treatment of NSCLC. 
In particular, monoclonal antibodies targeting the PD-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 (10, 11, 12, 13), however 
only a few patients (20% to 30%) respond 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 in patients with advanced/metastatic NSCLC. 
Tusamitamab ravtansine is being investigated in ongoing trials including 4 studies enrolling 
participants with NSCLC: 
• First-in-human (FIH) Study TED13751 to evaluate safety, PK, and antitumor activity of 
tusamitamab ravtansine in patients with advanced solid tumors. 
• Phase 3 trial EFC15858, a randomized, open-label, multicenter study comparing 
tusamitamab ravtansine and docetaxel in patients with metastatic NSQ NSCLC expressing 
CEACAM5 and previously treated with platinum-based chemotherapy and an ICI, 
if indicated.  
• Phase 2 trial ACT16525, an open-label, single-arm trial to evaluate antitumor activity, 
safety, and pharmacokinetics of tusamitamab ravtansine used in combination with 
ramucirumab in metastatic NSQ NSCLC patients with CEACAM5-positive tumors, 
previously treated with platinum-based chemotherapy and an ICI. 
• Phase 2 trial ACT17241, an open-label trial evaluating the efficacy and safety of 
tusamitamab ravtansine in participants with NSQ NSCLC who have tumors with negative 
or moderate CEACAM5 expression and high circulating CEA. 
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2.3 
BENEFIT/RISK ASSESSMENT  
The benefit-risk assessment incorporates an evaluation of the key safety and efficacy information 
that is presently available. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of tusamitamab ravtansine may be found in the Investigator’s brochure (IB). Details 
regarding important identified risks and expected benefits for pembrolizumab can be found in the 
Product Information. 
2.3.1 Risk assessment  
In the completed main escalation phase of TED13751, 31 patients have been treated across 8 DLs 
ranging from 5 to 150 mg/m². 
Treatment-emergent adverse events (TEAEs) were seen in 29 of 31 patients in the main dose 
escalation, 54.8% patients experienced a Grade 3 or higher TEAE and 41.9% patients had at least 
1 serious TEAE. Grade ≥3 TEAEs related to tusamitamab ravtansine were seen in 7 patients 
(22.6%), and were reported as SAEs in 2 patients (6.5%). One patient experienced the Grade 4 
events of neutropenia and colitis erosive, and 1 patient experienced the Grade 1 event of colitis. The 
most frequent (in ≥4 of 31 patients [≥12.9%]) all-cause TEAE PTs were asthenia, nausea, and 
decreased appetite (8 patients [25.8%] each); keratopathy (8 patients [25.8%] any grade; 6 patients 
[19.4%] Grade ≥3); diarrhea and constipation (7 patients [22.6%] each); diarrhea/colitis combined 
(9 patients [29%]); fatigue (6 patients [19.4%]); abdominal pain (5 patients [16.1%]); dry eye and 
xerophthalmia combined (7 patients [22.6%]); and blurred vision and cough (4 patients [12.9%] 
each). Nervous system disorders occurred in 8 patients; these included paresthesia in 4 patients 
(12.9%), peripheral sensory neuropathy in 2 patients (6.5%), neuropathy in 1 patient (3.3%), and 
dysesthesia in 1 patient (3.3%). Infectious conditions, which included 3 Grade ≥3 events, were 
observed in 5 patients (16.1%). Except for keratopathy, these events were predominantly of low 
severity (Grade 1/Grade 2). The main clinically relevant laboratory abnormality was 
thrombocytopenia (51.6% [versus 9.7% at baseline]). Neutropenia has been observed in 5 patients 
(16.1%); 3 had Grade >3 events. Events possibly linked to allergic processes were documented in 
2 patients (1 patient with Grade 2 infusion reaction, and 1 patient with Grade 1 eczematous lesions). 
During the assessment of preliminary safety data as a data extraction from ongoing expansion 
cohorts, among 114 patients treated at 100 mg/m² tusamitamab ravtansine and treated with right-
eye prophylaxis in the expansion phase, a TEAE of the cornea was reported in 31 patients; 
29 patients had clear laterality assessment. Preliminary results showed that about 93% of corneal 
events (27 of 29 events) were bilateral, and thus were not impacted by prophylactic treatment. 
Based on this preliminary result, it has been decided to discontinue primary ocular prophylaxis, 
and instead consider secondary prophylaxis on a case-by-case basis following 
an ophthalmologist’s recommendation based on assessment of an individual patient. 
In Study TCD15054 to evaluate safety and PK of tusamitamab ravtansine monotherapy in 
Japanese patients, TEAEs have been reported in 8 patients (88.9%) and 2 (22.2%) of them were 
reported as Grade ≥3 events. TEAEs related to tusamitamab ravtansine were reported in 6 patients 
(66.7%); only 1 patient (11.1%) had Grade ≥3 event (Gastrointestinal hemorrhage). One patient 
permanently discontinued study treatment due to an AE (Grade 1 blurred vision event).  
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To date, efficacy and safety data from ongoing studies of tusamitamab ravtansine (TED13751 and 
TCD15054) support continued clinical development. Based on available safety data, the main 
anticipated risk to participants is corneal toxicity presenting as keratitis/microcystic keratopathy, 
which is reversible and manageable with dose delay and dose reduction in some participants. 
Peripheral neuropathy is an identified risk in participants previously exposed to neurotoxic drugs. 
Other potential risks include colitis (including hemorrhagic), bone marrow toxicity, cardiotoxicity 
(myocardial or conduction abnormalities) and increases in liver enzymes, as well as systemic 
acute hypersensitivity reactions (including anaphylaxis and local infusion site reaction to 
tusamitamab ravtansine). More detailed information about the known and expected benefits and 
risks and reasonably expected AEs of tusamitamab ravtansine may be found in the current 
Investigator’s Brochure.  
Pembrolizumab is most commonly associated with immune-related adverse reactions. The safety 
of pembrolizumab as monotherapy has been evaluated in 5,884 patients with advanced melanoma, 
resected Stage III melanoma (adjuvant therapy), NSCLC, classical Hodgkin’s lymphoma, 
urothelial carcinoma, or head and neck squamous-cell carcinoma (HNSCC) across 4 doses 
(2 mg/kg Q3W, 200 mg Q3W, or 10 mg/kg every 2 or 3weeks) in clinical studies. The most 
frequent adverse reactions with pembrolizumab were fatigue (32%), nausea (20%), and diarrhea 
(20%). The majority of adverse reactions reported for monotherapy were of Grade 1 or 2 severity. 
The most serious adverse reactions were immune-related adverse reactions and severe 
infusion-related reactions. 
The safety of pembrolizumab in combination with chemotherapy (pemetrexed and platinum) has 
been evaluated in 1 067 patients with NSCLC or HNSCC receiving 200 mg, 2 mg/kg, or 
10 mg/kg pembrolizumab Q3W in clinical studies. In this patient population, the most frequent 
adverse reactions were nausea (50%), anemia (50%), fatigue (37%), constipation (35%), diarrhea 
(30%), neutropenia (30%), decreased appetite (28%), and vomiting (25%). Incidences of 
Grade 3-5 adverse reactions were 67% for pembrolizumab combination therapy and 66% for 
chemotherapy alone. In general, the frequency of adverse reactions from treatment with 
pembrolizumab in combination is higher than for pembrolizumab as monotherapy or for 
chemotherapy alone, reflecting the contribution of each of these components. 
Given the significant risks of AEs associated with pembrolizumab (see US Package Insert or EU 
Summary of Product Characteristics for Keytruda or the EU Summary of risk management plan 
for pembrolizumab), and AEs associated with platinum-based chemotherapy, a specific interest 
will be given to closely monitor the safety profile of the combination of tusamitamab ravtansine 
and pembrolizumab with or without platinum-based chemotherapy. 
Commonly reported AEs of pemetrexed include nausea, vomiting, loss of appetite, diarrhea, 
stomach upset, changes in taste, constipation, mouth sores, and tiredness, of which nausea, 
vomiting, and diarrhea can be severe. Common side effects of platinum-based chemotherapy 
include anaphylaxis, cytopenia (including leukopenia and neutropenia, thrombocytopenia, and 
anemia), hepatotoxicity, ototoxicity, cardiotoxicity, nausea and vomiting, diarrhea, mucositis, 
stomatitis, pain, alopecia, anorexia, cachexia, and asthenia. Identified dose-limiting toxicities 
include nephrotoxicity for cisplatin, myelosuppression for carboplatin, and neurotoxicity for 
oxaliplatin.  
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Given the considerable toxicity associated with pemetrexed and/or platinum chemotherapies, the 
combination of tusamitamab ravtansine with pembrolizumab and with or without platinum-based 
chemotherapy should lead to improved outcomes, as compared to a combination with untargeted, 
toxic chemotherapy. As hematological toxicity is minimal for tusamitamab ravtansine, its 
combination with the standard of care may lead to better efficacy with acceptable safety profile. 
2.3.2 Benefit assessment  
Based on the current data obtained in the ongoing monotherapy studies of tusamitamab ravtansine 
(TED13751 and TCD15054), the perceived balance between the anticipated benefits and the 
reported risks of tusamitamab ravtansine with advanced malignancies is acceptable and supports 
continued clinical development of the agent, including in combination with chemotherapy and 
immunotherapy agents. 
As of 28 Nov 2022, preliminary efficacy analysis of data was performed on the 25 participants 
treated in the 3 combination treatment cohorts with encouraging data.   
2.3.3 Overall benefit: risk conclusion  
Taking into account the measures taken to minimize risk to participants, the potential risks 
identified in association with tusamitamab ravtansine combined with pembrolizumab with or 
without platinum-based chemotherapy and with or without pemetrexed are justified by the 
anticipated benefits that may be afforded to participants with advanced/metastatic NSCLC. 
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3 
OBJECTIVES AND ENDPOINTS  
Table 1 - Objectives and endpoints  
Objectives 
Endpoints 
Primary 
• 
Safety run-in part: to assess the tolerability and to 
determine the recommended doses of tusamitamab 
ravtansine in combination with pembrolizumab and 
tusamitamab ravtansine in combination with 
pembrolizumab and platinum-based chemotherapy 
with or without pemetrexed to be tested in the 
expansion part of the study in the NSQ NSCLC 
population 
• 
Incidence of study drug-related dose-limiting toxicity 
(DLTs) at Cycle 1 (C1D1 to C1D21), including but 
not limited to corneal toxicity 
• 
Expansion part (including participants treated at the 
recommended dose for expansion [RDE] from the 
Safety Run-in part): to assess the antitumor activity 
of several dose levels (DLs; if applicable) of 
tusamitamab ravtansine in combination with 
pembrolizumab and of several DLs of tusamitamab 
ravtansine in combination with pembrolizumab, 
platinum-based chemotherapy, and pemetrexed in 
the NSQ NSCLC population  
• 
Objective response rate (ORR) defined as 
proportion of participants who have a confirmed 
complete response (CR) or partial response (PR) as 
per best overall response RECIST v1.1 (2) 
Secondary 
• 
To assess the safety and tolerability of several DLs 
(if applicable) of tusamitamab ravtansine in 
combination with pembrolizumab and of 1 DL of 
tusamitamab ravtansine in combination with 
pembrolizumab and platinum-based chemotherapy, 
and of several DLs of tusamitamab ravtansine in 
combination with pembrolizumab and platinum-
based chemotherapy with pemetrexed in the NSQ 
NSCLC population. 
• 
Incidence of treatment-emergent adverse events 
(TEAEs), serious adverse events (SAEs) and 
laboratory abnormalities according to the National 
Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE) V5.0 
• 
To assess the antitumor activity of several DLs (if 
applicable) of tusamitamab ravtansine in 
combination with pembrolizumab and of 1 DL of 
tusamitamab ravtansine in combination with 
pembrolizumab and platinum-based chemotherapy, 
and of several DLs of tusamitamab ravtansine in 
combination with pembrolizumab, and platinum-
based chemotherapy, with pemetrexed in the NSQ 
NSCLC population 
• 
Progression-free survival (PFS), 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 (not for Part B) 
• 
Disease control rate (DCR), defined as the 
percentage of participants who have achieved 
confirmed CR, confirmed PR or stable disease as 
best overall response per RECIST v1.1 
• 
To assess the durability of the response to 
treatment with several DLs (if applicable) of 
tusamitamab ravtansine in combination with 
pembrolizumab and of 1 DL of tusamitamab 
ravtansine in combination with pembrolizumab and 
platinum-based chemotherapy, and of several DLs 
of tusamitamab ravtansine in combination with 
pembrolizumab,platinum-based chemotherapy, and 
pemetrexed in the NSQ NSCLC population. 
• 
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 
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Objectives 
Endpoints 
• 
To assess the antitumor activity of tusamitamab 
ravtansine in combination with pembrolizumab and 
platinum-based chemotherapy in the NSQ NSCLC 
population 
• 
Objective response rate defined as proportion of 
participants who have a confirmed complete 
response (CR) or partial response (PR) as per BOR 
per RECIST v1.1 (2) 
• 
To assess the pharmacokinetics (PK) of 
tusamitamab ravtansine, pembrolizumab, 
pemetrexed, cisplatin, and carboplatin, each when 
given in combination as a doublet (tusamitamab 
ravtansine + pembrolizumab) or triplet (tusamitamab 
ravtansine + pembrolizumab + platinum-based 
chemotherapy) or a quadruplet (tusamitamab 
ravtansine + pembrolizumab + platinum-based 
chemotherapy + pemetrexed)  
• 
Pharmacokinetic concentrations of tusamitamab 
ravtansine (SAR408701, DM4, Me-DM4), 
pembrolizumab, pemetrexed, cisplatin, and 
carboplatin 
• 
To assess the immunogenicity of tusamitamab 
ravtansine in combination with pembrolizumab and 
tusamitamab ravtansine in combination with 
pembrolizumab and platinum-based chemotherapy 
with or without pemetrexed 
• 
Incidence of antitherapeutic antibodies (ATAs) 
against tusamitamab ravtansine 
Tertiary/Exploratory 
• 
To explore modulations of circulating 
carcinoembryonic antigen (CEA) as a potential 
pharmacodynamic (PD) biomarker of response to 
tusamitamab ravtansine treatment and to evaluate 
circulating CEA levels at prescreening 
• 
Circulating CEA at prescreening, screening, and 
during the treatment period 
• 
To explore the relationship between the tumor 
mutation profiles detected in the circulating free 
deoxyribonucleic acid (cfDNA) at baseline with 
efficacy outcome and to explore decrease in cfDNA 
in response to treatment 
• 
Plasma analysis for tumor cfDNA at baseline and 
Cycle 5 
• 
To explore CEACAM5 expression on circulating 
tumoral cells (CTCs) 
• 
CEACAM5 expression assessment on CTCs from 
patients with positive (high) CEACAM5 expression 
on tumor tissue 
• 
To explore potential sets of biomarkers from tumor 
DNA and RNA analyses, beside target expression, 
as potential biomarkers of response to treatment 
• 
Biomarker annotation for tumor DNA and RNA at 
baseline 
• 
To explore PK-PD relationships 
• 
Relationship between tusamitamab ravtansine PK 
exposure and safety endpoints of interest may be 
investigated as well as between tusamitamab 
ravtansine PK and efficacy endpoints (eg, ORR) 
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, multicenter study which will comprise 3 parts: Part A, Part B, and 
Part C. Part A is to assess safety, efficacy (antitumor activity), and PK of the tusamitamab 
ravtansine combined with pembrolizumab in NSQ NSCLC participants with CEACAM5 high or 
moderate expression (high expression is defined as CEACAM5 IHC intensity ≥2+ in ≥50% of 
tumor cells or moderate expression as intensity ≥2+ in ≥1% and <50% of tumor cells). Part B is to 
assess safety, efficacy (antitumor activity), and PK of the tusamitamab ravtansine combined with 
pembrolizumab and platinum-based chemotherapy in NSQ NSCLC participants with CEACAM5 
high or moderate expression tumors. Part C is to assess safety, efficacy (antitumor activity), and 
PK of the tusamitamab ravtansine combined with pembrolizumab, platinum-based chemotherapy 
and pemetrexed in NSQ NSCLC participants with CEACAM5 high or moderate expression 
tumors. A safety run-in phase will be conducted for each part of the study to define the 
recommended doses of tusamitamab ravtansine in a combination regimen with pembrolizumab for 
the expansion part. An expansion part consisting of the evaluation of the antitumor activity, safety, 
and PK of tusamitamab ravtansine at 2 or 3 DLs combined with pembrolizumab will be performed 
in Part A and C to further evaluate the efficacy, safety, and PK of tusamitamab ravtansine to 
determine the recommended tusamitamab ravtansine DL for evaluation in Phase 3 studies. 
During the prescreening phase, patients’ tumor samples will be collected to evaluate CEACAM5 
status (central assessment by IHC); PD-L1 status by an approved test will be collected and 
assessed locally or centrally, and circulating CEA will be assessed locally. 
During the screening phase, participants with NSQ NSCLC determined to be CEACAM5 high 
expression (≥50%) or moderate expression (≥1% and <50%) tumors will go through protocol 
screening procedures and be enrolled in Part A, Part B or Part C per Investigator’s choice. 
4.1.1 Safety run-in part: DLT observation period  
In Parts A, B and C, the DLT observation period is the first cycle (21 days). Depending on the 
DLTs observed, up to 3 DLs of tusamitamab ravtansine can be tested: 150 mg/m², 170 mg/m², and 
120 mg/m². 
For each DL of each combination arm, a minimum of 1 week is mandatory between the first dose 
of the first participant treated at this DL and the first dose of the next participant treated at the 
same DL. Once 3 participants assigned to a combination arm have been treated at a DL and are 
DLT-evaluable, the tolerability of the combination is assessed according to the decision algorithm 
as illustrated in Figure 1.  
PART A:  
The tolerability and safety of the pembrolizumab and tusamitamab ravtansine combination will be 
assessed. The first 3 participants will receive Q3W a 200 mg pembrolizumab infusion followed by 
a tusamitamab ravtansine infusion at the starting dose of 150 mg/m². The rules to determine the 
recommended doses for expansion are detailed in Section 6.6.1. 
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The tolerability of the doublet combination will be assessed in approximately 6 to 18 participants 
to determine the RDE. 
PART B: 
The tolerability and safety of the pembrolizumab, tusamitamab ravtansine, and platinum-based 
chemotherapy combination will be assessed. Participants can be assigned to either cisplatin or 
carboplatin per Investigator choice.  
• Cisplatin combination arm: participants will receive Q3W pembrolizumab 200 mg 
+ tusamitamab ravtansine (150 mg/m², 170 mg/m², or 120 mg/m²) + cisplatin 75 mg/m² on 
Day 1 of the first 4 cycles, followed by Q3W pembrolizumab 200 mg + tusamitamab 
ravtansine (150 mg/m², 170 mg/m², or 120 mg/m²) on Day 1 of subsequent cycles 
• Carboplatin combination arm: participants will receive Q3W pembrolizumab 200 mg 
+ tusamitamab ravtansine (150 mg/m², 170 mg/m², or 120 mg/m²) + carboplatin AUC 5, 
on Day 1 of the first 4 cycles followed by pembrolizumab 200 mg + tusamitamab 
ravtansine (150 mg/m², 170 mg/m², or 120 mg/m²) on Day 1 of subsequent cycles 
The tolerability of each triplet platinum combination will be assessed in approximately 6 to 
18 participants to determine the RDE in each triplet platinum combination arm (carboplatin or 
cisplatin). It is planned to have a total of 6 participants treated at the RDE in each triplet 
combination arm (leading to a total of approximately 36 participants treated in Part B). The rules 
to determine the recommended dose are detailed in Section 6.6.1. The starting DL of tusamitamab 
ravtansine is 150 mg/m². 
If the quadruplet combination investigated in Part C has an acceptable toxicity profile, and as the 
triplet combination was explored in Part B only in case the quadruplet would not be well 
tolerated, enrollment in Part B will be stopped as soon as the safety run-in Part C ends. 
PART C: 
The tolerability and safety of the pembrolizumab, tusamitamab ravtansine, platinum-based 
chemotherapy and pemetrexed combinations will be assessed. Participants can be assigned to 
either cisplatin or carboplatin, per Investigator choice.  
• Cisplatin combination arm: participants will receive Q3W pembrolizumab 200 mg + 
tusamitamab ravtansine (150 mg/m², 170 mg/m², or 120 mg/m²) + pemetrexed 500 mg/m2 
(with vitamin supplementation) + cisplatin 75 mg/m² all on Day 1 for the first 4 cycles, 
followed by Q3W pembrolizumab 200 mg + tusamitamab ravtansine (150 mg/m², 
170 mg/m², or 120 mg/m²) + pemetrexed 500 mg/m2 (with vitamin supplementation) on 
Day 1 of subsequent cycles 
• Carboplatin combination arm: participants will receive Q3W pembrolizumab 200 mg 
+ tusamitamab ravtansine (150 mg/m², 170 mg/m², or 120 mg/m²) + pemetrexed 
500 mg/m2 (with vitamin supplementation) + carboplatin AUC 5 all on Day 1 for the 
first 4 cycles, followed by Q3W pembrolizumab 200 mg + tusamitamab ravtansine 
(150 mg/m², 170 mg/m² or 120 mg/m² Q3W) + pemetrexed 500 mg/m2 (with vitamin 
supplementation) on Day 1 of subsequent cycles 
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The tolerability of each quadruplet platinum combination (ie, tusamitamab ravtansine, 
pembrolizumab, pemetrexed, and either cisplatin or carboplatin) will be assessed in approximately 
6 to 18 participants to determine the RDE.  The rules to determine the recommended dose are 
detailed in Section 6.6.1. The starting DL of tusamitamab ravtansine is 150 mg/m². 
4.1.2 Expansion cohorts (Parts A & C)  
The Expansion Phase will determine the recommended tusamitamab ravtansine DL for Phase 3 
studies based on safety, efficacy, safety, and PK–PD modeling at least 2 DLs of tusamitamab 
ravtansine, as detailed below.  
• In Part A, at least 20 participants will be treated at the RDE (150 mg/m2 Q3W), and at 
least to 20 participants will be treated at a lower DL (100 mg/m2 Q3W). An optional 
10 participants may be treated at an additional DL after these cohorts are completed. 
- 
If fewer than 3 of 10 participants at 100 mg/m2 have a confirmed objective response, 
early stopping rules will be applied such that enrollment to this DL will be stopped, 
and at least 20 participants will then be treated an intermediate DL (120 mg/m2). If the 
100 mg/m2 DL is not stopped early, enrollment will continue at this DL to treat at least 
20 participants. 
• In Part C, at least 20 participants will be treated at the RDE (150 mg/m2 Q3W) and at least 
20 participants will be treated at a lower DL (100 mg/m2). An optional 10 participants may 
be treated at an intermediate DL after these cohorts are completed.  
- 
If fewer than 4 of 10 participants at 100 mg/m2 have a confirmed objective response, 
early stopping rules will be applied such that enrollment to this DL will be stopped, 
and at least 20 participants will then be treated an intermediate DL (120 mg/m2). If the 
100 mg/m2 DL is not stopped early, enrollment will continue at this DL to treat at least 
20 participants. 
• Enrollment into Part C and Part A will be based on Investigator’s choice. 
For each part, expansion cohorts will be opened for enrollment after completion of the safety Run-
In for the considered part. Opening of each cohort and enrollment of participants in each cohort 
will be defined by the Sponsor based on discussions with the SC and approval of the protocol 
amendment by health authorities and/or IRB/EC (where applicable). 
If it is determined that more than 20 participants are necessary to better assess 1 DL of 
tusamitamab ravtansine in combination with pembrolizumab, the sample size for this DL will not 
exceed 30 participants. 
4.1.3 Duration of the study  
The duration of the study for a participant (irrespective of the study part) will include: 
• Screening period: up to 28 days.  
NOTE: To consider approximately 10 days between screening visit and initiation of 
therapy to ensure availability of IMP at the site. 
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• Treatment period: once successfully screened, enrolled participants may receive study 
intervention 4 cycles of cisplatin or carboplatin (Part B and C), and pemetrexed (Part C) 
and tusamitamab ravtansine and pembrolizumab until confirmed disease progression, 
unacceptable toxicity, new anticancer therapy initiation, death, or the participant’s or 
investigator’s decision to stop the treatment. Each cycle of treatment will last for 3 weeks. 
After discontinuing study intervention, participants will return to the study site 
approximately 30 days (±5 days) after the last IMP administration or before the participant 
receives another anticancer therapy, whichever is earlier, for EOT assessments. 
• Safety follow-up visit: will be performed 90 (±7 days) days after the last IMP 
administration. SAEs/AESIs (regardless of relationship with study treatment) and IMP-
related AEs ongoing at the end of study treatment, and any new IMP-related 
AE/SAE/AESI will be followed until resolution or stabilization. If ongoing related 
AE/SAE are resolved or stabilized, no further follow-up visit will be needed.  
• 
A participant who stops treatment before documented progressive disease (PD) should 
undergo tumor assessments every 6 weeks during the first 24 weeks, and then every 
9 weeks (±7 days) until radiological disease progression, death, the data cut-off date for 
secondary endpoints, initiation of further anticancer therapy, or withdrawal of the 
participant’s consent, whichever comes first.  
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN  
4.2.1 Participant input into design  
Lung cancer is the leading cause of death and only 18% of all lung cancer patients survive 5 years 
or more after initial diagnosis. 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: Nonsquamous 
carcinoma (including adenocarcinoma, large-cell carcinoma and other subtypes) and squamous 
cell (epidermoid) carcinoma. Adenocarcinoma is the most common subtype of NSQ NSCLC (14).  
The past decade has dramatically changed the approach on diagnosis and treatment of lung cancer 
with the concept of personalized medicine, which led to the discovery of several therapeutic 
options that are only approved for treatment of patients with specific histopathologic 
characteristics (15). 
Accurate pathologic assessment with tumor mutation profile and staging are essential for 
treatment decisions. In general, systemic therapy is recommended for patients with metastatic 
(Stage IV) disease, especially in disseminated metastasis. The type of systemic therapy depends 
on the histologic type, whether there are genetic alterations that can be targeted for therapy and 
the performance status of the patient.  
In the 92 NSQ NSCLC patients treated in Study TED13751, tusamitamab ravtansine showed 
encouraging antitumor activity in 64 heavily pretreated patients with NSQ NSCLC CEACAM5 
≥50%. This antitumor activity was associated with an overall response rate of 20.3% per 
RECIST◦1.1 (95%◦CI: 12.27%-31.71%), warranting further development of tusamitamab 
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ravtansine to treat this patient population. In 28 heavily pretreated patients with NSQ NSCLC 
CEACAM5 ≥1% and <50%, the overall response rate was 7.1% per RECIST◦1.1 (95%◦CI: 
1.98%-22.65%). Pembrolizumab is the first approved and the mostly used ICI in the first-line 
NSCLC in combination with standard of care and as a single agent therapy (6, 16). The 
combination with an ICI should lead to improve outcomes, as compared to a combination with 
untargeted, toxic systemic chemotherapy. 
4.3 
JUSTIFICATION FOR DOSE  
In the FIH study of tusamitamab ravtansine (TED13751), dose escalation design explored doses 
between 5 and 150 mg/m2 administered once every 2 weeks (Q2W). The recommended dose was 
determined as 100 mg/m2 Q2W. In this trial, tusamitamab ravtansine Q3W was evaluated in 
a dose-escalation cohort of CEACAM5-positive, heavily pretreated patients. No DLT has been 
observed in participants treated with 120 mg/m², 150 mg/m², or 170 mg/m² tusamitamab 
ravtansine Q3W. Two DLTs have been reported at the dose of 190 mg/m²: 1 patient experienced 
Grade 2 keratopathy leading to a dose delay of more than 14 days, and 1 patient experienced 
Grade 3 AST/ALT increase considered by the investigator to be treatment-related. Based on these 
findings, 190 mg/m2 is confirmed as the MAD (Maximum Administered Dose). The 
recommended dose for tusamitamab ravtansine as monotherapy on a Q3W schedule was 
determined as 170 mg/m² in Study TED13751. In Study ACT16146, the starting tusamitamab 
ravtansine dose in combination with pembrolizumab and platinum-based chemotherapy, with or 
without pemetrexed, will be 150 mg/m² Q3W, as it corresponds to the same dose intensity as with 
the recommended 100 mg/m² Q2W dose (50 mg/m²/week) and well tolerated in the monotherapy 
Q3W expansion cohort of the FIH. If no DLT is observed among the 3 first participants with good 
safety profile, after discussion with the Study Committee, the dose may be increased to 
170 mg/m² Q3W. The rules will be applicable as described in Section 6.6.1. 
After completion of the Safety Run-In part, 2 to 3 DLs including the RDE (150 mg/m2), a lower 
DL (100 mg/m2), and if needed, an intermediate DL (120 mg/m2), will be evaluated in the 
expansion phase for Parts A and C to further evaluate the efficacy, safety, and PK of tusamitamab 
ravtansine to determine the recommended dose for Phase 3 studies. An optional 10 patients may 
be treated at this additional dose of tusamitamab ravtansine.   
This choice is based on safety and PK considerations. Analyses from the FIH study, which 
evaluated the tusamitamab ravtansine Q2W regimen, demonstrated a significant association 
between corneal events and tusamitamab ravtansine exposure. The exposure at 100 mg/m2 Q3W 
is expected to be lower than that with 150 mg/m2 Q3W, which suggests that the lower dosage to 
be tested in this study may be associated with a decrease in corneal events and a better global 
safety profile, including fewer SAEs and permanent treatment discontinuations.  
In addition to a potential benefit to the safety profile, a lower dosage of tusamitamab ravtansine is 
hypothesized to be sufficient to achieve clinical efficacy when used in combination with 
pembrolizumab-based regimens. Nonclinical studies have demonstrated that ADCs synergize with 
ICIs through induction of immunogenic cell death and recruitment of tumor-infiltrating CD8+ 
T-cells, thereby expanding the therapeutic benefit of ICIs (1). Maximal tumor cell killing with 
ADCs may not be required to prime the response to checkpoint blockade, which often depends on 
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neoantigen release that is not necessarily proportional to cells killed. Specifically, nonclinical 
studies with combinations of tusamitamab ravtansine and an antibody to murine PD-1 
(anti-muPD-1), anti-PD-L1, or anti-murine CTLA-4 surrogate blockade antibody, in 
a subcutaneous colon MC38 syngeneic tumor implanted in female C57Bl/6 mice, revealed that 
tusamitamab ravtansine synergized with anti-muPD-1 or an anti-PD-L1 surrogate blockade 
antibody. When used as single agents, either tusamitamab ravtansine or surrogate blockade 
antibodies showed marginal activity; however the combination led to robust tumor regression. 
As such, tusamitimab ravtansine has the ability to both induce direct cytotoxic effects on 
CEACAM5-expressing tumor cells and stimulate the immune response to certain antigens 
released by dying cancer cells leading to immunogenic cell death. Therefore, when used in 
combination with immuno-oncology therapy, a lower dosage of tusamitamab ravtansine may be 
justified. 
Ultimately, the recommened DL for tusamitamab ravtansine in combination with 
a pembrolizumab-based regimen to be evaluated in Phase 3 studies will be defined based on 
evaluation of safety and efficacy and PK-PD analyses of at least 2 tested DLs in the Expansion 
Phase. If at any time the activity observed with tusamitamab ravtansine treatment at the RDE or 
a lower DL is below expected activity, further enrollment may be considered. 
4.4 
 END OF STUDY DEFINITION  
The end of the study is defined as the date of the last visit of the last participant or last scheduled 
procedure shown in the SoA for the last participant in the study. It will occur at the final study 
cut-off date (estimated at 4.5 months after the last participant’s first IMP administration) or when 
all participants complete the EOT and the Follow-Up visit approximately 90 days after the 
last IMP administration, whichever is the latest. 
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5 
STUDY POPULATION  
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1 
INCLUSION CRITERIA  
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
I 01. 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-confirmed diagnosis of advanced or metastatic NSQ 
NSCLC with no EGFR sensitizing mutation or BRAF mutation or ALK/ROS alterations. 
I 03. No prior systemic chemotherapy for the treatment of the participant’s advanced or 
metastatic disease (treatment with chemotherapy and/or radiation as part of 
neoadjuvant/adjuvant therapy is allowed as long as completed at least 6 months prior to 
diagnosis of advanced or metastatic disease). 
I 04. Expression of CEACAM5 as demonstrated prospectively by a centrally assessed IHC 
assay of ≥2+ in intensity involving at least 1% of the tumor cell population in archival 
tumor sample (or if not available fresh biopsy sample will be collected if considered 
an acceptable risk by the treating physician). 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 05. This inclusion criterion was removed in Amended Protocol 03. 
I 06. Measurable disease based on RECIST 1.1. 
I 07. Eastern Cooperative Oncology Group (ECOG) performance Status 0-1. 
Sex 
I 08. All (male and female) 
Contraceptive use by men or women should be consistent with local regulations regarding 
the methods of contraception for those participating in clinical studies. 
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a) Male participants 
Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least 4 months after the last dose of tusamitamab 
ravtansine or pembrolizumab, and at least 6 months after the last dose of 
platinum-based chemotherapy or pemetrexed: 
• Refrain from donating sperm 
PLUS either: 
• Be abstinent from heterosexual or homosexual intercourse as their preferred and 
usual lifestyle (abstinent on a long term and persistent basis) and agree to remain 
abstinent  
OR 
• Must agree to use contraception/barrier as detailed below  
- 
Agree to use a male condom  
b) Female participants 
A female participant is eligible to participate if she is not pregnant, not breastfeeding, 
and at least one of the following conditions applies: 
• Not a woman of childbearing potential (WOCBP). 
OR 
• Is a WOCBP and agrees to use a contraceptive method that is highly effective 
(with a failure rate of <1% per year), preferably with low user dependency, as 
described in Section 10.4 during the intervention period and for at least 7 months 
after the last dose of study intervention and agrees not to donate eggs (ova, 
oocytes) for the purpose of reproduction during this period. 
• A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as 
required by local regulations) before the first dose of study intervention. 
• Additional requirements for pregnancy testing during and after study intervention 
are located in Section 10.2. 
• The investigator is responsible for review of medical history, menstrual history, 
and recent sexual activity to decrease the risk for inclusion of a woman with 
an early undetected pregnancy. 
Informed Consent 
I 09. Capable of giving signed informed consent, as described in Section 10.1.2, which includes 
compliance with the requirements and restrictions listed in the ICF and in this protocol. 
New criterion introduced with amended protocol06 
I 10. Life expectancy of at least 3 months. 
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5.2 
EXCLUSION CRITERIA  
Participants are excluded from the study if any of the following criteria apply: 
Medical conditions 
E 01. This exclusion criterion was removed in Amended Protocol 06. 
E 02. Medical conditions requiring concomitant administration of strong CYP3A inhibitor 
(see Section 10.8), unless it can be discontinued at least 2 weeks before the 
first administration of study intervention and for the entire study treatment period. 
E 03. Uncontrolled brain metastases and history of leptomeningeal disease. Patients with 
previously treated brain metastases may participate provided that: 
- 
they are stable (ie, without evidence of progression by imaging for at least 4 weeks 
prior to the first administration of study 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.  
- 
Patients with known untreated, asymptomatic brain metastases (ie, no neurological 
symptoms, no requirements for corticosteroids, no or minimal surrounding edema, and 
no lesion >1.5 cm) may participate. 
E 04. 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.  
E 05. History within the last 3 years of an invasive malignancy other than the one treated in this 
study, with the exception of resected/ablated basal or squamous cell carcinoma of the skin 
or carcinoma in situ of the cervix, or other local tumors considered cured by local 
treatment.  
E 06. History of known acquired immunodeficiency syndrome (AIDS) related illnesses or 
known HIV disease requiring antiretroviral treatment, or active hepatitis A, B (defined as 
either positive HbsAg or positive hepatitis B viral DNA test above the lower limit of 
detection of the assay), or C (defined as a known positive hepatitis C antibody result and 
known quantitative HCV RNA results greater than the lower limits of detection of the 
assay) infection. HIV serology will be tested at screening only for participants enrolled at 
German sites or in any country where mandatory per local requirements.  
E 07. History of active autoimmune disease that has required systemic treatment in the past 
2 years. 
E 08. History of allogeneic tissue/solid organ transplantation. 
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E 09. Active infection requiring IV systemic therapy within 2 weeks prior to first study 
intervention administration or active tuberculosis. 
E 10. Interstitial lung disease or history of pneumonitis that has required oral or IV steroids. 
E 11. 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 12. 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 13. Symptomatic herpes zoster within 3 months prior to screening. 
E 14. Significant allergies to humanized monoclonal antibodies. 
E 15. Clinically significant multiple or severe drug allergies, intolerance to topical 
corticosteroids, or severe post-treatment hypersensitivity reactions (including, but not 
limited to, erythema multiforme major, linear immunoglobulin A [IgA] dermatosis, toxic 
epidermal necrolysis, and exfoliative dermatitis). 
Prior/concomitant therapy  
E 16. Concurrent treatment with any other anticancer therapy. 
E 17. Have received prior chemotherapy treatment for advanced/metastatic NSCLC. 
E 18. The patient is a candidate for a curative treatment with either surgical resection and/or 
chemoradiation. 
E 19. 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 any investigational treatment.  
E 20. Any prior therapy targeting CEACAM5. 
E 21. Any prior treatment with any other anti-PD-1, or PD-L1 or programmed death-ligand 
2 (PD-L2), anti-CD137, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) 
antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell 
co-stimulation or checkpoint pathways). 
E 22. Any prior maytansinoid treatment (DM1 or DM4 ADC). 
E 23. Is receiving systemic steroid therapy ≤3 days prior to the first dose of study therapy or 
receiving any other form of immunosuppressive medication. Daily steroid replacement 
therapy or any corticosteroid premedication if applicable are allowed. 
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E 24. Any radiation therapy to lung >30 Gy within 6 months of first study intervention 
administration. 
E 25. Has received or will receive a live vaccine within 30 days prior to the first study 
intervention administration. 
E 26. Any major surgery within the preceding 3 weeks of the first study intervention 
administration. 
Prior/concurrent clinical study experience 
E 27. Current participation in any other clinical study involving an investigational study 
treatment or any other type of medical research. 
Diagnostic assessments 
E 28. Poor organ function as defined by any one of the following:  
1. Serum creatinine >1.5 × upper limit of normal (ULN) or 1.0-1.5 × 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.  
2. Total bilirubin >1.0 × ULN.  
3. AST, ALT >2.5 × ULN or AST, ALT >1.5 × ULN concomitant with ALP >2.5 × ULN. 
ALP >5 × ULN with normal ALT/AST, for patients with bone metastases.  
4. Neutrophils <1.5 × 109/L or platelet count <100 × 109/L or hemoglobulin <9 g/dL 
(no blood infusion within 2 weeks before screening)  
5. 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 
6. INR >1.5 unless participant is receiving anticoagulant therapy or within therapeutic range 
if receiving anticoagulation that would affect the INR 
Other exclusions 
E 29. Individuals accommodated in an institution because of regulatory or legal order; prisoners 
or participants who are legally institutionalized. 
E 30. Any country-related specific regulation that would prevent the participant from entering 
the study – see Section 10.7 (country-specific requirements). 
E 31. 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. 
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E 32. Participants are employees of the clinical study site or other individuals directly involved 
in the conduct of the study, or immediate family members of such 
individuals (in conjunction with Section 1.61 of the ICH-GCP Ordinance E6). 
E 33. Any specific situation during study implementation/course that may rise ethics 
considerations. 
E 34. Sensitivity to any of the study interventions, or components thereof, or drug or other 
allergy that, in the opinion of the Investigator, contraindicates participation in the study. 
5.3 
LIFESTYLE CONSIDERATIONS  
No restrictions are required. 
5.4 
SCREEN FAILURES  
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently assigned to study intervention. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the Consolidated 
Standards of Reporting Trials (CONSORT) publishing requirements and to respond to queries 
from regulatory authorities. Minimal information includes demography, screen failure reasons, 
eligibility criteria, and any SAE. 
Individuals who do not meet the criteria for participation in this study (screen failure) and for 
whom resolution of the screen failure reason may not be expected within a reasonable time frame, 
the screen failure will be recorded. Individuals who do not meet the criteria for participation in 
this study (screen failure) may be rescreened. Rescreened participants should be assigned 
a different participant number to the initial screening, and all the screening procedures will be 
repeated and entered in the screening visit pages. In case the participant is a temporary screen 
failure, there is no need to have participant re-consent (ie, new ICF signed) if the participant 
finally participates in the trial. However, if the reason for temporary screen failure is a reason that 
might have altered the initial given agreement of the participant to participate, the Investigator 
should ensure the willingness of the participant to continue or redo some screening procedures 
and his/her participation to the trial. This oral agreement should be documented in the 
participant’s chart. All the tests out of protocol-specified window should be repeated and entered 
to the additional pages. 
5.5 
CRITERIA FOR TEMPORARILY DELAYING ENROLLMENT  
During a regional or national emergency declared by a governmental agency, the Investigator/site 
should assess the site’s capacity to conduct procedures for a new participant to be enrolled into the 
study before initiating any screening procedures. Site capacity also should be ensured before 
enrollment of a participant. If the site is unable to adequately follow protocol-mandated 
procedures, contingency measures proposed in Appendix 11 (Section 10.11).  
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6 
STUDY INTERVENTION  
Study intervention is defined as any investigational intervention(s), marketed product(s), placebo, 
or medical device(s) intended to be administered to a study participant according to the study 
protocol. 
6.1 
STUDY INTERVENTIONS ADMINISTERED  
Table 2 - Overview of study interventions administered  
Intervention 
name 
Tusamitamab 
ravtansine 
Pembrolizumab 
Cisplatin 
Carboplatin 
Pemetrexed 
Type  
Biologic 
Biologic 
Drug 
Drug 
Drug 
Dose 
formulation 
Concentrate for 
solution for infusion 
Concentrate for 
solution for 
infusion 
Lyophilized 
powder for 
reconstitution in 
solution for 
infusiona 
Concentrate for 
solution for 
infusiona 
Concentrate 
for solution 
for infusiona 
Unit dose 
strength(s) 
5 mg/mL 
25 mg/mL 
Lyophilized 
powder to be 
reconstituted to 
1 mg/mL 
10 mg/mL 
25 mg/mL 
Dosage level(s) 
150 mg/m² (or 
170 mg/m² or 
120 mg/m²) on Day 1 
and then Q3W 
100 mg/m2 (or 
alternative) on Day 1 
and then Q3W  
BSA will be 
determined using the 
most recent weight 
(assuming it was 
assessed in 
a reasonable time 
frame according to the 
investigator) and 
baseline height; dose 
may not be adjusted if 
body weight change is 
≤5%. For participants 
with a BSA >2.2 m², 
the dose will be 
calculated based on 
a BSA of 2.2 m². 
200 mg on Day 1 
and then Q3W 
75 mg/m2 on 
Day 1 and then 
Q3W for the first 
4 cycles  
Body surface 
area (BSA) will 
be determined 
using the most 
recent weight 
(assuming it was 
assessed in 
a reasonable 
time frame 
according to the 
investigator) and 
baseline height; 
dose may not be 
adjusted if body 
weight change is 
≤5%.  
AUC 5 mg/mL/min 
on Day 1 and then 
Q3W for the 
first 4 cycles. 
Carboplatin dose 
should not exceed 
750 mg. The dose 
should be 
calculated using 
the calvert formula 
and CrCl should 
be calculated by 
Cockcroft-Gault 
equationb.  
500 mg/m² 
on Day 1 
and then 
Q3W. 
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Route of 
administration 
IV infusionc over 1 
hour 30 minutes after 
administration of 
pembrolizumab. 
IV infusionc over 
30 minutes 
through an IV line 
containing 
a sterile, 
nonpyrogenic, 
low-protein 
binding 
0.2 micron to 
5 micron in-line or 
add-on filter. 
IV infusionc over 
30 minutes 
immediately 
after 
administration of 
tusamitamab 
ravtansine or 
pemetrexed 
(where 
applicable) 
IV infusionc over 
15 to 60 minutes 
immediately after 
administration of 
tusamitamab 
ravtansine or 
pemetrexed 
(where applicable) 
IV infusionc 
over 
10 minutes 
after 
administration 
of 
tusamitamab 
ravtansine 
Use 
experimental 
active 
combination 
component  
active 
combination 
component 
active combination 
component 
active 
combination 
component 
IMP and NIMP 
IMP 
IMP 
IMP 
IMP 
IMP 
Packaging and 
labeling 
Supplied in 30 mL glass 
vials with a white plastic 
flip-off cap, containing 
125 mg/25 mL 
tusamitamab 
ravtansine, labelled 
with a multilingual 
booklet. 1 vial per 
treatment box. 
Supplied in 
single-dose vials 
containing 
100 mg/4 mL 
pembrolizumab 
labelled with 
a multilingual 
booklet. 1 vial per 
treatment box. 
To be locally 
sourced as 
locally 
available/59arke
tman where 
possible. Central 
sourcing only for 
the countries 
where local 
sourcing is not 
possible.  
To be locally 
sourced as locally 
available/marketed 
where possible. 
Central sourcing 
only for the 
countries where 
local sourcing is 
not possible.  
To be locally 
sourced as 
locally 
available/ma
rketed where 
possible. 
Central 
sourcing only 
for the 
countries 
where local 
sourcing is 
not possible.  
[Current/Former 
name(s) or 
alias(es)] 
N/A 
Keytruda 
Refer to labeling 
for formulation 
of cisplatin for 
injection. 
Refer to labeling 
for formulation of 
carboplatin for 
injection. 
Refer to 
labeling for 
formulation 
of 
pemetrexed 
for injection. 
a For locally sourced IMP, if the recommended formulation is not available. Local approved formation can be used after confirmed with the 
Sponsor. 
b Cockcroft-Gault: Total Dose (mg) = (target AUC) × (CrCl + 25); CrCl = (140 – age) × (weight in kg)/serum creatinine (mg/dl) × 72 × (0.85 if 
female). The CrCl used in the Calvert formula should not exceed 125 mL/min; Maximum carboplatin dose (mg) = target AUC 5 (mg*min/mL) 
× (125 + 25) = 5 × 150 mL/min = 750 mg 
c Infusion via a central line is preferred (line will be flushed before infusion), if available. Prior to dosing, each participant’s dose will be 
individually prepared by the study pharmacist and labeled with protocol number, participant number, and treatment description 
After first study administration 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.  
After the study cut-off date for ORR (see Section 9.4.1), patients with observed clinical benefit 
who are still receiving study treatment can continue study treatment. 
Study intervention will be administered until confirmed disease progression, unacceptable 
toxicity, new anticancer therapy initiation, death, or the participant’s or investigator’s decision to 
stop the treatment. 
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Noninvestigational medicinal product:  
Premedication for tusamitamab ravtansine  
Tusamitamab ravtansine has potential risk of infusion-related allergic reaction and premedication 
should be used. All the drugs used as premedication will be entered to the premedication page. 
Premedication with Histamine H1 antagonist (diphenhydramine 50 mg PO or equivalent  
[eg, dexchlorpheniramine] given approximately 15 minutes to 1 hour before tusamitamab 
ravtansine administration depending on the administration form IV or oral [15 minutes prior for 
IV and 1 hour prior for oral]) is required for all participants. If a participant has previously 
experienced an infusion-related reaction in a previous tusamitamab ravtansine administration, 
premedication will also include dexamethasone 10 mg IV for future infusions. In case participant 
does not experience any hypersensitivity reactions after 4 cycles, the pre-medications can be 
discontinued at the discretion of the investigator. 
Premedication will be supplied by the study sites. If oral diphenhydramine is not available, other 
Histamine H1 antagonist or other form of diphenhydramine can be given per local label and 
clinical practice. 
Vitamin supplementation for pemetrexed  
All subjects should receive the appropriate supplementation of vitamin B12 and folic acid and 
corticosteroid prophylaxis as listed below (or as per local label): 
• Folic Acid 350-1000 μg oral: at least 5 doses of folic acid must be taken during the 7 days 
preceding the first dose of pemetrexed, and folic acid dosing must continue during the full 
course of therapy and for 21 days after the last dose of pemetrexed. 
• Vitamin B12 1000 μg IM injection in the week preceding the first dose of pemetrexed and 
once every 3 cycles thereafter. Subsequent vitamin B12 injections may be given the same 
day as pemetrexed administration. 
• Dexamethasone prophylaxis 4 mg, orally twice per day (or equivalent). Taken the day 
before, day of, and day after pemetrexed administration. Higher or additional doses are 
permitted for antiemetic prophylaxis during Cycles 1-4 but not to exceed doses in MASCC 
guidelines (Section 10.10). 
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. 
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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. 
Any quality issue noticed with the receipt or use of an IMP (deficiency in condition, appearance, 
pertaining documentation, labeling, expiration date, etc) must be promptly notified to the Sponsor. 
Some deficiencies may be recorded through a complaint procedure (see Section 8.3.9). 
A potential defect in the quality of IMP may be subject to initiation of a recall procedure by the 
Sponsor. In this case, the Investigator will be responsible for promptly addressing any request 
made by the Sponsor, in order to recall the IMP and eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP to a third party, allow the IMP to be 
used other than as directed by this clinical trial protocol, or dispose of IMP in any other manner. 
Treatment preparation and administration (including compatible materials) will be further detailed 
in the pharmacy manual. 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING  
Not applicable.  
6.4 
STUDY INTERVENTION COMPLIANCE  
When the individual dose for a participant is prepared from a bulk supply, the preparation of the 
dose will be confirmed by a second member of the study site staff.  
When participants are dosed at the site, they will receive study intervention directly from the 
Investigator or designee, under medical supervision. The person responsible for drug dispensing is 
required to maintain adequate records of the IMPs. These records (eg, drug movement form) 
include the date the IMPs are received from the Sponsor, dispensed to the participant and 
destroyed or returned to the Sponsor. The packaging batch number (IP number) and the treatment 
number on the vial must be recorded on the drug accountability form. The person responsible for 
drug administration to the participant will precisely record the date and the time of the drug 
administration to the participant. Deviation(s) from the prescribed dosage regimen should be 
recorded in the e-CRF. The dose of study intervention and study participant identification will be 
confirmed at the time of dosing by a member of the study site staff other than the person 
administering the study intervention. 
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6.5 
CONCOMITANT THERAPY  
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment or receives 
during the study must be recorded along with: 
• Reason for use 
• Route of administration 
• Dates of administration including start and end dates 
Concomitant medications 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 Aes. 
Concomitant medication may be considered on a case-by-case basis by the Investigator, in 
accordance with the following guidelines:  
• Palliative radiotherapy may be given for control of pain (for palliative intent). If palliative 
radiotherapy is being considered, the Sponsor should be contacted for approval prior to 
initiating treatment, and prior to resuming therapy on the study. The irradiated area should 
be as small as possible and should involve no more than 20% of the bone marrow in any 
given 3-week period. In all such cases, the possibility of tumor progression should be ruled 
out by physical and radiological assessments of the tumor. The irradiated area cannot be 
used as a parameter for response assessment. If the only evaluable lesions are to be 
irradiated, the participant will stop the study intervention.  
• 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 participant’s wellbeing may be prescribed 
at the Investigator’s discretion. Every medication or treatment taken by the participants 
during the trial and the reason for its administration must be recorded on the eCRF.  
The following treatments are not permitted during this study:  
• Other investigational drugs.  
• Any other anticancer therapy not specified in the protocol, including immunotherapy, 
hormonal therapy, targeted therapy, or biological therapies.  
• Primary prophylactic use of Granulocyte-Colony Stimulating Factor is not allowed during 
the DLT observation period. Secondary prophylaxis or therapeutic administration is 
allowed.  
• Prophylactic erythropoietin during the first cycle.  
• Concomitant use of strong CYP3A inhibitors (see Section 10.8) should be avoided from 
2 weeks before tusamitamab ravtansine administration up to the last tusamitamab 
ravtansine administration.  
• The use of contact lenses will not be permitted during the study treatment period.  
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6.6 
DOSE MODIFICATION  
6.6.1 Determination of recommended doses  
During Part A, the RDE of tusamitamab ravtansine in combination with pembrolizumab will be 
determined for the expansion cohort according to the DLTs observed in participants receiving the 
combination study intervention and other available relevant information, including the overall 
safety and efficacy. 
During Part B, the RDE of tusamitamab ravtansine in combination with pembrolizumab and 
platinum-based chemotherapy will be determined according to the DLTs observed in participants 
receiving the combination with cisplatin or with carboplatin and other available relevant 
information, including the overall safety and efficacy.  
During Part C, the RDE of tusamitamab ravtansine in combination with pembrolizumab, 
platinum-based chemotherapy and pemetrexed will be determined according to the DLTs 
observed in participants receiving the combination with cisplatin or with carboplatin and other 
available relevant information, including the overall safety and efficacy. 
Definitions of DLTs are provided in Table 3.  
Table 3 - Definition of dose-limiting toxicity  
Type of abnormality 
Details 
Hematological abnormalities 
Grade 4 neutropenia for 7 or more consecutive days 
 
