Conditions: Adenocarcinoma Gastric Gastrooesophageal Cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 35
Healthy volunteers: no

Brief summary:
Primary Objectives:

Part 1: to confirm the recommended tusamitamab ravtansine loading dose Q2W in combination with ramucirumab in advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma population

Part 2: to assess the antitumor activity of tusamitamab ravtansine loading dose Q2W in combination with ramucirumab in advanced gastric or GEJ adenocarcinoma

Secondary Objectives:

* To assess safety and tolerability
* To assess durability of response (DOR)
* To assess progression-free survival (PFS)
* To assess the disease control rate (DCR)
* To assess the pharmacokinetics (PK)
* To assess the immunogenicity

Detailed description:
34 weeks (up to 4 weeks for screening, a median of 18 weeks for treatment, and a median of 12 weeks for end-of-treatment assessments and the safety follow-up visit).

Arms:
arm 1: Participants received ramucirumab 8 milligram/kilogram (mg/kg) via intravenous (IV) infusion followed by tusamitamab ravtansine loading dose at 170 mg/meter square (m\^2) via IV infusion on Cycle 1 Day 1 (each cycle was 2 weeks); and then ramucirumab 8 mg/kg via IV infusion followed by tusamitamab ravtansine 100 mg/m\^2 via IV infusion at Cycle 2 and every 2 weeks (Q2W) in all subsequent cycles until disease progression, unacceptable adverse event (AE), death, initiation of a new anticancer therapy, or the participant's or investigator's decision to stop the treatment.

Interventions: intervention 1: Ramucirumab (CYRAMZA®) intervention 2: Tusamitamab ravtansine (SAR408701)
Intervention descriptions: intervention 1: Pharmaceutical Form: Concentrate for solution for infusion

Route of Administration: Intravenous Infusion intervention 2: Pharmaceutical Form: Concentrate for solution for infusion

Route of Administration: Intravenous Infusion

Protocol document:
Prot_000.pdf: 
 
 
 
A ny a n d all i nf or m ati o n pres e nt e d i n t his d oc u me nt s h all b e tre at e d as c o nfi d e nti al a n d s h all re mai n t h e excl usiv e pro p erty o f S a n ofi ( or a ny of its 
affili at e d c o m p ani es). T h e us e of s uc h c o nfi d enti al i nf or m ati o n m ust b e r estrict e d t o t h e reci pi e nt f or t h e a gre e d p urp os e a n d m ust not b e 
discl os e d, p u blis h ed or ot h er wis e c o m m u nic at e d t o a ny u n a ut h oriz e d p ers o ns, f or a ny re as o n, i n a ny f or m w h ats o ev er wit h o ut t h e pri or writt en 
c o ns e nt of S a n ofi (or t he c o nc ern e d affili at e d c o m p any); ‘ affili at e d c o m p a ny’ m e a ns a ny c orp orati o n, p art n ers hi p or ot h er e nt ity w hic h at t he d at e 
of c o m m u nic ati o n or aft er w ards (i) c o ntrols directly or i n dir ec tly S a n ofi, (ii) is directly or i n directly c o ntroll e d by S a n ofi, wit h ‘c o ntr ol’ m e ani n g 
dir ect or i n direct o wn ers hi p of m or e t h an 5 0 % of t h e c a pit al st ock or t h e v oti n g ri g hts i n s uc h c or p or ati o n, p art n ers hi p or o t h er e ntity 
A c c or di n g t o T e m pl at e: S a n ofi O n e D o c u m e nt V er si o n 4. 1, d at e d 9 -O C T -2 0 2 0  
P a g e 1  
 
C LI NI C A L T RI A L P R O T O C O L     
Pr ot o c ol titl e:  
O p e n -l a b el st u d y of t u s a mit a m a b r a vt a n si n e 
( S A R 4 0 8 7 0 1) i n c o m bi n ati o n wit h r a m u cir u m a b i n 
p arti ci p a nt s pr e vi o u sl y tr e at e d f or a d v a n c e d g a stri c or 
g a str o e s o p h a g e al j u n cti o n ( G E J) a d e n o c ar ci n o m a  wit h 
C E A C A M 5 -p o siti v e t u m or s  
Pr ot o c ol n u m b er:  
A C T 1 6 4 4 4  
A m e n d m e nt n u m b er:  
N ot a p pli c a bl e  
C o m p o u n d n u m b er 
(I N N/ Tr a d e m ar k): 
S A R 4 0 8 7 0 1  
t u s a mit a m a b r a vt a n si n e/n ot a p pli c a bl e  
Bri ef titl e:  
T u s a mit a m a b r a vt a n si n e ( S A R 4 0 8 7 0 1) i n c o m bi n ati o n 
wit h r a m u cir u m a b i n pr etr e at e d p arti ci p a nt s wit h 
g a stri c c a n c er  
C A R M E N -G C 0 1  
St u d y p h a s e:  
P h a s e 2  
S p o n s or n a m e:  
S a n ofi a v e nti s r e c h er c h e & d é v el o p p e m e nt  
L e g al r e gi st er e d 
a d dr e s s:  
1 a v e n u e Pi err e Br o s s ol ett e,  
9 1 3 8 0 C hill y - M a z ari n  
F R A N C E  
M a n uf a ct ur er: S a m e a s S p o n s or  
M o nit ori n g t e a m’ s 
r e pr e s e nt ati v e n a m e a n d 
c o nt a ct i nf or m ati o n  
 
R e g ul at or y a g e n c y i d e ntifi er n u m b er( s):  
I N D: 
N o t a p pli c a bl e 
E u dr a C T:  
2 0 2 1 -0 0 1 9 6 7 -2 6  
N C T:  
N ot a p pli c a bl e  
W H O:  
N ot a p pli c a bl e  
E U D A M E D:  
N ot a p pli c a bl e  
Ot h er:  
N ot a p pli c a bl e  
D at e:  
1 9 -A pr -2 0 2 1  
T ot al n u m b er of p a g e s:  1 1 4  
 
V V- C LI N- 0 6 0 8 4 8 7 2. 0
Cli c k h er e a n d t y p e
N C T 0 5 0 7 1 0 5 3