Grade 3 to 4 neutropenia complicated by fever (temperature ≥38.5°C on more than 
1 occasion) or microbiologically or radiographically documented infection 
 
Grade ≥3 thrombocytopenia associated with clinically significant bleeding requiring 
clinical intervention 
Nonhematological abnormalities 
Grade 4 non-hematologic AE, except AE symptoms related to the underlying disease 
as per the investigator’s judgment 
 
Grade ≥3 keratopathy 
Miscellaneous 
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 
The DLT observation period is the first cycle (21 days; duration will be longer for participants 
who delay initiation of Cycle 2 due to treatment-related AE whose duration must be assessed to 
determine whether this AE meets the definition of a DLT). Depending on the DLTs observed, 
DLs of tusamitamab ravtansine can be tested during the safety run-in phase of the study in Part A, 
Part B, and Part C: 150 mg/m², 170 mg/m², and 120 mg/m².  
For each DL of the combination arms (starting dose, DL plus 1 [DL+1] and DL minus 1 [DL-1], if 
applicable), a minimum of 1 week is mandatory between the first dose of the first participant 
treated at this DL and the first dose of the next participant treated at the same DL. Once 
3 participants have been treated at this DL and are DLT-evaluable, the tolerability of the 
combination is assessed according to the following algorithm, as depicted in Figure 1. 
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• If 0/3 participants experiences a DLT at the starting dose, the dose will be escalated to 
DL+1 for the next 3 participants of the combination arm. 
- 
If 0/3 participants experiences a DLT at the DL+1 dose, the next 3 participants of the 
combination arm will be treated at the same DL to confirm the tolerability of the 
combination at DL+1. 
- 
If ≤1/6 participants treated at the DL+1 experiences a DLT, the DL+1 will be the 
RDE. 
- 
If ≥2/6 participants treated at the DL+1 experiences a DLT, the next 3 participants 
of the combination arm will be treated at starting dose to confirm the tolerability of 
the combination at the starting dose. 
- 
If ≥1/3 participants treated at the DL+1 experiences a DLT, the next 3 participants of 
the combination arm will be treated at starting dose to confirm the tolerability of the 
combination at the starting dose. 
• If 1/3 participants experiences a DLT at the starting dose, the next 3 participants of the 
combination arm will be treated at the same DL to confirm the tolerability of the 
combination at the starting dose.  
- 
If ≤1/6 participants treated at the starting dose experiences a DLT, the starting dose 
will be the RDE. 
- 
If ≥2/6 participants treated at the starting dose experience a DLT, the dose will be  
de-escalated to DL-1 for the next 3 participants of the combination arm. 
• If ≥2/3 participants experience a DLT at the starting dose, the dose will be de-escalated to 
DL-1 for the next 3 participants of the combination arm. 
- 
If ≤1/3 participants treated at the DL-1 experiences a DLT, the next 3 participants of 
the combination arm will be treated at the same DL to confirm the tolerability of the 
combination at DL-1. 
- 
If ≤1/6 participant treated at the DL-1 experiences a DLT, the DL-1 will be the 
RDE. 
- 
If ≥2/6 participants treated at the DL-1 experience a DLT, an alternative dosage 
might be considered or the study part may be stopped. 
- 
If ≥2/3 participants treated at DL-1 experience a DLT, an alternative dosage might be 
considered or the study part may be stopped. 
Dose modification and dose schedules are shown in Table 4. The decision tree for tusamitamab 
ravtansine doses is summarized in Figure 1. The Study Committee will review clinical data, on 
a regular basis, approximately every 2 weeks during the study (Section 10.1.4) and will decide on 
whether to escalate to the next DL, de-escalate, stay at the current DL, or to add alternative DLs. 
Dosage decisions for the doublet combination, triplet combinations, and quadruplet combinations 
will be discussed during this Study Committee meeting and will be clearly documented in the 
meeting minutes. Beyond recommended dose selection driven by DLT incidence, the SC could 
decide to explore lower DLs to better support final dose selection. Ultimately, the overall safety 
and efficacy will be evaluated in totality to determine the RDE. 
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Table 4 - Dose levels (safety run-in part)  
Dose level 
(DL) 
Tusamitamab 
ravtansine 
Pembrolizumab 
Cisplatin 
(Cycles 1-4) 
Carboplatin 
(Cycles 1-4) 
Pemetrexed 
Starting dose 
150 mg/m² Q3W 
200 mg Q3W 
75 mg/m2 Q3W  
AUC 5 mg/mL/min Q3W  
500 mg/m2 Q3W 
Plus 1 (DL+1) 
170 mg/m² Q3W 
200 mg Q3W 
75 mg/m2 Q3W 
AUC 5 mg/mL/min Q3W  
500 mg/m2 Q3W 
Minus 1 (DL-1) 
120 mg/m² Q3W 
200 mg Q3W 
75 mg/m2 Q3W 
AUC 5 mg/mL/min Q3W  
500 mg/m2 Q3W 
DL=dose level; Q3W=every 3 weeks. 
For participants with a BSA >2.2 m², the dose of tusamitamab ravtansine will be calculated based on a BSA of 2.2 m². 
Note: In case a participant is treated at a tusamitamab ravtansine DL, and the Study Committee decides another DL to be the recommended 
dose, the participant will continue to be treated at the participant’s initial DL unless individual dose modification is required (Section 6.6).  
6.6.2 Individual dose modification  
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. 
The dose may be adjusted if body weight change is >5%. Dose adjustment and/or cycle delays are 
permitted in case of adverse reaction. In case of toxicity, cycle delays and dose modifications 
should be implemented to manage adverse reactions according to Section 10.6 (Table 10 for 
tusamitamab ravtansine, Table 11 for pembrolizumab, Table 12 for cisplatin/carboplatin and 
pemetrexed hematologic toxicity and Table 13 for cisplatin/carboplatin and pemetrexed 
nonhematologic toxicity). Every effort will be made to administer the full dose regimen and 
maximize dose intensity. Recommended dose modifications for key chemotherapy toxicities serve 
as a guide and do not replace investigator judgment and applicable local label recommendations 
if more stringent. 
Dose modification 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 modification recommended should be followed. 
The acceptable treatment window is 3 days. Dose delay is allowed for safety management. 
Retreatment of patients that require more than 6 weeks’ dose delay need to be justified with 
case-by-case risk-benefit assessment. See Section 10.6 (Table 10, Table 11, Table 12, and 
Table 13) for guidance in dose modification or discontinuation.  
Administration of the study treatment will be discontinued in the event of a TEAE that persists 
despite appropriate cycle delay or any other AE that, in the opinion of the Investigator, warrants 
discontinuation. All changes to study treatment administration must be recorded in the eCRF. 
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Recommendations in the event of neutropenia are provided in Section 8.3.11.4. 
Pembrolizumab dose reduction is not recommended. Approved product labels should be followed 
for patients receiving pembrolizumab, cisplatin/carboplatin or pemetrexed treatment for 
supportive care and dose modification requirement due to not listed Aes. Reduction of 
tusamitamab ravtansine, cisplatin/carboplatin, or pemetrexed and not pembrolizumab is 
appropriate if, in the opinion of the Investigator, the toxicity is clearly related to the other agent 
not pembrolizumab.  
If appropriate, and if in the opinion of the Investigator, the toxicity is related to one of the 
treatments, pembrolizumab, tusamitamab ravtansine, cisplatin/carboplatin or pemetrexed instead 
of the combination and more than 1 cycle delay is needed, this drug may be interrupted upon 
discussion with the Sponsor, and the other drug(s) can be continued and this drug can only be 
resumed at following cycle after the toxicity recovers to Grade ≤1. If the toxicity is related to the 
combination of several agents (pembrolizumab, tusamitamab ravtansine, cisplatin/carboplatin or 
pemetrexed), all agents should be reduced (if applicable), interrupted or permanently discontinued 
according to the recommended dose modifications. If one of the drugs (pembrolizumab, 
tusamitamab ravtansine, cisplatin/carboplatin or pemetrexed) is prematurely permanently 
discontinued, the other drug(s) can be continued until the conditions for treatment discontinuation 
as described in Section 6.1 are met.  
One dose reduction is allowed for tusamitamab ravtansine due to safety reason. Once the dose is 
reduced, it is permanently reduced. During the conduct of the study, second dose reduction of 
tusamitamab ravtansine may be needed, and need to be decided case by case discussion with the 
Sponsor. In case a dose reduction is necessary, dose reduction of tusamitamab ravtansine will be 
administered as follows:  
Table 5 - Individual tusamitamab ravtansine dose reduction  
Drug name 
Initial dose 
1st reduced dose 
2nd reduced dose 
Tusamitamab ravtansine 
170 mg/m2 Q3W 
150 mg/m2 Q3W 
120 mg/m2 Q3W 
Tusamitamab ravtansine 
150 mg/m2 Q3W 
120 mg/m2 Q3W 
100 mg/m2 Q3W 
Tusamitamab ravtansine 
120 mg/m2 Q3W 
100 mg/m2 Q3W 
80 mg/m2 Q3W 
Tusamitamab ravtansine 
100 mg/m2 Q3W 
80 mg/m2 Q3W 
- 
A participant can have a maximum of 2 dose modifications (if applicable) to cisplatin/carboplatin 
or pemetrexed dosing for toxicities throughout the course of the study. A participant who requires 
a third dose modification to any particular component will have that agent discontinued. 
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Table 6 - Individual cisplatin/carboplatin and pemetrexed dose reduction  
Drug name 
Initial dose 
Dose reduction level -1  
Dose reduction level -2 
Cisplatin 
75 mg/m2 
56 mg/m2 
38 mg/m2 
Carboplatin 
AUC 5 
Maximum dose 
750mg 
AUC 3.75 
Maximum dose 
562.5mg 
AUC 2.5 
Maximum dose 
375mg 
Pemetrexed 
500 mg/m2  
375 mg/m2 
250 mg/m2 
6.7 
INTERVENTION AFTER THE END OF THE STUDY  
After the end of the study (see definition in Section 4.4), interventions should be decided by the 
Investigator per clinical practice. 
6.8 
TREATMENT OF OVERDOSE  
An overdose if a treatment is given via infusion as an increase of at least 30% of the dose to be 
administered in the specified duration or if the dose is administered in less than half the 
recommended duration of administration. 
The Sponsor does not recommend specific treatment for an overdose.  
In the event of an overdose, the Investigator should: 
• Contact the Medical Monitor immediately. 
• Closely monitor the participant for any AE/SAE and laboratory abnormalities. 
• Obtain a plasma sample for PK analysis if requested by the Medical Monitor (determined 
on a case-by-case basis). 
• Document the quantity of the excess dose as well as the duration of the overdose in the 
CRF. 
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant. 
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7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL  
7.1 
DISCONTINUATION OF STUDY INTERVENTION  
7.1.1 Permanent discontinuation  
The study intervention should be continued until the confirmed progressive disease whenever 
possible. Permanent study intervention discontinuation before disease progression should be 
discussed with the investigator. Any study intervention discontinuation must be fully documented 
in the eCRF. 
Study intervention should be discontinued in any of the following cases: 
• At the participant’s request, at any time and irrespective of the reason (consent’s 
withdrawal), or at the request of their legally authorized representative. “Legally 
authorized representative” is considered to be an individual or judicial or other body 
authorized under applicable law to consent on behalf of a prospective participant to the 
patient’s participation in the procedure(s) involved in the research.  
• If, in the Investigator’s opinion, continuation of the study treatment would be detrimental 
to the participant’s wellbeing, such as:  
- 
Unacceptable AE. 
- 
Confirmed disease progression. 
- 
Poor compliance to the study protocol. 
- 
Other, such as concurrent illness, that prevents further administration of study 
intervention. 
• Patient is lost to follow-up. 
• Sponsor decision to discontinue the study. 
• Pregnancy of female participant. 
If a participant in a combination arm prematurely permanently discontinues only one of the IMPs, 
the other IMP(s) can be continued until the conditions for treatment discontinuation as described 
in Section 6.1 are met. 
See Section 10.6 (Table 10, Table 11, Table 12, and Table 13) for more details on discontinuation. 
See the SoA (Section 1.3) for data to be collected at the time of intervention discontinuation and 
follow-up and for any further evaluations that need to be completed. Any abnormal laboratory 
value or ECG parameter will be immediately rechecked for confirmation (please specify, eg, after 
24 hours) before making a decision of permanent discontinuation of the IMP for the concerned 
participant. 
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Handling of participants after permanent intervention discontinuation 
Participants will be followed-up according to the study procedures specified in this protocol up to 
the scheduled date of study completion, or up to recovery or stabilization of any AE to be 
followed-up as specified in this protocol, whichever comes last. 
If possible, and after the permanent discontinuation of intervention, the participants will be 
assessed using the procedure normally planned for the last dosing day with the IMP tumor 
assessment, safety laboratory assessment and immunogenicity sample, if appropriate. 
All cases of permanent intervention discontinuation must be recorded by the Investigator in the 
appropriate pages of the eCRF when considered as confirmed. 
7.1.2 Temporary discontinuation  
Temporary intervention discontinuation may be considered by the Investigator because of 
suspected Aes. For all temporary intervention discontinuations, duration should be recorded by 
the Investigator in the appropriate pages of the eCRF.  
See Section 10.6 (Table 10, Table 11, Table 12 and Table 13) for more details on discontinuation. 
If the temporary discontinuation corresponds to more than 6 weeks delay of study intervention, all 
measures should be taken to ensure the participant’s wellbeing, and the management plan for each 
ongoing patient should be guided by the clinical judgment of the treating physician based on 
an individual benefit-risk assessment and the evolving emergency situation. 
7.1.2.1 Rechallenge  
Reinitiation of intervention with the IMP will be done under close and appropriate clinical/and or 
laboratory monitoring once the Investigator will have considered according to his/her best medical 
judgment that the responsibility of the IMP(s) in the occurrence of the concerned event was 
unlikely and if the selection criteria for the study are still met (refer to Section 5). 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Appendix 11 (Section 10.11). During a regional or national emergency declared by 
a governmental agency, reinitiation of IMP after temporary discontinuation can occur only once 
the Investigator has determined, according to his/her best judgment, that the participant would 
likely benefit from continued study treatment, and the IMP(s) was unlikely to contribute to the 
occurrence of an event of epidemic (eg, COVID-19). The Investigator should discuss the restart of 
IMP after prolonged cycle delay with Sponsor’s Medical Monitor. 
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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, as shown in the SoA. See SoA for data to be collected at the time of 
study discontinuation and follow-up and for any further evaluations that need to be 
completed. 
• The participant will be permanently discontinued both from the study intervention and 
from the study at that time. 
• If the participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
• If a participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the Investigator must document this in the site study records. 
If participants no longer wish to take the IMP, they will be encouraged to remain in the study. 
The Investigators should discuss with them key visits to attend. The value of all their study data 
collected during their continued involvement will be emphasized as important to the public health 
value of the study. 
Participants who withdraw from the study intervention should be explicitly asked about the 
contribution of possible Aes to their decision, and any AE information elicited must be 
documented. 
All study withdrawals should be recorded by the Investigator in the appropriate screens of the 
eCRF and in the participant’s medical records. In the medical record, at least the date of the 
withdrawal and the reason should be documented. 
In addition, a participant may withdraw his/her consent to stop participating in the study. 
Withdrawal of consent for intervention should be distinguished from withdrawal of consent for 
follow-up visits and from withdrawal of consent for non-participant contact follow-up, 
eg, medical record checks. The site should document any case of withdrawal of consent. 
Participants who have withdrawn from the study cannot be reallocated (treated) in the study. Their 
inclusion and intervention numbers must not be reused.  
7.3 
LOST TO FOLLOW UP  
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  
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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 Section 10.1. 
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8 
STUDY ASSESSMENTS AND PROCEDURES  
• Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed. 
• Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The Investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.  
• Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA. 
• In the event of a significant study-continuity issue (eg, caused by a pandemic), alternate 
strategies for participant visits, assessments, medication distribution and monitoring may 
be implemented by the Sponsor or the Investigator, as per local Health Authority/ethics 
requirements (see Appendix 11 [Section 10.11]). 
• Tumor CEACAM5 expression, tumor PD-L1 expression status, circulating CEA and age 
will be collected during the prescreening visit. 
• During screening period, demography, medical/surgical, and disease history will be 
evaluated. Demography includes, 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, previous antitumor therapy (type, start and end dates, reason for discontinuation 
and response to the therapy, and date of relapse/progression), previous surgery for 
NSCLC, and smoking history. 
• For a regional or national emergency declared by a governmental agency, contingency 
measures are included in Appendix 11 (Section 10.11). 
8.1 
EFFICACY ASSESSMENTS  
All efficacy endpoints are based on tumor assessment. Schedule of tumor assessments is provided 
in SoA. Assessment of antitumor activity of tusamitamab ravtansine based on ORR per RECIST 
v1.1 is the primary efficacy objective. 
Tumor assessment method per RECIST 1.1 is detailed in Section 10.9. 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 first 24 weeks, and then every 9 weeks until 
radiological disease progression, initiation of further anticancer therapy, death, or the data cut-off for 
secondary endpoints, whichever comes first. Confirmatory radiological evaluation will be performed 
at least 4 weeks after initial documentation of response. After IMP discontinuation, tumor assessment 
should be performed at EOT for patients without imaging performed within past 4 weeks. 
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Imaging assessments during the on-treatment period are to be scheduled using the Cycle 1 Day 1 
date as the reference for all time points, and are not to be scheduled based on the date of the 
previous imaging time point. Imaging assessment delay to conform to treatment delay is not 
permitted. The same tumor assessment technique must be used throughout the study for a given 
lesion/participant. 
Brain CT-scan or MRI should be performed at baseline only if clinically indicated and followed 
only for patients with brain lesions at baseline. 
Objective response rate (ORR) will be derived based on investigator review at each time point at 
which a response assessment occurred using the RECIST 1.1 (see Section 10.9). 
The secondary endpoints (DOR, PFS, and DCR) will also be derived. 
Participants who stopped treatment before documented progressive disease (PD) should undergo 
a tumor assessment every 6 weeks during the first 24 weeks, and then every 9 weeks (±7 days) 
until radiological disease progression, death, the data cut-off date for secondary endpoints, 
initiation of further anticancer therapy, or withdrawal of the participant’s consent, whichever 
comes first. Participants with or without documented disease progression should attend an on-site 
follow-up visit 90 days after the last dose of study medication. 
8.2 
SAFETY ASSESSMENTS  
Planned time points for all safety assessments are provided in the SoA. 
8.2.1 Physical examinations  
• A complete physical examination will include, at a minimum, assessments of the 
cardiovascular, central nervous system, respiratory system, hepatomegaly, splenomegaly, 
and lymphadenopathy. 
• Height (at screening only) and weight will also be measured and recorded. 
• Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
• Any new finding or worsening of previous finding should be reported as a new AE. 
8.2.2 Performance status  
• Performance status will be evaluated using ECOG scale (17). 
8.2.3 Specific ocular test  
Standard specific ocular tests by an ophthalmologist include: 
• Assessment of ocular/visual symptoms, (ie, blurred vision, photophobia, dry eye, etc). 
• Visual acuity. 
• Slit lamp under dilatation. 
• Schirmer’s test. 
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Standard specific ocular tests are planned at screening and EOT but can also be performed 
whenever clinically indicated. Assessment of ocular/visual symptoms should be performed at each 
visit before each study intervention. 
In participants with any ocular/visual symptom(s) (eg, blurred vision, photophobia) the complete 
ocular tests will be repeated at the time of the occurrence of the ocular toxicity, if any regardless 
of the grade. Then, visual acuity, slit lamp examination under dilatation, and Schirmer’s test will 
be repeated once weekly (if not recommended to have less frequent 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. 
8.2.4 Vital signs  
• Temperature, pulse rate and blood pressure will be assessed. 
• Blood pressure and pulse measurements will be assessed with a completely automated 
device. Manual techniques will be used only if an automated device is not available. 
• Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest 
for the participant in a quiet setting without distractions (eg, television, cell phones). 
8.2.5 Electrocardiogram  
• Single 12-lead ECG is required as outlined in the SoA (see Section 1.3). ECG is to be 
repeated as clinically indicated. This test can be performed before the study intervention 
administration on the same day or the day before. 
• Single 12-lead ECG will be obtained using an ECG machine that automatically calculates 
the heart rate and measures PR, QRS, QT, and QTc intervals. 
8.2.6 Clinical safety laboratory assessments  
• See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed and 
to the SoA for the timing and frequency.  
• Clinical safety assessments will be conducted at each cycle. Tests can be performed on the 
same day or within the 2 days before initiating study intervention. During first 2 cycles, 
hematology and liver function tests (ie, ALT, AST, ALP, total and direct bilirubin) will be 
assessed weekly. Tests can be done 1 day before or after the planned date. If Grade 4 
neutropenia occurs, ANC will be assessed every 2 to 3 days until ANC ≥0.5 × 109/L. In 
case of a Grade ≥3 abnormality in liver function tests, additional tests will be done every 
2 to 3 days until recovery to baseline value. Additional tests will be performed when 
clinically appropriate.  
• The Investigator must review the laboratory report and document this review. The 
laboratory reports must be filed with the source documents. Clinically significant 
abnormal laboratory findings are those which are not associated with the underlying 
disease, unless judged by the Investigator to be more severe than expected for the 
participant’s condition. 
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• All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 30 days after the last dose of study intervention should 
be repeated until the values return to normal or baseline or are no longer considered 
clinically significant by the Investigator or Medical Monitor. 
- 
If such values do not return to normal/baseline within a period of time judged 
reasonable by the Investigator, the etiology should be identified and the Sponsor 
notified. 
- 
All protocol-required laboratory assessments, as defined in Appendix 2 (Section 10.2), 
must be conducted in accordance with the laboratory manual and the SoA. 
- 
If laboratory values from non-protocol specified laboratory assessments performed at 
the institution’s local laboratory require a change in participant management or are 
considered clinically significant by the Investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the CRF. 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS  
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).  
8.3.1 Time period and frequency for collecting AE and SAE information  
All Aes/SAEs will be collected from the signing of the screening ICF at the time points specified 
in the SoA (Section 1.3). During prescreening period, only Aes/SAEs related to the fresh biopsy 
procedure (if applicable) and occurring within 1 month after the fresh biopsy will be recorded in 
the eCRF. 
All SAEs and AESI will be recorded and reported to the Sponsor or designee immediately and 
under no circumstance should this exceed 24 hours, as indicated in Appendix 3 (Section 10.3). 
The Investigator will submit any updated SAE data to the Sponsor within 24 hours of it being 
available. 
Investigators are not obligated to actively seek AE or SAE after conclusion of the study 
participation. However, if the Investigator learns of any SAE, including a death, at any time after 
a participant has been discharged from the study, and he/she considers the event to be reasonably 
related to the study intervention or study participation, the Investigator must promptly notify the 
Sponsor. 
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8.3.2 Method of detecting Aes and SAEs  
The method of recording, evaluating, and assessing causality of Aes and SAEs and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3 (Section 10.3). 
Care will be taken not to introduce bias when detecting Aes and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.  
8.3.3 Follow-up of Aes and SAEs  
After the initial AE/AESI/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. At the pre-specified study end-date, all SAEs, and Aes of 
special interest (as defined in Section 8.3.8), will be followed until resolution, stabilization, the 
event is otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). 
Further information on follow-up procedures is provided in Appendix 3 (Section 10.3). 
8.3.4 Regulatory reporting requirements for SAEs  
• Prompt notification by the Investigator to the Sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met.  
• The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and Investigators. 
• Adverse events that are considered expected will be specified in the reference safety 
information (IB).  
• Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy and 
forwarded to Investigators as necessary. 
• An Investigator who receives an Investigator safety report describing an SAE, SUSAR or 
any other specific safety information (eg, summary or listing of SAEs) from the Sponsor 
will review and then file it along with the Investigator’s Brochure and will notify the 
IRB/IEC, if appropriate according to local requirements. It is the responsibility of the 
Sponsor to assess whether an event meets the criteria for a SUSAR, and therefore, is 
expedited to regulatory authorities. 
8.3.5 Pregnancy  
• Details of all pregnancies in female participants and female partners of male participants 
will be collected after the start of study intervention and until 7 months after the last dose 
of study intervention. 
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• 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 Section 8.3.4. 
• Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
8.3.6 Cardiovascular and death events  
Cardiovascular events will be treated as regular events. Refer to Section 8.3.7 for specificities 
linked to death events. 
8.3.7 Disease-related events and/or disease-related outcomes not qualifying as Aes or 
SAEs  
Not applicable. 
8.3.8 Adverse event of special interest  
Adverse event of special interest 
An AESI is an AE (serious or nonserious) of scientific and medical concern specific to the 
Sponsor’s product or program, for which ongoing monitoring and immediate notification by the 
Investigator to the Sponsor is required. Such events may require further investigation in order to 
characterize and understand them. Adverse events of special interest may be added, modified or 
removed during a study by protocol amendment. 
• Pregnancy of a female participant entered in a study as well as pregnancy occurring in 
a female partner of a male participant entered in a study with IMP/NIMP;  
- 
Pregnancy occurring in a female participant entered in the clinical trial or in a female 
partner of a male participant entered in the clinical trial. It will be qualified as an SAE 
only if it fulfills one of the seriousness criteria (see Appendix 3 [Section 10.3]). 
- 
In the event of pregnancy in a female participant, IMP should be discontinued.  
- 
Follow-up of the pregnancy in a female participant or in a female partner of a male 
participant is mandatory until the outcome has been determined (See Section 8.3.5). 
• Grade ≥3 keratopathy 
• Bundle branch blocks or any conduction defects 
• Grade ≥3 liver enzyme increased (symptomatic or asymptomatic) 
• Symptomatic overdose (serious or 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 (not based on systematic 
pills count) and defined as an increase of at least 30% of the dose to be administered in 
the specified duration or if the dose is administered in less than half the recommended 
duration of administration. 
• Dose-limiting toxicity as defined in Section 6.6.1. 
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8.3.9 Overdose, medication errors, misuses or abuses of medicinal product  
All reports of overdose, medication error, misuse or abuse in relation to the IMP with or without 
an AE must be recorded on the corresponding page(s) of the CRF and transmitted to the Sponsor’s 
representative following standard processes. The Investigator will assess whether or not the 
overdose, medication error, misuse or abuse event has to be reported together with an AE or SAE. 
An overdose definition is given in Section 6.8.  
A medication error is an unintended failure in the drug treatment process (ie, mistake in the 
process of prescribing, storing, dispensing, preparing, or administering medicinal products in 
clinical practice) that leads to, or has the potential to lead to harm to the participant.  
A misuse refers to situations where the medicinal product is intentionally and inappropriately 
used, ie, not in accordance with the terms of the marketing authorization or outside what is 
foreseen in the protocol, by the participant for a therapeutic purpose.   
An abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects, ie, intentional non-
therapeutic use of a medicinal product by a participant for a perceived reward or desired non-
therapeutic effect including, but not limited to, “getting high”(euphoria). 
This includes situations in which a participant was involved or not (eg, even if the error was 
recognized and intercepted before the participant received or used the product), and whether it 
resulted in harm to the participant or not. Of note, if a medication error or misuse meets the 
protocol definition of an overdose, it will be recorded in the overdose page of the CRF. 
8.3.10 Guidelines for reporting product complaints  
Any defect in the IMP must be reported as soon as possible by the Investigator to the monitoring 
team that will complete a product complaint form within required timelines. 
Appropriate information (eg, samples, labels or documents like pictures or photocopies) related to 
product identification and to the potential deficiencies may need to be gathered. The Investigator 
will assess whether or not the quality issue has to be reported together with an AE or SAE. 
8.3.11 Guidelines for managing specific adverse events  
8.3.11.1 Hypersensitivity reactions  
Premedication treatments provided for treatment of hypersensitivity reactions are detailed in 
Section 6.1. 
In case of event of hypersensitivity reactions, please refer to the recommended dose modification 
or discontinuation table (Table 10 and Table 11) in Appendix 6 (Section 10.6). 
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8.3.11.2 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 SoA. If ocular symptoms are present before IMP infusion, then a formal 
ocular examination should be performed. In patients with any ocular/visual symptom(s)  
(eg, blurred vision, photophobia, etc) the ocular evaluation should be repeated once weekly if not 
less frequent assessment recommended by ophthalmologist based on lesion characteristics, until 
resolution to Grade 1. Photographs of the cornea are recommended to be taken at the site, 
if possible, when ocular findings are first documented and to follow progression when relevant. 
Tonometry and additional ocular assessment can be performed at discretion of ophthalmologist 
when applicable.  
8.3.11.2.1 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 PT unless otherwise specified by 
ophthalmologist due to inflammatory findings on eye exams leading to diagnosis of keratitis. 
The potential ocular/visual toxicity symptoms could include, but are not limited to, blurred vision, 
dry eye, and photophobia. Curative treatment may be used as recommended by an ophthalmologist. 
No primary prophylaxis is recommended but prevention of dry eye with artificial tears and 
avoidance of using contact lenses should be ensured during treatment period. Corticosteroid 
containing ocular drugs are recommended in case ocular symptom occurs for the management of 
keratopathy/keratitis and treatment will be performed at the discretion of ophthalmologist. Dose 
modification and recommendations are further described in Section 10.6.  
8.3.11.3 Management of anemia  
Patients should not start Cycle 1 treatment if hemoglobin is <9.0 mg/dL. Red blood cell 
transfusion is allowed during the screening window, but a 2 weeks washout period should be 
applied. During the treatment, erythrocyte transfusion can be given, upon Investigator decision. 
Erythropoietin can be given based on the discretion of the Investigator, except during screening 
and first cycle. Current clinical practice should be followed for management of anemia. 
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8.3.11.4 Management of neutropenia  
In patients who experienced either febrile neutropenia or neutrophil count <1000 cells/mm3 for 
more than one week during study intervention, the prophylactic G-CSF should be implemented to 
ensure dose intensity and the dose should be reduced in case of recurrent event even after 
prophylactic G-CSF use.  
If the patient continues to experience these reactions at lower dose, the treatment should be 
discontinued as describe in Section 6.6.2. 
Dose modification and recommendations are further described in Section 10.6. 
8.3.11.5 Liver function tests  
Hepatic enzyme increase has been reported with tusamitamab ravtansine administration as 
monotherapy. Patients should be carefully followed and in case of Grade ≥3 abnormal liver 
function tests, additional liver function tests will be done every 2-3 days until recovery to baseline 
value. Tusamitamab ravtansine should be permanently discontinued in case of drug-induced 
Grade 4 liver enzyme increase. For stopping rules for pembrolizumab administration, current 
product leaflet should be followed. 
Grade ≥3 liver enzymes increase events should be reported as AESIs. 
8.3.11.6 Immune-related adverse reactions  
Immune-related adverse reactions have been reported with pembrolizumab administration and the 
following procedures should be followed: 
• Immune-mediated pneumonitis: withhold for Grade 2, and permanently discontinue for 
Grade 3, Grade 4 or recurrent Grade 2 pneumonitis.  
• Immune-mediated colitis: withhold for Grade 2 or 3, and permanently discontinue for 
Grade 4 or recurrent Grade 3 colitis. 
• Immune-mediated hepatitis: monitor for changes in hepatic function. Based on severity of 
liver enzyme elevations, withhold or discontinue pembrolizumab. Consider corticosteroid 
therapy.  
• Immune-mediated endocrinopathies: 
- 
Hypophysitis: withhold for Grade 2 and withhold or permanently discontinue for 
Grade 3 or 4 hypophysitis. 
- 
Thyroid disorders: monitor for changes in thyroid function. Withhold or permanently 
discontinue for Grade 3 or 4 hyperthyroidism. 
- 
Type 1 diabetes mellitus: monitor for hyperglycemia. Withhold pembrolizumab in 
cases of Grade 3 hyperglycemia. 
• Immune-mediated nephritis: monitor for changes in renal function. Withhold for Grade 2, 
and permanently discontinue for Grade 3 or 4 nephritis. 
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• Immune-mediated skin adverse reactions including Stevens-Johnson syndrome (SJS) and 
toxic epidermal necrolysis (TEN): withhold for Grade 3 and permanently discontinue for 
Grade 4 skin reactions.  
8.3.11.7 Peripheral neuropathy  
Participants with a known history of peripheral neuropathies and/or patients having received 
medications known to cause peripheral neuropathies (eg, prior antitubulin, platinum and/or 
taxanes) are at high risk of developing neuropathy. Peripheral neuropathies potentially present as 
signs and symptoms of sensory (paresthesia, dysesthesias, pain, and change in proprioception), 
motor (weakness), and neural dysfunctions. There is no further recommendation beyond routine 
guidance on prevention and treatment of peripheral neuropathy. Cycle delays or modifications 
should be compliant with Section 10.6.  
8.3.11.8 Colitis (including hemorrhagic)  
In Study TED13751 evaluating tusamitamab ravtansine in patients with several cancer types, 
a limited number of participants developed colitis. Based on clinical observations, patients with 
known underlying colitis or gastrointestinal tract conditions are noted to be at highest risk for such 
events. Cycle delays or modifications for symptoms of colitis should be compliant with 
Section 6.6.2. 
8.4 
PHARMACOKINETICS  
Blood samples will be collected for the measurement of tusamitamab ravtansine (SAR408701, 
DM4, Me-DM4), pembrolizumab, cisplatin or carboplatin and pemetrexed concentrations as 
described in the PK/ATA flowcharts (Section 1.3.2). 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.  
Samples collected for analyses of tusamitamab ravtansine concentration may also be used to 
evaluate safety or efficacy aspects related to concerns arising during or after the study. 
Pharmacokinetic samples could be used for testing analytical method performance such as 
comparability and incurred sample reproducibility and for possible exploratory analysis of drug 
metabolites. The exploratory data may not be included in the study report but will be kept on file. 
Concentrations of tusamitamab ravtansine (SAR408701, DM4, Me-DM4), pemetrexed and 
cisplatin or carboplatin will be used for population PK analysis by nonlinear mixed-effects 
modeling. Empirical Bayesian estimation of individual exposure parameters such as maximum 
concentration (Cmax), trough concentration (Ctrough) and area under the curve (AUC) will be 
derived.  
Pembrolizumab Ctrough values for Part A, Part B and Part C will be reported.  
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8.5 
PHARMACODYNAMICS  
Circulating CEA levels will be collected at prescreening, baseline and during the treatment period 
at the time of laboratory assessment as close as possible to tumor assessment (and no more than 
2 weeks from the tumor assessment) until EOT. It will be assessed using local testing. For CEA 
sample collection scheduled on the day of a treatment visit, samples should be drawn prior to 
initiation of any IMP infusion. 
Venous blood samples of approximately 3 mL (volume may change depending on local laboratory 
assay) will be collected for measurement at the local laboratory. 
8.6 
GENETICS  
8.6.1 Plasma cfDNA  
A 20 mL blood sample corresponding to about 10 mL of plasma for tumor cfDNA isolation will 
be collected at pre-infusion of Cycle 1 Day 1 and Cycle 5 Day 1. At Cycle 1 Day 1 an additional 
2 mL blood sample for germline DNA. 
In the event of DNA extraction failure, a replacement genetic blood sample may be requested 
from the participant. Signed informed consent will be required to obtain a replacement sample 
unless it was included in the original consent. 
Samples are planned to be transferred to a central laboratory for cfDNA/DNA extraction and 
mutational profiling of key cancer genes to understand the significance of existing mutation 
during tusamitamab ravtansine treatment. 
Fragmented cfDNA is released from the tumor in the plasma and can readily be extracted and 
analyzed for mutation of common cancer genes. Subtractive mutation analysis will be performed 
with germline DNA data to identify tumor specific somatic genetic aberrations. Mutation profiling 
analysis will be performed and the potential correlation of specific mutation(s) with clinical 
outcomes will be assessed. 
List (not exhaustive) of the genes that could be mutated is: AKT1, ALK, BRAF, CDKN1B, 
CDKN2A, CDKN2D, EGFR, ESR1, FGFR4, HER2, HRAS, KRAS, MDM2, MED1, MET, 
NRAS, PIK3CA, PTEN, RB1, RET, ROS1, TP53. 
8.6.2 Tumor DNA and RNA analyses  
Although tumor CEACAM5 expression is a major parameter driving the activity of 
an antiCEACAM5 ADC such as tusamitamab ravtansine, other factors may significantly 
contribute. Tumor tissue will therefore also be requested if enough tissue is available to explore 
the potential relationship between clinical endpoints following tusamitamab ravtansine therapy 
and potential sets of biomarkers besides target expression that could be predictive of response. For 
that purpose, 3 × 10 μm slides (or equivalent such as 6 × 3-5 μm or other) from the same sample 
as the one sent for CEACAM5 assessment at prescreening are requested if enough tissue material 
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is available at screening or Cycle 1 Day 1. An additional section at 5 µm should be sent for 
hematoxylin-eosine staining. The samples may serve to investigate other potential biomarkers of 
response. In tumor tissue, biomarker annotation could include, but may not be restricted to, 
genomic annotation by sequencing, gene copy number variation, gene expression (mRNA and 
miRNA), and proteomic profiling. 
See Appendix 5 (Section 10.5) for information regarding genetic research. Details on processes 
for collection and shipment and destruction of these samples can be found in the study laboratory 
manual. 
8.7 
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: 
- 
Blood sample will be collected for IgG dosage to explore impact of IgG level on PK of 
tusamitamab ravtansine. 
- 
Tumor tissue samples will be collected and assayed for CEACAM5 expression to 
determine eligibility for this study. 
- 
Blood sample will be collected for circulating tumoral cell (CTC) detection to assess 
the expression of CEACAM5 on these cells (optional). 
• Instructions for the collection and handling of biological samples will be provided by the 
Sponsor in a separate laboratory manual.  
• The level of IgG in blood at pre-infusion of Cycle 1 Day 1 will be determined by a central 
laboratory. For this test 2 mL of blood will be collected, corresponding to 1mL of serum. 
• The level of CEACAM5 expression in tumor tissues will be determined by a central 
laboratory using CEACAM5 IHC 769 assay provided by a third party. CEACAM5 IHC 769 
is a qualitative immunohistochemical assay using monoclonal mouse anti-CEACAM5, 
Clone 769 intended for use in the detection of CEACAM5 protein in FFPE nonsquamous 
NSCLC tissue using EnVision FLEX visualization system on Dako Omnis platform.  
• Assessment of CTC at pre-infusion of Cycle 1 Day 1 will be determined by a central 
laboratory. For this test, 10 mL of blood will be collected. Sample will be taken in 
a maximum of 10 participants. 
8.8 
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 1.3.2). These samples will be tested by the Sponsor’s designee.  
Refer to the laboratory manual for details regarding sample collection, processing, storage, and 
shipment.  
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A 3-tiered approach will be employed to assess the immunogenicity of tusamitamab ravtansine 
when applicable: Samples will be screened and then confirmed for antibodies binding to 
tusamitamab ravtansine and the titer of confirmed positive samples will be reported. Other 
analyses may be performed to further characterize the immunogenicity of tusamitamab ravtansine. 
8.9 
HEALTH ECONOMICS  
No health economics data will be collected. 
8.10 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH  
Future research may help further the understanding of disease and development of new medicines. 
Reuse of coded data and biological samples (leftover and additional) will be limited to future 
scientific research conducted under a research plan for the purpose of diagnosing, preventing, or 
treating diseases. The future research projects will be conducted under the Sponsor’s and/or its 
affiliates’ and/or, if applicable, the partner of the Sponsor which has licensed the study drug to the 
Sponsor or which is co-developing the study drug with the Sponsor’s control, acting alone or in 
collaboration with research partners such as universities, research institutions or industrial 
partners with whom the coded data may be shared.  
Data and biological samples will be stored and used for future research only when consented to by 
participants (see Section 10.1.2) and, when applicable, further information on the future research 
has been provided to the study participant, unless prohibited by local laws or IRBs/IECs (in such 
case, consent for future use of sample will not be included in the local ICF). The conditions for 
reuse will be adapted locally with the appropriate language in the ICF. 
In any case, a specific consent will be collected for the performance of genetic analyses on 
leftover and/or additional samples.  
Data protection – Processing of coded clinical data  
The study participant will be provided will all mandatory details of the data processing in 
Section 2 of the core ICF.   
The Sponsor adopts safeguards for protecting participant confidentiality and personal data 
(Section 10.1.3). 
Use of leftover samples and additional samples for future research 
Remaining leftover samples will be used only after the study ends, ie, end of study as defined in 
the study protocol. Additional/extra samples can be collected and used during the study conduct at 
a given timepoint (eg, at randomization visit) as defined in the study protocol. 
The study participant will be provided with all mandatory details of the use of the human 
biological samples (leftover and additional) in Section 2 of the Core ICF.  
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Relating data will be stored for up to 25 years for regulatory purposes and future research. 
Biological samples of future use will be stored for up to 25 years after the end of the study. Any 
samples remaining at the end of retention period will be destroyed. If a participant requests 
destruction of his/her samples before the end of the retention period, the Investigator must notify 
the Sponsor (or its contract organization) in writing. In such case, samples will be destroyed and 
related coded data will be anonymized unless otherwise required by applicable laws. 
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9 
STATISTICAL CONSIDERATIONS  
9.1 
STATISTICAL HYPOTHESES  
PART A: 
Safety run-in of Part A aims to establish the RDE of tusamitamab ravtansine in combination with 
pembrolizumab according to DLTs observed. 
Expansion of Part A is designed to obtain preliminary efficacy, safety, and PK data on 
tusamitamab ravtansine administered in combination with pembrolizumab. As the expansion part 
is not intended to explicitly test a hypothesis, calculations of power and Type I error were not 
considered in the study design.  
PART B: 
The Safety run-in of Part B of the study aims to establish the RDEs of tusamitamab ravtansine in 
combination with pembrolizumab and platinum-based chemotherapy (cisplatin or carboplatin) 
according to DLTs observed. 
PART C: 
The Safety run-in of Part C of the study aims to establish the RDEs of tusamitamab ravtansine in 
combination with pembrolizumab, pemetrexed and platinum-based chemotherapy (cisplatin or 
carboplatin) according to DLTs observed. 
The Expansion of Part C is designed to obtain preliminary efficacy, safety, and PK data on 
tusamitamab ravtansine administered in combination with pembrolizumab, pemetrexed and 
platinum-based chemotherapy (cisplatin or carboplatin). As the expansion part is not intended to 
explicitly test a hypothesis, calculations of power and Type I error were not considered in the study 
design. 
For Parts A and C, the expansion part is designed to optimize dose selection to maximize the 
treatment benefit and to minimize the toxicity (dose optimization). 
9.2 
SAMPLE SIZE DETERMINATION  
PART A: 
The actual sample size is expected to vary depending on DLTs observed. It is anticipated that 6 to 
62 participants will be treated with tusamitamab ravtansine + pembrolizumab: up to 12 DLT-
evaluable participants at a DL other than the RDE in the safety run-in, at least 20 participants at 
the RDE (including participants at the RDE from the safety run-in) and a total of 20 to 
30 participants at a DL lower than the RDE (100 mg/m2 Q3W) or at an intermediate DL 
(120 mg/m2). At the 100 mg/m2 DL, early stopping rules will be applied based on an interim 
analysis (ie, fewer than 3 of 10 participants achieve a confirmed objective response). If the 
100 mg/m2 DL is stopped early,  
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at least 20 participants will then be treated at an intermediate DL (120 mg/m2). If the 100 mg/m2 
DL is not stopped early, at least 20 participants will be treated at this DL. An optional 
10 participants may be treated at an additional DL which may range from 100 to 150 mg/m2. This 
DL will be determined by PK modeling, safety, and efficacy of the RDE and lower DL cohorts.  
Assuming a prescreening failure rate of 80% (as per the initial protocol) and a study screening 
failure rate of 20%, approximately 38 to 388 participants would be prescreened to achieve 
approximately 62 participants. Assuming a prescreening failure rate of 45% the number of 
participants to be prescreened could significantly be decreased (approximately 141 participants 
need to be prescreened to achieve 62 participants). 
PART B: 
The actual sample size could vary depending on DLTs observed. It is anticipated that in each 
triplet combination arm, 6 to 18 participants will be treated with tusamitamab ravtansine + 
pembrolizumab + cisplatin or carboplatin: including up to 12 DLT-evaluable participants in each 
triplet combination arm at DL other than the RDE and 6 DLT-evaluable participants in each 
triplet combination arm at the RDE.  
Assuming a prescreening failure rate of 80% (as per the initial protocol) and a study screening 
failure rate of 20%, approximately 75 to 225 participants will be prescreened to achieve 12 to 
36 DLT-evaluable participants in Part B. Assuming a prescreening failure rate of 45%, the 
number of participants to be prescreened could significantly be decreased (approximately 
82 participants need to be prescreened to achieve 36 participants).  
PART C: 
The actual sample size could vary depending on DLTs observed. It is anticipated that, overall, 
12 to 74 participants will be treated with tusamitamab ravtansine + pembrolizumab + pemetrexed 
+ cisplatin or carboplatin: up to 12 DLT-evaluable participants in each quadruplet combination 
arm treated at a DL other than the RDE; at least 20 participants treated at the RDE (regardless of 
the quadruplet platinum combination, and including participants at the RDE (150 mg/m2) from the 
safety run-in), and a total of 20 to 30 participants treated at a lower DL (100 mg/m2 Q3W) or at an 
intermediate DL (120 mg/m2). At the 100 mg/m2 DL, early stopping rules will be applied based 
on an interim analysis (ie, fewer than 4 of 10 participants achieve a confirmed objective 
response). If the 100 mg/m2 DL is stopped early, at least 20 participants will then be treated at 
an intermediate DL (120 mg/m2). If the 100 mg/m2 DL is not stopped early, at least 
20 participants will be treated at this DL. An optional 10 participants may be treated at 
an additional DL which may range from 100 to 150 mg/m2. This dose will be determined by PK 
modeling, safety, and efficacy of the RDE and lower DL cohorts.  
Assuming a prescreening failure rate of 45% and a study screening failure rate of 20%, 
approximately 28 to 169 participants will be prescreened to achieve 12 to 74 participants in Part C. 
Note: “Enrolled” means a participant’s agreement to participate in a clinical study following 
completion of the informed consent process. Potential participants who are screened for the 
purpose of determining eligibility for the study, but do not participate in the study, are not 
considered enrolled, unless otherwise specified by the protocol. 
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 Table 7. 
Table 7 - 
9.3 
POPULATIONS FOR ANALYSES  
The following populations are defined (Table 8): 
Table 8 - Populations for analyses  
Population 
Description 
Prescreened 
All participants who signed the prescreening informed consent for CEACAM5 assessment of their biopsy. 
Screened 
All participants who signed screening informed consent for study participation. 
All-treated 
All participants assigned to study intervention and who have actually received at least 1 dose of study 
intervention. 
DLT-evaluable 
Participants who received 1 cycle with at least 80% of the intended dose for each IMP of the combination 
during the safety run-in part of Part A, Part B or Part C. Participants should have completed Cycle 1 
unless they experienced a DLT before the end of Cycle 1. 
PK 
All treated participants with at least 1 available concentration result postbaseline (whichever the cycle and 
even if dosing is incomplete) with adequate documentation of date and time of dosing and date and time 
of sampling.  
ATA 
All treated participants with at least 1 ATA result (negative, positive, or inconclusive) postbaseline.  
9.4 
STATISTICAL ANALYSES  
The first version of the statistical analysis plan (SAP) has been developed according to the initial 
version of the protocol (original protocol dated 26 February 2020) and approved before the 
first participant was randomized in Part A. The SAP will be updated to reflect the protocol 
amendments and finalized before the primary safety endpoints analysis (DLT). It will describe the 
participant populations to be included in the analyses, and procedures for accounting for missing, 
unused, and spurious data. This section is a summary of the planned statistical analyses of the 
primary and secondary endpoints. 
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9.4.1 General considerations  
Efficacy analyses (ORR and DCR for all parts, DOR and PFS for Parts A and C as per 
RECIST 1.1) will be performed on the all-treated population bypart, by DL, and overall. 
Objective response rates will be derived using the local radiologist’s/Investigator’s assessment. 
The study cut-off for ORR (primary efficacy endpoint analysis) corresponds to the date on which 
all treated participants have had at least 2 postbaseline tumor assessments, experienced confirmed 
objective response, or have discontinued the study for any reason. This study cut-off will occur by 
part (Parts A & C) upon completion of enrollment at a given DL (unless cut-off dates for DLs are 
close) and will be approximately 4.5 months after the date of the first IMP administration of the 
last participant in each part: 3 months for 2 tumor assessments and 1.5 months if a confirmation of 
response is needed. The DCR will also be assessed at this cut-off.  
For Part A and Part C, an interim analysis will be performed when the first 10 participants treated 
at the lower DL (100 mg/m2) have had at least 2 postbaseline tumor assessments, experienced 
confirmed objective response, or have discontinued the study for any reason. The interim analysis 
is anticipated to occur approximately 4.5 months (3 months for 2 tumor assessments, and 
1.5 months to permit confirmation of a response) after the date of the first IMP administration of 
the tenth participant in each part. 
The study cut-off for the secondary efficacy endpoints (DOR and PFS) will be performed 
6 months after the data cut-off date for ORR. At that time, the primary analysis of ORR and DCR 
will also be updated. 
All safety analyses will be performed on the all-treated population, by part, by DL and overall. 
For each safety parameter, a baseline value will be defined as the latest value or measurement 
taken up to the first administration of the IMP.  
In addition, for Parts B and C, select endpoints (such as ORR and key safety analyses) will be 
summarized by combination arm (carboplatin or cisplatin) separately. 
The observation period will be divided into 4 segments: 
• The pretreatment period is defined as the period up to first IMP administration. 
- 
The prescreening period is defined as the time from when the participants give 
prescreening informed consent to the day before the screening informed consent. 
- 
The screening period is defined as the time from when the participants give screening 
informed consent to the first administration of IMP. 
• The treatment period is defined as the time from the first administration of IMP up to 
30 days after the last administration of IMP. 
• The post-treatment period is defined as the time from the end of the treatment period. 
9.4.2 Primary endpoint  
There are 2 primary endpoints: incidence of DLTs at Cycle 1 and ORR per RECIST 1.1 for 
Parts A and C. 
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9.4.2.1 Incidence of DLTs at Cycle 1  
The primary safety endpoint is the incidence of study drug-related DLTs at Cycle 1 (C1D1 to 
C1D21). DLT includes but is not limited to corneal toxicity. 
DLTs observed during the DLT observation period (Cycle 1) will be summarized on the 
DLT-evaluable population, by part, DL, and overall (if applicable). In addition, AEs that meet the 
DLT criteria in subsequent cycles will be summarized on the all-treated population. Details will 
be provided for each participant. 
9.4.2.2 Objective response rate (RECIST)  
The primary efficacy endpoint is the ORR. The ORR will be estimated, by dividing the number of 
participants with confirmed objective response (CR or PR as BOR), determined according to 
RECIST 1.1, by the number of participants from the analysis population.  
The BOR is the best overall response observed from the date of first administration of IMP until 
disease progression, death, cut-off date, or initiation of post-treatment anticancer therapy, 
whichever occurs first.  
Objective response rate will be summarized on the all-treated population by part, DL, and overall 
using descriptive statistics. In addition, 2-sided 95% CIs will be computed using the 
Clopper-Pearson method. 
9.4.3 Secondary endpoints  
Secondary endpoints include DOR and DCR for all parts, PFS for Parts A and C, and ORR for 
Part B per RECIST 1.1, safety, immunogenicity, and PK. Analyses of ORR for Part B will be 
similar to those for Parts A and C. 
9.4.3.1 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 anticancer therapy or death due to any cause. 
In the absence of disease progression or death before the cut-off date, DOR will be censored at the 
date of the last valid tumor assessment performed before the date of initiation of new anticancer 
therapy. Duration of response will be summarized with descriptive statistics using Kaplan-Meier 
methods. The median DOR and associated 95% CI will be provided.  
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9.4.3.2 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 before the cut-off date prior to the initiation of 
a further anticancer therapy, then PFS will be censored at the date of the last valid tumor 
assessment performed before the date of initiation of a further anticancer 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.  
9.4.3.3 Disease control rate  
The disease control rate (DCR) 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 in the all-treated population with descriptive statistics. In addition, 
2-sided 95% CIs will be computed using the Clopper-Pearson method.  
9.4.3.4 Adverse events  
Adverse events will be collected from the time prescreening informed consent is signed until at 
least 30 days after the last infusion of the study treatment. All AEs will be categorized according 
to NCI-CTCAE V5.0 and classified by SOC and PT according to the latest available version of 
the medical dictionary for regulatory activities (MedDRA). 
• Pretreatment AEs are defined as AEs occurring during the pretreatment 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. Pretreatment and posttreatment AEs will be 
described separately. 
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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 permanent treatment discontinuation 
• Treatment-related TEAEs 
• Treatment-related TEAEs Grade ≥3 
• Serious treatment-related TEAEs 
• Adverse events of special interest (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 premature 
discontinuation, TEAEs leading to permanent 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.  
9.4.3.5 Deaths  
The following deaths summaries will be generated: 
• Number and percentage of participants who died by study period (treatment, 
post-treatment) and reasons for death (disease progression, AE, or other reason). 
• Deaths in enrolled but not treated participants. 
• All TEAEs leading to death by primary SOC and PT showing number (%) of participants. 
9.4.3.6 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 abnormalities (out of normal range laboratory values) will be displayed. 
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9.4.3.7 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. 
9.4.3.8 Pharmacokinetic variables  
Pharmacokinetic analysis will be described in the SAP. 
The population PK and PK/PD analyses will be described and reported separately. 
9.4.4 Other analyses  
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Appendix 11 (Section 10.11). 
9.5 
INTERIM ANALYSES  
At the end of the safety run-in, the occurrence of DLT and other safety data will be reviewed by 
the Study Committee to determine the RDE. 
For Parts A and Part C, an interim analysis will be performed for the lower DL (100 mg/m2) based 
on the number of confirmed objective responses observed in 10 participants treated at this DL. 
The study cut-off date for the interim analysis in each part corresponds to the date on which 
10 treated participants have had at least 2 postbaseline tumor assessments, experienced confirmed 
objective response, or have discontinued the study for any reason. For participants with 
2 postbaseline tumor assessments and occurrence of response at the second postbaseline tumor 
assessment, the confirmatory assessment will also be included.  
For Part A, if fewer than 3 objective responses are observed among 10 treated participants, 
enrollment at this DL will be stopped. For Part C, if fewer than 4 confirmed objective responses 
are observed among 10 treated participants, the enrollment at this DL will be stopped. If 
enrollment at the lower DL (100 mg/m2) is stopped early, at least 20 participants will be treated at 
an intermediate DL (120 mg/m2). Otherwise, the enrollment will continue with 10 additional 
participants at the 100 mg/m2 DL to total at least 20 participants.  An optional 10 participants may 
be treated at an additional DL determined by several factors including PK modeling, safety, and 
efficacy of the RDE and lower DL cohorts. The statistical analysis plan will describe the planned 
interim analyses in greater detail. 
In addition, to support project strategic planning and design of future studies, informal interim 
analysis may be conducted during the study. 
9.6 
DATA MONITORING COMMITTEE (DMC) OR OTHER REVIEW BOARD  
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 
- 
The General Data Protection Regulation (GDPR) and any other applicable data 
protection laws 
- 
Any other applicable laws and regulation 
• 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, as applicable: 
- 
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 
- 
sDetermining whether an incidental finding (as per Sanofi policy) should be returned 
to a participant and, if it meets the appropriate criteria, to ensure the finding is returned 
(an incidental finding is a previously undiagnosed medical condition that is discovered 
unintentionally and is unrelated to the aims of the study for which the tests are being 
performed). The following should be considered when determining the return of 
an incidental finding: 
1. The return of such information to the study participant (and/or his/her designated 
healthcare professional, if so designated by the participant) is consistent with all 
applicable national, state, or regional laws and regulations in the country where the 
study is being conducted, and 
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2. The finding reveals a substantial risk of a serious health condition or has 
reproductive importance, AND has analytical validity, AND has clinical validity.  
3. The participant in a clinical study has the right to opt out of being notified by the 
Investigator of such incidental findings. In the event that the participant has opted 
out of being notified and the finding has consequences for other individuals, eg, the 
finding relates to a communicable disease, Investigators should seek independent 
ethical advice before determining next steps. 
4. In case the participant has decided to opt out, the Investigator must record in the 
site medical files that she/he does not want to know about such findings. 
As applicable, according to Directive 2001/20/EC, the Sponsor will be responsible for obtaining 
approval from the Competent Authorities of the EU Member States and/or Ethics Committees, as 
appropriate, for any amendments to the clinical trial that are deemed as “substantial” (ie, changes 
which are likely to have a significant impact on the safety or physical or mental integrity of the 
clinical trial participants or on the scientific value of the trial) prior to their implementation. 
10.1.2 Informed consent process  
• The Investigator or his/her representative will explain the nature of the study to the 
participant and answer all questions regarding the study.  
• Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 
50, local regulations, ICH guidelines, Health Insurance Portability and Accountability Act 
(HIPAA) requirements, where applicable, and the IRB/IEC or study center.  
• The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF. 
• Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study.  
• A copy of the ICF(s) must be provided to the participant.  
• 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 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 will be rescreened after this period 
screen failed and then rescreen need to re-sign a new screening ICF, here will be no 
re-prescreening for CEACAM5 expression, and the initial value will be applicable within 
the maximum allowed window for prescreening.  
• The ICF will contain separate sections that address the use of biological samples and data 
for Future Research and the use of the optional blood sample for CEACAM5 expression 
assessment on CTCs.  
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For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Appendix 11 (Section 10.1.1). 
10.1.3 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 (General Data Protection Regulation). The 
study Sponsor is the Sanofi company responsible for ensuring compliance with this matter, when 
processing data from any individual who may be included in the Sanofi databases, including trial 
participants, Investigators, nurses, experts, service providers, Ethics Committee members, etc. 
When archiving or processing personal data pertaining to the Investigator and/or to the 
participants, the Sponsor shall take all appropriate measures to safeguard and prevent access to 
this data by any unauthorized third party. 
Protection of participant personal data 
Data collected must be adequate, relevant and not excessive, in relation to the purposes for which 
they are collected. Each category of data must be properly justified and in line with the study 
objective. 
Participant race and ethnicity will be collected in this study because these data are required by 
regulatory agencies (eg, on African-American population for the FDA or on Japanese population 
for the Pharmaceuticals and Medical Devices Agency in Japan). 
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor or its service providers, when applicable, will contain 
the identifier only; participant names or any information which would make the participant 
identifiable will not be transferred to the Sponsor. 
Participants must be informed that their 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 as described in the informed consent.  
Participants must be informed that their 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. 
Protection of personal data related to professionals involved in the study  
• Personal data (eg, contact details, affiliation(s) details, job title and related professional 
information, role in the study, professional resume, training records) are necessary to 
allow Sanofi to manage involvement in the study and/or the related contractual or pre-
contractual relationship. They may be communicated to any company of the Sanofi group 
(“Sanofi”) or to Sanofi service providers, where needed. 
• Personal data can be processed for other studies and projects. At any time, objection to 
processing can be made by contacting the Sanofi Data Protection Officer (link available at 
Sanofi.com).  
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• In case of refusal to the processing of personal data by or on behalf of Sanofi, it will be 
impossible to involve the professionals in any Sanofi study. In case the professionals have 
already been involved in a Sanofi study, they will not be able to object to the processing of 
their personal data as long as they are required to be processed by applicable regulations. 
The same rule applies in case the professionals are listed on a regulatory agencies 
disqualification list. 
• Personal data can be communicated to the following recipients:  
- 
Personnel within Sanofi or partners or service providers involved in the study  
- 
Judicial, administrative and regulatory authorities, in order to comply with legal or 
regulatory requirements and/or to respond to specific requests or orders in the 
framework of judicial or administrative procedures. Contact details and identity may 
also be published on public websites in the interest of scientific research transparency 
• Personal data may be transferred towards entities located outside the Economic European 
Area, in countries where the legislation does not necessarily offer the same level of data 
protection or in countries not recognized by the European Commission as offering 
an adequate level of protection. Those transfers are safeguarded by Sanofi in accordance 
with the requirement of European law including, notably:  
- 
The standard contractual clauses of the European Commission for transfers towards 
our partners and service providers, 
- 
Sanofi’s Binding Corporate Rules for intra-group transfers.  
• Professionals have the possibility to lodge a complaint with Sanofi leading Supervisory 
Authority, the “Commission Nationale de l’Informatique et des Libertés” (CNIL) or with 
any competent local regulatory authority. 
• Personal data of professionals will be retained by Sanofi for up to thirty (30) years, unless 
further retention is required by applicable regulations. 
• In order to facilitate the maintenance of Investigators personal data, especially if they 
contribute to studies sponsored by several pharmaceuticals companies, Sanofi participates 
in the Shared Investigator Platform (SIP) and in the TransCelerate Investigator Registry 
(IR) project (https://transceleratebiopharmainc.com/initiatives/investigator-registry). 
Therefore, personal data will be securely shared by Sanofi with other pharmaceutical 
company members of the TransCelerate project. This sharing allows Investigators to keep 
their data up-to-date once for all across pharmaceutical companies participating in the 
project, with the right to object to the transfer of the data to the TransCelerate project.  
• Professionals have the right to request the access to and the rectification of their personal 
data, as well as their erasure (where applicable) by contacting the Sanofi Data Protection 
Officer: Sanofi DPO - 54 rue La Boétie - 75008 PARIS - France (to contact Sanofi by 
e-mail, visit https://www.sanofi.com/en/our-responsibility/sanofi-global-privacy-
policy/contact). 
Participant data are intended to be used for the whole drug development program from collection 
to reimbursement. 
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10.1.4 Committees structure  
Composition of the Study Committee will vary based on the matter discussed, however it will 
generally include sponsor representatives and at least 2 investigators with participants. Sponsor 
representatives and Investigators will review clinical data approximately every 2 weeks during the 
study. The dosage decision for the doublet combination, triplet combinations and quadruplet 
combinations will be made during this meeting. 
There is no Data Monitoring Committee (DMC) or Independent Radiological review committee 
(IRC) in this study. 
10.1.5 Dissemination of clinical study data and results 
At the end of the clinical study, the Sponsor may publish the study results in scientific journal(s). 
As part of the review for publication, independent scientists may need to use “coded” data of all 
the study participants to independently verify the study’s results.  
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, euclinicaltrials.eu, and sanofi.com, as well as some national 
registries. For pediatric and adult trials, the results will generally be submitted/released 6 and 
12 months respectively, after the end of the clinical trial worldwide (ie, the last active, 
participating country). 
In addition, results from clinical trials in patients are required to be submitted to peer-reviewed 
journals following internal company review for accuracy, fair balance and intellectual property. 
For those journals that request sharing of the analyzable data sets that are reported in the 
publication, interested researchers are directed to submit their request to https//vivli.org. 
Individual anonymized participant data and supporting clinical documents are available for 
request at vivli.org. While making information available we continue to protect the privacy of 
participants in our clinical trials. Details on data sharing criteria and process for requesting access 
can be found at this web address: https//vivli.org.  
10.1.6 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. 
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• 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.  
10.1.7 Source documents  
• Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the Investigator’s site. 
• Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The Investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 
• Every data point recorded in the CRF must have a source document. The 
investigator/delegated site staff will report all the original data in the participant’s medical 
chart or in a study specific source document created by him/her. If such document is used, 
the template should be reviewed by the CRA. A list of source documents and their 
locations will be filed in the Investigator Study File. 
10.1.8 Study and site start and closure  
The study start date is the date on which the clinical study will be open for recruitment of participants. 
The first act of recruitment is the first site open and will be the study start date. 
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. 
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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 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The Investigator shall promptly inform the subject and should assure 
appropriate subject therapy and/or follow-up. 
10.1.9 Publication policy  
• The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor 
before submission. This allows the Sponsor to protect proprietary information and to 
provide comments.  
• The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data. In 
this case, a coordinating Investigator will be designated by mutual agreement. 
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS  
• The tests detailed in Table 9 will be performed by the local laboratory with the exception 
of CEACAM5, which will be performed in the central 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 (urine or serum as required by local regulations) should be conducted 
every 3 weeks before each IMP administration. 
• Pregnancy testing (urine or serum as required by local regulations) should be conducted at 
least 30 days after the end of relevant systemic exposure corresponding with the time 
frame for female participant contraception in Section 5.1. 
• Additional serum or urine pregnancy tests may be performed, as determined necessary by 
the investigator or required by local regulation, to establish the absence of pregnancy at 
any time during the subject's participation in the study. 
Table 9 - Protocol-required laboratory assessments  
Laboratory assessments 
Parameters 
Hematology 
 