Clinical Trial Protocol 
SAR408701/ACT16444 - tusamitamab ravtansine 
19-Apr-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 2 
TABLE OF CONTENTS 
CLINICAL TRIAL PROTOCOL ....................................................................................................................... 1 
TABLE OF CONTENTS .................................................................................................................................. 2 
LIST OF TABLES ........................................................................................................................................... 7 
LIST OF FIGURES .......................................................................................................................................... 7 
1 
PROTOCOL SUMMARY ................................................................................................................. 8 
1.1 
SYNOPSIS ....................................................................................................................................... 8 
1.2 
SCHEMA ........................................................................................................................................ 15 
1.3 
SCHEDULE OF ACTIVITIES (SOA) .............................................................................................. 16 
1.3.1 
Study flow chart .............................................................................................................................. 16 
1.3.2 
Pharmacokinetic/Antitherapeutic antibody flow chart for Part 1 and Part 2 ................................... 19 
2 
INTRODUCTION ............................................................................................................................ 20 
2.1 
STUDY RATIONALE...................................................................................................................... 20 
2.2 
BACKGROUND ............................................................................................................................. 22 
2.3 
BENEFIT/RISK ASSESSMENT ..................................................................................................... 22 
2.3.1 
Risk assessment ............................................................................................................................ 22 
2.3.2 
Benefit assessment ........................................................................................................................ 26 
2.3.3 
Overall benefit-risk conclusion ....................................................................................................... 27 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................. 28 
3.1 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 29 
4 
STUDY DESIGN ............................................................................................................................ 30 
4.1 
OVERALL DESIGN ........................................................................................................................ 30 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ......................................................................... 31 
4.3 
JUSTIFICATION FOR DOSE ........................................................................................................ 31 
4.4 
END OF STUDY DEFINITION ....................................................................................................... 32 
5 
STUDY POPULATION .................................................................................................................. 33 
5.1 
INCLUSION CRITERIA .................................................................................................................. 33 
5.2 
EXCLUSION CRITERIA ................................................................................................................ 35 
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5.3 
LIFESTYLE CONSIDERATIONS ................................................................................................... 38 
5.4 
SCREEN FAILURES...................................................................................................................... 38 
5.5 
CRITERIA FOR TEMPORARILY DELAYING ENROLLMENT ...................................................... 38 
6 
STUDY INTERVENTIONS AND CONCOMITANT THERAPY ..................................................... 39 
6.1 
STUDY INTERVENTIONS ADMINISTERED ................................................................................ 39 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY....................................................... 41 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ....................................... 41 
6.4 
STUDY INTERVENTION COMPLIANCE ...................................................................................... 42 
6.5 
DOSE MODIFICATION .................................................................................................................. 42 
6.5.1 
Retreatment criteria: Part 1 and Part 2 .......................................................................................... 44 
6.6 
CONTINUED ACCESS TO INTERVENTION AFTER THE END OF THE STUDY....................... 45 
6.7 
TREATMENT OF OVERDOSE ...................................................................................................... 45 
6.8 
CONCOMITANT THERAPY .......................................................................................................... 45 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................................... 48 
7.1 
DISCONTINUATION OF STUDY INTERVENTION ...................................................................... 48 
7.1.1 
Permanent discontinuation ............................................................................................................ 48 
7.1.2 
Temporary discontinuation ............................................................................................................. 48 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY .................................. 48 
7.3 
LOST TO FOLLOW UP ................................................................................................................. 49 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................... 51 
8.1 
EFFICACY ASSESSMENTS ......................................................................................................... 51 
8.2 
SAFETY ASSESSMENTS ............................................................................................................. 52 
8.2.1 
Physical examinations ................................................................................................................... 52 
8.2.2 
Specific ocular tests ....................................................................................................................... 52 
8.2.3 
Vital signs ....................................................................................................................................... 53 
8.2.4 
Electrocardiograms ........................................................................................................................ 53 
8.2.5 
Echocardiogram or MUGA scan .................................................................................................... 53 
8.2.6 
Clinical safety laboratory assessments .......................................................................................... 54 
8.2.7 
Guidelines for management of adverse events ............................................................................. 54 
8.2.7.1 
Hypersensitivity reactions .............................................................................................................. 54 
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8.2.7.2 
Ocular toxicity ................................................................................................................................. 55 
8.2.7.3 
Management of anemia ................................................................................................................. 56 
8.2.7.4 
Management of neutropenia .......................................................................................................... 56 
8.2.7.5 
Liver function tests ......................................................................................................................... 57 
8.2.7.6 
Hypertension .................................................................................................................................. 57 
8.2.7.7 
Proteinuria ...................................................................................................................................... 57 
8.2.7.8 
Bleeding/hemorrhage ..................................................................................................................... 57 
8.2.7.9 
Arterial thromboembolic events ..................................................................................................... 58 
8.2.7.10 Peripheral neuropathy .................................................................................................................... 58 
8.2.7.11 Colitis (including hemorrhagic) ....................................................................................................... 58 
8.2.8 
Pregnancy testing .......................................................................................................................... 58 
8.3 
ADVERSE EVENTS (AES), SERIOUS ADVERSE EVENTS (SAES) AND OTHER 
SAFETY REPORTING ................................................................................................................... 59 
8.3.1 
Time period and frequency for collecting AE and SAE information ............................................... 59 
8.3.2 
Method of detecting AEs and SAEs ............................................................................................... 59 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................................... 59 
8.3.4 
Regulatory reporting requirements for SAEs ................................................................................. 60 
8.3.5 
Pregnancy ...................................................................................................................................... 60 
8.3.6 
Cardiovascular and death events .................................................................................................. 61 
8.3.7 
Adverse event of special interest ................................................................................................... 61 
8.3.8 
Guidelines for reporting product complaints .................................................................................. 62 
8.4 
PHARMACOKINETICS .................................................................................................................. 62 
8.4.1 
Tusamitamab ravtansine ................................................................................................................ 62 
8.4.2 
Ramucirumab ................................................................................................................................. 62 
8.5 
GENETICS ..................................................................................................................................... 62 
8.6 
BIOMARKERS ............................................................................................................................... 63 
8.7 
IMMUNOGENICITY ASSESSMENTS ........................................................................................... 64 
8.8 
HEALTH ECONOMICS OR MEDICAL RESOURCE UTILIZATION ............................................. 64 
8.9 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH ................................ 64 
9 
STATISTICAL CONSIDERATIONS .............................................................................................. 66 
9.1 
SAMPLE SIZE DETERMINATION ................................................................................................. 66 
9.2 
POPULATIONS FOR ANALYSES ................................................................................................. 67 
9.3 
STATISTICAL ANALYSES ............................................................................................................ 68 
9.3.1 
General considerations .................................................................................................................. 68 
9.3.2 
Primary endpoints .......................................................................................................................... 69 
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9.3.2.1 
Incidence of study-drug related DLT at Cycle 1 and Cycle 2 ........................................................ 69 
9.3.2.2 
Objective response rate ................................................................................................................. 69 
9.3.3 
Secondary endpoints ..................................................................................................................... 70 
9.3.3.1 
Duration of response ...................................................................................................................... 70 
9.3.3.2 
Progression-free survival ............................................................................................................... 71 
9.3.3.3 
Disease control rate ....................................................................................................................... 72 
9.3.4 
Exploratory endpoints .................................................................................................................... 73 
9.3.5 
Other safety analyses .................................................................................................................... 73 
9.3.5.1 
Adverse events .............................................................................................................................. 73 
9.3.5.2 
Laboratory variables, vital signs and electrocardiograms (ECGs) ................................................. 74 
9.3.6 
Other analyses ............................................................................................................................... 75 
9.4 
INTERIM ANALYSES .................................................................................................................... 75 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................ 76 
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ....... 76 
10.1.1 
Regulatory and ethical considerations ........................................................................................... 76 
10.1.2 
Financial disclosure........................................................................................................................ 77 
10.1.3 
Informed consent process .............................................................................................................. 77 
10.1.4 
Data protection ............................................................................................................................... 78 
10.1.5 
Committees structure ..................................................................................................................... 80 
10.1.5.1 Study committee ............................................................................................................................ 80 
10.1.6 
Dissemination of clinical study data ............................................................................................... 81 
10.1.7 
Data quality assurance .................................................................................................................. 81 
10.1.8 
Source documents ......................................................................................................................... 82 
10.1.9 
Study and site start and closure ..................................................................................................... 82 
10.1.10 Publication policy ........................................................................................................................... 83 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS ......................................................................... 84 
10.3 
APPENDIX 3: AES AND SAES: DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING ......................................................................... 85 
10.3.1 
Definition of AE .............................................................................................................................. 85 
10.3.2 
Definition of SAE ............................................................................................................................ 87 
10.3.3 
Recording and follow-up of AE and/or SAE ................................................................................... 88 
10.3.4 
Reporting of SAEs.......................................................................................................................... 89 
10.4 
APPENDIX 4: CONTRACEPTIVE AND BARRIER GUIDANCE ................................................... 90 
10.4.1 
Definitions ...................................................................................................................................... 90 
10.4.2 
Contraception guidance ................................................................................................................. 91 
10.4.3 
Statistical analyses and deviation .................................................................................................. 92 
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10.5 
APPENDIX 5: GENETICS ............................................................................................................. 92 
10.6 
APPENDIX 6: RECOMMENDED SUPPORTIVE CARE AND/OR DOSE MODIFICATION 
GUIDELINES FOR DRUG-RELATED ADVERSE EVENTS ......................................................... 93 
10.7 
APPENDIX 7: AES, ADES, SAES, SADES, USADES AND DEVICE DEFICIENCIES: 
DEFINITIONS AND PROCEDURES FOR RECORDING, EVALUATING, FOLLOW-UP, 
AND REPORTING IN MEDICAL DEVICE STUDIES .................................................................... 98 
10.8 
APPENDIX 8: COUNTRY-SPECIFIC REQUIREMENTS .............................................................. 98 
10.9 
APPENDIX 9: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY ................................... 98 
10.9.1 
Remote prescreening process ....................................................................................................... 98 
10.9.2 
Screening procedures .................................................................................................................... 99 
10.9.3 
Study intervention .......................................................................................................................... 99 
10.9.4 
Study procedures ......................................................................................................................... 100 
10.9.5 
Informed consent process ............................................................................................................ 100 
10.10 
APPENDIX 10: DEFINITION OF WELL CONTROLLED HUMAN IMMUNODEFICIENCY 
VIRUS INFECTION ...................................................................................................................... 100 
10.11 
APPENDIX 11: CYP450 SUBSTRATES WITH NARROW THERAPEUTIC INDICES ............... 101 
10.12 
APPENDIX 12: STRONG CYP3A INHIBITORS .......................................................................... 102 
10.13 
APPENDIX 13: RESPONSE EVALUATION CRITERIA IN SOLID TUMORS VERSION 1.1 ..... 103 
10.13.1 Measurability of tumor at baseline ............................................................................................... 103 
10.13.2 Special considerations regarding lesion measurability ................................................................ 103 
10.14 
APPENDIX 14: ABBREVIATIONS AND DEFINITIONS .............................................................. 110 
10.15 
APPENDIX 15: PROTOCOL AMENDMENT HISTORY .............................................................. 112 
11 
REFERENCES ............................................................................................................................. 113 
 