 
Platelet count 
 
Hemoglobin 
 
Hematocrit 
 
White blood cell (WBC) count with differential: 
 
Neutrophilsa 
 
Lymphocytes 
 
Monocytes 
 
Eosinophils 
 
Basophils 
Coagulation 
International normalized ratio (INR) 
Clinical chemistryb 
 
 
Blood urea nitrogen (BUN) or urea 
 
Creatinine 
 
Potassium 
 
Sodium 
 
Calcium 
 
Phosphate 
 
Chloride 
 
Aspartate aminotransferase (AST)/Serum glutamic-oxaloacetic transaminase (SGOT) 
 
Alanine aminotransferase (ALT)/Serum glutamic-pyruvic transaminase (SGPT) 
 
Alkaline phosphatase 
 
Total and conjugated bilirubin 
 
Glucose 
 
Lactate dehydrogenase (LDH) 
 
Albumin 
 
Total protein 
 
Circulating carcinoembryonic antigen (CEA) 
Thyroid function 
Thyroid-stimulating hormone (TSH) 
Total tri-iodothyronine (T3) c 
Free thyroxine (FT4) 
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Laboratory assessments 
Parameters 
Other screening tests 
• 
Follicle-stimulating hormone and estradiol (as needed in women of 
non-childbearing potential only) 
• 
Highly sensitive serum or urine human chorionic gonadotropin (hCG) pregnancy 
test (as needed for women of childbearing potential) d 
• 
Serology (HIV antibody if required, hepatitis B surface antigen [HBsAg], and 
hepatitis C virus antibody)  
• 
The results of each test must be entered into the CRF. 
NOTES: 
a If Grade 4 neutropenia, assess ANC every 2-3 days until ANC ≥0.5 x 109/L 
b Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or monitoring event are 
given in Section 8.3.11.5. All events of ≥ Grade 3 ALT/AST increase must be reported as an AESI. Investigators must document their 
review of each laboratory safety report. 
c Total T3 is preferred; if not available free T3 may be tested 
d Serum pregnancy test will be performed at screening and end of treatment. If required to repeat during treatment period, local urine 
testing will be standard for the protocol unless serum testing is required by local regulation or IRB/IEC. 
Investigators must document their review of each laboratory safety report. 
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 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), or more severe than expected for the participant’s condition), 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. 
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• New conditions detected or diagnosed after study intervention administration even though 
it may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. 
• “Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy assessments. 
However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy 
will be reported as AE or SAE if they fulfill the definition of an AE or SAE.  
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 
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outpatient setting. Complications that occur during hospitalization are AEs. 
If a complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
D) Results in persistent disability/incapacity 
- 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
- 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
E) Is a congenital anomaly/birth defect 
F) Other situations: 
- 
Medical or scientific judgment should be exercised in deciding whether SAE reporting 
is appropriate in other situations such as important medical events that may not be 
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 CRF. 
• 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 CRF page. 
• There may be instances when copies of medical records for certain cases are requested by 
Sanofi. In this case, all participant identifiers, with the exception of the participant 
number, will be redacted on the copies of the medical records before submission to the 
Monitoring team. 
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• 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 intensity categories according to NCI-CTCAE v.5.0. 
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as described 
in the definition of an SAE, NOT when it is rated as severe. 
Assessment of causality 
• The Investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. 
• A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
• The Investigator will use clinical judgment to determine the relationship. 
• 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 makes 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. 
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• If a participant dies during participation in the study or during a recognized follow-up 
period, the Investigator will provide the Sponsor with a copy of any post-mortem findings 
including histopathology. 
• 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 Sanofi will be the electronic data 
collection tool. 
• If the electronic system is unavailable, then the site will use the paper SAE data collection 
tool (see next section) in order to report the event within 24 hours. 
• The site will enter the SAE data into the electronic system as soon as it becomes available. 
• After the study is completed at a given site, the electronic data collection tool will be taken 
off-line to prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken off-
line, then the site can report this information on a paper SAE form (see next section) or to 
the Monitoring team by telephone. 
• 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: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION  
DEFINITIONS: 
Woman of childbearing potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below). 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention, additional evaluation should be considered. 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
- 
Documented hysterectomy 
- 
Documented bilateral salpingectomy 
- 
Documented bilateral oophorectomy 
- 
For individuals with permanent infertility due to an alternate medical cause other than 
the above, (eg, mullerian agenesis, androgen insensitivity), Investigator discretion 
should be applied to determining study entry. 
Note: Documentation can come from the site personnel’s: review of the participant’s 
medical records, medical examination, or medical history interview. 
3. Postmenopausal female 
- 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
- 
A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence of 
12 months of amenorrhea, confirmation with more than one FSH measurement is 
required. 
- 
Females on HRT and whose menopausal status is in doubt will be required to use 
one of the non-estrogen hormonal highly effective contraception methods if they 
wish to continue their HRT during the study. Otherwise, they must discontinue 
HRT to allow confirmation of postmenopausal status before study enrollment. 
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CONTRACEPTION GUIDANCE: 
 
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
Highly Effective Methodsb That Have Low User Dependency  
• 
Implantable progestogen-only hormone contraception associated with inhibition of ovulationc 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS)c 
• 
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  
• 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulationc 
- 
oral 
- 
intravaginal 
- 
transdermal 
- 
injectable 
• 
Progestogen-only hormone contraception associated with inhibition of ovulationc 
- 
oral 
- 
injectable 
• 
Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse 
during the entire period of risk associated with the study intervention. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the study and the preferred and usual lifestyle of the participant.) 
a Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive methods for those 
participating in clinical studies.  
b Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those when used consistently and 
correctly. 
c If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable contraceptive methods are limited to 
those which inhibit ovulation as the primary mode of action. 
Note: Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and 
lactational amenorrhoea method (LAM) are not acceptable methods of contraception for this study. Male condom and female condom should 
not be used together (due to risk of failure with friction) 
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COLLECTION OF PREGNANCY INFORMATION:  
Male participants with partners who become pregnant  
• The Investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This 
applies only to male participants who receive study intervention. 
• After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. The 
female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to the Sponsor. 
Generally, the follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. 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. The initial 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. Any termination of 
pregnancy will be reported, regardless of fetal status (presence or absence of anomalies) or 
indication for the procedure. 
• Any pregnancy complication or elective termination of a pregnancy for medical reasons 
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 8.3.4. While the Investigator is not obligated to actively seek this information in 
former study participants, he or she may learn of an SAE through spontaneous reporting.  
• Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention. 
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10.5 
APPENDIX 5: GENETICS  
Use/Analysis of DNA 
• Genetic variation may impact a participant’s response to study intervention, susceptibility 
to, and severity and progression of disease. Variable response to study intervention may be 
due to genetic determinants that impact drug absorption, distribution, metabolism, and 
excretion; mechanism of action of the drug; disease etiology; and/or molecular subtype of 
the disease being treated. Therefore, where local regulations and IRB/IEC allow, a blood 
sample will be collected for DNA analysis from consenting participants. 
• DNA/RNA samples will be used for research related to tusamitamab ravtansine or 
nonsquamous NSCLC and related diseases. They may also be used to develop tests/assays 
including diagnostic tests related to CEACAM5 targeting drug and NSQ NSCLC. Genetic 
research may consist of the analysis of one or more candidate genes or the analysis of 
genetic markers throughout the genome (as appropriate). 
• DNA samples will be analyzed for determination of tumor mutation profile on plasma 
cfDNA. Subtractive mutation analysis will be performed with germline DNA data to 
identify tumor specific somatic genetic aberrations.  
• The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to tusamitamab ravtansine or study interventions of this class to 
understand study disease or related conditions. 
• The results of genetic analyses may be reported in the clinical study report (CSR) or in 
a separate study summary. 
• The Sponsor will store the DNA/RNA samples in a secure storage space with adequate 
measures to protect confidentiality. 
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10.6 
APPENDIX 6: RECOMMENDED SUPPORTIVE CARE AND/OR DOSE MODIFICATION 
GUIDELINES FOR DRUG-RELATED ADVERSE EVENTS  
Table 10 - Recommended dose modification or discontinuation for tusamitamab ravtansine  
Event 
Symptoms severity (NCI 
CTCAE v5) 
Dose modification  
Supportive care guidelines 
Infusion related 
reaction  
Grade 1-2 
Eg, Grade ≤2 nausea, 
headache, tachycardia, 
hypotension, rash, shortness of 
breath. 
Interrupt tusamitamab ravtansine 
infusion. 
Tusamitamab ravtansine may be 
resumed only after patient 
recovery, at half the previous 
infusion ratea. 
Give diphenhydramine 50 mg IV 
and/or dexamethasone 10 mg IV.  
Dexamethasone can be added as 
premedication for upcoming cycles 
for tusamitamab ravtansine 
Grade 3-4 
Eg, symptomatic bronchospasm, 
urticaria lesions covering >30% 
BSA, hypotension, angioedema. 
Interrupt tusamitamab ravtansine 
infusion and permanently 
discontinue tusamitamab 
ravtansine. 
Give diphenhydramine 50 mg IV 
and/or dexamethasone 10 mg IV 
and/or epinephrine and any 
required treatment per investigator 
judgment. 
Ocular toxicity:  
Keratopathy/ 
keratitisb 
associated with 
tusamitamab 
ravtansine 
Grade 1 - Asymptomatic 
Corneal lesions only observed 
on routine ocular examination 
and not requiring topical 
treatment. 
Next infusion of tusamitamab 
ravtansine at the same dose, 
with or without cycle delay, 
depending on the 
recommendation from the 
ophthalmologist (nature and 
extent of the lesion). 
Standard ocular examination is 
planned as recommended by the 
ophthalmologist. 
 
Grade 2 
Symptomatic, moderate 
decrease in visual acuity (best 
corrected visual acuity 20/40 and 
better or 3 lines or less 
decreased vision from known 
baseline) 
1st episode: tusamitamab 
ravtansine cycle delay until 
resolution to Grade 1 
(asymptomatic) and restart 
tusamitamab ravtansine at the 
same dose. 
2nd episode: delay cycle until 
resolution to Grade 1 
(asymptomatic) and 
tusamitamab ravtansine dose 
reduction. 
Standard ocular examination 
weekly until resolutionc, d. 
Start curative treatment per 
ophthalmologist recommendation.  
After resuming study treatment, 
participant should be followed with 
standard ocular examination by 
every two cycles, even 
asymptomatic during next four 
cycles. If no recurrence, standard 
process with follow-up with ocular 
symptom is resumed.  
Management of study drug and 
follow-up process upon recurrence 
to be discussed according to Grade 
of the event at recurrence, clinical 
benefit from study drug and 
recommendation from the 
ophthalmologist.  
Grade 3 
Symptomatic with marked 
decrease in visual acuity (best 
corrected visual acuity worse 
than 20/40 or more than 3 lines 
of decreased vision from known 
baseline, up to 20/200); corneal 
ulcer; limiting self care ADL. 
1st episode: tusamitamab 
ravtansine cycle delay until 
resolution (asymptomatic) and 
restart tusamitamab ravtansine 
with dose reduction. 
2nd episode: permanent 
discontinuation of tusamitamab 
ravtansine.  
 
Grade 4 
Perforation, best corrected visual 
acuity of 20/200 or worse in the 
affected eye 
Permanent discontinuation of 
tusamitamab ravtansine. 
 
Complete the corneal examination 
as recommended by 
ophthalmologist. Repeat the 
standard ocular examination 
weeklyc until resolutiond. 
Start curative treatment per 
ophthalmologist recommendation.  
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Event 
Symptoms severity (NCI 
CTCAE v5) 
Dose modification  
Supportive care guidelines 
Conduction 
disorder 
associated with 
tusamitamab 
ravtansine 
Grade 1 
Mild symptoms 
Tusamitamab ravtansine 
administration to be continued 
upon decision by the Investigator 
and Sponsor, depending on the 
nature of the conduction 
disorder. 
ECG performed once weekly until 
event resolution. 
Additional evaluations such as 
LVEF and Holter monitoring should 
be performed when relevant. 
Grade ≥2 
Permanent discontinuation of 
tusamitamab ravtansine. 
 
ECG to be repeated twice weekly 
until event resolution. 
Prompt cardiology consultation 
Additional evaluations such LVEF 
and Holter monitoring should be 
performed when relevant. 
Neutrophil 
count 
decreased 
Grade 1 
<LLN - 1500/mm3; <LLN - 1.5 × 
109/L 
No change in IMPs 
administration. 
No 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. 
No intervention. 
Grade 3 
<1000 - 500/mm3; <1.0 - 0.5 × 
109/L 
Or 
Grade 4 
<500/mm3; <0.5 × 109/L 
Delay the cycle. 
Restart the treatment when 
absolute neutrophil count 
>1500/mm3 at the same dose. 
Prophylactic G-CSF can be 
considered in all subsequent 
cycle 
Follow ASCO guidelines on usage 
G-CSF and antibiotherapy (18). 
Repeat the 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 at the same dose and 
administer growth factors 
2nd episode: administer 
tusamitamab ravtansine at 
reduced dose 
3rd episode: permanent 
discontinuation 
Follow ASCO guidelines on usage 
G-CSF and antibiotherapy (18). 
Repeat the test every 3 days.  
Febrile 
neutropenia 
Grade 3 
Absolute neutrophil count 
<1000/mm3 with a single 
temperature of >38.3ºC (101ºF) 
or a sustained temperature of 
≥38ºC (100.4ºF) for more than 
1 hour 
Delay cycle until absolute 
neutrophil count >1500/mm3. 
1st episode: administer next 
cycle at the same dose and 
administer G-CSF 
2nd episode: administer 
tusamitamab ravtansine at 
reduced dose 
3rd episode: permanent 
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 (18). 
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Event 
Symptoms severity (NCI 
CTCAE v5) 
Dose modification  
Supportive care guidelines 
Grade 4 
Life-threatening consequences 
Administration changes to be 
decided at the Investigator’s 
discretion. 
1st episode: administer next 
cycle at reduced dose and 
administer G-CSF or 
permanently discontinue  
2nd episode: permanent 
discontinuation  
 
Hepatic 
enzyme 
increase 
Grade 1-2 
Administer tusamitamab 
ravtansine as planned. 
No intervention. 
Grade 3 
1st episode: Delay the cycle. 
Restart the treatment until 
recovery to Grade 1.  
2nd episode: Delay the cycle. 
Restart the treatment until 
recovery to Grade 1 and restart 
at reduced dose.  
3rd Episode: permanent 
discontinuation 
Additional liver function tests will be 
done every 2-3 days until recovery 
to baseline value. 
Grade 4 
Tusamitamab ravtansine should 
be permanently discontinued. 
Additional liver function tests will be 
done every 2-3 days until recovery 
to baseline value. 
Peripheral 
neuropathy  
Grade 1 
Asymptomatic  
No action 
Patient who has ongoing Grade 1 
neuropathy has high risk of 
worsening of his/her symptoms and 
should be closely followed.  
Grade 2 
Moderate symptoms; limiting 
instrumental Activities of Daily 
Living  
Delay cycle, dose reduction if no 
improvement with dose delay  
Grade 3 
Severe symptoms; limiting self 
care Activities of Daily Living  
Permanent discontinuation  
 
Grade 4 
Life-threatening consequences; 
urgent 
Permanent discontinuation 
Hemorrhage 
Grade 3 or 4 
Permanently discontinue 
tusamitamab ravtansine 
 
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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Table 11 - Recommended dose modification or discontinuation for pembrolizumab  
Event 
Symptoms severity 
(NCI CTCAE v4) 
Dose modification  
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. 
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Table 12 - Recommended dose modification for cisplatin/carboplatin and pemetrexed 
hematological toxicity  
Platelets 
ANC 
Pemetrexed 
Cisplatin/Carboplatin 
≥50 × 109/L AND  
≥0.5 × 109/L  
No dose modification 
No dose modification 
≥50 × 109/L AND  
<0.5 × 109/L  
Dose reduction by 1 level 
Dose reduction by 1 level 
<50 × 109/L without bleeding AND  
ANY  
Dose reduction by 1 level 
Dose reduction by 1 level 
<50 × 109/L with Grade ≥2 bleeding AND  
ANY  
Dose reduction by 2 levels 
Dose reduction by 2 levels 
ANY AND  
<1 × 109/L + fever 
≥38.5°C  
Dose reduction by 1 level 
Dose reduction by 1 level 
 
Table 13 - Recommended dose modification for cisplatin/carboplatin and pemetrexed 
nonhematological toxicity  
 
 
Pemetrexed 
Cisplatin 
Carboplatin 
Events 
CTC Grade 
Dose adjustment 
Nausea or vomiting  
Grade 3 or 4 
No dose modification 
No dose modification 
No dose 
modification 
Diarrhea  
Grade 3 or 4  
Dose reduction by 1 level 
Dose reduction by 1 level 
No dose 
modification 
Mucositis  
Grade 3 or 4 
Dose reduction by 
2 levels 
No dose modification 
No dose 
modification 
Neurotoxicity  
Grade 2  
No dose modification 
Dose reduction by 2 levels 
No dose 
modification 
Grade 3 or 4 
Dose reduction by 1 level 
Discontinue 
Dose reduction by 
1 level 
Transaminase elevation 
Grade 3 
Dose reduction by 1 level 
Dose reduction by 1 level  
Dose reduction by 
1 level  
Grade 4 
Discontinue 
Discontinue 
Discontinue 
Other nonhematological 
toxicity  
Grade 3 or 4  
Dose reduction by 1 level 
Dose reduction by 1 level 
Dose reduction by 
1 level 
 
10.7 
APPENDIX 7: COUNTRY-SPECIFIC/REGION REQUIREMENTS  
Serology for HBsAg and HCV and HIV test at screening will be performed only if required at the 
country level, such as Czech Republic. 
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10.8 
APPENDIX 8: STRONG CYP3A INHIBITORS  
Table 14 - List of strong CYP3A inhibitors  
STRONG CYP3A INHIBITORS 
CYP3A 
inhibitors 
Precipitant Therapeutic 
Class 
Victim  
(oral, unless otherwise specified) 
AUC Ratio 
Potent CYP3A Inhibitors (yielding substrate AUC ratio >5) 
VIEKIRA PAK  
Antivirals 
Tacrolimus 
55.76 
Telaprevir  
Antivirals 
Midazolam 
13.5 
Indinavir/RIT  
Protease inhibitors 
Alfentanil 
36.50 
Tipranavir/RIT  
Protease inhibitors 
Midazolam 
26.91 
Ritonavir  
Protease inhibitors 
Midazolam 
26.41 
Cobicistat  
Pharmacokinetic Enhancer 
Midazolam 
19.03 
Indinavir  
Protease inhibitors 
Midazolam 
9.67 
Ketoconazole  
Antifungals 
Midazolam 
17.08 
Troleandomycin  
Antibiotics 
Midazolam 
14.80 
Saquinavir/RIT  
Protease inhibitors 
Midazolam 
12.48 
Itraconazole  
Antifungals 
Midazolam 
10.80 
Voriconazole 
Antifungals 
Midazolam 
9.63 
Mibefradil  
Calcium Channel Blockers 
Midazolam 
8.86 
Clarithromycin  
Antibiotics 
Midazolam 
8.39 
Danoprevir/RIT  
Antivirals 
Midazolam 
13.42 
Lopinavir/RIT  
Protease inhibitors 
Alfentanil 
11.47 
Elvitegravir/RIT  
Treatments of AIDS 
Midazolam 
12.8 
Posaconazole  
Antifungals 
Midazolam 
6.23 
Telithromycin  
Antibiotics 
Midazolam 
6.2 
Conivaptan  
Vasopressin antagonists 
Midazolam 
5.76 
Nefazodone  
Antidepressants 
Midazolam 
5.44 
Nelfinavir  
Protease inhibitors 
Midazolam 
5.29 
Saquinavir  
Protease inhibitors 
Midazolam 
5.18 
Boceprevir  
Antivirals 
Midazolam 
5.05 
Idelalisib  
Kinase inhibitors 
Midazolam 
5.15 
LCL161  
Cancer treatments 
Midazolam 
8.80 
Mifepristone  
Antiprogestins 
Simvastatin 
10.40 
Ceritinib  
Kinase Inhibitors 
Midazolam 
5.42 
Ribociclib  
Kinase Inhibitors 
Midazolam 
5.17 
Josamycin  
Antibiotics 
Ivabradine 
7.70 
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STRONG CYP3A INHIBITORS 
CYP3A 
inhibitors 
Precipitant Therapeutic 
Class 
Victim  
(oral, unless otherwise specified) 
AUC Ratio 
Potent CYP3A Inhibitors (yielding substrate AUC ratio >5) 
Tucatinib  
Kinase Inhibitors 
Midazolam 
5.74 
Lonafarnib 
Other 
Midazolam 
7.39 
List extracted from the Drug Interaction Database from the University of Washington (Home Page: www.druginteractioninfo.org; 
https://didb.druginteractionsolutions.org/resources/list-of-substrates-inhibitors-and-inducers/?Oid=1130), updated in 
October 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. 
10.9 
APPENDIX 9: RESPONSE EVALUATION CRITERIA IN SOLID TUMORS VERSION 1.1  
Details provided in bibliographic reference (2). 
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 truly non-measurable 
lesions. Lesions considered non-measurable include: leptomeningeal disease, ascites, pleural or 
pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, 
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: 
1. Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts. 
2. ‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
• Lesions with prior local treatment: 
1. Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion. 
Method of assessment 
All measurements should be recorded in metric notation, using calipers if clinically assessed. All 
baseline evaluations should be performed as close as possible to the treatment start and never 
more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging based evaluation should 
always be performed rather than clinical examination unless the lesion(s) being followed cannot 
be imaged but are assessable by clinical examination. 
• Clinical lesions: Clinical lesions will only be considered measurable when they are 
superficial and ≥10 mm diameter as assessed using calipers. For the case of skin lesions, 
documentation by color photography including a ruler to estimate the size of the lesion is 
suggested. As noted above, when lesions can be evaluated by both clinical exam and 
imaging, imaging evaluation should be undertaken since it is more objective and may be 
reviewed at the end of the study. 
• Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is 
an important endpoint, since CT is more sensitive than X-ray, particularly in identifying 
new lesions. However, lesions on chest X-ray may be considered measurable if they are 
clearly defined and surrounded by aerated lung. 
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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’). 
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Response criteria 
Response criteria are described in Table 15. 
Table 15 - 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. 
• Progressive Disease: Unequivocal progression of existing non-target lesions. (Note: the 
appearance of 1 or more new lesions is also considered progression). 
The concept of progression of non-target disease requires additional explanation as follows: 
When the participant also has measurable disease; in this setting, to achieve ‘unequivocal 
progression’ on the basis of the non-target disease, there must be an overall level of substantial 
worsening in non-target disease such that, even in presence of SD or PR in target disease, the 
overall tumor burden has increased sufficiently to merit discontinuation of therapy. A modest 
‘increase’ in the size of 1 or more non-target lesions is usually not sufficient to qualify for 
unequivocal progression status. 
When the participant has only non-measurable disease; to achieve ‘unequivocal progression’ on 
the basis of the non-target disease, there must be an overall level of substantial worsening such 
that the overall tumor burden has increased sufficiently to merit discontinuation of therapy. 
A modest ‘increase’ in the size of 1 or more non-target lesions is usually not sufficient to qualify 
for unequivocal progression status. Because worsening in non-target disease cannot be easily 
quantified (by definition: if all lesions are truly non-measurable) a useful test that can be applied 
when assessing patients for unequivocal progression is to consider if the increase in overall 
disease burden based on the change in non-measurable disease is comparable in magnitude to the 
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 pre-existing lesions). This is particularly 
important when the participant’s baseline lesions show PR or CR. For example, necrosis of a liver 
lesion may be reported on a CT scan report as a ‘new’ cystic lesion, which it is not. 
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A lesion identified on a follow-up study in an anatomical location that was not scanned at baseline 
is considered a new lesion and will indicate disease progression. An example of this is the patient 
who has visceral disease at baseline and while on study has a CT or MRI brain ordered which 
reveals metastases. The participant’s brain metastases are considered to be constitute PD even if 
he/she did not have brain imaging at baseline. 
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents new disease. If repeat scans confirm that there is 
a new lesion, then progression should be declared using the date of the initial scan. 
While fluorodeoxyglucose-positron emission tomography (FDG-PET) response assessments need 
additional study, it is sometimes reasonable to incorporate the use of FDG-PET scanning to 
complement CT scanning in assessment of progression (particularly possible ‘new’ disease). New 
lesions on the basis of FDG-PET imaging can be identified according to the following algorithm: 
1. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
2. No FDG-PET at baseline and a positive FDG-PET at follow-up: 
If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this 
is PD. 
If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional 
follow-up CT scans are needed to determine if there is truly progression occurring at that site 
(if so, the date of PD will be the date of the initial abnormal FDG-PET scan). If the positive 
FDG-PET at follow-up corresponds to a pre-existing site of disease on CT that is not progressing 
on the basis of the anatomic images, this is not PD. 
Evaluation of best overall response 
Time point response: At each protocol specified time point, a response assessment should occur. 
Table 16 provides a summary of the overall response status calculation at each time point for 
patients who have measurable disease at baseline. 
Table 16 - Response in patients with target disease  
Target lesions 
Non-target lesions 
New lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
Inevaluable 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Abbreviations: CR=complete response; PD=progressive disease; PR=partial response; SD=stable disease.  
When patients have non-measurable (therefore non-target) disease only, Table 17 is to be used. 
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Table 17 - 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 duration of overall response is measured from the time measurement criteria are first met for 
CR/PR (whichever is first recorded) until the first date that recurrent or PD is objectively 
documented (taking as reference for PD the smallest measurements recorded on study). 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that recurrent disease is objectively documented. 
Duration of stable disease 
Stable disease is measured from the start of the treatment until the criteria for progression are met, 
taking as reference the smallest sum on study (if the baseline sum is the smallest, this is the 
reference for calculation of PD). 
Reproduced from: Eisenhauer EA, Therasse P, Bogaerts J et al. New response evaluation criteria 
in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228-47.(2) 
10.10 APPENDIX 10: MASCC CORTICOSTEROID DOSING GUIDELINES 
(2016 GUIDELINES)  
Table 18 - Recommended corticosteroid (dexamethasone) dosing  
Dexamethasonea 
Dose and Schedule 
High Risk 
Acute Emesis 
20 mg once 
(12 mg when used with [fos] aprepitant or netupitant)b 
Delayed Emesis 
8 mg bid for 3 - 4 days 
(8 mg once daily when used with (fos)aprepitant or netupitant) 
Moderate Risk 
Acute Emesis 
8 mg once 
Delayed Emesis 
8 mg daily for 2 - 3 days 
(many panelists give the dose as 4 mg bid) 
Low Risk 
Acute Emesis 
4 - 8 mg once 
a While corticosteroids other than dexamethasone are effective antiemetics, the dose and schedule of dexamethasone coupled with its 
wide availability in various dose forms established it as the guideline agent of choice. 
b The 12 mg dose of dexamethasone is the only one tested with (fos)aprepitant/netupitant in large randomized trials. 
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 the COVID-19 
pandemic. 
Continuation of the study in the event of a regional or national emergency declared by 
a governmental agency: 
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A regional or national emergency declared by a governmental agency (eg, public health 
emergency, natural disaster, pandemic, and terrorist attack) may prevent access to the clinical trial 
site. 
Contingency procedures to ensure the safety of the participants, to protect trial integrity, to maintain 
continuity of study conduct, and to support compliance with GCP in Conduct of Clinical Trials 
Guidance for an emergency that prevents access to the study site are suggested below and in 
Section 5.5, Section 7.1.2, Section 8, Section 9.4.4, and Section 10.1.2. The agreement of the Sponsor 
MUST be obtained prior to the implementation of these procedures for the duration of the emergency. 
During the emergency, if the site will be unable to adequately follow protocol-mandated 
procedures, alternative treatment outside the clinical trial should be proposed, and 
screening/enrollment/administration of study intervention may be temporarily delayed/halted 
(see also Section 5.5). Attempts should be made to perform all assessments in accordance with the 
approved protocol to the extent possible. In case this is not possible due to a temporary disruption 
caused by an emergency, focus should be given to assessments necessary to ensure the safety of 
participants and those important to preserving the main scientific value of the study. 
Contingencies implemented due to emergency will be documented. 
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 
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. 
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• If a participant agrees to participate in the prescreening phase, the participant should print 
out, sign, and date 2 copies of the ICF. A scan of a signed ICF should be sent via secured 
e-mail (if available), and 1 of the signed original ICFs to be filed in the Investigator Study 
File should be sent via postal mail.  
• 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. After properly documenting this consent process, the site may proceed to prepare 
and send the slides for CEACAM5 assessment. It is mandatory for the Investigator to ensure 
the collection of the original signed ICF sent by mail; the signed original should be attached to 
any previously filed signed printout of an electronically submitted signed ICF. 
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 judgment and depending on 
the country/site status, should be communicated to the participant. The participant should satisfy 
all eligibility criteria before enrolling to the study; 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, reinitiation) of the 
IMP can occur only once the Investigator has determined, according to his/her best judgment, that 
the contribution of the IMP(s) to the occurrence of the epidemic event (eg, COVID-19) was unlikely. 
Any further safety measure (eg, interim laboratory assessment such as neutrophil count 
monitoring; regular contact with site staff) to follow the safety of patients during the regional or 
national emergency period can be considered.  
10.11.4 Study procedures  
All efforts should be made to ensure that measurements of key parameters for efficacy endpoints 
can be performed at the site. If the Investigator is unable to guarantee that the protocol-required 
efficacy assessments can be conducted, no participant should be screened until the site confirms 
its capacity to perform the assessments.  
As part of a site’s contingency plan, a back-up site should be identified in advance in the case that 
the site delegated to perform the radiological tumor assessment is prevented from performing the 
assessment by a regional or national emergency situation (eg, COVID-19 outbreak). The 
Investigator should ensure that the back-up site conducts the RECIST assessment in same manner 
as that used for baseline tumor assessments.  
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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. 
Depending on site status, if needed, 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.  
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. 
10.11.6 Informed consent process  
For a regional or national emergency declared by a governmental agency, contingency procedures 
may be implemented for the duration of the emergency. The participant should be informed 
verbally prior to initiating any change that is to be implemented for the duration of the emergency 
(eg, study visit delays, use of back-up sites for safety laboratory or tumor assessment). 
10.12 APPENDIX 12: ABBREVIATIONS  
 