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LIST OF TABLES  
Table 1 - Dose levels for Part 1 (safety run-in) ............................................................................................. 10 
Table 2 - Risk assessment for tusamitab ravtanisine .................................................................................... 23 
Table 3 - Objectives and endpoints ............................................................................................................... 28 
Table 4 - Overview of study interventions administered ............................................................................... 39 
Table 5 - Single arm interventions ................................................................................................................. 39 
Table 6 - Dose-limiting toxicities .................................................................................................................... 43 
Table 7 - Dose modification for toxicity ......................................................................................................... 44 
Table 8 - Estimated objective response rate (ORR) depending on number of responders .......................... 66 
Table 9 - Populations for analyses ................................................................................................................ 67 
Table 10 - Protocol-required safety laboratory assessments ........................................................................ 84 
Table 11 - List of CYP substrates with narrow therapeutic range ............................................................... 101 
Table 12 - List of strong CYP3A inhibitors .................................................................................................. 102 
Table 13 - Response criteria ....................................................................................................................... 106 
Table 14 - Response in participants with target disease ............................................................................. 108 
Table 15 - Response in participants with non-target disease only .............................................................. 109 
 
LIST OF FIGURES  
Figure 1 - Decision tree for tusamitamab ravtansine loading dose in Part 1 ................................................ 11 
Figure 2 - Graphical study design ................................................................................................................. 15 
 
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1 
PROTOCOL SUMMARY  
1.1 
SYNOPSIS  
Protocol title:  
Open-label study of tusamitamab ravtansine (SAR408701) in combination with ramucirumab in 
participants previously treated for advanced gastric or gastroesophageal junction (GEJ) 
adenocarcinoma with CEACAM5-positive tumors 
Brief title: 
Tusamitamab ravtansine (SAR408701) in combination with ramucirumab in 
pretreated participants with gastric cancer 
Rationale: 
Tusamitamab ravtansine monotherapy shows a significant level of activity and a favorable safety 
profile in heavily pretreated participants with metastatic nonsquamous, non-small-cell lung cancer 
(NSQ NSCLC) expressing carcinoembryonic antigen-related cell adhesion molecule 5 
(CEACAM5; 1). In participants with gastric cancer (GC) in the main dose escalation part of 
first-in-human (FIH) study TED13751, 1 partial response (PR) was observed. In the GC FIH 
expansion cohort, participants received tusamitamab ravtansine as monotherapy at 100 mg/m² 
administered every 2 weeks (Q2W); in total, 16 participants were treated, and no objective 
response was reported. Stable disease (SD) was reported for 37.5% of the participants enrolled 
from this heavily pretreated (median of 3 prior treatments) participant population; 81.3% of these 
participants had prior taxane therapy. In the FIH “loading dose” escalation cohort, 2 participants 
with GC were treated at the recommended dosing regimen (170 mg/m² then 100 mg/m² Q2W): a 
single participant who had been overdosed with twice the loading dose had a nonconfirmed PR, 
the other participant had SD. 
Ramucirumab (a monoclonal antibody antagonist of vascular endothelial growth factor receptor 2 
[VEGFR2]) combined with the antitubulin agent paclitaxel provides improved efficacy as compared 
to single-agent paclitaxel as second-line therapy for GC. This combination therapy was approved 
as second-line treatment based on the results of the Phase 3 RAINBOW study (2). 
Synergy of tusamitamab ravtansine (containing the cytotoxic antitubulin agent DM4) activity in 
combination with ramucirumab may lead to improved efficacy in treating GC patients with a high 
unmet need; further the combination of tusamitamab ravtansine and ramucirumab may have a 
better safety profile compared to the combination of paclitaxel with ramucirumab. Nonclinical 
evaluations of the combination of tusamitamab ravtansine with a VEGFR2 antagonist were 
performed in mice with GC patient-derived xenografts (PDXs) to evaluate the substitution of 
tusamitamab ravtansine for paclitaxel in the combination with ramucirumab. Improved efficacy, 
optimized treatment duration, and a favorable safety profile were observed for combinations of 
tusamitamab ravtansine with an anti-VEGFR2 agent as compared to combinations of paclitaxel 
with an anti-VEGFR2 agent. The positive data from this work support replacing paclitaxel with 
tusamitamab ravtansine in combination with ramucirumab in a clinical study. Combining 
ramucirumab with tusamitamab ravtansine rather than with paclitaxel may lead to improved 
efficacy with a favorable safety profile of the combination in participants with GC. 
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Objectives and endpoints  
 