ADC: 
antibody-drug conjugate 
AE: 
adverse event 
AESI: 
adverse event of special interest 
AIDS: 
acquired immunodeficiency syndrome 
ALK: 
anaplastic lymphoma kinase 
ALT: 
alanine aminotransferase 
ANC: 
absolute neutrophil count 
AP: 
alkaline phosphatase 
AST: 
aspartate aminotransferase 
BSA: 
body surface area 
BUN: 
blood urea nitrogen 
C: 
cycle 
CEA: 
carcinoembryonic antigen 
CEACAM5: 
carcinoembryonic antigen-related cell adhesion molecule 5 
cfDNA: 
circulating free deoxyribonucleic acid 
CI: 
confidence interval 
CR: 
complete response 
CT: 
computed tomography 
CTLA-4: 
cytotoxic T-lymphocyte-associated antigen 4 
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D: 
day 
DCR: 
disease control rate  
DL: 
dose level 
DL-1: 
dose level minus 1 
DLT: 
dose-limiting toxicity 
DNA: 
deoxyribonucleic acid 
DOR: 
duration of response 
ECG: 
electrocardiogram 
ECOG: 
Eastern Cooperative Oncology Group 
eCRF: 
electronic case report form 
eGFR: 
glomelular filtration rate (estimated) 
EGFR: 
epidermal growth factor receptor 
EOT: 
end of treatment 
FDG-PET: 
fluorodeoxyglucose-positron emission tomography 
FFPE: 
formalin-fixed, paraffin embedded 
FIH: 
first-in-human 
GCP: 
Good Clinical Practice 
HBsAg: 
hepatitis B surface antigen 
HCV: 
hepatitis C virus 
HIV: 
human immunodeficiency virus 
HNSCC: 
head and neck squamous cell carcinoma 
ICF: 
informed consent form 
ICH: 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
ICI: 
immune-checkpoint inhibitor 
IMP: 
investigational medicinal product 
INR: 
international normalized ratio 
IV: 
intravenous 
LDH: 
lactate dehydrogenase 
MDRD: 
modification of diet in renal disease 
MedDRA: 
medical dictionary for regulatory activities 
MRI: 
magnetic resonance imaging 
NE: 
not evaluable 
NSCLC: 
non-small-cell lung cancer 
NSQ: 
nonsquamous 
NSQ NSCLC: 
nonsquamous, non-small-cell lung cancer 
ORR: 
objective response rate 
OS: 
overall survival 
PD: 
pharmacodynamic 
PD-1: 
programmed cell death protein 1 
PD-L1: 
programmed death-ligand 1 
PD-L2: 
programmed death-ligand 2 
PFS: 
progression-free survival 
PS: 
performance status 
PT: 
preferred term 
RECIST: 
response evaluation criteria in solid tumors 
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RNA: 
ribonucleic acid 
SAP: 
statistical anlysis plan 
SGOT: 
serum glutamic-oxaloacetic transaminase 
SGPT: 
serum glutamic-pyruvic transaminase 
SJS: 
Stevens-Johnson syndrome 
SoA: 
schedule of activities 
SOC: 
system organ class 
TEN: 
toxic epidermal necrolysis 
TPS: 
tumor proportion score 
TSH: 
thyroid-stimulating hormone 
ULN: 
upper limit of normal 
US: 
United States 
VS: 
vital signs 
WBC: 
white blood cell 
WOCBP: 
woman of childbearing potential 
10.13 APPENDIX 13: PROTOCOL AMENDMENT HISTORY  
There have been 5 previous amendments (Amended protocol 05, 04 July 2022; 
Amended protocol 01, 23 November 2020; Amended protocol 02, 25 January 2021; 
Amended protocol 03, 04 May 2021, Amended protocol 04, 18 August 2021); these changes are 
summarized in this section. The Protocol Amendment Summary of Changes Table for the current 
amendment (Amended protocol 05) is located directly before the Table of Contents (TOC). 
Amended protocol 01 (23 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.  
OVERALL RATIONALE FOR THE AMENDMENT 
This amendment is intended primarily to add a SAR408701 dose level of 170 mg/m2 Q3W to be 
evaluated in Part A based on data from the SAR408701 170 mg/m2 Q3W cohort in 
Study TED13751 and to add Part B of two treatment arms to evaluate the safety and anti-tumor 
activity of SAR408701 in combination with pembrolizumab and platinum-based chemotherapy in 
NSQ NSCLC patients positive for CEACAM5 (≥50%).  
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Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Cover page and 1.1 Synopsis, Short title 
CARMEN-LC05 was added. 
To include study acronym. 
OVERALL RATIONALE FOR THE 
AMENDMENT 
Added rationales for new SAR408701 
170 mg/m2 Q3W cohort in Part A and 
2 new treatment arms in Part B.  
To explain reasons for important 
changes to study design. 
1.1 Synopsis, Objectives and endpoints; 
Section 3 Objectives and endpoints; 
9.1 Statistical hypotheses 
Added “Part A” to Part 1 and Part 2 
primary objective and endpoint, and 
added new primary objective and endpoint 
for Part B; specified hypotheses for Part A 
and new Part B.  
To clarify primary objectives and 
endpoints for Part A and introduce 
new primary objective and endpoint 
for new Part B. 
1.1 Synopsis, Section 3 Objectives and 
endpoints 
Modified secondary safety and tolerabilty 
objective to include SAR408701 in 
combination with pembrolizumab and 
platinum-based chemotherapy. 
To reflect addition of new Part B to 
study. 
1.1 Synopsis, Section 3 Objectives and 
endpoints; 8.5 Pharmacokinetics 
Modified secondary PK objective and 
endpoints to include cisplatin and 
carboplatin pharmacokinetics, and added 
assessments. 
To reflect addition of new Part B to 
study. 
1.1 Synopsis, Objectives and endpoints; 
Section 3 Objectives and endpoints 
Modified secondary immunogenicity 
objective to include platinum-based 
chemotherapy. 
To reflect addition of new Part B to 
study. 
1.1 Synopsis, Objectives and endpoints; 
Section 3 Objectives and endpoints 
Added new secondary objective to include 
antitumor activity of SAR408701 
administered with pembrolizumab and 
with pembrolizumab combined with 
platinum-based chemotherapy. 
To reflect addition of new Part B to 
study. 
1.1 Synopsis, Objectives and endpoints; 
Section 3 Objectives and endpoints 
Added secondary endpoint of objective 
response rate in participants treated with 
pembrolizumab and platinum-based 
chemotherapy. 
To reflect addition of new Part B to 
study. 
Section 3 Objectives and endpoints 
Modified tertiary/exploratory objective of 
circulating CEA evaluation to include CEA 
assessments at prescreening, and 
specified endpoint at prescreening, 
screening, and during the treatment 
period. 
To reflect addition of new 
prescreening time point for 
assessment of circulating CEA. 
1.1 Synopsis, Overall design; 
4.3 Justification for dose; 6.1 Study 
interventions; 6.6.1 Determination of 
recommended doses (Part 1 and 
Part B); 6.6.2 Individual dose 
modification (Part A and Part B) 
The dose level of SAR408701 170 mg/m2 
was added. 
Based on the results of TED13751 
study, the recommended dose of 
SAR408701 can be 170 mg/m2 Q3W. 
1.1 Synopsis, Overall design; 
9.2 Sample size determination 
Updated planned numbers of participants 
in Part A and added numbers of 
participants planned for Part B. 
To update estimates of numbers of 
participants to be enrolled based on 
addition of new doses and study 
arms. 
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Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis, Figure 1 
Modified decision tree for SAR408701 
dose selection was moved to synopsis 
and specified both for Part 1 of Part A and 
for Part B. 
To clarify that it applies to both Part A 
and Part B of the study. 
1.1 Synopsis, Overall design; 
1.3 Schedule of activities; 8.1 Efficacy 
assessments 
specified timing of tumor assessments 
after End of Treatment visit as every 
12 weeks (±7 days) after the last tumor 
assessment.  
To clarify scheduling of tumor 
assessments for participants who 
discontinue study treatment. 
1.2 Schema 
Original study schema labeled Part A; 
new schema added for Part B.  
To accommodate addition of Part B to 
the study. 
1.3 Schedule of activities (SoA) 
Correction of “PD-L1 positivity” to “PD-L1 
Expression”. 
For clarity. 
1.3 Schedule of activities (SoA) 
“Correction of Randomization/allocation” 
to “Randomization (Part A)”. 
For clarity. 
1.3 Schedule of activities (SoA); 
8.2.6 Clinical safety laboratory 
assessements 
Hematology, Liver function tests. 
Hematology and liver function tests 
will be repeated during first 2 cycles 
of Part 2 to monitor the safety of 
SAR408701 treatment. 
1.3 Schedule of activities (SoA); 
10.2 Appendix 2 
Glucose assessment was added. 
Glucose is part of blood chemistry 
test. 
1.3.2.2 PK/ATA flow chart for Part B 
New table added. 
To reflect PK analysis of new arms of 
triplet combination treatment. 
4.1 Overall design 
Part B was added to the overall study 
design. 
To reflect new arms of triplet 
combination treatment. 
4.3 Justification for dose  
Rationale of SAR408701 170 mg/m2 Q3W 
was added. 
Based on the results of TED13751 
study, the recommended dose of 
SAR408701 can be 170 mg/m2 Q3W. 
4.4 End of study definition 
Specified estimated study cut-off date at 
10 months after the last participant’s 
randomization in Part A”. 
For clarity. 
5.1 Inclusion criteria, I04 
5 slides required instead of 7. 
CEACAM5 IHC requirement changed. 
5.1 Inclusion criteria, I05 
For participants enrolled to Part A added.  
Only applicable to Part A. 
5.1 Inclusion criteria, I08 
required contraception for at least 
6 months after the last dose of platinum-
based chemotherapy. 
In accordance with male 
contraception guidance for platinum-
based chemotherapy.  
5.2 Exclusion criteria, E11 
Specified required resolution of toxicity of 
prior therapy to CTCAE Grade <2, rather 
than to Grade 2. 
For clarity. 
5.2 Exclusion criteria, E19 
Specified that required washout period for 
prior treatment is the shorter of 3 weeks or 
5 × half life. 
For clarity. 
5.4 screen failures 
Procedure for screen failures modified 
such that rescreened participants are to 
be assigned a different participant number 
from that issued for the initial screening, 
rather than the same number, as originally 
specified. 
According to FDA guidance, 
a different participant number should 
be assigned to the rescreened 
participant. 
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Section # and Name 
Description of Change 
Brief Rationale 
5.5 Criteria for temporary delaying 
enrollment 
Section updated to include details of 
guidance in case of regional or national 
emergency; link to new Appendix 11.  
As guidance for standardization 
across studies.  
6.1 Study interventions administered 
Cisplatin and carboplatin added to the 
interventions. 
To reflect new arms of triplet 
combination treatment. 
6.6.1 Determination of recommended 
dose 
The dose level of SAR408701 170 mg/m2 
was added. 
Based on the results of TED13751 
study, the recommended dose of 
SAR408701 can be 170 mg/m2 Q3W. 
6.6.2 Individual dose modification 
(Part 1 and Part 2) 
Specified that dose is permanently 
reduced after a dose reduction. 
For clarity. 
7.1.1 Definitive discontinuation 
Added pregnancy to list of reasons study 
intervention should be discontinued. 
For clarity, in keeping with 
requirement to discontinue in case of 
participant pregnancy. 
7.1.2 Temporary discontinuation 
Section updated to include details of 
guidance in case of regional or national 
emergency; link to new Appendix 11.  
As guidance for standardization 
across studies. 
7.1.2.1 Rechallenge 
Section updated to include details of 
guidance in case of regional or national 
emergency; link to new Appendix 11.  
As guidance for standardization 
across studies.  
7.2 Participant 
discontinuation/withdrawal 
“rerandomized” changed to 
“rerandomized/reallocated”. 
Clarification regarding prohibition of 
re-enrollment of withdrawn 
participants, whether or not they are 
randomized. 
8 Study Assessments and Procedures 
Section updated to include details of 
guidance in case of regional or national 
emergency; link to new Appendix 11.  
As guidance for standardization 
across studies.  
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. 
8.3.4 Regulatory reporting requirement 
for SAEs 
Updated with deletion of the text on 
reporting timelines for SUSARs.  
Aligned with the internal PV 
guidelines. 
8.3.7 Disease-related events and/or 
disease-related outcomes not qualifying 
as AEs or SAEs 
The paragraph deleted. 
For clarity. 
8.3.8 Adverse event of special interest 
Added dose-limiting toxicity (DLT) to list of 
adverse events of special interest (AESI). 
Change to reporting of DLT events. 
8.11 Use of biological samples and data 
for future research 
Section added to include details of use of 
biological samples and data for future 
research. 
Requirement from new protocol 
template. 
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Section # and Name 
Description of Change 
Brief Rationale 
9.4 Statistical analyses 
Section updated to include statistical 
analyses for Part B 
To reflect new arms of triplet 
combination treatment. 
9.4.4 Study assessments and 
procedures 
Section updated to include details of 
guidance in case of regional or national 
emergency; link to new Appendix 11.  
As guidance for standardization 
across studies.  
9.5 Interim analyses 
Added possible interim analysis for Part A 
when study cut-off for primary analysis of 
Part B is reached. 
To permit project planning. 
10.1.2 Informed consent process 
Updated ICF process for re-screening and 
use of biological samples and data.  
For clarity. 
10.1.2 Informed consent process 
Section updated to include details of 
guidance in case of regional or national 
emergency; link to new Appendix 11.  
Per guidance for standardization 
across studies.  
10.1.4 Committee structure 
Language modified with regard to 
investigators who may be included in the 
Study Committee.  
To reflect addition of new Part B of 
the study. 
10.2 Appendix 2 
Removed CEACAM5 expression and 
PD-L1 expression.  
For clarity. 
10.2 Appendix 2 
Updated footnote for pregnancy test. 
For clarity. 
10.6 Appendix 6: Recommended 
supportive care and/or dose modification 
guidelines for drug-related adverse 
events 
New section for managing GI toxicity. 
For clarity of safety management 
guidelines. 
10.7 Appendix 7: Country-specific 
requirements 
Mentioned Czech Republic as a specific 
example of a country requiring additional 
serological testing at screening. 
Per Health Authority’s request. 
10.11 Appendix 11 
New appendix added to detail contingency 
measures for a regional or national 
emergency.  
To harmonize across sites actions 
taken in response to regional or 
national emergency.  
Throughout 
Correction of typographical errors and 
standardization of wording. 
To increase clarity. 
Amended protocol 02 (25 January 2021) 
This amended protocol 02 (Amendment 02) is considered to be nonsubstantial based on the 
criteria set forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the 
Council of the European Union.  
OVERALL RATIONALE FOR THE AMENDMENT 
This amendment is intended to correct the typographical errors in Table 6 and Table 13 to clarify 
the first and second reduced doses of carboplatin in response to toxicity, as well as recommended 
hematological thresholds for carboplatin/cisplatin dose reductions.  
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Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
6.6 Dose modification, Table 5 
Staring dose updated to Initial dose. 
To clarify 
6.6 Dose modification, Table 6 
DL 0 updated to Initial dose 
DL -1 updated to Dose reduction level -1 (DL -1) 
DL -2 updated to Dose reduction level -2 (DL -2) 
To clarify 
6.6 Dose modification, Table 6 
Carboplatin dose level -1 updated from AUC 5 to 
AUC 3.75  
Carboplatin dose level -2 updated from AUC 5 to 
AUC 2.5 
To correct typographical errors and 
to clarify carboplatin dose reductions 
in response to toxicity 
10.6 Appendix 6 Recommended 
supportive care and/or dose 
modification guidelines for drug-
related adverse events, Table 13 
Specified recommended platelet threshold for 
reducing cisplatin/carboplatin to DL -1 as 
<50 × 109/L; and platelet threshold for reducing to 
DL –2 as <50 × 109/L with Grade ≥2 bleeding 
To correct typographical errors to 
clarify recommended 
thrombocytopenia thresholds for 
cisplatin/carboplatin dose reduction 
10.6 Appendix 6 Recommended 
supportive care and/or dose 
modification guidelines for drug-
related adverse events, Table 13 
Specified recommended threshold of ANC 
<1 × 109/L with fever with any platelet value for 
reducing cisplatin/carboplatin dose level to DL -1 
To correct typographical errors to 
clarify recommended neutropenia 
threshold for dose reduction 
10.6 Appendix 6 Recommended 
supportive care and/or dose 
modification guidelines for drug-
related adverse events, Table 13 
Updated DL 0, DL -1, and DL -2 respectively to  
No dose modification, Dose reduction by 1 level, 
and Dose reduction by 2 levels 
To clarify 
10.6 Appendix 6 Recommended 
supportive care and/or dose 
modification guidelines for drug-
related averse events 
(Cisplatin/Carboplatin 
hematological toxicity, Table 14) 
Updated DL 0, DL -1, and DL --2 respectively to  
No dose modification, Dose reduction by 1 level, 
and Dose reduction by 2 levels 
To clarify 
Amended protocol 03 (04 May 2021) 
This amended protocol 03 (Amendment 03) is considered to be substantial based on the criteria 
set forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of 
the European Union.  
OVERALL RATIONALE FOR THE AMENDMENT 
The main purpose of this amendment is to remove the pembrolizumab single agent arm from 
Part A of this study. This is due to difficulties in enrolling participants with NSCLC expression 
PD-L1 TPS ≥1% to be treated, given in many investigational sites, the standard of care for 
patients PD-L1 TPS <50% is to combine pembrolizumab with chemotherapy. Even though in the 
US pembrolizumab single agent is approved for the first line treatment of patients with NSCLC 
expressing PD-L1 TPS ≥1%, it is challenging for investigators to enroll in Part A.  
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Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Cover page Title, 
Section 1.1: Protocol title 
Replaced “pembrolizumab alone” with 
“tusamitamab ravtansine (SAR48701) combined 
with pembrolizumab and platinum-based 
chemotherapy in patients with CEACAM5-positive” 
“Randomized, and PD-L1 positive” were removed 
from title 
Added “Tusamitamab ravtansine” INN name 
To reflect the change: 
• 
Removing pembrolizumab 
alone arm in Part A. 
• 
Adding the platinum-based 
chemotherapy Part B as per 
protocol amendment 1.  
The approved product name was added  
Cover page Compound 
number (INN/Trademark) 
INN name, tusamitamab ravtansine was added 
The newly approved INN name was 
added 
Section 1.1:Short title 
Replaced “pembrolizumab alone” with 
“tusamitamab ravtansine (SAR408701) in 
combination with pembrolizumab and platinum-
based chemotherapy” 
 
 
 
Added “Tusamitamab ravtansine” product name 
To reflect the change of study design by: 
• 
Removing pembrolizumab 
alone arm in Part A. 
• 
Adding the platinum-based 
chemotherapy Part B as per 
protocol amendment 1. 
The approved product name was added 
Cover page Regulatory 
agency identifier number(s) 
Added the NCT number  
The missing NCT number was added 
Document history 
“Amended Clinical Trial Protocol 03” and 
information was added  
To reflect the change of this amended 
protocol  
1.1 Synopsis (Rationale) 
“TED13751” study number added  
 
“and for PD-L1 (≥1%)” was removed  
 
“in US” was added  
To provide details on the ongoing Phase 
1 study  
To reflect the change of removing the 
pembrolizumab alone arm 
To clarify the first line treatment of 
patients with NSCLC 
1.1 Synopsis (Objectives 
and endpoints), Section 3 
Objectives and endpoints 
Removed objectives and endpoints of 
pembrolizumab single agent arm 
 
Removed “response evaluation criteria in solid 
tumors” from secondary endpoints 
 
Added: “first investigational medicinal product 
(IMP) administration” to the third secondary 
endpoint 
To reflect the change of removing the 
pembrolizumab alone arm 
 
To maintain only the abbreviation 
 
 
The first IMP added since randomization 
was removed (only single arm in Part A) 
1.1 Synopsis (Overall 
Design), Section 4.1 Study 
Design 
Sections were updated to remove pembrolizumab 
single agent arm and PD-L1 requirement for Part A 
Sample size updated 
 
"During the screening phase, only participants with 
NSQ NSCLC determined to be CEACAM5 
positive will go through protocol screening 
procedures. Participants will be enrolled in Part A 
or Part B per investigator’s choice” was added 
 
The following text was added “(±5 days) and  
(±7 days) 
To reflect the change of removing the 
pembrolizumab alone arm 
 
Remove pembrolizumab alone arm 
 
To clarify 
 
 
 
Added to be consistent with schedule of 
activities 
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Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis (Number of 
participants), 
Section 9.2 (Sample Size 
Determination) 
The following text was added: “Note: "Enrolled" 
means a participant's, or their legally acceptable 
representative’s, agreement to participate in 
a clinical study following completion of the 
informed consent process. Potential participants 
who are screened for the purpose of determining 
eligibility for the study, but do not participate in the 
study, are not considered enrolled, unless 
otherwise specified by the protocol” 
Added to be consistent with template 
language 
1.1 Synopsis (Intervention 
groups and duration) 
The safety cut-off for primary safety endpoint 
analysis added 
 
The following text was removed: “except PK” 
 
“15 minutes to”; “depending on the administration 
form IV or oral [15 minutes prior for IV and 1 hour 
prior for oral] were added 
Cut-off updated to include primary safety 
endpoint analysis in Part A in addition to 
Part B 
To clarify that the patients will undergo all 
assessments, including PK 
To provide detailed NIMP instructions 
1.1 Synopsis (Statistical 
considerations) 
Changes made to sample size and primary 
population for analysis.  
To reflect the change of removing the 
pembrolizumab alone arm 
1.2 Schema 
Removed pembrolizumab single agent arm and 
PD-L1 requirement for Part A; PD-L1 TPS and 
footnote relating to PD-L1 TPS is removed from 
Figure 2 
To reflect the change of removing the 
pembrolizumab alone arm and PD-L1 
requirement for Part A 
1.2 Schema 
“to -10 days” is added to screening ICF in  
Figures 2 and 3 
“Confirmed disease progression” added to  
Figure 3 
Figure updated to be consistent with 
Section 4.1 
1.2 Schema 
“DLT” abbreviation removed from Figure 3 
footnote, and “NSQ NSCLC” was added 
Changes made according to the figure 
update 
1.3.1 Schedule of activities 
(SOA) 
Removed “randomization (Part A)” and “Every 
effort should be made to start first IMP 
administration within 3 working days of 
randomization (Part A)”  
No randomization as only single arm in 
Part A 
1.3.1 Schedule of activities 
(SOA) 
Text related to “PD-L1 (Part A)” was removed from 
footnotes a and b  
To reflect the change of removing the 
pembrolizumab alone arm and PD-L1 
requirement for Part A 
1.3.1 Schedule of activities 
(SOA) 
Tumor assessment notes were updated to “every 
12 weeks (±7 days) after the last TA until 
confirmed disease progression, initiation of a new 
anticancer treatment, death, withdrawal of 
participant’s consent, or study cut-off date for 
secondary efficacy endpoints, whichever comes first 
To provide additional information to the 
tumor assessment 
1.3.2 PK/ATA flowchart 
"in combination arm for both drugs and in control 
arm for pembrolizumab only" was deleted 
To reflect the change of removing the 
pembrolizumab alone arm 
2.1 Study rationale 
“In the 64 treated patients, tusamitamab ravtansine 
showed encouraging anti-tumor activity associated 
with a response rate of 20.3% per RECIST1.1 
(95% CI: 12.27%–31.71%), warranting further 
development of tusamitamab ravtansine to treat 
this patient population” was added. 
Updated efficacy data of high CEACAM5 
expressors with NSCLC; new data 
available since last protocol amendment. 
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Section # and Name 
Description of Change 
Brief Rationale 
2.1 Study rationale 
“considering pembrolizumab alone as calibrator 
arm in patients with CEACAM5 and PD-L1 positive 
untreated advanced/metastatic NSQ NSCLC" was 
removed. 
To reflect the change of removing the 
pembrolizumab alone arm and PD-L1 
requirement for Part A 
2.1 Study rationale 
The following text was added: “untreated locally 
advanced/metastatic 
To clarify the participant population 
2.1 Study rationale 
“Overall” was added to the response rate 
To explain the analysis  
2.2 Background 
Information on ongoing NSCLC studies (5 ongoing 
clinical trials, and the phase 2 trial ACT16525) is 
added  
To provide additional details on ongoing 
studies with tusamitamab ravtansine 
4.2 Scientific rationale for 
study design 
Updated efficacy data of high CEACAM5 
expressors with NSCLC. 
“Overall” was added to the response rate 
New data available since last protocol 
amendment 
To explain the analysis 
4.4 End of study definition 
“First IMP administration” was added. 
To define and clarify end of study  
5.1 Inclusion criteria 
Original criterion I05 removed. 
As the pembrolizumab single agent arm 
was removed, participants in Part A with 
any PD-L1 expression can be enrolled 
5.2 Exclusion criteria 
Criterion E03 updated 
To allow patients with untreated 
asymptomatic brain metastases to be 
enrolled 
5.2 Exclusion criteria 
Criterion E09 was updated to replace 
“randomization” with first study intervention 
“administration.” 
No randomization as only single arm in 
Part A 
5.2 Exclusion criteria 
“x ULN” was removed from criterion E28. 
Fixed units  
5.5 Criteria for temporarily 
delaying enrollment 
Randomization was updated to enrollment 
No randomization as only single arm in 
Part A 
6.1 Study intervention(s) 
administered 
In Table 2, the text “comparator” was replaced by 
“combination component”.  
To reflect the change of removing the 
pembrolizumab alone arm 
Study intervention(s) 
administered 
“Carboplatin dose should not exceed 750 mg. The 
dose should be calculated using the Calvert 
formula and CrCl should be calculated by 
Cockcroft-Gault equation” and footnote “b” was 
added to Table 2  
To provide details on the Cockcroft-Gault 
equation 
Study intervention(s) 
administered 
The following text was added to dosage levels on 
Table 2: “on Day 1” 
To be consistent with the schedule of 
activities 
Study intervention(s) 
administered 
The following text was added:  
“15 minutes to”; “depending on the administration 
form IV or oral [15 minutes prior for IV and 1 hour 
prior for oral]; and “If oral diphenhydramine is not 
available, other Histamine H1 antagonist or other 
form of diphenhydramine can be given per local 
label and clinical practice.” 
To provide detailed NIMP instructions 
6.3 Measures to minimize 
bias: randomization and 
blinding 
Removed the text in this section, as it is no longer 
applicable  
The randomization and blinding text is no 
longer applicable 
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Section # and Name 
Description of Change 
Brief Rationale 
6.6.2 Individual dose 
modification (Part A and 
Part B) 
Second reduced doses added to Table 5  
To introduce additional reduced doses 
6.6.2 Individual dose 
modification (Part A and 
Part B) 
The following text was removed “one”. 
To clarify the dose reduction of 
tusamitamab ravtansine  
7.1.1 Definitive 
discontinuation 
The following text was added: “Any abnormal 
laboratory value or ECG parameter will be 
immediately rechecked for confirmation (please 
specify, eg after 24 hours) before making 
a decision of permanent discontinuation of the IMP 
for the concerned participant.” 
To maintain standard, template language 
8 Study assessment and 
procedures 
 “Except PK” was removed and “safety” was added  To clarify that the patients will undergo all 
assessments, including PK 
8.1 Efficacy assessments 
Reference date updated 
Randomization is no longer applicable 
8.1 Efficacy assessments 
“Progressive disease” was replaced with 
“response” 
To clarify the radiological evaluation 
documentation  
9.1 Statistical hypothesis  
The following text was removed: “pembrolizumab 
single agent” 
To reflect the change of removing the 
pembrolizumab alone arm 
9.2 Sample size 
determination 
Text related to randomization was removed and 
sample size updated. 
To reflect the change of removing the 
pembrolizumab alone arm 
9.3 Population for analysis 
Intent to treated population for Part A was 
removed and all-treated population was updated 
as the primary population for analysis of all 
efficacy parameters. The screened and Activity 
population were also updated.  
No randomization as only single arm in 
Part A 
9.4 Statistical analysis 
The statistical analysis plan was updated. 
The SAP will be updated to reflect the 
protocol amendments 
Section 9.4.1 General 
Considerations 
The safety cut-off for primary safety endpoint 
analysis added 
 
Changes made to efficacy analysis population 
from ITT to alltreated and to the cut-off data 
Cut-off updated to include primary safety 
endpoint analysis in Part A in addition to 
Part B 
To reflect the change of removing the 
pembrolizumab alone arm 
9.4.2 Primary endpoints 
The following text was removed: “for each 
treatment arm”  
“Tumor” was replaced by “overall” and 
“randomization” was replaced by “first IMP 
administration” 
“for the doublet combination arm” was added  
To reflect the change of removing the 
pembrolizumab alone arm 
To be consistent with the synopsis 
section 
9.4.3 Secondary endpoints 
“ITT” and “by treatment arm” were removed; “all-
treated” was added  
To reflect the change of removing the 
pembrolizumab alone arm 
9.5 Interim analyses  
Removed the text in this section, as it is no longer 
applicable  
Cut-off for primary safety analysis in 
Part A and Part B added instead  
10.8 Appendix 8 CYP 
substrates with narrow 
therapeutic range and 
strong CYP3A inhibitors, 
Table 16 
Update list of strong CYP3A inhibitors 
Drug interaction list updated  
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Section # and Name 
Description of Change 
Brief Rationale 
10.13 Appendix 13 Protocol 
amendment history  
Amendment history was updated with Amended 
Protocol 2  
“Hematological” added to the rationale for 
amendment.  
Updated section to include Amended 
Protocol 2 
To clarify the threshold for 
carboplatin/cisplatin dose reductions 
Throughout 
“Randomization” was removed  
No randomization as only single arm in 
Part A 
Throughout 
SAR408701 replaced by tusamitamab ravtansine 
The approved product name was added 
Throughout 
RD replaced by RP2D 
To clarify the dose 
Throughout 
Reference to Pregnancy cross-sections updated 
Cross-section formatting was fixed 
Throughout 
Minor editorial, typographical error corrections and 
standardization of wording 
For clarity 
Amended protocol 04 (18 August 2021) 
This amended protocol 04 (Amendment 04) is considered to be substantial based on the criteria 
set forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of 
the European Union.  
OVERALL RATIONALE FOR THE AMENDMENT 
The main purpose of this amendment is to add Part C to evaluate the safety and anti-tumor 
activity of tusamitamab ravtansine in combination with the SOC in first line, pembrolizumab, 
platinum-based chemotherapy and pemetrexed in NSQ NSCLC participants with CEACAM5 high 
(≥50%) or moderate expression (≥1% and <50%) tumors and to move primary objective of Part A 
with assessment of anti-tumor activity to secondary objective, as the primary objective is to assess 
the tolerability of the combination and to confirm the recommended dose as for the other parts, 
and consequently decrease the sample size in Part A to get approximately the same number of 
participants treated at the recommended dose in each part.  
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Cover page Title, Section: 1.1: 
Protocol title, Section: 1.1: Short 
title 
Added “with or without pemetrexed”  
To reflect the change of adding the 
combination arm of tusamitamab 
ravtansine with the SOC 
pembrolizumab, platinum-based 
chemotherapy and pemetrexed as 
Part C.  
Section 1.1: Synopsis (Rationale), 
Section 2.1: Study rationale 
Added rationale for Part C 
To reflect the change of adding the 
combination arm of tusamitamab 
ravtansine with the SOC 
pembrolizumab, platinum-based 
chemotherapy and pemetrexed as 
Part C, in order to evaluate the safety 
of the combination 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1: Synopsis (Objectives 
and endpoints), Section 3: 
Objectives and endpoints 
Moved anti-tumor activity of tusamitamab 
ravtansine in combination with pembrolizumab 
from primary endpoint to secondary endpoint 
Added objectives and endpoints for Part C  
 
Removed duration of response and 
progression-free survival from secondary 
endpoints 
Removed exploration of efficacy parameters for 
immune based therapy with tusamitamab 
ravtansine in combination with pembrolizumab 
and removed ORR of Part A per iRECIST from 
exploratory endpoint 
To reflect the change of primary 
endpoint and sample size for Part A 
 
To reflect the change of adding 
Part C 
To reflect the change of secondary 
endpoints and sample size of Part A 
To reflect the change of exploratory 
endpoints and sample size of Part A 
Section 1.1: Synopsis (Overall 
Design), Section 4.1: Study 
Design, 9.1: Statistical 
hypotheses 
Added Part C details to Study Design 
 
Removed Part 2 of Part A details and updated 
Figure 1 
To reflect the change of adding 
Part C 
To reflect the change of primary 
endpoints and sample size of Part A 
Section 1.1: Synopsis (Number of 
participants), Section 9.2: 
(Sample Size Determination) 
Updated sample size details for Part A 
 
Added sample size details for Part C 
To reflect the change in secondary 
end points and Sample size of Part A 
To reflect the change of adding 
Part C 
Section 1.1: Synopsis 
(Intervention groups and duration) 
Updated pemetrexed details (formulation, route of 
administration, dose regimen) to the study 
intervention 
 
 
Removed the text related to Part A study cut-off 
for secondary efficacy endpoint analysis (PFS 
and DOR) 
To reflect the change of adding the 
combination arm of tusamitamab 
ravtansine with the SOC 
pembrolizumab, platinum-based 
chemotherapy and pemetrexed as 
Part C 
To reflect the change of secondary 
endpoints for Part A 
Section 1.1: Synopsis (Statistical 
considerations), Section 9.3: 
Populations for analysis, 
 
 
 
 
 
Section 9.4.2: Primary endpoint 
 
Section 9.4.3: Secondary 
endpoint 
Updated sample size calculation for Part A 
 
Added sample size calculation for Part C 
 
Removed “Activity population (Part A)” definition 
from Main analysis populations 
 
Removed ORR from Primary end point analysis 
of Part A 
 
Removed DOR and PFS from Secondary 
endpoint analysis from Part A 
To reflect the removal of Part 2 of 
Part A 
To reflect the change of adding 
Part C 
To reflect the removal of Part 2 of 
Part A 
 
To reflect the change in Primary 
endpoint for Part A 
 
To reflect the change in Secondary 
endpoint for Part A 
Section 1.2: Schema 
Updated Figure 1-Decision tree for tusamitamab 
ravtansine dose in Part A, Part B, and Part C  
 
Removed Part 2 in Figure 2 
 
Added Figure 4 representing the Part C 
To reflect the change in removal of 
Part 2 of Part A 
To reflect the change in removal of 
Part 2 of Part A 
To reflect the change of adding 
Part C 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 1.3: SoA and Section 8.4: 
Pharmacodynamic assessments 
Removed Tumor assessment and Circulating 
CEA assessments at follow-up visit 
To reflect as there is no DOR/PFS 
assessment 
Section 1.3: SoA, Section 3: 
Objective and Endpoints and 
Section 8.7: Genetics 
Updated the text corresponding to additional 
plasma sampling timepoint (at Cycle 5 Day 1) for 
cfDNA isolation 
To assess cfDNA changes in 
response to treatment 
Section 1.3.2: PK/ATA flowchart 
and Section 8.5: 
Pharmacokinetics 
Removed the PK/ATA flow chart for Part 1 of 
Part A and updated the PK/ATA flow chart for 
Part B and Part C 
Updated PK details pertaining to Part C 
To reflect the change in 
measurement of PK parameters 
 
To reflect the change of adding 
Part C 
Section 2.2: Background 
Added ACT16432 study details  
To update the list of on-going trials of 
tusamitamab ravtansine 
Section 2.3.2: Benefit 
assessment 
Added the following text” As no overlap in the 
safety profiles for pemetrexed and platinum 
chemotherapies and for tusamitamab ravtansine 
is anticipated and for which hematological toxicity 
is minimal, the addition of tusamitamab 
ravtansine to the SOC may lead to better efficacy 
with acceptable safety profile” 
To clarify anticipated benefit of 
addition of pemetrexed  
Section 4.2.1: Participant input 
into design 
Updated the number of patients treated and the 
efficacy data in Study TED13751 
New data available since 
last protocol amendment 
Section 4.2: Justification for dose 
Added “pemetrexed” in the text 
To reflect the change of adding the 
combination arm of tusamitamab 
ravtansine with the SOC 
pembrolizumab, platinum-based 
chemotherapy and pemetrexed as 
Part C 
Section 4.4: End of Study 
definition 
Replaced the following text “estimated at 
10 months after the last participant’s first IMP 
administration in Part A” with “estimated at 
4.5 months after the last participant’s first IMP 
administration” and added “the Follow-Up visit 
approximately 90 days after the last IMP 
administration” 
To clarify 
Section 5.1: Inclusion criteria, I04 
Updated type of participant and disease 
characteristics for Part C 
To reflect the change in addition of 
Part C 
Section 5.1: Inclusion criteria, I08 
Added contraception for at least 6 months after 
the last dose of pemetrexed. 
In accordance with male 
contraception guidance for 
pemetrexed  
Section 6.1: Study interventions 
administered 
Updated “Table 2 Overview of study interventions 
administered” with pemetrexed details 
To reflect the change of adding the 
combination arm of tusamitamab 
ravtansine with the SOC 
pembrolizumab, platinum-based 
chemotherapy and pemetrexed as 
Part C 
Section 6.5: Concomitant therapy 
Replaced “route of use” with “route of 
administration” 
To clarify 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 6.6.1: Determination of 
recommended doses 
Details on determination of recommended dose 
for Part C are added 
Dose modification and dose schedules for 
pemetrexed are added in Table 4 
To clarify the dose recommendation 
for Part C 
To clarify the dose recommendation 
for Part C 
Section 6.6.2: Individual dose 
modification 
Added following text “If appropriate, and if in the 
opinion of the Investigator, the toxicity is related 
to one of the treatments, pembrolizumab, 
tusamitamab ravtansine, cisplatin/carboplatin or 
pemetrexed instead of the combination and more 
than 1 cycle delay is needed, this drug may be 
interrupted upon discussion with the sponsor, and 
the other drug(s) can be continued and this drug 
can only be resumed at following cycle after the 
toxicity recovers to Grade ≤1” 
Dose reduction details of pemetrexed are added 
to Table 6 
To clarify the dose modification for 
quadruplet combinations 
To reflect the change of adding the 
combination arm of tusamitamab 
ravtansine with the SOC 
pembrolizumab, platinum-based 
chemotherapy and pemetrexed as 
Part C 
 
To reflect the change of adding the 
combination arm of tusamitamab 
ravtansine with the SOC 
pembrolizumab, platinum-based 
chemotherapy and pemetrexed as 
Part C 
Section 7.1.1: permanent 
discontinuation 
Removed the following text “If study intervention 
is permanently discontinued, the participant may 
remain in the study for tumor assessment as 
described in Section 8.1. See the SoA for data to 
be collected at the time of discontinuation of 
study intervention”. 
To reflect the removal of tumor 
assessment 
Section 8.1: Efficacy 
assessments 
Removed the text related to RECIST 1.1 and 
ORR of Part A 
To reflect the change of endpoints 
and sample size of Part A 
Section 8.3.1: Time period and 
frequency for collecting AE and 
SAE information 
Added following text “During prescreening period, 
only AEs/SAEs related to the fresh biopsy 
procedure (if applicable) and occurring within 
1 month after the fresh biopsy will be recorded in 
the eCRF”. 
To clarify AEs/SAEs related to the 
fresh biopsy are recorded in eCRF 
Section 8.5.1: Non-
compartmental analysis 
Removed the Table 7 “List of pharmacokinetic 
parameters and definitions” 
To reflect the change in PK analysis 
(non-compartmental analysis will be 
replaced by population PK analysis) 
Section 8.11: Use of Biological 
Samples and Data for Future 
Research 
Section was updated as per new template text 
To be consistent with the text in ICF 
Section 9.4.1: General 
consideration 
Removed Part A Statistical analysis details 
To reflect the change of primary 
endpoint and sample size of Part A 
Section 9.4.3.8: Pharmacokinetic 
variables 
Removed the following text “The non-
compartmental PK analysis will be described in 
the SAP and will be performed on the PK 
population”. 
To reflect the change in PK analysis 
(non-compartmental analysis will be 
replaced by population PK analysis) 
Appendix 1: 
Section 10.1.4 Committees 
structure 
Removed the following text “to safety run-in 
phase or Part B (as appropriate)” 
To reflect the change in removal of 
Part 2 of Part A 
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Section # and Name 
Description of Change 
Brief Rationale 
Appendix 2: 
Section 10.2: CLINICAL 
LABORATORY TESTS 
Replaced “tri-iodothyronine” with “Total 
tri-iodothyronine” and updated corresponding 
footnote in Table 7- Protocol-required laboratory 
assessments  
To clarify that total T3 is preferred; if 
not available free T3 may be tested 
Appendix 6 
Added recommended dose modification details of 
pemetrexed to Table 12 (hematological toxicity) 
and Table 13 (nonhematological toxicity) 
To reflect the change of adding the 
combination arm of tusamitamab 
ravtansine with the SOC 
pembrolizumab, platinum-based 
chemotherapy and pemetrexed as 
Part C 
Appendix 10 
Replaced the previous Appendix “MODIFIED 
RESPONSE EVALUATION CRITERIA IN SOLID 
TUMORS FOR IMMUNE BASED 
THERAPEUTICS” with “MASCC Corticosteroid 
Dosing Guidelines (2016 Guidelines)”  
To reflect the removal of iRECIST 
Throughout 
Removed Part A and Part B and added “with or 
without pemetrexed” 
Corresponding text modified to be 
suitable for Part A, Part B and Part C 
Amended protocol 05 (04 July 2022) 
This amended protocol 05 (Amendment 05) is considered to be substantial based on the criteria 
set forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of 
the European Union.  
OVERALL RATIONALE FOR THE AMENDMENT 
The main purpose of this amendment is: 
• To increase the number of participants treated at recommended Phase 2 dose (RP2D) in 
Part A (up to 20), Part B (up to 10 in each triplet) and Part C (up to 10 in each quadruplet), 
to better assess the safety data of each combination. 
• To add moderate CEACAM5 expressors in Part A and in Part B in order to assess whether 
a doublet, or triplet combination might benefit to such patients.  
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Whole document  
Number and date of the amendment has been 
updated  
To fit with the current amendment 
number and timeline. 
Overall rationale for the 
amendment 
This section is revised/ updated with the changed 
meant for amended protocol 05. Protocol 
amendment summary of changes (SOC) table 
also inserted with the necessary details. This is 
done in view of the objective of the amendment of 
assessing the safety data of each combination in 
a higher number of participants  
To be compliant with the rationale of 
this new amendment.  
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Section # and Name 
Description of Change 
Brief Rationale 
1.1. Synopsis: Rationale 
Text was added to present the results from the 
NSCLC-Moderate CEACAM5 expressor cohort of 
Study TED13751 
Text was added to define the moderate and high 
CEACAM5 expression  
To justify the inclusion of moderate 
CEACAM5 population. 
 
To justify the inclusion of moderate 
CEACAM5 population. 
Section 1.1 Synopsis: Overall 
design, Part A; Part B; Part C; 
and Section 4.1 Overall Design, 
Part A; Part B; Part C 
Number of participants has been updated in 
study overall design Part Am and the 
corresponding text is updated us follows. Total of 
up to 20 participants treated at the RP2D (leading 
to a total of up to 32 participants treated in 
Part A). Based on current enrollment, at least 
9 DLT-evaluable participants will be included. 
To assess the safety data in a higher 
number of participants. 
Number of participants has been updated in study 
overall design Part B, and the corresponding text is 
updated as follows: “The tolerability of each triplet 
platinum combination will be assessed in 
approximately 6 to 18 participants to determine the 
RP2D in each triplet platinum combination arm 
(carboplatin or cisplatin). It is planned to enroll 
additional participants to have a total of up to 
10 participants treated at the RP2D in each triplet 
combination arm (leading to a total of approximately 
up to 44 participants treated in Part B)." 
To assess the safety data in a higher 
number of participants. 
Section 1.1 Synopsis: Number of 
Participants: Part A, Part B, and 
Part C. Statistical considerations: 
Part A and Part B, & 9.2. 
Statistical considerations: Sample 
size determination; Part A and 
Part B 
Text was modified in order to reflect new number 
of participants to be enrolled in Part A, Part B, 
and Part C, according to new sample size 
calculation, after addition of moderate and high 
CEACAM5 expressors.  
To align with new sample size 
calculation. 
1.1. Synopsis, overall design & 
2.1 Study Rationale  
Text was added to define high and moderate 
expression of CEACAM5 in 
immunohistochemistry analysis.  
To have a concise definition of IHC 
analysis.  
1.3.2. PK/ATA Flowchart,  
1.3.2.1 
PK/ATA flow chart for 
Part A  
1.3.2.2. PK/ATA flow chart for 
Part B &  
1.3.2.2. PK/ATA flow chart for 
Part C. 
Note regarding sampling time and stopping rules 
for PK and ATA was modified.  
For clarity sampling procedures for 
site.  
Section 1.2 Schema: Figure 2 
“DLTs at C1” has been removed from figure and 
DLT description has been removed from footnote. 
To be consistent with Figure 3 and 
Figure 4 data. 
Section 1.2 Schema: Figure 2; 3; 
4 
The number of participants has been updated in 
all the figures.  
To be compliant with the new higher 
number of participants in the whole 
study design. 
Section 1.3.1 Study procedures 
flowchart  
Changed PS to ECOG. 
To clarify collection of ECOG status. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 1.3.1. Study procedures 
flowchart. 
A new row was added to describe collection of 
age data. 
The number of participants in Parts A, B & C 
have been updated. 
 
Text has been added to clarify the recommended 
dose selection, escalation / de-escalation by DLT 
incidence.  
To clarify the collection of age data.  
 
To comply to new sample size 
determination. 
 
To clarify recommended dose 
selection.  
1.2 Schema Figure 2 Graphical 
representation for Part A 
Figure 3. Graphical 
representation for Part B & 
Figure 4. Graphical 
representation for Part C  
Text was added:  
“up to 30 patients to be treated in RP2D”.  
“up to 10 patients to be treated in RP2D” 
“up to 22 patients to be treated in RP2D” 
“At least 2” is replaced by “At least 1” 
“90 Days (±7 days) after last IMP” was added in 
the timeline 
To reflect new study design and 
population. 
Section 1.3.1 Study procedure 
flowchart 
Footnote “m” was added  
To clarify procedures under the new 
study design.  
Section 2.1 Study rationale  
Text was added to present the results from the 
NSCLC-Moderate CEACAM5 expressor cohort of 
Study TED13751. 
Text was modified to describe patient population 
include moderate and high CEACAM5 
expressors.  
To justify the inclusion of moderate 
CEACAM5 population.  
Section 2.3 Benefit/risk 
assessment 
Text was added to refer to further risk/benefit 
data in the IB and Product Information 
documents.  
To provide more information on 
risk/benefit assessment. 
Section 4.1 Study design 
Text has been added to describe collection of 
samples for CEACAM5 evaluation  
Text was deleted: “'Participants with CEACAM5 
moderate expression (≥1% and <50%) tumors 
will go through protocol screening procedures 
and be enrolled in Part C”. 
To clarify CEACAM5 evaluation. 
 
To align with new study design that 
includes both moderate an high 
CEACAM5 expressos.  
5.1. Inclusion criteria 
Text was added in inclusion criterion I04 to 
account for IHC intensity.  
Text added: “≥2+ in intensity involving at least 
1% of the tumor cell population in archival tumor 
sample” 
To accommodate evaluation of 
CEACAM5 moderate and high 
status. 
Section 6.6.1 Determination of 
recommended doses 
“And other available information” has been added 
in selected paragraphs. 
To provide further information on 
determining RP2D. 
Section 1.1 Synopsis: Number of 
participants, 6.2.2 Preparation/ 
handling/storage/ accountability, 
7.1.1 Heading  
9.4.3.2 Adverse events, Section 
10 Appendix 6 
The word “definite” was replaced by the word 
“permanent”.  
For better clarity of the term 
permanent discontinuation. 
8.6. Pharmacodynamics 
Text has been added to specify sample collection 
related to IMP administration. 
To clarify sampling procedures.  
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Section # and Name 
Description of Change 
Brief Rationale 
Section 10.1.5 Dissemination of 
clinical study data 
Wed address with data sharing criteria was 
changed. 
To update source for dissemination 
of clinical study data.  
Section 10.3.1 Definition of AE 
The two sentences: 
“Symptomatic and/or”  
- “Requiring either corrective treatment or 
consultation, and/or” have been removed in 
events meeting the AE definition. 
To be consistent with AE reporting 
rules of oncology studies. 
10.8. Appendix 8. Table 14 
Table was updated with information on potent 
CYP3A Inhibitors. 
To homogenize with other clinical 
trials from this program. 
Section 10.6, Appendix 6, 
Table 9.  
Change in recommendation in case of hepatic 
enzyme increase Grade 3.  
To homogenize with other clinical 
trials from this program. 
10.13 Appending 13: Protocol 
amendment history 
Text has been modified to include amendment 05. To comply with Amendment 
protocol 05. 
In addition, other minor editorial changes (eg, grammatical, stylistic, and minor typographical 
corrections) were implemented throughout the protocol. 
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11 
REFERENCES  
1. Mok TSK, Wu YL, Kudaba I, Kowalski DM, Cho BC, Turna HZ, et al. Pembrolizumab 
versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or 
metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, 
phase 3 trial. Lancet. 2019;393(10183):1819-30. 
2. Eisenhauer EA, Therasse P, Bogaerts J Schwartz LH, Sargent D, Ford R, et al. New response 
evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer. 
2009;45(2):228-47. 
3. Gold P, Freedman SO. Specific carcinoembryonic antigens of the human digestive system. J 
Exp Med. 1965;122(3):467-81. 
4. Thompson JA. Molecular cloning and expression of carcinoembryonic antigen family 
members. Tumor Biol. 1995;16(1):10-6. 
5. Hammarstrom S. The carcinoembryonic antigen (CEA) family: structures, suggested 
functionsand expression in normal and malignant tissues. Semin Cancer Biol. 1999;9(2):67-
81. 
6. Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, et al. 
Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 
2018;378(22):2078-92. 
7. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66(1):7-30. 
8. Leighl NB. Treatment paradigms for patients with metastatic non-small-cell lung cancer: first-
, second-, and third-line. Curr Oncol. 2012;19(Suppl 1):S52-8. 
9. Hanna N, Johnson D, Temin S, Baker S Jr, Brahmer J, Ellis PM, et al. Systemic therapy for 
stage IV non-small-cell lung cancer: american society of clinical oncology clinical practice 
guideline update. J Clin Oncol. 2017;35(30):3484-515. 
10. Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al. Nivolumab versus 
docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 
2015;373(17):1627-39. 
11. Herbst RS, Baas P, Kim DW, Felip E, Pérez-Gracia JL, Han JY, et al. Pembrolizumab versus 
docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer 
(KEYNOTE-010): a randomized controlled trial. Lancet. 2016;387(10027):1540-50. 
12. Rittmeyer A, Barlesi F, Waterkamp D, Park K, Ciardiello F, Von Pawel J, et al. Atezolizumab 
versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a 
phase 3, open-label, multicenter randomised controlled trial. Lancet. 2017;389(10066):255-65. 
13. Langer CJ, Gadgeel SM, Borghaei H, Papadimitrakopoulou VA, Patnaik A, Powell SF, et al. 
KEYNOTE-021 investigators. Carboplatin and pemetrexed with or without pembrolizumab 
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Page 148 
for advanced, non-squamous non-small-cell lung Cancer: a randomised, phase 2 cohort of the 
open-label KEYNOTE-021 study. Lancet Oncol. 2016;17(11):1497-508. 
14. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology (NCCN 
guidelines); Non-small cell lung cancer [Online]. Version 3. 2013 [cited on 2020 Feb 25]. 
Available from: URL:https://www.nccn.org 
15. Travis WD, Brambilla E, Nicholson AG, Yatabe Y, Austin JHM, Beasley MB, et al. WHO 
Panel. The 2015 World Health Organization Classification of Lung Tumors: Impact of 
Genetic, Clinical and Radiologic Advances Since the 2004 Classification. J Thorac Oncol. 
2015;10(9):1243-60. 
16. Tony SKM, Yi-Long W, Iveta K, Dariusz MK, Byoung Chul C, Hande ZT, et al. 
Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally 
advanced or metastatic non-small lung cancer (KEYNOTE-042): a randomised, open-label, 
controlled, phase 3 trial. Lancet. 2019;393(10183):1819-30. 
17. Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and 
response criteria of the eastern cooperative oncology group. Am J Clin Oncol. 1982;5(6):649-
55. 
18. Smith TJ, Bohlke K, Lyman GH, Carson KR, Crawford J, Cross SJ, et al. Recommendations 
for the Use of WBC Growth Factors: American Society of Clinical Oncology Clinical Practice 
Guideline Update. J Clin Oncol. 2015;33(28):3199-212. 
 
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SAP_001.pdf: 
 
 
 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive 
property of Sanofi (or any of its affiliated companies). The use of such confidential information must be restricted to the 
recipient for the agreed purpose and must not be disclosed, published or otherwise communicated to any unauthorized 
persons, for any reason, in any form whatsoever without the prior written consent of Sanofi (or the concerned affiliated 
company); ‘affiliated company’ means any corporation, partnership or other entity which at the date of communication 
or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ 
meaning direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, 
partnership or other entity 
According to template: QSD-002643 VERSION 8.0 (17-JUN-2020) 
Page 1 
STATISTICAL ANALYSIS PLAN    
Protocol title: 
Open-label, Phase 2 study of tusamitamab ravtansine 
(SAR408701) combined with pembrolizumab and 
tusamitamab ravtansine (SAR408701) combined with 
pembrolizumab and platinum-based chemotherapy with 
or without pemetrexed in patients with CEACAM5 positive 
expression advanced/metastatic non-squamous 
non-small-cell lung cancer (NSQ NSCLC) 
Protocol number: 
ACT16146 
Compound number 
(INN/Trademark): 
SAR408701 
Tusamitamab ravtansine/Not applicable 
Study phase: 
Phase 2 
Short title: 
Tusamitamab ravtansine (SAR408701) in combination 
with pembrolizumab and tusamitamab ravtansine 
(SAR408701) in combination with pembrolizumab and 
platinum-based chemotherapy with or without 
pemetrexed in patients with NSQ NSCLC (CARMEN-LC05) 
Statistician: 
 
Statistical project 
leader: 
 
Date of issue: 
09-Nov-2021 
Regulatory agency identifier number(s): 
IND: 
IND 144484 
EudraCT: 
2020-000035-50 
WHO: 
U1111-1233-9798 
NCT: 
NCT04524689 
 
 
Total number of pages: 
50 
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Statistical Analysis Plan  
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Page 2 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ................................................................................................................... 1 
TABLE OF CONTENTS .................................................................................................................................. 2 
LIST OF TABLES ........................................................................................................................................... 4 
VERSION HISTORY ....................................................................................................................................... 5 
1 
INTRODUCTION .............................................................................................................................. 7 
1.1 
STUDY DESIGN .............................................................................................................................. 7 
1.2 
OBJECTIVES AND ENDPOINTS .................................................................................................... 8 
1.2.1 
Estimands ........................................................................................................................................ 9 
2 
SAMPLE SIZE DETERMINATION ................................................................................................ 11 
3 
ANALYSIS POPULATIONS .......................................................................................................... 12 
4 
STATISTICAL ANALYSES ........................................................................................................... 13 
4.1 
GENERAL CONSIDERATIONS .................................................................................................... 13 
4.2 
PARTICIPANT DISPOSITIONS ..................................................................................................... 14 
4.3 
PRIMARY ENDPOINT ANALYSIS ................................................................................................ 15 
4.3.1 
Definition of endpoint ..................................................................................................................... 15 
4.3.2 
Main analytical approach ............................................................................................................... 15 
4.3.3 
Sensitivity analysis ......................................................................................................................... 16 
4.3.4 
Supplementary analyses ................................................................................................................ 16 
4.3.5 
Subgroup analyses ........................................................................................................................ 16 
4.4 
SECONDARY ENDPOINT ANALYSIS .......................................................................................... 16 
4.4.1 
Key/Confirmatory secondary endpoint ........................................................................................... 16 
4.4.2 
Supportive secondary endpoint ..................................................................................................... 16 
4.4.2.1 
Definition of endpoint ..................................................................................................................... 16 
4.4.2.2 
Main analytical approach ............................................................................................................... 17 
4.5 
TERTIARY/EXPLORATORY ENDPOINTS ANALYSIS ................................................................ 17 
4.6 
MULTIPLICITY ISSUES ................................................................................................................ 17 
4.7 
OTHER SAFETY ANALYSES ....................................................................................................... 18 
4.7.1 
Extent of exposure ......................................................................................................................... 18 
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4.7.1.1 
Overall exposure ............................................................................................................................ 18 
4.7.1.2 
Tusamitamab ravtansine exposure ................................................................................................ 19 
4.7.1.3 
Pembrolizumab exposure .............................................................................................................. 20 
4.7.1.4 
Cisplatin exposure (Part B and Part C) .......................................................................................... 22 
4.7.1.5 
Carboplatin exposure (Part B and Part C) ..................................................................................... 23 
4.7.1.6 
Pemetrexed exposure (Part C) ...................................................................................................... 25 
4.7.2 
Adverse events .............................................................................................................................. 27 
4.7.3 
Additional safety assessments ....................................................................................................... 33 
4.7.3.1 
Laboratory variables, vital signs and electrocardiograms (ECGs) ................................................. 33 
4.7.3.2 
Ocular examinations ...................................................................................................................... 35 
4.8 
OTHER ANALYSES....................................................................................................................... 35 
4.8.1 
PK analyses ................................................................................................................................... 35 
4.8.1.1 
Tusamitamab ravtansine, pembrolizumab, cisplatin, carboplatin and pemetrexed ....................... 35 
4.8.1.2 
Population PK analysis .................................................................................................................. 35 
4.8.1.3 
Immunogenicity impact on PK ....................................................................................................... 36 
4.8.2 
Immunogenicity analyses ............................................................................................................... 36 
4.8.3 
Biomarkers analyses ...................................................................................................................... 38 
4.8.3.1 
Circulating CEA .............................................................................................................................. 38 
4.8.3.2 
Circulating free DNA ...................................................................................................................... 39 
4.8.3.3 
CEACAM5 expression on circulating tumoral cells (CTCs) ........................................................... 39 
4.9 
INTERIM ANALYSES .................................................................................................................... 40 
5 
SUPPORTING DOCUMENTATION .............................................................................................. 41 
5.1 
APPENDIX 1 LIST OF ABBREVIATIONS ..................................................................................... 41 
5.2 
APPENDIX 2 CHANGES TO PROTOCOL-PLANNED ANALYSES ............................................. 42 
5.3 
APPENDIX 3 DEMOGRAPHICS AND BASELINE CHARACTERISTICS, PRIOR OR 
CONCOMITANT MEDICATIONS .................................................................................................. 43 
5.4 
APPENDIX 4 DATA HANDLING CONVENTIONS ........................................................................ 45 
5.5 
APPENDIX 5 SANOFI SPONSOR GENERIC RANGES FOR HEMATOLOGICAL AND 
BIOCHEMISTRY PARAMETERS .................................................................................................. 46 
5.6 
APPENDIX 6 LIST OF TERMS IN COMPANY MEDDRA QUERIES (CMQ) ................................ 47 
6 
REFERENCES ............................................................................................................................... 50 
 
 
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LIST OF TABLES  
Table 1 - Major changes in statistical analysis plan ........................................................................................ 5 
Table 2 - Objectives and endpoints ................................................................................................................. 8 
Table 3 - Summary of primary estimands for main endpoints ....................................................................... 10 
Table 4 - Populations for analyses ................................................................................................................ 12 
Table 5 - Tusamitamab ravtansine dose reduction criteria ........................................................................... 20 
Table 6 - Cisplatin dose reduction criteria ..................................................................................................... 23 
Table 7 - Carboplatin dose reduction criteria ................................................................................................ 24 
Table 8 - Pemetrexed dose reduction criteria ............................................................................................... 26 
Table 9 - Sorting of AE tables ....................................................................................................................... 28 
Table 10 - Analyses of adverse events ......................................................................................................... 29 
Table 11 - Selections for AESIs and other AEs of interest ............................................................................ 31 
Table 12 - Major statistical changes in protocol amendments ...................................................................... 42 
Table 13 - Generic ranges for hematological and coagulation parameters .................................................. 46 
Table 14 - Generic ranges for biochemistry parameters ............................................................................... 46 
 
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VERSION HISTORY  
This amended statistical analysis plan (SAP) for Study ACT16146 is based on the amended 
protocol 04 dated 18-Aug-2021. This section summarizes the major changes to the statistical 
analysis features in the SAP. The first participant was randomized on 11-Mar-2021. The initial 
version of the SAP was approved before the first participant was randomized. This amended SAP 
is approved before the first step analysis is conducted. 
The major changes in the SAP are related to changes following the protocol amendments: 
• Protocol amendment 01: Adding a dose level of 170 mg/m² in safety run-in part of Part A 
for the tusamitamab ravtansine + pembrolizumab arm, and adding Part B, which consists 
of a safety run-in in 2 new triplet combination arms (tusamitamab ravtansine + 
pembrolizumab + cisplatin/carboplatin) 
• Protocol amendment 03: Removing the pembrolizumab single-agent arm in Part A  
• Protocol amendment 04: Adding Part C, which consists of a safety run-in in 2 new 
quadruplet combination arms (tusamitamab ravtansine + pembrolizumab + pemetrexed + 
cisplatin/carboplatin), removing Part 2 of Part A, moving ORR in Part A as secondary 
endpoint, and removing the other secondary efficacy endpoints (PFS, DOR, ORR per 
iRECIST) 
Table 1 - Major changes in statistical analysis plan  
SAP 
Version 
Approval 
Date 
Changes 
Rationale 
1.0 
16-Sep-2020 
Not Applicable 
Original version 
2.0 
09-Nov-2021 
Study design has been updated to add Part B and Part 
C, to remove pembrolizumab single-agent arm in Part A, 
and therefore to remove randomization in Part A, to 
remove Part 2 of Part A, to remove PD-L1 requirements 
in Part A, to add a dose level of 170 mg/m² in Part A, to 
update sample size of Part A. 
To reflect last amended protocol 04. 
 
 
Study cut-offs have been updated 
To reflect last amended protocol 04. 
 
 
Sample size of Part A has been updated. 
To reflect last amended protocol 04. 
 
 
Objectives, endpoints and estimands have been updated 
to include Part B and Part C, to remove pembrolizumab 
single-agent arm in Part A, to move ORR in Part A as 
secondary endpoint, to remove other secondary efficacy 
endpoints (PFS, DOR, ORR per iRECIST). 
To reflect last amended protocol 04. 
 
 
Statistical analyses have been added for Part B and 
Part C. 
To reflect last amended protocol 04. 
 
 
Statistical analyses have been updated for Part A. 
To reflect last amended protocol 04. 
 
 
Analysis populations have been updated to include 
Part B and Part C, and changes in Part A. 
To reflect last amended protocol 04. 
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SAP 
Version 
Approval 
Date 
Changes 
Rationale 
 
 
Analyses on COVID-19 have been added. 
To assess the impact of the 
COVID-19 on the study. 
 
 
Analyses on slit lamp examination and on corneal events 
have been added. 
To assess the occurrence and 
recurrence of corneal events, that 
are adverse events of interest. 
 
 
Tertiary/exploratory objective and endpoint of circulating 
CEA evaluation has been updated, and biomarkers 
analyses have been updated accordingly. 
To reflect the additional collection 
of circulating CEA at pre-
screening. 
 
 
Tertiary/exploratory objective and endpoint of cfDNA 
evaluation has been updated, and biomarkers analyses 
have been updated accordingly. 
To reflect the additional collection 
of cfDNA at Cycle 5 Day 1. 
 
 
Analysis on time-to-next therapy has been removed. 
Not appropriate with limited sample 
size and short follow-up duration in 
each study part. 
 
 
Pre-screening and screening categories for AE have 
been removed. 
Pre-treatment category is sufficient 
for the analyses. 
 
 
Formula of corrected calcium was updated. 
Correction of the formula. 
 
 
Details added in Section 4.9 on the different steps of 
analyses planned in the study. 
To clarify the different steps of 
analyses planned in the study. 
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1 
INTRODUCTION  
1.1 
STUDY DESIGN  
This is a Phase 2, multicenter, multinational, open-label study which comprises 3 parts: Part A, 
Part B and Part C. 
Part A is a single-group study part evaluating tusamitamab ravtansine in combination with 
pembrolizumab in Non-squamous Non-Small Cell Lung Cancer (NSQ NSCLC) participants with 
CEACAM5 high expression (CEACAM5 immunohistochemistry [IHC] intensity ≥2+ in ≥50% of 
tumor cells) tumors. 
Part B is a 2 parallel-group study part evaluating tusamitamab ravtansine in combination with 
pembrolizumab and platinum-based chemotherapy (cisplatin or carboplatin) in NSQ NSCLC 
participants with CEACAM5 high expression tumors. 
Part C is a 2 parallel-group study part evaluating tusamitamab ravtansine in combination with 
pembrolizumab, platinum-based chemotherapy (cisplatin or carboplatin), and pemetrexed in NSQ 
NSCLC participants with CEACAM5 high or moderate expression (CEACAM5 IHC intensity 
≥2+ in ≥1% and <50% of tumor cells) tumors. 
Screening phase will only be performed in pre-screened participants with NSQ NSCLC 
determined to be CEACAM5 moderate or high expressors by central IHC assessment. Participants 
with CEACAM5 high expression will be enrolled either in Part A, Part B, or Part C per 
investigator’s choice. Participants with CEACAM5 moderate expression will be enrolled in 
Part C. 
PART A: 
In Part A, the tolerability and safety will be assessed and the recommended Phase 2 dose (RP2D) 
of tusamitamab ravtansine in combination with pembrolizumab will be determined. 
Approximately 6 to 18 participants will be treated in order to determine the RP2D. It is planned to 
enroll additional participants to have a total of approximately 12 participants treated at the RP2D 
(leading to a total of approximately 6 to 24 participants treated in Part A). 
PART B: 
In Part B, the tolerability and safety of tusamitamab ravtansine in combination with 
pembrolizumab and platinum-based chemotherapy (cisplatin or carboplatin) will be assessed and 
the RP2Ds will be determined. Participants can be assigned to either cisplatin or carboplatin, per 
Investigator’s choice.  
Approximately 12 to 36 treated participants in the cisplatin and carboplatin combination arms in 
Part B (6 to 18 for each arm) are expected to be evaluable for tolerability and safety. 
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PART C: 
In Part C, the tolerability and safety of tusamitamab ravtansine in combination with 
pembrolizumab, platinum-based chemotherapy (cisplatin or carboplatin), and pemetrexed will be 
assessed and the RP2Ds will be determined. Participants can be assigned to either cisplatin or 
carboplatin, per Investigator’s choice.  
Approximately 12 to 36 treated participants in the cisplatin and carboplatin combination arms in 
Part C (6 to 18 for each arm) are expected to be evaluable for tolerability and safety. 
In Parts A, B and C, the cycle duration is 21 days for all combination arms. The DLT observation 
period is the first cycle. Depending on the DLTs observed, up to 3 dose levels (DLs) of 
tusamitamab ravtansine can be tested: 150 mg/m², 170 mg/m², and 120 mg/m². The tolerability of 
each combination will be assessed in at least 6 participants. 
The median expected duration of study per participant is estimated at 10 months (up to 1 month for 
screening, a median of 6 months for study intervention administration, a median of 1 month for end 
of treatment (EOT), and follow-up visit 90 days after the last administration of study intervention). 
Participants will continue to receive their assigned study intervention until confirmed disease 
progression, further anticancer therapies, unacceptable toxicity, or upon participant’s request to stop 
the study intervention, or Investigator’s decision, whichever occurs first. 
1.2 
OBJECTIVES AND ENDPOINTS  
Table 2 - Objectives and endpoints  
 
Objectives 
Endpoints 
Primary 
 
 
 
• 
To assess the tolerability and to determine the 
recommended doses of tusamitamab ravtansine 
in combination with pembrolizumab and 
tusamitamab ravtansine in combination with 
pembrolizumab and platinum-based 
chemotherapy with or without pemetrexed in the 
NSQ NSCLC population 
• 
Incidence of study drug-related dose-limiting 
toxicity (DLTs) at Cycle 1 (C1D1 to C1D21), 
including but not limited to corneal toxicity 
Secondary 
 
 
 
• 
To assess the safety and tolerability of 
tusamitamab ravtansine in combination with 
pembrolizumab and tusamitamab ravtansine in 
combination with pembrolizumab and platinum-
based chemotherapy with or without pemetrexed 
• 
To assess the antitumor activity of tusamitamab 
ravtansine in combination with pembrolizumab 
and tusamitamab ravtansine in combination with 
pembrolizumab and platinum-based 
chemotherapy with or without pemetrexed in the 
NSQ NSCLC population 
• 
Incidence of treatment-emergent adverse events 
(TEAEs), serious adverse events (SAEs) and 
laboratory abnormalities according to the 
National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events 
(CTCAE) V5.0 
• 
Objective response rate (ORR) defined as 
proportion of participants who have a confirmed 
complete response (CR) or partial response (PR) 
as per response evaluation criteria in solid 
tumors (RECIST) 1.1 
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Objectives 
Endpoints 
 
• 
To assess the pharmacokinetics (PK) of 
tusamitamab ravtansine, pembrolizumab, 
pemetrexed, cisplatin, and carboplatin, each 
when given in combination as a doublet 
(tusamitamab ravtansine + pembrolizumab) or 
triplet (tusamitamab ravtansine + pembrolizumab 
+ platinum-based chemotherapy) or quadruplet 
(tusamitamab ravtansine + pembrolizumab + 
platinum-based chemotherapy + pemetrexed) 
 
• 
To assess the immunogenicity of tusamitamab 
ravtansine when given in combination with 
pembrolizumab and tusamitamab ravtansine in 
combination with pembrolizumab and platinum-
based chemotherapy with or without pemetrexed 
• 
Pharmacokinetic parameters of tusamitamab 
ravtansine, pembrolizumab, pemetrexed, 
cisplatin, and carboplatin 
 
 
 
 
 
 
• 
Incidence of anti-therapeutic antibodies (ATAs) 
against tusamitamab ravtansine 
Tertiary/exploratory 
 
 
• 
To explore modulations of circulating 
carcinoembryonic antigen (CEA) as a potential 
pharmacodynamic (PD) biomarker of response 
to tusamitamab ravtansine treatment and to 
evaluate circulating CEA levels at pre-screening 
• 
To explore the relationship between the tumor 
mutation profiles detected in the circulating free 
deoxyribonucleic acid (cfDNA) at baseline with 
efficacy outcome and to explore decrease in 
cfDNA in response to treatment 
• 
To explore CEACAM5 expression on circulating 
tumoral cells (CTCs) 
• 
Circulating CEA at pre-screening, screening, and 
during the treatment period 
 
 
• 
Plasma analysis for tumor cfDNA at baseline and 
at Cycle 5 
 
 
• 
CEACAM5 expression assessment on CTCs 
from patients with positive (moderate or high) 
CEACAM5 expression on tumor tissue 
1.2.1 Estimands   
Primary estimand defined for the primary endpoint is summarized in below Table 3. More details 
are provided in Section 4. 
In this study, study interventions of interest are: 
• tusamitamab ravtansine in combination with pembrolizumab in Part A, 
• tusamitamab ravtansine in combination with pembrolizumab and platinum-based 
chemotherapy (cisplatin or carboplatin) in Part B, 
• tusamitamab ravtansine in combination with pembrolizumab and platinum-based 
chemotherapy (cisplatin or carboplatin) and pemetrexed in Part C. 
 
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Table 3 - Summary of primary estimands for main endpoints  
Endpoint 
Category 
(estimand) 
Estimands 
Endpoint 
Population 
Intercurrent event(s) handling 
strategy 
Population-level summary  
(Analysis and missing data handling) 
Primary objective: To assess the tolerability and to determine the recommended doses of tusamitamab ravtansine in combination with pembrolizumab and tusamitamab 
ravtansine in combination with pembrolizumab and platinum-based chemotherapy with or without pemetrexed in the NSQ NSCLC population 
Primary endpoint 
(primary estimand) 
Study drug-related dose-
limiting toxicity at Cycle 1, 
by dose level (if applicable). 
DLT-evaluable population 
Participants from the DLT-evaluable 
population will not experience any anticipated 
intercurrent events before experiencing a DLT 
at Cycle 1 or before completing the Cycle 1, 
whichever is earlier. 
Incidence of study drug-related DLTs at Cycle 1, 
defined as the rate of participants with study-drug 
related DLTs at Cycle 1. 
 