Objectives 
Endpoints 
Primary 
• 
Part 1: to confirm the recommended tusamitamab 
ravtansine loading dose Q2W when given in 
combination with ramucirumab in advanced gastric 
or gastroesophageal junction (GEJ) 
adenocarcinoma population 
• 
Part 2: To assess the antitumor activity of 
tusamitamab ravtansine loading dose Q2W in 
combination with ramucirumab in advanced gastric 
or GEJ adenocarcinoma 
• 
Part 1: Incidence of study drug related dose-limiting 
toxicities (DLTs) at Cycle 1 and Cycle 2 (C1D1 to 
C2D14) 
• 
Part 2: Objective Response Rate (ORR), defined as 
the proportion of participants with confirmed 
complete response (CR) or partial response (PR) 
as best overall response (BOR) per Response 
Evaluation Criteria in Solid Tumors (RECIST) 1.1 
Secondary 
• 
To assess the safety and tolerability of tusamitamab 
ravtansine loading dose Q2W in combination with 
ramucirumab 
• 
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 durability of the response to 
treatment with tusamitamab ravtansine loading dose 
Q2W in combination with ramucirumab 
• 
Duration of response (DOR), defined as the time 
from first documented evidence of CR or PR until 
progressive disease (PD) determined per 
RECIST 1.1 or death from any cause, whichever 
occurs first 
• 
To assess progression-free survival (PFS) of 
tusamitamab ravtansine loading dose Q2W in 
combination with ramucirumab 
• 
Progression-free survival, defined as the time from 
the first investigational medicinal product (IMP) 
administration to the date of the first documented 
disease progression or death due to any cause, 
whichever comes first  
• 
To assess the disease control rate (DCR) of 
tusamitamab ravtansine loading dose Q2W in 
combination with ramucirumab 
• 
Disease control rate, defined as the proportion of 
participants with confirmed CR or PR or SD as BOR 
per RECIST 1.1 
• 
To assess the pharmacokinetics (PK) of 
tusamitamab ravtansine loading dose Q2W and 
ramucirumab when given in combination 
• 
Pharmacokinetic parameters of tusamitamab 
ravtansine and ramucirumab 
• 
To assess the immunogenicity of tusamitamab 
ravtansine loading dose Q2W when given in 
combination with ramucirumab 
• 
Incidence of antitherapeutic antibodies (ATAs) 
against tusamitamab ravtansine 
 
 
Overall design: 
Brief summary:  
This is a single group, treatment, Phase 2, open-label, single-arm study to confirm the 
recommended dose (RD), safety, PK, and preliminary antitumor activity of tusamitamab 
ravtansine combined with ramucirumab in participants previously treated for gastric or 
gastroesophageal adenocarcinoma with CEACAM5-positive (defined as CEACAM5 
immunohistochemical [IHC] intensity ≥2+ in ≥50% of cells) tumors. 
This will be a 2-part study. 
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Part 1 (safety run-in):  
In Part 1, participants will receive ramucirumab 8 mg/kg followed by tusamitamab ravtansine at 
170 mg/m2 (150 mg/m2) at Day 1 Cycle 1, and ramucirumab 8 mg/kg followed by tusamitamab 
ravtansine 100 mg/m2 at Cycle 2 and Q2W in all subsequent cycles. In the case that it is decided 
to reduce the initial loading dose of tusamitamab ravtansine to DL-1 (Table 1), a tusamitamab 
ravtansine loading dose of 150 mg/m2 will be administered to participants on Day 1 of Cycle 1. 
Table 1 - Dose levels for Part 1 (safety run-in)  
Dose level (DL) 
Tusamitamab ravtansine 
Ramucirumab 
Starting dose 
170 mg/m2 Q2W Cycle 1; 
100 mg/m2 Q2W Cycle 2 and thereafter 
8 mg/kg Q2W 
Minus -1 (DL -1) 
150 mg/m2 Q2W Cycle 1; 
100 mg/m2 Q2W Cycle 2 and thereafter 
8 mg/kg Q2W 
BSA = body surface area; DL -1=dose level -1; Q2W = every 2 weeks. 
Infusion of tusamitamab ravtansine will be administered at least 1 hour after the end of ramucirumab infusion for at least the first 2 cycles. For 
participants with a BSA >2.2 m2, the tusamitamab ravtansine dose will be calculated based on a BSA of 2.2 m2. 
As no overlap in the safety profiles for ramucirumab and tusamitamab ravtansine is anticipated, 
the starting dose for tusamitamab ravtansine is selected as the maximum tolerated dose (MTD) 
used in studies evaluating tusamitamab ravtansine as loading-dose monotherapy. Enough 
participants will be enrolled in Part 1 to achieve 6 to 12 participants evaluable for DLTs to 
confirm the recommended dose. The tolerability of the combination is assessed in Part 1 
according to the algorithm illustrated in Figure 1. The DLT observation period is the first 2 cycles 
(approximately 28 days). A DLT-evaluable participant must have completed 2 cycles of treatment 
or have been discontinued from study treatment because of a DLT; DLT-nonevaluable 
participants will be replaced. A minimum delay of 1 week is required between the initial dose in 
the first participant treated in a DL cohort and dosing of the next 2 participants treated at the same 
DL. 
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Participants who stopped treatment before documented progressive disease (PD; ie, achieving SD 
or CR or PR) should undergo a tumor assessment and an on-site follow-up visit every 8 weeks 
(±7 days) after the last tumor assessment until radiological disease progression, start of a new 
anticancer therapy, death, withdrawal of a participant’s consent, or cut-off date for secondary 
efficacy endpoints, whichever comes first. After PD or a start of new anticancer therapy, a 
participant will be followed until any ongoing related AE/AESI/SAE is resolved or stabilized. 
The study cut-off for analysis of the primary endpoint, ORR, corresponds to the date on which all 
evaluable treated participants have had at least 2 postbaseline tumor assessments, experienced 
confirmed objective response, or have discontinued the study for any reason. This study cut-off 
can be up to approximately 16 weeks (12 weeks for 2 tumor assessments and 4 weeks for 
confirmation of response, if needed) after the last participant’s first IMP administration. 
The final study cut-off date for analysis of the secondary efficacy endpoints, which include DOR 
and PFS, will be 4 months after the cut-off date for the primary analysis. At that time, the primary 
analysis of ORR and DCR will also be updated.  
After the cut-off date for the analysis of secondary efficacy endpoints, participants still receiving 
study treatment can continue study treatment, if clinical benefit is observed, until PD, 
unacceptable toxicity, initiation of a new anticancer therapy, or withdrawal of participants’ 
consent, and will continue to undergo all assessments as per the study flow chart.  
The expected duration of study intervention for participants may vary, based on disease 
progression date; median expected duration of study per participant is estimated as 34 weeks (up 
to 4 weeks for screening, a median of 18 weeks for treatment, and a median of 12 weeks for 
end-of-treatment assessments and the safety follow-up visit). 
Study interventions 
Study interventions include tusamitamab ravtansine and ramucirumab. To prevent 
hypersensitivity reactions, each administration will be preceded by premedication.  
Administration of tusamitamab ravtansine will be initiated after the completion of ramucirumab 
infusion. As infusion-related reactions (IRRs) may occur during or following ramucirumab 
administration, a 1 hour observation period following the ramucirumab infusion is mandatory 
prior to the initiation of tusamitamb ravtansine administration for the first 2 infusions. If the 
patient shows no evidence of an IRR with the first 2 infusions of ramucirumab, no observation 
period is required for subsequent infusions. In the event an IRR occurs thereafter, the 1 hour 
observation should be reinstituted. 
Each cycle of treatment will have a duration of 2 weeks.  
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Investigational medicinal products 
Ramucirumab 
Ramucirumab will be administered prior to administration of tusamitamab ravtansine.  
• Formulation: CYRAMZA® (ramucirumab) is a concentrate for solution for infusion 
supplied in 10 mL or 50 mL single-use vial. Each vial contains either 100 mg 
ramucirumab in 10 mL (10 mg/mL) or 500 mg ramucirumab in 50 mL (10 mg/mL). 
• Route of administration: IV infusion 
• Dose regimen: Ramucirumab will be administered as an 8 mg/kg IV infusion administered 
over 1 hour on Day 1 of every 2 week cycle.  
Tusamitamab ravtansine 
• 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: intravenous (IV) infusion. 
• Dose regimen: tusamitamab ravtansine loading dose at 170 mg/m² (or RD) will be 
administered via IV infusion over 1 hour 30 minutes on Day 1 of Cycle 1, followed by 
100 mg/m² Q2W from Cycle 2 and in all other cycles.  
• For participants with a body surface area (BSA) >2.2 m², the dose will be calculated based 
on a BSA of 2.2 m². 
Noninvestigational medicinal products 
Both tusamitamab ravtansine and ramucirumab have potential risk for IRR; therefore, 
premedication with an IV histamine H1 antagonist (diphenhydramine 50 mg IV or equivalent; 
eg, cetirizine, promethazine, dexchlorpheniramine, according to local approval and availability) 
given approximately at least 15 minutes before ramucirumab administration is required for all 
participants. If a participant previously experienced an IRR following a dose of ramucirumab or 
tusamitamab ravtansine, premedication for subsequent infusions will also include dexamethasone 
10 mg IV and acetominophen (paracetamol). All drugs used as premedication will be entered on 
the concomitant premedication page. 
 
 
 
  
 
 
Posttrial access to study medication:  
Not applicable. 
Statistical considerations: 
• Analysis of primary endpoint:  
- 
Incidence of DLTs during the DLT observation period (Cycle 1 and Cycle 2) will be 
summarized on the DLT-evaluable population, by DL (if applicable). 
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- 
Objective response rate (ORR) will be summarized on the all-treated population using 
descriptive statistics and 95% exact confidence intervals (CIs) will be provided using 
the Clopper-Pearson method. As a supplementary analysis, ORR will also be 
summarized on the activity population. 
• Analysis of secondary efficacy endpoints: 
- 
Duration of response will be summarized for the subgroup of participants who achieve 
confirmed objective response on 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 on the all-treated population using 
Kaplan-Meier methods. The median PFS times and associated 95% CI will be 
provided, along with probabilities of being progression-free at different time points. 
- 
Disease control rate will be summarized on the all-treated population using descriptive 
statistics and 95% CIs will be provided using the Clopper-Pearson method. As a 
supplementary analysis, DCR will also be summarized on the activity population. 
• Analysis of safety endpoints: 
- 
Number and percentage of participants experiencing TEAEs by primary system organ 
class (SOC) and preferred term will be summarized by NCI-CTCAE V5.0 Grade (all 
grades, and Grade ≥3) on the all-treated population. Similar summaries will be 
prepared for TEAEs related to IMP, TEAEs leading to permanent full/partial 
intervention discontinuation, TEAEs leading to dose modification or dose interruption, 
serious TEAEs, TEAEs with fatal outcome, adverse events of special interest (AESIs), 
and AEs/SAEs occurring during the posttreatment period. In addition, the number (%) 
of participants with any Grade 5 AE (TEAE and posttreatment) 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 on-
treatment period will be provided on the all-treated population. 
Data Monitoring/Other committee: Yes 
Study Committee (SC; Part 1) 
The SC includes the Investigators or designees and Sponsor team members and, when 
appropriate, ad hoc experts. The SC will have regular meetings every 2 weeks during Part 1 
(safety run-in phase) of the study. 
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1.2 
SCHEMA  
A graphical representation of study design is shown in Figure 2: 
Figure 2 - Graphical study design  
 
Abbreviations: C1 = Cycle 1; C2 = Cycle 2; D1 = Day 1; DL = dose level; DLT = dose-limiting toxicity; EOT = end of treatment; ICF = informed consent form; IMP = investigational medicinal product; 
Q2W = every 2 weeks. 
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1.3 
SCHEDULE OF ACTIVITIES (SOA)  
1.3.1 Study flow chart  
 
 
Pre-
screeninga Screeningb Treatment Cycle 1 
Treatment Cycle 2 and 
thereafter 
End of 
treatment 
90 (±7) day 
(3 month) 
Follow-upd 
Notes 
Day 
 
Days to 
first 
infusion 
D1 
14 (±2) days from previous 
infusion 
30 (±5) days 
from last 
infusion 
 
 
 
 
 
Pre-infusionc EOI 
Pre-
infusionc 
Every 6 weeks 
(±7 days) 
 