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2 
SAMPLE SIZE DETERMINATION  
PART A: 
Part A aims to establish the RP2D of tusamitamab ravtansine in combination with pembrolizumab 
according to DLTs observed.  
The actual sample size is expected to vary depending on DLTs observed. It is anticipated that 6 to 
24 DLT-evaluable participants (as defined in Section 3) will be treated with tusamitamab 
ravtansine + pembrolizumab: up to 12 DLT-evaluable participants at DL other than the RP2D, 
and 12 DLT-evaluable participants at the RP2D. 
Assuming a pre-screening failure rate of 80% and a study screening failure rate of 20%, 
approximately 38 to 150 participants will be pre-screened to achieve 6 up to 24 DLT-evaluable 
participants. 
PART B: 
Part B of the study aims to establish the RP2Ds of tusamitamab ravtansine in combination with 
pembrolizumab and platinum-based chemotherapy (cisplatin or carboplatin) according to DLTs 
observed. 
The actual sample size is expected to vary depending on DLTs observed. It is anticipated that in 
each triplet combination arm, 6 to 18 DLT-evaluable participants (as defined in Section 3) will be 
treated with tusamitamab ravtansine + pembrolizumab + cisplatin or carboplatin: up to 12 DLT-
evaluable participants in each triplet combination arm at DL other than the RP2D, and 6 DLT-
evaluable participants at the RP2D. 
Assuming a pre-screening failure rate of 80% and a study screening failure rate of 20%, 
approximately 75 to 225 participants will be pre-screened to achieve 12 to 36 DLT-evaluable 
participants in Part B (6 to 18 DLT-evaluable participants in each triplet combination arm). 
PART C: 
Part C of the study aims to establish the RP2Ds of tusamitamab ravtansine in combination with 
pembrolizumab, pemetrexed and platinum-based chemotherapy (cisplatin or carboplatin) 
according to DLTs observed. 
The actual sample size is expected to vary depending on DLTs observed. It is anticipated that in 
each quadruplet combination arm, 6 to 18 DLT-evaluable participants (as defined in Section 3) 
will be treated with tusamitamab ravtansine + pembrolizumab + pemetrexed + cisplatin or 
carboplatin: up to 12 DLT-evaluable participants in each quadruplet combination arm at DL other 
than the RP2D, and 6 DLT-evaluable participants at the RP2D. 
Assuming a pre-screening failure rate of 45% and a study screening failure rate of 20%, 
approximately 28 to 82 participants will be pre-screened to achieve 12 to 36 DLT-evaluable 
participants in Part C (6 to 18 DLT-evaluable participants in each quadruplet combination arm). 
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3 
ANALYSIS POPULATIONS  
The following populations for analyses are defined: 
Table 4 - Populations for analyses  
Population 
Description 
Pre-screened 
All participants who signed the pre-screening informed consent for CEACAM5 assessment of their biopsy. 
Screened 
All participants who signed screening informed consent for study participation. 
Enrolled 
Participants from screened population who have been allocated to intervention regardless of whether 
the intervention was received or not. 
All-treated 
All participants assigned to study intervention and who have actually received at least one dose of study 
intervention. 
DLT-evaluable 
Participants who received 1 cycle with at least 80% of the intended dose for each IMP of the 
combination during the safety run-in of Part A, Part B or Part C. Participants should have completed 
Cycle 1 unless they experienced a DLT before the end of Cycle 1. 
PK 
All participants from the all-treated population with at least 1 post-baseline PK concentration with 
adequate documentation of dosing and sampling dates and times. 
ATA 
All participants from the all-treated population with at least 1 post-baseline ATA result (negative, 
positive, or inconclusive).  
Population without 
trial impact 
(disruption) due to 
COVID-19 
All treated participants: 
• without any critical or major deviation related to COVID-19,  
• and who did not permanently discontinue study intervention due to COVID-19,  
• and who did not permanently discontinue study due to COVID-19. 
ATA = anti-therapeutic antibodies; CEACAM5 = carcinoembryonic antigen-related cell adhesion molecule 5; DLT = dose-limiting toxicity;  
IMP = investigational medicinal product; PK = pharmacokinetic. 
In practice, a participant will be included in the enrolled population if the question “Will the 
subject continue in the treatment phase?” has been answered as “Yes” in the “Completion of 
screening phase” e-CRF page. It includes any participants randomized in Part A before protocol 
amendment 03. 
In practice, a participant will be included in the DLT-evaluable population if “Dose Limiting 
Toxicities” e-CRF page has been filled in at the end of Cycle 1. This includes participants 
followed up to the end of the DLT observation period or participants having experienced a DLT 
before the end of the DLT observation period and validated by the Study Committee. Participants 
with an overdose (defined as a dose received at least 30% above the intended dose) of any IMP of 
the combination at Cycle 1 will be excluded from the DLT-evaluable population. 
Participants treated with study intervention before or without being enrolled will not be 
considered enrolled and will not be included in any analysis population. The safety experience of 
these participants will be reported separately. 
Enrolled participants for whom it is unclear whether they took the study intervention will be 
considered as treated and will be included in the all-treated population. 
For any participant enrolled more than once, only the data associated with the first enrollment will 
be used in any analysis population. The safety experience associated with any later enrollment 
will be reported separately. 
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4 
STATISTICAL ANALYSES  
4.1 
GENERAL CONSIDERATIONS  
Efficacy endpoint based on radiological assessments of tumor burden (confirmed objective 
response) will be derived using the local radiologist’s/Investigator’s assessment. 
In general, continuous data will be summarized using the number of observations available, mean, 
standard deviation (SD), median, Q1, Q3, minimum, and maximum. Categorical and ordinal data 
will be summarized using the count and percentage of participants. 
The baseline value is defined as the last available value before the first dose of investigational 
medicinal product (IMP). 
Unless otherwise specified, analyses will be performed by intervention arm (and overall, for 
baseline, demographics characteristics and safety) on each study part separately. 
The study cut-off for the primary safety endpoints analysis (DLT) will be at the end of the first 
cycle of the last participant treated to determine the RP2D in Part A, Part B or Part C. 
The study cut-off for ORR (secondary efficacy endpoint analysis) corresponds to the date on 
which all treated participants 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. All analyses will be updated at this time. 
The analysis cut-off date is defined as the date of the database extraction that will be performed 
for the analysis. 
Observation period 
The observation period will be divided into 4 segments: 
• The pre-treatment period is defined as the period up to first IMP administration. 
- 
The pre-screening period is defined as the period from the pre-screening informed 
consent to the day before the screening informed consent. 
- 
The screening period is defined as the period from the screening informed consent up 
to the first IMP administration. 
• The on-treatment period (ie, treatment-emergent period) is defined as the period from 
the first IMP administration to the last IMP administration +30 days. 
• The post-treatment period is defined as the period from the end of the on-treatment 
period. 
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4.2 
PARTICIPANT DISPOSITIONS  
The number (%) of participants included in each of the analysis populations listed in Table 4 will 
be summarized. Reasons for exclusion from the population without trial impact (disruption) due to 
COVID-19 will be summarized.  
Pre-screen failures are defined as participants who consent to participate in the pre-screening 
phase of the study but are not subsequently screened. The number (%) of pre-screen failures and 
reasons for pre-screen failures will be provided in the pre-screened population. 
Screen failures are defined as participants who consent to participate in the study but are not 
subsequently enrolled. The number (%) of screen failures and reasons for screen failures will be 
provided in the screened population. 
Regarding study intervention discontinuation, the following definitions will be used: 
• Permanent partial intervention discontinuation is defined as the discontinuation of at least 
one of the study drugs but at least one is continued. 
• Permanent full intervention discontinuation is defined as the discontinuation of all the 
study drugs. 
The number (%) of participants in the following categories will be provided: 
• Enrolled participants 
• Enrolled but not treated participants 
• Enrolled and treated participants 
• Participants still on study intervention 
• Participants who discontinued the study intervention and main reason for permanent full 
intervention discontinuation 
• Participants who discontinued the study intervention and main reason for permanent 
partial discontinuation of tusamitamab ravtansine 
• Participants who discontinued the study intervention and main reason for permanent 
partial discontinuation of pembrolizumab 
• Participants who discontinued the study intervention and main reason for permanent 
partial discontinuation of cisplatin 
• Participants who discontinued the study intervention and main reason for permanent 
partial discontinuation of carboplatin 
• Participants who discontinued the study intervention and main reason for permanent 
partial discontinuation of pemetrexed 
• Participants who discontinued the study and main reason for study discontinuation 
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Reasons for permanent full/partial study intervention discontinuation and study discontinuation 
such as “adverse event” and “other reasons” will be split as related or not related to COVID-19 
(if applicable). 
The number (%) of treated and not enrolled participants will also be summarized. 
In addition, the number (%) of participants pre-screened, pre-screen failed, screened, screen 
failed, enrolled, enrolled and treated, with permanent full study intervention discontinuation and 
with study discontinuation, will be provided by country and site. 
For all categories of participants (except for the pre-screened, screened and non-enrolled 
categories) percentages will be calculated using the number of participants in the all-treated 
population as the denominator. 
Protocol deviations 
Critical and major protocol deviations (automatic or manual) will be summarized in the all-treated 
population as well as displayed separately as related or not related to COVID-19 (if applicable). 
4.3 
PRIMARY ENDPOINT ANALYSIS  
4.3.1 Definition of endpoint   
The primary endpoint is study-drug related DLT at Cycle 1 (from C1D1 to C1D21). List of DLTs 
to be considered in the study is defined in the protocol (see Section 6.6.1 of the study protocol). 
For analysis purposes, DLTs will be identified based on the AEs reported on the e-CRF DLT page 
during the DLT observation period. 
4.3.2 Main analytical approach  
The primary safety analysis is based on the primary estimand introduced in Section 1.2.1. It is 
defined according to the following attributes: 
• The endpoint is study-drug related DLT during the DLT observation period, ie, Cycle 1, 
from Cycle 1 Day 1 to Cycle 1 Day 21. 
• The treatment condition of interest is: 
- 
For Part A: tusamitamab ravtansine in combination with pembrolizumab, by dose level 
(if applicable). 
- 
For Part B: tusamitamab ravtansine in combination with pembrolizumab and platinum-
based chemotherapy (cisplatin or carboplatin), by dose level (if applicable). 
- 
For Part C: tusamitamab ravtansine in combination with pembrolizumab, pemetrexed 
and platinum-based chemotherapy (cisplatin or carboplatin), by dose level 
(if applicable). 
• The analysis population is the DLT-evaluable population (defined in Section 3). 
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• No intercurrent events handling strategy is defined due to the definition of the analysis 
population. Indeed, participants from the DLT-evaluable population will not experience 
any anticipated intercurrent events (study intervention discontinuation, start of an 
anticancer therapy and death) before experiencing a DLT at Cycle 1 or before completing 
the Cycle 1, whichever is earlier. 
• Population-level summary will include the incidence of DLTs at Cycle 1, defined as 
number and percentage of participants experiencing at least one study-drug related DLT. 
There will be no missing data in the analysis population. 
4.3.3 Sensitivity analysis  
No sensitivity analysis is planned in this study. 
4.3.4 Supplementary analyses  
No supplementary analysis is planned in this study. 
4.3.5 Subgroup analyses  
No subgroup analysis is planned in this study. 
4.4 
SECONDARY ENDPOINT ANALYSIS  
The secondary endpoint detailed in this section is the confirmed objective response. Other 
secondary endpoints analyses are defined in Section 4.7 (AE, SAE, laboratory abnormalities) and 
Section 4.8 (PK, immunogenicity). 
4.4.1 Key/Confirmatory secondary endpoint  
No key/confirmatory secondary endpoint. 
4.4.2 Supportive secondary endpoint  
4.4.2.1 Definition of endpoint  
The secondary efficacy endpoint is confirmed objective response determined according to 
RECIST 1.1. A confirmed objective response is defined as a confirmed CR or PR as best overall 
response (BOR). 
The BOR will be derived according to RECIST 1.1 definitions (1, 2) based on the investigator’s 
assessment. The BOR is the best overall response observed from the date of the first 
administration of IMP until documented disease progression, death, start of an anticancer therapy, 
or analysis cut-off date, whichever occurs first. 
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4.4.2.2 Main analytical approach  
The secondary efficacy analysis is based on an estimand defined according to the following 
attributes: 
• The endpoint is confirmed objective response (confirmed CR or PR as BOR) as per 
RECIST 1.1. 
• The treatment condition of interest is: 
- 
For Part A: tusamitamab ravtansine in combination with pembrolizumab, by dose level 
(if applicable). 
- 
For Part B: tusamitamab ravtansine in combination with pembrolizumab and platinum-
based chemotherapy (cisplatin or carboplatin), by dose level (if applicable). 
- 
For Part C: tusamitamab ravtansine in combination with pembrolizumab, pemetrexed 
and platinum-based chemotherapy (cisplatin or carboplatin), by dose level 
(if applicable). 
• The analysis population is the all-treated population (defined in Section 3). 
• Intercurrent events: 
- 
The study intervention discontinuation intercurrent event will be handled with the 
treatment policy strategy. Confirmed objective response will be assessed based on 
tumor assessments regardless of study intervention discontinuation. 
- 
The further anticancer therapy (including further systemic anticancer therapies) 
intercurrent event will be handled with the “while not initiating further anticancer 
therapy” strategy. Confirmed objective response will be assessed based on tumor 
assessments up to the time of initiation of further anticancer therapy. 
• The population-level summary will include the ORR, by combination arm, defined as the 
rate of participants with confirmed objective response and two-sided 95% confidence 
intervals using the Clopper-Pearson method. In addition, ORR may be summarized 
combining both triplet combination arms, and both quadruplet combination arms. In 
addition, the number (%) of participants within each BOR category, including not 
evaluable as per RECIST 1.1 and reason for being not evaluable will be provided. 
In the absence of confirmed objective response before the analysis cut-off date (taking into 
account the intercurrent event handling strategies), participants will be considered as non-
responders, whatever the reason (including participants with non-evaluable BOR). 
4.5 
TERTIARY/EXPLORATORY ENDPOINTS ANALYSIS  
Other tertiary/exploratory endpoints (eg, biomarkers) are defined in Section 4.8. 
4.6 
MULTIPLICITY ISSUES  
No multiplicity issues. 
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4.7 
OTHER SAFETY ANALYSES  
All safety analyses will be performed on the all-treated population as defined in Section 3, by 
dose level (if applicable) and overall, unless otherwise specified, using the following common 
rules: 
• The analysis of the safety variables will be essentially descriptive, and no testing is 
planned. 
• Safety data in participants who do not belong to the all-treated population (eg, treated but 
not enrolled) will be provided. 
4.7.1 Extent of exposure  
4.7.1.1 Overall exposure  
The dose information will be assessed by the following variables: 
• Overall number of cycles started, defined by the number of cycles in which at least one 
dose of any study intervention is administered. 
• Duration of IMP exposure (in weeks), defined as (last day of exposure - first day of 
exposure + 1)/7. 
- 
The first day of exposure is defined as the first administration date with non-zero dose 
for at least one of the IMP (tusamitamab ravtansine, pembrolizumab, pemetrexed, 
cisplatin, or carboplatin). 
- 
The last day of exposure is the day before the theoretical date of the next 
administration (after the last administration), defined as last administration date of at 
least one IMP + 21 days - 1 (for tusamitamab ravtansine, pembrolizumab, pemetrexed, 
cisplatin or carboplatin). 
The total number of cycles started, and the number of cycles started by participants will be 
summarized as a quantitative variable and by category (number (%) of participants receiving at 
least 1 cycle, at least 2 cycles, etc.). The duration of overall exposure will be summarized 
quantitatively. 
The following variable will be computed to describe overall dose modification (cycle delay): 
• Cycle delay: A cycle is deemed as delayed if the start date of the current cycle - 21 days - 
start date of the previous cycle is >3 days. Cycle delay is not defined for the first cycle.  
Cycle delay will be analyzed at the participant (with number of participants used as denominator) 
and cycle (with number of cycles used as denominator) levels, as follows: 
• Number (%) of participants with a least 1 cycle delayed 
- 
Number (%) of participants with a cycle delayed between 4 and 7 days (using 
maximum delay across all cycles) 
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- 
Number (%) of participants with a cycle delayed >7 days (using maximum delay 
across all cycles) 
• Number (%) of cycles delayed 
- 
Number (%) of cycles delayed between 4 and 7 days 
- 
Number (%) of cycles delayed >7 days 
In addition, summaries will be provided by trial impact (disruption) due to COVID-19 
(if applicable). 
4.7.1.2 Tusamitamab ravtansine exposure   
The dose information will be assessed by the following: 
• Total number of cycles started 
• Number of cycles started per participant 
• Duration of tusamitamab ravtansine exposure (in weeks) is defined by date of last 
administration of tusamitamab ravtansine + 21 days - date of first administration of 
tusamitamab ravtansine/7 
• Actual dose (in mg/m²). In case of dose interruption, actual dose will be the sum of the 
actual doses administered before and after the dose interruption. 
• Cumulative dose (in mg/m²): the cumulative dose is the sum of all actual doses of 
tusamitamab ravtansine, given from first to last administration 
• Actual dose intensity (ADI in mg/m²/week), defined as the cumulative dose divided by the 
duration of tusamitamab ravtansine exposure (in weeks) 
• Planned dose intensity (PDI in mg/m²/week): corresponds to the planned dose multiplied 
by the theoretical total number of doses started and divided by the theoretical cycle 
duration expressed in weeks (ie, 3 weeks per cycle started) 
• Relative dose intensity (RDI, in %):100 ×
ADI (mg/m²/week) 
PDI (mg/m²/week) 
The total number of cycles started, and the number of cycles started by participant will be 
summarized as a quantitative variable and by category (number [%] of participants receiving at 
least 1 cycle, at least 2 cycles, etc). Duration of tusamitamab ravtansine exposure, cumulative 
dose, ADI and RDI will be summarized quantitatively. 
The following variables will be derived to describe dose modifications and dose interruptions: 
• Dose reduction: The first administration will not be counted as a dose reduction. For the 
second and subsequent tusamitamab ravtansine administrations, dose reduction will be 
determined using the dose level intervals provided in Table 5, by comparing the current 
dose level to the previous dose level. If the current dose level is below the dose level 
interval of the previous dose administration, then the current dose level is considered 
reduced. 
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Table 5 - Tusamitamab ravtansine dose reduction criteria  
Actual dose level 
Dose level interval 
Dose level +1 (170 mg/m²) 
>160 mg/m² 
Starting dose (150 mg/m²) 
>135 mg/m² and ≤160 mg/m² 
Dose level -1 (120 mg/m²) 
>110 mg/m² and ≤135 mg/m² 
Dose level -2 (100 mg/m²) 
>90 mg/m² and ≤110 mg/m² 
Dose level -3 (80 mg/m²) 
>70 mg/m² and ≤90 mg/m² 
Low dose 
>0 mg/m² and ≤70 mg/m² 
• Dose delay: A dose will be considered as delayed if the tusamitamab ravtansine 
administration date of the current cycle – 21 days – tusamitamab ravtansine administration 
date of the previous cycle is >3 days. Dose delay is not defined for the first cycle, and for 
subsequent cycles in case tusamitamab ravtansine is not administered at previous cycle. 
• Dose omission is defined as a dose not administered at the scheduled visit but 
administered afterwards. 
• Dose interruption: A dose will be considered to be interrupted if the tusamitamab 
ravtansine administration is stopped during an infusion regardless of whether it is restarted 
or not. 
Dose modifications will be analyzed by participant and cycle as follows: 
• Participant (number of participants treated will be used as denominator) 
- 
Number (%) of participants with at least 1 dose modification 
- 
Number (%) of participants with at least 1 dose delayed 
- 
Number (%) of participants with at least 1 dose reduction 
- 
Number (%) of participants with at least 1 dose omission 
- 
Number (%) of participants with a least 1 dose interruption 
• Cycle (number of cycles started will be used as denominator) 
- 
Number (%) of cycles with at least 1 dose modification 
- 
Number (%) of participants with at least 1 dose delayed 
- 
Number (%) of cycles with at least 1 dose reduction 
- 
Number (%) of cycles with at least 1 dose omission 
- 
Number (%) of cycles with at least 1 dose interruption 
4.7.1.3 Pembrolizumab exposure  
The dose information will be assessed by the following: 
• Total number of cycles started 
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• Number of cycles started per participant 
• Duration of pembrolizumab exposure (in weeks), defined by date of last administration of 
pembrolizumab + 21 days - date of first administration of pembrolizumab/7. 
• Actual dose (in mg). In case of dose interruption, actual dose will be the sum of the actual 
doses administered before and after the dose interruption. 
• Cumulative dose (in mg): the cumulative dose is the sum of all actual doses of 
pembrolizumab, given from first to last administration 
• Actual dose intensity (ADI in mg/week): defined as the cumulative dose divided by the 
duration of pembrolizumab exposure (in weeks) 
• Planned dose intensity (PDI in mg/week): corresponds to the planned dose multiplied by 
the theoretical total number of doses started and divided by the theoretical cycle duration 
expressed in weeks (ie, 3 weeks per cycle started) 
• Relative dose intensity (RDI, in %):100 ×
ADI (mg/week) 
PDI (mg/week) 
The total number of cycles started, and the number of cycles started by participant will be 
summarized as a quantitative variable and by category (number [%] of participants receiving at 
least 1 cycle, at least 2 cycles, etc). Duration of pembrolizumab exposure, cumulative dose, ADI 
and RDI will be summarized quantitatively. 
The following variable will be derived to describe dose modifications and dose interruptions: 
• Dose delay: A dose will be considered as delayed if the pembrolizumab administration 
date of the current cycle – 21 days – pembrolizumab administration date of the previous 
cycle is >3 days. Dose delay is not defined for the first cycle, and for subsequent cycles in 
case pembrolizumab is not administered at previous cycle. 
• Dose interruption: A dose will be considered to be interrupted if the pembrolizumab 
administration is stopped during an infusion regardless of whether it is restarted or not. 
• Dose omission is defined as a dose not administered at the scheduled visit but 
administered afterwards. 
Dose modifications will be analyzed by participant and cycle as follows: 
• Participant (number of participants treated will be used as denominator) 
- 
Number (%) of participants with at least 1 dose modification 
- 
Number (%) of participants with at least 1 dose delayed 
- 
Number (%) of participants with at least 1 dose omission 
- 
Number (%) of participants with a least 1 dose interruption 
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• Cycle (number of cycles started will be used as denominator) 
- 
Number (%) of cycles with at least 1 dose modification 
- 
Number (%) of cycles with at least 1 dose delayed 
- 
Number (%) of cycles with at least 1 dose omission 
- 
Number (%) of cycles with at least 1 dose interruption 
4.7.1.4 Cisplatin exposure (Part B and Part C)  
The dose information will be assessed by the following: 
• Total number of cycles started 
• Number of cycles started per participant 
• Duration of cisplatin exposure (in weeks) is defined by date of last administration of 
cisplatin + 21 days - date of first administration of cisplatin/7 
• Actual dose (in mg/m²). In case of dose interruption, actual dose will be the sum of the 
actual doses administered before and after the dose interruption. 
• Cumulative dose (in mg/m²): the cumulative dose is the sum of all actual doses of 
cisplatin, given from first to last administration 
• Actual dose intensity (ADI in mg/m²/week), defined as the cumulative dose divided by the 
duration of cisplatin exposure (in weeks) 
• Planned dose intensity (PDI in mg/m²/week): corresponds to the planned dose multiplied 
by the theoretical total number of doses started and divided by the theoretical cycle 
duration expressed in weeks (ie, 3 weeks per cycle started) 
• Relative dose intensity (RDI, in %):100 ×
ADI (mg/m²/week) 
PDI (mg/m²/week) 
The total number of cycles started, and the number of cycles started by participant will be 
summarized as a quantitative variable and by category (number [%] of participants receiving at 
least 1 cycle, at least 2 cycles, etc). Duration of cisplatin exposure, cumulative dose, ADI and RDI 
will be summarized quantitatively. 
The following variables will be derived to describe dose modifications and dose interruptions: 
• Dose reduction: The first administration will not be counted as a dose reduction. For the 
second and subsequent cisplatin administrations, dose reduction will be determined using 
the dose level intervals provided in Table 6, by comparing the current dose level to the 
previous dose level. If the current dose level is below the dose level interval of the 
previous dose administration, then the current dose level is considered reduced. 
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Table 6 - Cisplatin dose reduction criteria  
Actual dose level 
Dose level interval 
Starting dose (75 mg/m²) 
>65.5 mg/m² 
Dose level -1 (56 mg/m²) 
>47 mg/m² and ≤65.5 mg/m² 
Dose level -2 (38 mg/m²) 
>29 mg/m² and ≤47 mg/m² 
Low dose 
>0 mg/m² and ≤29 mg/m² 
• Dose delay: A dose will be considered as delayed if the cisplatin administration date of the 
current cycle – 21 days – cisplatin administration date of the previous cycle is >3 days. 
Dose delay is not defined for the first cycle, and for subsequent cycles in case cisplatin is 
not administered at previous cycle. 
• Dose omission is defined as a dose not administered at the scheduled visit but 
administered afterwards. 
• Dose interruption: A dose will be considered to be interrupted if the cisplatin 
administration is stopped during an infusion regardless of whether it is restarted or not. 
Dose modifications will be analyzed by participant and cycle as follows: 
• Participant (number of participants treated will be used as denominator) 
- 
Number (%) of participants with at least 1 dose modification 
- 
Number (%) of participants with at least 1 dose delayed 
- 
Number (%) of participants with at least 1 dose reduction 
- 
Number (%) of participants with at least 1 dose omission 
- 
Number (%) of participants with a least 1 dose interruption 
• Cycle (number of cycles started will be used as denominator) 
- 
Number (%) of cycles with at least 1 dose modification 
- 
Number (%) of participants with at least 1 dose delayed 
- 
Number (%) of cycles with at least 1 dose reduction 
- 
Number (%) of cycles with at least 1 dose omission 
- 
Number (%) of cycles with at least 1 dose interruption 
4.7.1.5 Carboplatin exposure (Part B and Part C)  
The dose information will be assessed by the following: 
• Total number of cycles started 
• Number of cycles started per participant 
• Duration of carboplatin exposure (in weeks) is defined by date of last administration of 
carboplatin + 21 days - date of first administration of carboplatin/7 
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• Actual dose (in mg/mL/min). In case of dose interruption, actual dose will be the sum of 
the actual doses administered before and after the dose interruption. 
• Cumulative dose (in mg/mL/min): the cumulative dose is the sum of all actual doses of 
carboplatin, given from first to last administration 
• Actual dose intensity (ADI in mg/mL/min/week), defined as the cumulative dose divided 
by the duration of carboplatin exposure (in weeks) 
• Planned dose intensity (PDI in mg/mL/min/week): corresponds to the planned dose 
multiplied by the theoretical total number of doses started and divided by the theoretical 
cycle duration expressed in weeks (ie, 3 weeks per cycle started) 
• Relative dose intensity (RDI, in %): 100 ×
ADI (mg/mL/min/week) 
PDI (mg/mL/min/week) 
The total number of cycles started, and the number of cycles started by participant will be 
summarized as a quantitative variable and by category (number [%] of participants receiving at 
least 1 cycle, at least 2 cycles, etc). Duration of carboplatin exposure, cumulative dose, ADI and 
RDI will be summarized quantitatively. 
The following variables will be derived to describe dose modifications and dose interruptions: 
• Dose reduction: The first administration will not be counted as a dose reduction. For the 
second and subsequent carboplatin administrations, dose reduction will be determined 
using the dose level intervals provided in Table 7, by comparing the current dose level to 
the previous dose level. If the current dose level is below the dose level interval of the 
previous dose administration, then the current dose level is considered reduced. 
Table 7 - Carboplatin dose reduction criteria  
Actual dose level 
Dose level interval 
Starting dose (5 mg/mL/min) 
>4.4 mg/mL/min 
Dose level -1 (3.75 mg/mL/min) 
>3.1 mg/mL/min and ≤4.4 mg/mL/min 
Dose level -2 (2.5 mg/mL/min) 
>1.9 mg/mL/min and ≤3.1 mg/mL/min 
Low dose 
>0 mg/mL/min and ≤1.9 mg/mL/min 
• Dose delay: A dose will be considered as delayed if the carboplatin administration date of 
the current cycle – 21 days – carboplatin administration date of the previous cycle is 
>3 days. Dose delay is not defined for the first cycle, and for subsequent cycles in case 
carboplatin is not administered at previous cycle. 
• Dose omission is defined as a dose not administered at the scheduled visit but 
administered afterwards. 
• Dose interruption: A dose will be considered to be interrupted if the carboplatin 
administration is stopped during an infusion regardless of whether it is restarted or not. 
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Dose modifications will be analyzed by participant and cycle as follows: 
• Participant (number of participants treated will be used as denominator) 
- 
Number (%) of participants with at least 1 dose modification 
- 
Number (%) of participants with at least 1 dose delayed 
- 
Number (%) of participants with at least 1 dose reduction 
- 
Number (%) of participants with at least 1 dose omission 
- 
Number (%) of participants with a least 1 dose interruption 
• Cycle (number of cycles started will be used as denominator) 
- 
Number (%) of cycles with at least 1 dose modification 
- 
Number (%) of participants with at least 1 dose delayed 
- 
Number (%) of cycles with at least 1 dose reduction 
- 
Number (%) of cycles with at least 1 dose omission 
- 
Number (%) of cycles with at least 1 dose interruption 
4.7.1.6 Pemetrexed exposure (Part C)  
The dose information will be assessed by the following: 
• Total number of cycles started 
• Number of cycles started per participant 
• Duration of pemetrexed exposure (in weeks) is defined by date of last administration of 
pemetrexed + 21 days - date of first administration of pemetrexed/7 
• Actual dose (in mg/m²). In case of dose interruption, actual dose will be the sum of the 
actual doses administered before and after the dose interruption. 
• Cumulative dose (in mg/m²): the cumulative dose is the sum of all actual doses of 
pemetrexed, given from first to last administration 
• Actual dose intensity (ADI in mg/m²/week), defined as the cumulative dose divided by the 
duration of pemetrexed exposure (in weeks) 
• Planned dose intensity (PDI in mg/m²/week): corresponds to the planned dose multiplied 
by the theoretical total number of doses started and divided by the theoretical cycle 
duration expressed in weeks (ie, 3 weeks per cycle started) 
• Relative dose intensity (RDI, in %):100 ×
ADI (mg/m²/week) 
PDI (mg/m²/week) 
The total number of cycles started, and the number of cycles started by participant will be 
summarized as a quantitative variable and by category (number [%] of participants receiving at 
least 1 cycle, at least 2 cycles, etc). Duration of pemetrexed exposure, cumulative dose, ADI and 
RDI will be summarized quantitatively. 
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The following variables will be derived to describe dose modifications and dose interruptions: 
• Dose reduction: The first administration will not be counted as a dose reduction. For the 
second and subsequent pemetrexed administrations, dose reduction will be determined 
using the dose level intervals provided in Table 8, by comparing the current dose level to 
the previous dose level. If the current dose level is below the dose level interval of the 
previous dose administration, then the current dose level is considered reduced. 
Table 8 - Pemetrexed dose reduction criteria  
Actual dose level 
Dose level interval 
Starting dose (500 mg/m²) 
>437.5 mg/m² 
Dose level -1 (375 mg/m²) 
>312.5 mg/m² and ≤437.5 mg/m² 
Dose level -2 (250 mg/m²) 
>187.5 mg/m² and ≤312.5 mg/m² 
Low dose 
>0 mg/m² and ≤187.5 mg/m² 
• Dose delay: A dose will be considered as delayed if the pemetrexed administration date of 
the current cycle – 21 days – pemetrexed administration date of the previous cycle is  
>3 days. Dose delay is not defined for the first cycle, and for subsequent cycles in case 
pemetrexed is not administered at previous cycle. 
• Dose omission is defined as a dose not administered at the scheduled visit but 
administered afterwards. 
• Dose interruption: A dose will be considered to be interrupted if the pemetrexed 
administration is stopped during an infusion regardless of whether it is restarted or not. 
Dose modifications will be analyzed by participant and cycle as follows: 
• Participant (number of participants treated will be used as denominator) 
- 
Number (%) of participants with at least 1 dose modification 
- 
Number (%) of participants with at least 1 dose delayed 
- 
Number (%) of participants with at least 1 dose reduction 
- 
Number (%) of participants with at least 1 dose omission 
- 
Number (%) of participants with a least 1 dose interruption 
• Cycle (number of cycles started will be used as denominator) 
- 
Number (%) of cycles with at least 1 dose modification 
- 
Number (%) of participants with at least 1 dose delayed 
- 
Number (%) of cycles with at least 1 dose reduction 
- 
Number (%) of cycles with at least 1 dose omission 
- 
Number (%) of cycles with at least 1 dose interruption 
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4.7.2 Adverse events  
General common rules for adverse events 
All AEs will be graded according to National cancer institute common terminology for adverse 
events (NCI-CTCAE Version 5.0) and coded to a lower-level term (LLT), preferred term (PT), 
high-level term (HLT), high-level group term (HLGT), and associated primary system organ class 
(SOC) using the Medical Dictionary for Regulatory Activities (MedDRA) version currently in 
effect at Sanofi at the time of database lock. 
The AEs will be analyzed in the following 3 categories: 
• Pre-treatment AEs: AEs that developed, worsened or became serious during the 
pre-treatment period. 
• Treatment-emergent adverse events (TEAEs): AEs that developed, worsened or became 
serious during the treatment-emergent period. 
• Post-treatment AEs: AEs that developed, worsened or became serious during the 
post-treatment period. 
Similarly, the deaths will be analyzed in the pre-treatment, treatment-emergent and post-treatment 
periods. 
The primary AE analyses will be on TEAEs. Pre-treatment AEs and post-treatment AEs will be 
described separately. 
An AE with incomplete or missing date/time of onset (occurrence, worsening, or becoming 
serious) will be classified as a TEAE unless there is definitive information to determine it is a 
pre-treatment or a post-treatment AE. 
If the assessment of the relationship to IMP is missing for an AE, this AE will be assumed as 
related to IMP if IMP is actually received by the participant, and as not related otherwise. Missing 
grade will be left as missing. 
Multiple occurrences of the same event in the same participant will be counted only once in the 
tables within a treatment phase, using the maximum (worst) grade by treatment phase. Summaries 
will be provided for all grades combined and for grade ≥3 (including Grade 5). Missing grades, if 
any, will be included in the “all grades” category. 
The AE tables will be sorted as indicated in Table 9. 
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Table 9 - Sorting of AE tables  
AE presentation 
Sorting rules 
SOC, HLGT, HLT and PT 
By the internationally agreed SOC order and by alphabetic order of HLGTs, HLTs and PTs.  
SOC and PT 
By the internationally agreed SOC order and decreasing frequency of PTsa, b 
SMQ/CMQ and PT 
By decreasing frequency of SMQs/CMQs and PTsa 
PT 
By decreasing frequency of PTsa 
a Sorting will be based on the experimental intervention arm at the highest dose level. 
b The table of all TEAEs presented by primary SOC and PT will define the presentation order for all other tables (eg, treatment-emergent 
SAE) presented by primary SOC and PT, unless otherwise specified.  
Analysis of all adverse events 
The overview of TEAE with the details below will be generated: 
• Any TEAE 
• Any grade ≥3 TEAE 
• Grade 5 TEAE (any TEAE with a fatal outcome during the treatment-emergent period) 
• Any treatment-emergent SAE 
• Any treatment emergent AESI 
• Any TEAE leading to permanent full study intervention discontinuation 
• Any TEAE leading to permanent partial discontinuation of tusamitamab ravtansine 
• Any TEAE leading to permanent partial discontinuation of pembrolizumab 
• Any TEAE leading to permanent partial discontinuation of cisplatin 
• Any TEAE leading to permanent partial discontinuation of carboplatin 
• Any TEAE leading to permanent partial discontinuation of pemetrexed 
• Any TEAE related to IMP 
• Any grade ≥3 TEAE related to IMP 
• Any treatment-emergent SAE related to IMP 
• Any treatment-emergent corneal event (CMQ “Corneal events compound level”) 
• Any ocular/visual symptoms TEAE (CMQ “Eye disorders exclude corneal disorders”), 
• Any treatment-emergent peripheral neuropathy event TEAE (SMQ “Peripheral 
neuropathy” (Narrow and Broad)) 
The AE summaries of Table 10 will be generated with number (%) of participants experiencing at 
least one event. The analyses will be performed for all grades combined and for grades ≥3. The all 
TEAE summary by primary SOC and PT (and other safety summaries (eg, SAEs, deaths), if 
deemed needed after TEAE evaluation) will be performed by trial impact (disruption) due to 
COVID-19. 
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Table 10 - Analyses of adverse events  
Type of AE 
MedDRA levels 
All TEAE 
Primary SOC, HLGT, HLT and PT 
 
Primary SOC and PT 
 
PT 
TEAE related to IMP as per Investigator’s judgment 
Primary SOC and PT 
TEAE related to tusamitamab ravtansine as per Investigator’s judgment 
Primary SOC and PT 
TEAE related to pembrolizumab as per Investigator’s judgment 
Primary SOC and PT 
TEAE related to cisplatin as per Investigator’s judgment 
Primary SOC and PT 
TEAE related to carboplatin as per Investigator’s judgment 
Primary SOC and PT 
TEAE related to pemetrexed as per Investigator’s judgment 
Primary SOC and PT 
Treatment emergent SAE 
Primary SOC, HLGT, HLT and PT 
 
Primary SOC and PT 
Treatment emergent SAE related to IMP as per Investigator’s judgment 
Primary SOC and PT 
Treatment emergent SAE related to tusamitamab ravtansine as per Investigator’s 
judgment 
Primary SOC and PT 
Treatment emergent SAE related to pembrolizumab as per Investigator’s judgment 
Primary SOC and PT 
Treatment emergent SAE related to cisplatin as per Investigator’s judgment 
Primary SOC and PT 
Treatment emergent SAE related to carboplatin as per Investigator’s judgment 
Primary SOC and PT 
Treatment emergent SAE related to pemetrexed as per Investigator’s judgment 
Primary SOC and PT 
TEAE leading to permanent full study intervention discontinuation 
Primary SOC and PT 
TEAE leading to permanent partial discontinuation of tusamitamab ravtansine 
Primary SOC and PT 
TEAE leading to permanent partial discontinuation of pembrolizumab 
Primary SOC and PT 
TEAE leading to permanent partial discontinuation of cisplatin 
Primary SOC and PT 
TEAE leading to permanent partial discontinuation of carboplatin 
Primary SOC and PT 
TEAE leading to permanent partial discontinuation of pemetrexed 
Primary SOC and PT 
TEAE leading to death (death as an outcome of the AE as reported by the Investigator in 
the AE page) 
Primary SOC and PT 
TEAE related to tusamitamab ravtansine and leading to death (death as an outcome of 
the AE as reported by the Investigator in the AE page) 
Primary SOC and PT 
Pre-treatment AE  
Overviewa 
 
Primary SOC and PT 
Pre-treatment SAE 
Primary SOC and PT 
Post-treatment AE 
Overviewa 
 
Primary SOC and PT 
Post-treatment SAE 
Primary SOC and PT 
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Type of AE 
MedDRA levels 
TEAE leading to dose modification of tusamitamab ravtansine (including dose delay, 
dose reduction and dose omission) 
Primary SOC and PT 
TEAE leading to dose modification of pembrolizumab (including dose delay and dose 
omission) 
Primary SOC and PT 
TEAE leading to dose modification of cisplatin (including dose delay, dose reduction and 
dose omission) 
Primary SOC and PT 
TEAE leading to dose modification of carboplatin (including dose delay, dose reduction 
and dose omission) 
Primary SOC and PT 
TEAE leading to dose modification of pemetrexed (including dose delay, dose reduction 
and dose omission) 
Primary SOC and PT 
TEAE leading to dose interruption of tusamitamab ravtansine 
Primary SOC and PT 
TEAE leading to dose interruption of pembrolizumab 
Primary SOC and PT 
TEAE leading to dose interruption of cisplatin 
Primary SOC and PT 
TEAE leading to dose interruption of carboplatin 
Primary SOC and PT 
TEAE leading to dose interruption of pemetrexed 
Primary SOC and PT 
a Will include the following AE categories: any AEs, any serious AEs, any AEs leading to death, any AEs leading to permanent full 
intervention discontinuation. 
Analysis of deaths 
In addition to the analyses of deaths included in Table 10, the number (%) of participants in the 
following categories will be provided: 
• Deaths during the treatment-emergent and post-treatment periods by study period and 
main reason for death 
• Summary of fatal AEs, by primary SOC and PT: 
- 
In context of disease progression (death within 30 days from last study intervention 
administration and the cause of death is disease progression). 
- 
In context other than disease progression (death within 30 days from last study 
intervention administration and for whom cause of death is not disease progression or 
the death occurred more than 30 days from last study intervention administration and 
the cause of death is AE). 
• An overview of Grade 5 AEs will be provided with the following categories: 
- 
Grade 5 AE (TEAE and post-treatment) 
- 
Fatal TEAE (regardless of date of death/period) 
- 
Grade 5 TEAE with a fatal outcome during the treatment-emergent period 
- 
Any Grade TEAE with a fatal outcome during the post-treatment period 
- 
Post-treatment Grade 5 AE (excluding a TEAE that worsened to Grade 5 during the 
post-treatment period) 
• Deaths in non-enrolled participants or enrolled but not treated participants 
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Analysis of adverse events of special interest (AESIs) and other AEs of interest 
Adverse events of special interest (AESIs) and other AEs of interest will be selected for analyses as 
indicated in Table 11. Number (%) of participants experiencing at least one event will be provided 
for each event of interest, by PT (if applicable). Tables will be sorted as indicated in Table 9. 
Table 11 - Selections for AESIs and other AEs of interest  
AESIs and other AEs of interest 
Selection 
AESIs 
 