 
 
CEACAM5 expression statusa (archival or fresh tumor 
tissue) - central IHC/prescreening Informed consent 
X 
 
 
 
 
 
 
 
 
Informed Consent 
 
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
 
≤28 
X 
 
 
 
 
 
Section 5.1, 
Section 5.2 
Demography, medical/surgical/disease historye 
 
≤28 
 
 
 
 
 
 
 
Tumor characteristicsf 
X 
≤28 
 
 
 
 
 
 
 
Height  
 
≤7 
 
 
 
 
 
 
 
Performance status (ECOG) 
 
≤7 
X 
 
X 
 
X 
X 
Section 8.2.1, 
Section 8.2.3 
Physical examination, including vital signs, body weightg 
 
≤7 
X 
 
X 
 
X 
X 
Section 8.2.1 
Hematologyh 
 
≤7 
X 
 
X 
 
X 
 
Section 8.2.6, 
Section 10.2 
(Appendix 2) 
Coagulationi 
 
≤7 
X 
 
X 
 
X 
 
Section 10.2 
(Appendix 2) 
Clinical blood chemistryj 
 
≤7 
X 
 
X 
 
X 
 
Section 8.2.6, 
Section 10.2 
(Appendix 2) 
Urinalysisk 
 
≤7 
X  
 
X 
 
 
 
Section 10.2 
(Appendix 2) 
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Pre-
screeninga Screeningb Treatment Cycle 1 
Treatment Cycle 2 and 
thereafter 
End of 
treatment 
90 (±7) day 
(3 month) 
Follow-upd 
Notes 
Day 
 
Days to 
first 
infusion 
D1 
14 (±2) days from previous 
infusion 
30 (±5) days 
from last 
infusion 
 
 
 
 
 
Pre-infusionc EOI 
Pre-
infusionc 
Every 6 weeks 
(±7 days) 
 
 
 
HBsAg & HCV serology and HIV test (only if required at 
country level)  
 
X 
 
 
 
 
 
 
 
Urine/serum pregnancy testl 
 
≤7 
 
 
X 
 
X 
X 
Section 8.2.8; 
Section 10.2 
(Appendix 2) 
Left ventricular ejection fraction (MUGA/echocardiogram)m 
 
≤28 
 
  
 
 
 
 
Section 8.2.5 
12-lead ECGn 
 
≤7 
X 
X 
X 
 
X 
 
Section 8.2.4 
Specific ocular testso 
 
≤28 
 
 
 
 
X 
 
Section 8.2.2 
Assessment of ocular/visual symptoms 
 
 
X 
 
X 
 
 
 
Section 8.2.2 
Tusamitamab ravtansine/Ramucirumab administration 
 
 
X 
 
X 
 
 
 
Section 6.1 
AE assessmentp 
X 
 
Continuously throughout the study period 
 
Concomitant medicationq 
 
X 
Continuously throughout the study period 
Section 6.8 
Tumor assessment – RECIST 1.1 - CT/MRIr 
 
≤28 
 
 
 
X 
X 
X 
Section 8.1, 
Section 10.13 
(Appendix 13) 
Circulating CEAs 
X 
≤28 
 
 
 
X 
X 
X 
Section 8.6 
Plasma and whole blood for future analysis (optional)t 
 
 
X 
 
 
 
 
 
Section 8.6 
IgG 
 
 
X 
 
 
 
 
 
 
Record further anticancer therapy 
 
 
 
 
 
 
 