Grade ≥3 keratopathy 
 
e-CRF AESI specific tick box on the AE page. It could 
include Grade ≥3 events with PTs from CMQ of corneal 
events 
Bundle branch blocks or any conduction defects 
e-CRF AESI specific tick box on the AE page. It could 
include events with PTs from SMQ “Conduction defects” 
Grade ≥3 liver enzyme increased (symptomatic or 
asymptomatic) 
e-CRF AESI specific tick box on the AE page. It could 
include Grade ≥3 events with the following PTs: “Alanine 
aminotransferase increased”, “Aspartate aminotransferase 
increased”, “Transaminases increased”, “Hepatic function 
abnormal”, “Hepatic enzyme increased”, “Liver function test 
increased”, “Transaminases abnormal”, “Hepatic enzyme 
abnormal”, or “Liver function test abnormal” 
Symptomatic overdose (serious or nonserious) with IMP/NIMP 
e-CRF symptomatic overdose specific tick box on the 
Overdose page 
Pregnancy of a female participant entered in a study as well as 
pregnancy occurring in a female partner of a male participant 
entered in a study with IMP/NIMP 
eCRF specific tick box for adverse event linked to pregnancy 
on the Pregnancy page 
Other AEs of interest 
 
Any AE meeting DLT criteria 
AEs reported on the e-CRF DLT page outside the DLT 
observation period 
Corneal events 
CMQ “Corneal events compound level” containing the PTs 
included in both SOC “Eye disorders” and SMQ “Corneal 
disorders” (Narrow)  
Ocular/visual symptoms (excluding corneal disorders) 
CMQ “Eye disorders exclude corneal disorders” containing 
PTs included in SOC “Eyes disorders” and excluding PTs in 
SMQ “Corneal disorders” (Narrow) 
Cardiac conduction defects 
SMQ “Conduction defects” (Narrow)  
Peripheral neuropathy events  
SMQ “Peripheral neuropathy” (Narrow and Broad) 
Gastrointestinal disorders 
CMQ “Bowel disorders” (see Section 5.6)a 
Infusion allergic reactions  
SMQ “Hypersensitivity” (Narrow) and adverse event 
occurring on the day or the day after infusion 
Hepatic disorders events 
SMQ “Hepatic Disorders” (Narrow and Broad) 
Hematological events 
SMQ “Haematopoietic cytopenias” (Narrow and Broad) 
AE related to COVID-19 illness 
SMQ “COVID-19” (Narrow) 
a The list of terms may be adjusted according to MedDRA version changes 
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An overview of corneal TEAE will be provided with the following AE categories: any corneal 
TEAE, Grade ≥3 corneal TEAE, treatment-emergent corneal SAE, corneal TEAE leading to 
permanent full intervention discontinuation, corneal TEAE leading to permanent partial 
discontinuation of tusamitamab ravtansine, corneal TEAE related to IMP, Grade ≥3 corneal 
TEAE related to IMP, and corneal TEAE leading to dose modification of tusamitamab ravtansine. 
In addition, descriptive analyses will be provided on ocular/visual symptoms reported as 
associated with the corneal adverse events. These analyses will be performed based on the 
Investigator’s reporting of ocular toxicities (using Investigator’s terms collected in the category 
“Ocular/visual symptoms” in the AE page and using associated symptoms reported in the 
ocular/visual symptoms page during each corneal event). A summary of treatment-emergent 
corneal events will be provided.  
• Number (%) of participants by worst grade 
• Cycle of first onset of corneal event regardless of the grade 
• Cycle of first onset of corneal event with the worst grade 
• Relationship to the study intervention: in case of multiple events with different 
relationships, if any event is related, then the relationship will be considered as related 
• Action taken with the study intervention: in case of multiple events with different actions, 
the most severe action taken will be tabulated and selected according to the following 
order of severity: drug withdrawn, dose reduced, drug interrupted, dose not changed 
• Outcome: in case of multiple events with different outcomes, the most severe outcome will 
be tabulated and selected according to the following order of severity: fatal, not recovered 
or resolved, recovering or resolving, recovered or resolved with sequelae, recovered or 
resolved, unknown 
In addition, analyses on occurrence and recurrence of corneal events will be provided. An 
occurrence of corneal event is defined as one or a group of concomitant corneal events. A 
recurrence is defined as any new occurrence of corneal event starting after a previous resolved 
occurrence. 
• The number of occurrences by participant 
• The time to first onset of corneal event will be described using Kaplan-Meier curves. Time 
to first onset is defined as the time from the date of first IMP administration to the date of 
the first occurrence of the event. In the absence of an event before the analysis cut-off 
date, it will be censored at the end date of the treatment-emergent period, analysis cut-off 
date or date of death, whichever occurs first. 
• The time to recovery will be summarized using descriptive statistics in participants who 
have had at least one recovered or resolved occurrence of corneal event (with or without 
sequelae), considering the longest duration, and the longest duration of the worst grade 
among all occurrences by participant. 
• The time to recurrence will be summarized using descriptive statistics in participants who 
have had at least one recurrence, considering the shortest time among all recurrences by 
participant.  
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4.7.3 Additional safety assessments  
4.7.3.1 Laboratory variables, vital signs and electrocardiograms (ECGs)  
The following laboratory variables, vital signs and electrocardiogram (ECG) variables will be 
analyzed. They will be converted into standard international units. 
• Hematology and coagulation: 
- 
Red blood cells and platelets and coagulation: hemoglobin, hematocrit, platelet count 
and prothrombin time (expressed as international normalized ratio [INR]). 
- 
White blood cells: white blood cell (WBC) count, neutrophils, lymphocytes, 
monocytes, basophils and eosinophils. 
• Clinical chemistry: 
- 
Metabolism: glucose, total protein and albumin. 
- 
Electrolytes: sodium, potassium, chloride, phosphate and corrected calcium. Corrected 
calcium (mmol/L) will be derived using the following formula: measured total calcium 
(mmol/L) + 0.8 x 0.25 x (4.0 - [serum albumin (g/L) x 0.1]), where 4.0 represents the 
average albumin level. 
- 
Renal function: creatinine, blood urea nitrogen (BUN), urea. 
- 
Liver function: alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
alkaline phosphatase (ALP), lactate dehydrogenase (LDH), total and conjugated 
bilirubin. 
- 
Thyroid function: thyroid-stimulating hormone (TSH), total or free tri-iodothyronine 
(T3) and free thyroxine (FT4) 
- 
Circulating carcinoembryonic antigen (CEA) 
• Vital signs: pulse rate, systolic and diastolic blood pressure, weight and ECOG 
Performance Status (PS). 
• ECG variables: heart rate, PR, QRS, QT, and corrected QTc (according to Fridericia). 
Data below the lower limit of quantitation/detection limit (LLOQ) will be replaced by half of the 
LLOQ, data above the upper limit of quantification will be replaced by ULOQ value. 
For hematological parameters and some selected coagulation and biochemistry parameters, Sanofi 
sponsor generic ranges (LLN, ULN) are defined and will be used for grading (see list of 
parameters in Section 5.5). For other coagulation and biochemistry parameters, grading will be 
derived using local laboratory normal ranges. 
Quantitative analyses 
For vital signs and ECG variables above, descriptive statistics for results and changes from 
baseline for each planned visit, and the worst value (minimum and/or maximum value depending 
on the parameter) during the treatment-emergent period will be provided. These analyses will be 
performed using local measurements. 
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For QRS and QTc variables, blood pressure, and heart rate, mean changes from baseline with the 
corresponding standard error will be plotted over time. 
Analyses according to potentially clinically significant abnormalities (PCSA) and NCI 
grading 
For laboratory variables, analyses according to NCI grading will be made based on NCI-CTCAE 
Version 5.0. In addition, for laboratory variables for which NCI-CTCAE scale is not applicable, 
vital signs and ECG variables, PCSA analyses will be performed based on the PCSA list currently 
in effect at Sanofi at the time of the database lock. 
Analyses according to PCSA and NCI grading will be performed based on the worst value during 
the treatment-emergent period, using all measurements (either local or central, either scheduled, 
nonscheduled or repeated). 
For laboratory variables, vital signs and ECG variables above, the incidence of participants with at 
least one PCSA during the treatment-emergent period will be summarized regardless of the 
baseline level and according to the following baseline status categories: 
• Normal/missing 
• Abnormal according to PCSA criterion or criteria 
For laboratory variables graded by NCI-CTCAE, 
• The number (%) of participants with abnormal laboratory tests at baseline will be 
presented by grade. 
• The number (%) of participants with abnormal laboratory tests during the 
treatment-emergent period will be summarized by grade. When appropriate, the number 
(%) of participants with abnormality of any grade and with Grade 3-4 abnormalities will 
be provided. 
For laboratory variables not graded by NCI-CTCAE nor by PCSA, the number (%) of participants 
with laboratory tests outside normal ranges will be provided. 
Additional analyses for drug-induced liver injury 
The following additional analyses will be performed for drug-induced liver injury: 
• A graph of the distribution of peak values of ALT versus peak values of total bilirubin 
during the treatment-emergent period will be provided. 
• For each liver function test (eg, ALT), participants having experienced a PCSA (eg, ALT 
>5 ULN) will be summarized using the following categories: Returned to baseline PCSA 
status (or returned to value ≤ ULN in case of missing baseline) before last IMP dose, 
Returned to baseline PCSA status after last IMP dose, Never returned to baseline PCSA 
status, No assessment after elevation. This summary will be performed by categories of 
elevation (ALT >3, >5, >10, >20 ULN). 
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4.7.3.2 Ocular examinations  
Schirmer test 
Participants reported Schirmer’s test will be classified into 3 classes at baseline: normal ≥15 mm, 
mild 15-5 mm, severe <5 mm. The worst classification between the laterality will be considered. 
The number (%) of participants by baseline status will be provided for participants with 
keratopathy/keratitis and for participants without event. 
Descriptive statistics on the changes from baseline at the time the keratopathy/keratitis (CMQ) 
occurred will be displayed. 
Visual acuity test 
Descriptive statistics on the changes from baseline at the time the keratopathy/keratitis (CMQ) 
occurred will be displayed. 
Slit lamp examination 
For participants experiencing keratopathy/keratitis (CMQ), descriptive statistics will be provided 
describing the type of lesions and the distribution. 
4.8 
OTHER ANALYSES  
4.8.1 PK analyses  
PK analyses will be performed on the PK population as defined in Section 3. 
4.8.1.1 Tusamitamab ravtansine, pembrolizumab, cisplatin, carboplatin and pemetrexed  
Individual concentrations will be listed and summarized by dose level (if applicable) and by drug 
using descriptive statistics (such as the number of observations, arithmetic and geometric means, 
median, standard deviation, standard error [SE], coefficient of variation [CV], minimum, and 
maximum). 
All concentration values below the LLOQ will be treated as zero in individual listing and 
respective descriptive statistics. 
4.8.1.2 Population PK analysis  
This analysis will be performed by PKDM department at Sanofi. Details of the analysis plan will 
be provided in a separate document. 
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4.8.1.3 Immunogenicity impact on PK  
Immunogenicity impact on PK of tusamitamab ravtansine may be explored, depending on the 
ATA incidence. 
Descriptive statistics of Ctrough will be provided at each cycle in the subset of negative participants 
by dose level (if applicable). 
The impact of immunogenicity on PK will be assessed graphically by plotting individual Ctrough 
profiles of ATA-positive participants along with mean (+/- SD) Ctrough profile of ATA-negative 
participants by dose level. In this plot, concentrations obtained at the time of an ATA-positive 
result will be highlighted. 
4.8.2 Immunogenicity analyses  
A summary table with number (%) of participants with pre-existing ATA, number (%) of 
participants with treatment-boosted ATA, number (%) of ATA-negative participants at baseline, 
number (%) of participants with treatment-induced ATA (either transient, persistent or 
indeterminate) (see definitions below) along with descriptive statistics of titer will be reported by 
dose level (if applicable) and overall on the ATA population (as defined in Section 3). Number 
(%) of ATA-positive participants and ATA incidence will also be presented. 
For ATA-positive participants, descriptive statistics on time to onset and duration of ATA 
response will be provided using a summary table. 
An individual data listing will be provided for participants having at least one positive or 
inconclusive ATA sample with study period (cycle), ATA sample study day, tusamitamab 
ravtansine Ctrough value, ATA samples result (positive, negative or inconclusive), ATA samples 
titer (if applicable), ATA participant status (positive, negative or inconclusive) and ATA 
participant response (kinetic of the immune response: indeterminate, transient or inconclusive). 
Note that treatment-boosted ATA are excluded from the analyses of ATA kinetics because this 
type of immune response differs mechanistically. 
The impact on safety and efficacy endpoints may be further explored by graphical methods or 
descriptively, depending on the ATA incidence. 
ATA endpoint 
Anti-therapeutic antibodies are biologic drug-reactive antibody, including pre-existing host 
antibodies that are cross-reactive with the administered biotherapeutic (baseline ATA). 
ATA attributes 
Pre-existing ATA is defined as ATA reactive with the biotherapeutic present in participants 
before first administration of intervention (or before initiation of the clinical study). 
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Treatment-boosted ATA is defined as pre-existing ATA that was boosted to a higher-level 
following administration of biotherapeutic (ie, any time after the initial drug administration) the 
ATA titer is significantly higher than the baseline titer. A low serial dilution schema (2-fold or 
3-fold) should be applied during titration. A difference in titer values of two titer steps between 
treatment or follow-up sample and its baseline sample is considered significant. For examples, at 
least a 4-fold increase in titers for 2-fold serial dilution schema (or 9-fold increase in titers for 
3-fold serial dilution schema). If no titer could be determined for a positive sample, the titer will 
be reported as the minimal required dilution of the assay. 
Treatment-induced ATA is defined as ATAs developed de novo (seroconversion) following 
administration of the biotherapeutic (ie, formation of ATAs any time after the initial drug 
administration in a participant without pre-existing ATAs). If the baseline ATA sample is missing 
or non-reportable and at least one reportable ATA sample is available during the treatment 
(including follow-up period) the baseline sample will be considered as “negative” for data 
analysis. This is considered being a conservative approach for ATA assessment. 
Participant status 
Among evaluable population for immunogenicity (described in Section 3), following participant 
status will be defined: 
• ATA-positive participant: A participant with at least one treatment-induced or treatment-
boosted ATA-positive sample at any time during the treatment or follow-up observation 
period. 
• ATA-negative participant: Participant without any treatment-induced or treatment-
boosted ATApositive sample during the treatment or follow-up observation period. 
• ATA-inconclusive participant: A participant who cannot irrefutably be classified as ATA 
negative (eg, all post baseline samples inconclusive). 
Overview of the ATA response 
• The term ATA incidence only defines the proportion of subjects found to either have 
seroconverted (treatment-induced ATAs) or boosted their pre-existing ATA response 
during the study. Only evaluable subjects (described in Section 3) are considered for 
computing ATA incidence. 
Kinetics of the immune response 
• Onset of ATA: refers to the time period between the initial drug administration and the 
first instance of treatment-induced ATAs. The use of real-elapsed days should be used for 
the calculations. The “median time to ATA development” and the quartiles Q1 and Q3 
should be reported. 
• Duration of ATA: ATA duration will be calculated as the date of last treatment-induced 
ATA sample minus date of first treatment-induced or treatment-boosted ATA sample +1; 
ATA duration will be calculated only for participants with at least two ATA positive 
samples. Median duration of an induced ATA response and the quartiles Q1 and Q3 
should be reported. 
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• Transient ATA response is defined by: 
- 
Treatment-induced ATA detected only at one sampling time point during the treatment 
or follow-up observation period (excluding the last sampling time point), OR 
- 
Treatment-induced ATA detected at two or more sampling time points during the 
treatment (including follow-up period if any), where the first and last ATA-positive 
samples (irrespective of any negative samples in between) are separated by a period 
less than 16 weeks, and the participant’s last sampling time point is ATA negative. 
• Persistent ATA response is defined by: 
- 
Treatment-induced ATA detected at two or more sampling time points during the 
treatment (including follow-up period if any), where the first and last ATA-positive 
samples are separated by at least 16 weeks (irrespective of any negative samples in 
between). 
• Indeterminate ATA is defined by: 
- 
Treatment-induced ATA detected only at the last sampling time point, OR 
- 
The last two samples being ATA-positive and separated by a period of less than 
16 weeks. 
4.8.3 Biomarkers analyses  
Several exploratory objectives related to pharmacodynamic/genomic endpoints will be considered 
in this study. 
 Unless otherwise specified, biomarkers analyses will be performed on participants with available 
data from the all-treated population. 
4.8.3.1 Circulating CEA  
The circulating CEA will be considered as a quantitative variable or as a binary variable when 
considering different binary thresholds: <3, <5, <50, <80 or <100 µg/L. 
Circulating CEA values below the LLOQ will be replaced by half of the LLOQ. 
4.8.3.1.1 Circulating CEA levels at pre-screening  
Biomarkers analyses described in this section will be performed on participants with available 
data from the pre-screening population. 
The circulating CEA levels at pre-screening will be presented using descriptive statistics. 
The association between the circulating CEA at pre-screening and the CEACAM5 expression 
from archival or fresh tumor tissue (IHC) may also be assessed. To this end, Pearson correlation, 
Spearman’s rank, or Kendall's tau coefficient will be considered depending on the nature of the 
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data. The time from tumor biopsies and pre-screening will be also described and investigated in 
the correlation between pre-screening circulating CEA levels and IHC CEACAM5 expression. 
4.8.3.1.2 Modulations of circulating CEA as a potential PD biomarker of response to 
tusamitamab ravtansine treatment  
The circulating CEA at different timepoints and its relative change from baseline will be 
presented using descriptive statistics by response status and overall. 
The association between the circulating CEA at baseline and the CEACAM5 expression on tumor 
tissue (% of tumor cells expressing CEACAM5 at intensity ≥2+) may also be assessed. To this 
end, Pearson correlation, Spearman’s rank or Kendall's tau coefficient will be considered 
depending on the nature of the data. The circulating CEA at baseline may also be associated with 
the baseline tumor burden considered as the sum of the longest diameters of the target lesions at 
baseline. 
The association between the circulating CEA at baseline and confirmed objective response per 
RECIST 1.1 may be assessed using a logistic regression model and providing prognostic effect 
(ie, main effect: overall effect of the circulating CEA level on the efficacy endpoint). 
4.8.3.2 Circulating free DNA  
4.8.3.2.1 Relationship between the tumor mutation profiles detected in the cfDNA at baseline 
with efficacy outcomes  
Descriptive statistics of the number of participants with mutations at baseline for each gene will 
be presented by response status, overall and possibly according to other demographic 
characteristics. Statistical testing to evaluate the association with the confirmed objective response 
may be implemented for genes with more than 5 participants with mutations. If needed, multiple 
testing correction using Benjamini-Hochberg method may be used to control the false discovery 
rate (FDR). 
4.8.3.2.2 Changes in cfDNA in response to tusamitamab ravtansine treatment  
The evolution between Cycle 1 Day 1 and Cycle 5 Day 1 of the number of participants with 
mutations for each gene will be described using descriptive statistics by response status and 
overall. For key genes of interest, the mutation allele frequency will be described at Cycle 1 
Day 1, Cycle 5 Day 1 in addition to the relative change from baseline, and visualize through 
graphical visualization method. 
4.8.3.3 CEACAM5 expression on circulating tumoral cells (CTCs)  
CEACAM5 expression on CTCs may be considered as a quantitative or categorical variable and 
will be presented using descriptive statistics. 
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The correlation between the CEACAM5 expression on CTCs and the CEACAM5 expression on 
tumor tissue may be assessed using Pearson correlation, Spearman’s rank or Kendall's tau 
coefficient depending on the nature of the data. 
4.9 
INTERIM ANALYSES  
No formal interim analysis is planned in this study. 
The study analysis will be conducted in three steps. 
The first analysis step will be conducted when the last participant treated to determine the RP2D 
in Part A, Part B or Part C has ended Cycle 1. 
The second analysis step will be conducted when all treated participants 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. All analyses will be updated at this time. 
The final analysis will be conducted at the end of the study. Only safety analyses will be updated 
at this time. 
For each analysis step, the analysis cut-off date will be defined as the date of the database 
extraction that will be performed for the analysis after the cut-off (study cut-off for the first and 
second analysis steps). 
Analyses methods and conventions described in the other sections of this SAP will be applied for 
all analyses as applicable. The following additional rules will apply for the first and second 
analysis steps: 
• Participants without end of treatment status performed at the time of the analysis cut-off 
date will be considered as ongoing. Therefore: 
- 
Participants who did not discontinue the study intervention at analysis cut-off date will 
be analyzed as “ongoing” in the disposition summary. 
- 
Their treatment-emergent (TE) period and concomitant medication period will end at 
the analysis cut-off date. 
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5 
SUPPORTING DOCUMENTATION  
5.1 
APPENDIX 1 LIST OF ABBREVIATIONS  
 
ADI: 
actual dose intensity 
AE: 
adverse event 
AESI: 
adverse event of special interest 
ALP: 
alkaline phosphatase 
ALT: 
alanine aminotransferase 
AST: 
aspartate aminotransferase 
ATA: 
anti-therapeutic antibody 
BOR: 
best overall response 
BUN: 
blood urea nitrogen 
CEA: 
carcinoembryonic antigen 
CEACAM5: 
carcinoembryonic antigen-related cell adhesion molecule 5 
cfDNA: 
circulating free deoxyribonucleic acid 
CMQ: 
company MedDRA queries 
COVID-19: 
coronavirus disease 2019 
CR: 
complete response 
CTC: 
circulating tumoral cell 
CTCAE: 
common terminology criteria for adverse events 
CV: 
coefficient of variation 
DLT: 
dose-limiting toxicity 
ECG: 
electrocardiogram 
ECOG: 
Eastern Cooperative Oncology Group 
e-CRF: 
electronic case report form 
EOT: 
end of treatment 
FT4: 
free thyroxine 
HLGT: 
high-level group term 
HLT: 
high-level term 
IHC: 
immunohistochemistry 
IMP: 
investigational medicinal product 
INR: 
international normalized ratio 
LDH: 
lactate dehydrogenase 
LLN: 
lower limit of normal 
LLOQ: 
lower limit of quantitation 
LLT: 
lower-level term 
MedDRA: 
medical dictionary for regulatory activities 
NCI: 
National Cancer Institute 
NSQ NSCLC: 
non-squamous non-small cell lung cancer 
ORR: 
objective response rate 
PCSA: 
potentially clinically significant abnormalities 
PD: 
pharmacodynamic 
PDI: 
planned dose intensity 
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PK: 
pharmacokinetics 
PR: 
partial response 
PS: 
performance status 
PT: 
preferred term 
RDI: 
relative dose intensity 
RECIST: 
response evaluation criteria in solid tumors 
RP2D: 
recommended phase 2 dose 
SAE: 
serious adverse event 
SAP: 
statistical analysis plan 
SD: 
standard deviation 
SE: 
standard error 
SMQ: 
standardized MedDRA queries 
SOC: 
system organ class 
T3: 
tri-iodothyronine 
TE: 
treatment-emergent 
TEAE: 
treatment-emergent adverse event 
TSH: 
thyroid stimulating hormone 
ULN: 
upper limit of normal 
ULOQ: 
upper limit of quantitation 
WHO-DD: 
World Health Organization-drug dictionary 
 
5.2 
APPENDIX 2 CHANGES TO PROTOCOL-PLANNED ANALYSES  
This section summarizes major statistical changes in the protocol amendments. 
Table 12 - Major statistical changes in protocol amendments  
Amendment 
Number 
Approval 
Date 
Changes 
Rationale 
1 
23-Nov-2020 
Added objectives and endpoints, 
statistical populations, and statistical 
analyses for Part B. 
 
 
 
 
Added a dose level of 170 mg/m2 
Q3W to be evaluated in Part 1 of 
Part A 
Updated sample size in Part A 
 
Added possible interim analysis for 
Part A when study cut-off for primary 
analysis of Part B is reached. 
To reflect the change of adding the 
combination arm of tusamitamab ravtansine 
in combination with pembrolizumab and 
platinum-based chemotherapy as Part B, in 
order to evaluate the safety of the 
combination. 
 
Decision based on data from the 170 mg/m2 
Q3W cohort in study TED13751. 
 
 
 
To permit strategic project decision. 
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Amendment 
Number 
Approval 
Date 
Changes 
Rationale 
2 
25-Jan-2021 
No major statistical changes 
 
3 
04-May-2021 
Removed objectives and endpoints 
of pembrolizumab single agent arm 
in Part A 
Removed randomization in Part A 
Remove PD-L1 requirement for Part 
A 
Update sample size and statistical 
population in Part A 
Remove blinding considerations. 
Remove interim analysis planned in 
Part A. 
To reflect the change of removing 
pembrolizumab alone arm in Part A. 
 
 
 
 
 
 
4 
26-Jul-2021 
Move anti-tumor activity of 
tusamitamab ravtansine in 
combination with pembrolizumab 
from primary endpoint to secondary 
endpoint. 
Decrease the sample size in Part A 
to get approximately the same 
number of participants treated at the 
recommended dose in each Part. 
Removed DOR and PFS from 
secondary endpoint analysis from 
Part A. 
Removed ORR per iRECIST from 
exploratory endpoints from Part A. 
Removed activity population. 
 
Added objectives and endpoints, 
statistical populations, and statistical 
analyses for Part C. 
 
 
 
Non-compartmental analysis 
replaced by population PK analysis. 
Primary objective of Part A is to assess the 
tolerability of the combination and to 
determine the recommended dose as for the 
other parts. 
 
 
 
 
 
 
 
 
 
 
To reflect the change of adding the 
combination arm of tusamitamab ravtansine 
with the SOC pembrolizumab, platinum-based 
chemotherapy and pemetrexed as Part C, in 
order to evaluate the safety of the 
combination. 
To reflect the change in PK analysis strategy. 
5.3 
APPENDIX 3 DEMOGRAPHICS AND BASELINE CHARACTERISTICS, PRIOR OR 
CONCOMITANT MEDICATIONS  
Demographics, baseline characteristics, medical surgical history 
The following demographics and baseline characteristics, medical and surgical history and disease 
characteristics at baseline will be summarized using descriptive statistics in the all-treated 
population. 
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Demographic and baseline characteristics: 
• Age in years as quantitative variable and in categories (<65, [65-75], ≥75) 
• Sex (Male, Female) 
• Race (American Indian or Alaska Native, Asian, Black or African American, Native 
Hawaiian or Other Pacific Islander, White, Not reported, Unknown) 
• Ethnicity (Hispanic or Latino, not Hispanic or Latino, Unknown) 
• ECOG PS (0, 1) 
• Weight in kg as quantitative variable 
• BSA in m² as quantitative variable 
Baseline safety and efficacy parameters (apart from those listed above) will be presented along 
with the safety and efficacy summaries. 
Medical (or surgical) history includes relevant history of previous pathologies and surgeries. 
Medical and surgical history will be coded to a LLT, PT, HLT, HLGT, and associated primary 
SOC using the MedDRA version currently in effect at Sanofi at the time of database lock. 
Specific disease history includes primary tumor site, histopathology type, staging, time from 
initial diagnosis to first administration of IMP (in months). 
Specific disease status at study entry includes extent of diseases, number and type of organs 
involved (including primary tumor location), PD-L1 expression (<1%, ≥1% and <1%, 1-49% and 
≥50%), circulating CEA (<100 µg/L, ≥100 µg/L and <80 µg/L, ≥80 µg/L), smoking status 
(current, former, never), smoking habits (in pack-years). 
Prior or concomitant medications 
All medications will be coded using the World Health Organization-Drug Dictionary (WHO-DD) 
using the version currently in effect at Sanofi at the time of database lock. 
• Prior medications are those the participant received prior to first IMP intake. Prior 
medications can be discontinued before first administration or can be ongoing during 
treatment period. 
• Concomitant medications are any medications received by the participant concomitantly to 
any IMP from the first administration of IMP to the last IMP intake + 30 days. 
• Post-treatment medications are those the participant received in the period running from 
the end of the concomitant medications period up to the end of the study. 
• A given medication can be classified as a prior medication and/or as a concomitant 
medication and/or as post-treatment medication. If it cannot be determined whether a 
given medication was received prior or concomitantly or post, it will be considered as 
prior, concomitant, and post-treatment medication. 
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The prior and concomitant medications will be summarized on the all-treated population, by 
anatomic and therapeutic level. Participants will be counted once in each ATC category (anatomic 
or therapeutic) linked to the medication. 
Premedications 
As defined in Section 6.1 of the study protocol, participants receive premedications prior to 
tusamitamab ravtansine infusion to prevent from infusion related allergic reactions and vitamin 
supplementation for pemetrexed. Premedications are defined as non-investigational medicinal 
products and are reported on a specific e-CRF page. 
To summarize premedications prior to tusamitamab ravtansine, number (%) of participants treated 
with dexamethasone and number (%) of participants treated with Histamine H1 antagonist after 
4 cycles will be provided. In addition, number of cycles of participants treated with Histamine H1 
antagonist will be summarized as a quantitative variable. 
In addition, for Part C, to summarize premedications prior to pemetrexed, number (%) of 
participants who received Folic Acid, number (%) of participants who received Vitamin B12 and 
number (%) of participants treated with dexamethasone will be provided. 
Anticancer therapies 
Prior anticancer therapies include chemotherapy, surgery and radiotherapy. 
• Prior chemotherapy: number (%) of participants with prior chemotherapy including 
neoadjuvant/adjuvant treatment, number (%) of participants with intent: neoadjuvant, 
adjuvant and time from completion of last chemotherapy to first administration of IMP (in 
months). 
• Prior surgery: number (%) of participants with any prior surgery related to lung cancer, 
type of surgery and time from the last surgery to first administration of IMP (in months). 
• Prior radiotherapy: number (%) of participants with any prior radiotherapy related to lung 
cancer, intent, analgesic intent if palliative and time from last dose of radiotherapy to first 
administration of IMP (in months). 
Further anticancer therapies (including systemic anticancer therapies, surgeries and 
radiotherapies) after discontinuation of study intervention will be summarized based on WHO-DD 
coding. 
5.4 
APPENDIX 4 DATA HANDLING CONVENTIONS  
Unscheduled visits 
Unscheduled visit measurements will be used for computation of baseline and worst treatment-
emergent values and/or grades. 
Unscheduled tumor assessments will be used for computation of efficacy endpoints based on 
radiological assessments of tumor burden. 
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5.5 
APPENDIX 5 SANOFI SPONSOR GENERIC RANGES FOR HEMATOLOGICAL AND 
BIOCHEMISTRY PARAMETERS  
The current list of generic ranges (for adults) for hematological, coagulation and biochemistry 
parameters (3) are provided in tables below. 
Table 13 - Generic ranges for hematological and coagulation parameters  
Parameter 
Gender 
Unit 
LLN 
ULN 
Basophils 
 
10^9/L 
0 
0.15 
Eosinophils 
 
10^9/L 
0 
0.4 
Hematocrit 
M 
Ratio 
0.41 
0.53 
Hematocrit 
F 
Ratio 
0.36 
0.46 
Hemoglobin 
M 
g/L 
135 
175 
Hemoglobin 
F 
g/L 
120 
160 
Leukocytes (WBC) count 
 
10^9/L 
4.5 
11 
Lymphocytes 
 
10^9/L 
1 
2 
Monocytes 
 
10^9/L 
0.18 
0.5 
Neutrophils 
 
10^9/L 
1.8 
3.15 
Platelets count 
 
10^9/L 
150 
350 
Prothrombin time 
 
INR 
0.8 
1.2 
Table 14 - Generic ranges for biochemistry parameters  
Parameter 
Unit 
LLN 
ULN 
Albumin 
g/L 
35 
55 
Blood Urea Nitrogen 
mmol/L 
3.6 
7.1 
Corrected calcium 
mmol/L 
2.2 
2.6 
Glucose 
mmol/L 
3.9 
7 
Chloride 
mmol/L 
80 
115 
Potassium 
mmol/L 
3.5 
5 
Sodium 
mmol/L 
-136 
145 
Phosphate 
mmol/L 
1 
1.4 
Protein 
g/L 
55 
80 
Urea 
mmol/L 
3.6 
7.1 
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5.6 
APPENDIX 6 LIST OF TERMS IN COMPANY MEDDRA QUERIES (CMQ)  
The following CMQ are using MedDRA Version 24.1. 
• CMQ “Bowel disorders” is based on the primary SOC “Gastrointestinal disorders” and the 
following HLGTs: 
- 
Anaemias nonhaemolytic and marrow depression 
- 
Anal and rectal conditions NEC 
- 
Aneurysms and artery dissections 
- 
Appetite and general nutritional disorders 
- 
Bacterial infectious disorders 
- 
Benign neoplasms gastrointestinal 
- 
Bile duct disorders 
- 
Blood and lymphatic system disorders congenital 
- 
Bone disorders (excl congenital and fractures) 
- 
Bronchial disorders (excl neoplasms) 
- 
Cardiac and vascular disorders congenital 
- 
Cardiac disorders, signs and symptoms NEC 
- 
Changes in physical activity 
- 
Chlamydial infectious disorders 
- 
Chromosomal abnormalities, gene alterations and gene variants 
- 
Congenital and hereditary disorders NEC 
- 
Connective tissue disorders (excl congenital) 
- 
Cornification and dystrophic skin disorders 
- 
Cutaneous neoplasms benign 
- 
Decreased and nonspecific blood pressure disorders and shock 
- 
Diverticular disorders 
- 
Eating disorders and disturbances 
- 
Endocrine and glandular disorders NEC 
- 
Endocrine neoplasms benign 
- 
Endocrine neoplasms malignant and unspecified 
- 
Epidermal and dermal conditions 
- 
Exposures, chemical injuries and poisoning 
- 
Food intolerance syndromes 
- 
Fungal infectious disorders 
- 
Gastrointestinal conditions NEC 
- 
Gastrointestinal haemorrhages NEC 
- 
Gastrointestinal infections 
- 
Gastrointestinal inflammatory conditions 
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- 
Gastrointestinal investigations 
- 
Gastrointestinal motility and defaecation conditions 
- 
Gastrointestinal neoplasms benign 
- 
Gastrointestinal neoplasms malignant and unspecified 
- 
Gastrointestinal signs and symptoms 
- 
Gastrointestinal stenosis and obstruction 
- 
Gastrointestinal tract disorders congenital 
- 
Gastrointestinal ulceration and perforation 
- 
Gastrointestinal vascular conditions 
- 
General system disorders NEC 
- 
Haemolyses and related conditions 
- 
Helminthic disorders 
- 
Hepatic and hepatobiliary disorders 
- 
Immune disorders NEC 
- 
Immune system disorders congenital 
- 
Infections - pathogen unspecified 
- 
Injuries NEC 
- 
Injuries by physical agents 
- 
Inner ear and VIIIth cranial nerve disorders 
- 
Joint disorders 
- 
Lymphomas non-Hodgkin's B-cell 
- 
Lymphomas non-Hodgkin's unspecified histology 
- 
Malabsorption conditions 
- 
Malignant and unspecified neoplasms gastrointestinal NEC 
- 
Maternal complications of pregnancy 
- 
Mesotheliomas 
- 
Metabolic and nutritional disorders congenital 
- 
Metastases 
- 
Miscellaneous and site unspecified neoplasms malignant and unspecified 
- 
Movement disorders (incl parkinsonism) 
- 
Muscle disorders 
- 
Musculoskeletal and connective tissue disorders NEC 
- 
Musculoskeletal and connective tissue disorders congenital 
- 
Mycobacterial infectious disorders 
- 
Mycoplasmal infectious disorders 
- 
Neuromuscular disorders 
- 
Procedural related injuries and complications NEC 
- 
Prostatic disorders (excl infections and inflammations) 
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- 
Protozoal infectious disorders 
- 
Psychiatric disorders NEC 
- 
Reproductive tract and breast disorders congenital 
- 
Reproductive tract disorders NEC 
- 
Respiratory and mediastinal neoplasms benign (excl mesotheliomas) 
- 
Respiratory and mediastinal neoplasms malignant and unspecified 
- 
Respiratory disorders congenital 
- 
Respiratory tract signs and symptoms 
- 
Skin and subcutaneous tissue disorders congenital 
- 
Skin vascular abnormalities 
- 
Soft tissue neoplasms malignant and unspecified 
- 
Somatic symptom and related disorders 
- 
Spleen, lymphatic and reticuloendothelial system disorders 
- 
Tissue disorders NEC 
- 
Upper respiratory tract disorders (excl infections) 
- 
Urinary tract signs and symptoms 
- 
Vascular disorders NEC 
- 
Viral infectious disorders 
- 
Vitamin related disorders 
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6 
REFERENCES  
1. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New 
guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst. 
2000;92(3):205-16. 
2. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response 
evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 
2009;45(2):228-47. 
3. Kratz A, Ferraro M, Sluss PM, Lewandrowski KB. Laboratory reference values. N Engl J 
Med. 2004;351(15):1548-63.  
 
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