X 
 
Tusamitamab ravtansine and ramucirumab PK 
 
 
Refer to PK/ATA flowchart, Section 1.3.2 
 
 
Section 8.4 
Tusamitamab ravtansine immunogenicity 
 
 
Refer to PK/ATA flowchart, Section 1.3.2 
 
 
Section 8.7 
Abbreviations: AE = adverse event; AESI = AE of special interest; ALP = alkaline phosphatase; ALT (SGPT) = alanine aminotransferase; aPTT = activated partial thromboplastin time; AST (SGOT) = aspartate 
aminotransferase; ATA = antitherapeutic antibody; BUN = blood urea nitrogen; CEA = carcinoembryonic antigen; CEACAM5 = carcinoembryonic antigen-related cell adhesion molecule 5; CR = complete response; 
CT = computed tomography; eCRF = electronic case report form; ECOG = Eastern Cooperative Oncology Group (performance status); ECG = electrocardiogram; eGFR = estimated glomerular filtration rate; 
EOI = end of infusion; HBsAg = hepatitis B virus surface antigen; HCV = hepatitis C virus; HIV = human immunodeficiency virus; IgG = immunogloubulin G; IHC = immunohistochemistry; IMP = investigational 
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medicinal product; INR = International Normalized Ratio; LDH = lactate dehydrogenase; LVEF = left ventricular ejection fraction; MRI = magnetic resonance imaging; MUGA = multigated acquisition scan; 
PD = progressive disease; PD-L1 = programmed death ligand 1; PK = pharmacokinetic; PR = partial response; RBC = red blood cells; RECIST = Response Evaluation Criteria in Solid Tumors; SAE = serious AE; 
SD = stable disease; WBC = white blood cells. 
a Prescreening: a prescreening Informed Consent will be signed by the participant for CEACAM5 assay on archival or fresh tumor tissue and circulating CEA assay. 
b Screening: Informed consent should be signed before any study-specific procedures. It can be signed more than 28 days prior to initiating study treatment. Screening time indicates the time frame in which exams 
used to support eligibility must be done prior to initiating therapy. All tests or procedures on D1 should be done at predose time unless otherwise stated. Assessments must be performed prior to first IMP 
administration: participants must have confirmed CEACAM5 expression as assessed centrally. Baseline evaluations should be completed within 1 week prior to initiation of therapy, except for tumor assessment, 
circulating CEA, echocardiography, and ocular tests that may be performed within 4 weeks prior to the first IMP administration. The Investigator should review results of these tests prior to initiating 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 D15 of the previous cycle. During treatment, D1 assessment 
can be done on the day of infusion (before infusion) or the day before. C1D1 hematology, blood chemistry, coagulation and urinalysis tests may be omitted if baseline test performed within 7 days are normal. If 
baseline tests are abnormal should be repeated within 2 days of first study intervention. 
d Follow-up visit: SAEs/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 (defined as an event ongoing without any change for at least 3 months). Date of disease progression and further anticancer treatment will be collected at the follow-up visit. Participants who stopped 
treatment before documented progressive disease (PD; ie, achieving stable disease [SD] or complete or partial response [CR or PR]) should undergo a tumor assessment and an on-site follow-up visit every 
8 weeks (±7 days) after the last tumor assessment until radiological disease progression, death, cut-off date for secondary endpoints, initiation of further anticancer therapy, or withdrawal of the participant’s 
consent, whichever comes first. Participants with documented disease progression should attend an on-site follow-up visit 90 days after the last dose of study medication. If every ongoing related AE/SAE/AESI is 
resolved or stabilized, no further follow-up visit is needed; otherwise an on-site follow-up visit will be performed every 12 weeks after the End of Treatment visit until resolution of the event.  
e Disease history includes previous antitumor therapy (type, start and end dates, reason for discontinuation and response to the therapy). 
f 
Tumor characteristics: data collected will include histologic types, stage at diagnosis, disease extent at study entry; known specific mutations (BRAF, KRAS, NRAS, PIK3CA, PTEN, PTP53, CCDN1, NTRK1, 
NTRK2, NTRK3), known HER2 and MET status (data collected at screening) and known PD-L1 expression (data to be collected only at prescreening). 
g Physical examination will include: vital signs (temperature, blood pressure, heart rate) and examination of major body systems. Signs and symptoms will be reported in the electronic case report form (eCRF) as 
AEs only if they are still present at the time of first IMP administration. 
h Hematology: Hemoglobin, hematocrit, RBC, WBC with differential, platelet counts. These tests will be done before IMP administration at each cycle. If Grade 4 neutropenia, assess absolute neutrophil count 
(ANC) every 2-3 days until ANC ≥0.5 x 109/L. During first 2 cycles, hematology will be performed weekly.  
i 
Coagulation: International normalized ratio (INR), activated partial thromboplastin time (aPTT). 
j 
Clinical blood chemistry: Liver function tests: AST (SGOT), ALT (SGPT), total bilirubin, conjugated bilirubin, ALP. Renal function tests: Urea (or BUN) & creatinine; eGFR. Electrolytes: Sodium, potassium, 
calcium, glucose, Others: LDH, albumin and total proteins. During first 2 cycles, liver function tests will be performed weekly. The liver function tests and renal function tests will be done before IMP administration 
at each cycle, unless clinically appropriate. In case of Grade ≥3 liver function test abnormal, additional tests will be repeated every 2-3 days until recovery to baseline value.  
k Urinalysis tests on morning spot will be performed by dipstick at baseline, and at every treatment cycle. In case of proteinuria ≥ ++ (dipstick), proteinuria quantification by proteinuria/24 h should be performed. If 
proteinuria >500 mg/24 h: blood tests including haptoglobin, LDH, platelet count and schizocytes should be performed systematically.  
l 
Serum pregnancy test: women of child-bearing potential must have a negative serum pregnancy test result within 7 days prior to the initial dose of IMP. A pregnancy test (serum/urine) will be repeated every 
4 weeks before IMP administration, and a serum test will be repeated at the End of Treatment evaluation (30 ±5 days after the last IMP administration), and at the Follow-up visit (90 ±7 days after last IMP dose).  
m Echocardiogram or MUGA scan: left ventricular ejection fraction (LVEF) will be evaluated during screening period, and whenever clinically indicated. 
n 12-lead ECG is required at baseline before starting and after completing the first IMP administration (within 30 minutes after the end of tusamitamab ravtansine infusion); before IMP administration at each cycle; 
and at the End of Treatment evaluation, 30 (±5) days after last IMP administration.  
o Specific ocular tests will include assessment of ocular/visual symptoms and ocular exams including visual acuity, slit lamp under dilatation, and Schirmer’s test at screening and whenever clinically indicated. 
p AE: For participant who was prescreened and had fresh biopsy, only the AEs related to the fresh biopsy procedure itself should also be reported in eCRF as general requirement of AE/SAE with the reporting time 
frame interval of 1 month for the prescreening period after fresh biopsy 
q Concomitant medication will be recorded in the eCRF from 28 days prior to the first study intervention administration, before every cycle during the study treatment period, and for up to 30 days after the final dose 
of study intervention. Once the participant has withdrawn from study treatment, concomitant medication should only be recorded if used to treat new or unresolved study treatment-related AEs. 
r 
Tumor assessment: Chest, abdomen, pelvic CT scan or MRI and any other examinations as clinically indicated will be performed to assess disease status at baseline and then every 6 weeks (±7 days) during the 
study treatment period until radiological disease progression; initiation of further anticancer therapy; death; or cut-off for secondary endpoints. The scheduled tumor assessment time point will not be modified in 
case of a cycle delay. Brain CT-scan or MRI should be performed at baseline only for known stable lesions or if clinically indicated and followed during treatment only for participants with brain lesions at baseline.  
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2 
INTRODUCTION  
Tusamitamab ravtansine (SAR408701) is an antibody-drug conjugate (ADC) combining 
hu769_4D4 (SAR408377), a humanized antibody that recognizes selectively the A3-B3 
extracellular domain of CEACAM5, a tumor-associated carcinoembryonic antigen, with the 
potent cytotoxic maytansinoid derivative, DM4, that inhibits microtubule assembly. Tusamitamab 
ravtansine is expected to selectively deliver DM4 to cancer cells expressing the CEACAM5 
antigen, such as colon, stomach and its signet-ring cell subtype as well as non-squamous NSCLC. 
Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) was first described in 
1965 as a tumor-associated antigen in human colon cancer tissue extracts (3). High levels of 
CEACAM5 expression have since been observed in several epithelial tumors while in normal 
adult tissue, its expression is limited to few tissues (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 adenocarcinoma of the colon, the stomach and its subtype 
signet ring cell as well as in non-squamous NSCLC. 
2.1 
STUDY RATIONALE  
In the FIH study TED13751, a cohort of participants with NSQ NSCLC tumors that were 
CEACAM5-positive (at least 50% of the tumor cell population with membrane 
immunohistochemical intensity ≥2+) was treated with tusamitamab ravtansine at the 
recommended dose of 100 mg/m² every 2 weeks. Participants were heavily pretreated before 
enrollment, with a median of 3 prior treatments (1 to 10 lines) for advanced disease, including 
antitubulin agents (60.9%) and anti-PD1/PD-L1 (70.3%; 1). Tusamitamab ravtansine showed 
encouraging antitumor activity in the 64 participants treated in this study, with a response rate of 
20.3% (95% CI: 12.27% to 31.71%); 28 participants (43.8%) had SD.  
Tusamitamab ravtansine is being developed as a treatment for NSQ NSCLC. The randomized 
Phase 3 study EFC15858 is currently ongoing to evaluate the efficacy and the safety of 
tusamitamab ravtansine versus docetaxel in participants previously treated for metastatic 
NSQ NSCLC who have CEACAM5-positive tumors. The use of combination therapy with 
tusamitamab ravtansine is also currently being studied in 2 Phase 2 trials in participants with 
NSQ NSCLC: in second or third-line settings (study ACT16525; tusamitamab ravtansine in 
combination with ramucirumab in participants with CEACAM5-positive tumors previously 
treated with platinum-based chemotherapy and an immune checkpoint inhibitor), and in a 
first-line setting (study ACT16146; tusamitamab ravtansine in combination with pembrolizumab, 
with or without platinum-based therapy, as first-line treatment in participants with CEACAM5-
positive and PD-L1-positive tumors).  
Other tumor types also express CEACAM5 in tumor cells known to be sensitive to antitubulin 
agents such as taxanes (eg, paclitaxel, docetaxel). In the “basket” trial, study ACT16432, the 
efficacy of tusamitamab ravtansine is being evaluated in metastatic breast cancer (10% prevalence 
of high expression, defined as ≥2+ in intensity involving at least 50% of the tumor cells) and 
pancreas (15% prevalence of high expression). The prevalence of high CEACAM expression in 
gastric cancer is 30%.  
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In the dose escalation phase of FIH study TED13751 evaluating tusamitamab ravtansine 
monotherapy, 1 PR was observed in 1 participant with GC. In the GC expansion cohort of this 
FIH study, a total of 16 participants received tusamitamab ravtansine as monotherapy at 
100 mg/m2. No objective response was reported for participants in the GC expansion cohort; SD 
was reported for 37.5% of heavily pretreated (median of 3 prior treatments) participants; 81.3% of 
participants had prior taxane therapy. In the “loading dose” escalation cohort, 2 participants with 
GC were treated at the recommended dose (170 mg/m2 then 100 mg/m2 Q2W); a single 
participant with GC had nonconfirmed PR (overdosed, having received twice the loading dose), 
and the other participant achieved SD. 
Ramucirumab, an antibody antagonist of vascular endothelial growth factor receptor 2 
(VEGFR2), was approved by the US Food and Drug Administration (FDA) as monotherapy for 
second-line gastric cancer in April 2014, based on the results from the Phase 3 REGARD study 
(6). The REGARD study compared ramucirumab monotherapy (8 mg/kg IV infusion on Days 1 
and 15 every 4 weeks) to best supportive care (BSC) in subjects refractory to previous 
fluoropyrimidine treatment (with or without platinum). Ramucirumab significantly improved OS 
(5.2 months compared to 3.8 months with BSC, hazard ratio [HR]=0.776, p=0.047) and PFS 
(2.1 months as compared to1.3 months with BSC, HR 0.483, p <0.0001).  
Ramucirumab (anti-VEGFR2) combined with the antitubulin agent paclitaxel leads to improved 
efficacy as compared to paclitaxel single agent as second-line therapy for the treatment of GC. 
The combination of ramucirumab plus paclitaxel was approved for second-line treatment of GC 
by the US FDA in November 2014, based on results from the Phase 3 RAINBOW study (2). This 
study evaluated paclitaxel (80 mg/m2 IV on Days 1, 8, and 15 of a 28 day cycle) with or without 
ramucirumab (8 mg/kg IV infusion on Days 1 and 15 of a 28 day cycle) in subjects with 
metastatic gastric cancer refractory or progressive after first-line platinum and fluoropyrimidine 
therapy. Median OS was significantly improved for the combination (9.6 months) compared to 
paclitaxel alone (7.4 months), with a HR 0.807 (p=0.017). Median PFS was 4.4 months with the 
combination and 2.9 months with monotherapy, with a HR of 0.635 (p <0.0001) favoring the 
combination. Adverse events of Grade ≥3 occurring in more than 5% of participants were more 
frequent with combination treatment as compared to paclitaxel alone; incidences appeared to be 
elevated with the combination as compared to paclitaxel monotherapy for neutropenia 
(41% compared to 19%), leukopenia (17% compared to 7%), hypertension (14% compared to 
2%), fatigue (12% compared to 5%), anemia (9% compared to 10%), and abdominal pain 
(6% compared to 3%). 
Synergy of the activity of tusamitamab ravtansine (containing the cytotoxic antitubulin agent 
DM4) in combination with ramucirumab may lead to improved efficacy in the treatment of GC 
patients with a high unmet need; furthermore, this combination may have a better safety profile as 
compared to the combination of paclitaxel with ramucirumab. Nonclinical evaluations of the 
combination of tusamitamab ravtansine with a VEGFR2 antagonist were conducted in mice with 
GC PDX to evaluate substitution of paclitaxel with tusamitamab ravtansine in combination with 
ramucirumab. The results of these evaluations support clinical investigation of tusamitamab 
ravtansine in combination with ramucirumab: more extensive and sustained regression observed 
in evaluations of tusamitamab ravtansine in combination with the VEGFR2 antagonist as 
compared with paclitaxel in combination with anti-VEGF2 agent in GC PDX. Additionally, the 
observed safety profile for the tusamitamab ravtansine and anti-VEGFR2 combination in PDX 
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mice compared favorably to that observed for the taxol and anti-VEGFR2 combination. Replacing 
paclitaxel with tusamitamab ravtansine in combination treatment with ramucirumab may improve 
efficacy and optimize DOR, as well as safety in participants with CEACAM5-positive, 
antitubulin-agent-sensitive GC, who represent a patient population with a high unmet need. 
2.2 
BACKGROUND  
Gastric cancer is the fifth most common cancer worldwide (7, 8), with 1 089 103 new cases 
diagnosed in 2020 (9). It is the third most common cause of cancer death, and incidence varies 
geographically, with approximately half of all cases occurring in east Asia (10). In the United 
States, an estimated 22 280 cases of gastric cancer were diagnosed and 11 430 participants died 
from this disease in 2006 (11). Although treatment for participants with unresectable or metastatic 
disease remains palliative, chemotherapy improves survival and quality of life when compared to 
BSC. Currently, platinum-based and fluoropyrimidine-based combinations are accepted 
worldwide as established first-line drug regimens (12). Trastuzumab is a HER2-targeted 
humanized monoclonal antibody that, in combination with chemotherapy, has also been approved 
as a first-line treatment for participants with HER2-positive advanced gastric cancer. 
Ramucirumab (anti-VEGFR2 agent) combined with paclitaxel is a standard-of-care option for 
second-line treatment.  
2.3 
BENEFIT/RISK ASSESSMENT  
Detailed information regarding known risks and precautions for patients receiving ramucirumab 
may be found in the Cyramza® prescribing information. 
2.3.1 Risk assessment  
Risk assessment for tusamitamab ravtansine  
Based on available safety data, the main identified risk to participants is corneal toxicity 
presenting as 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.  
Among the 16 participants in the GC cohort treated in FIH study TED13751, the most common 
TEAEs (reported in >10% of participants) were Asthenia (37.5%), Decreased appetite (31.3%), 
Fatigue (25%), Dyspnea, Nausea, Abdominal pain, Back pain, Dyspepsia, Disease progression 
(each in 18.8%), Anemia, Dizziness, Dry eye, Constipation, Vomiting, Ascites, and Edema 
peripheral (each in 12.5%).  
In the loading-dose escalation phase from the FIH study, among the 28 participants treated, the 
most common TEAEs were: Nausea and Asthenia (each in 21.4%), Keratopathy and Abdominal 
pain (each in 17.9%), Peripheral sensory neuropathy, Keratitis, Dry eye, Dyspnea, and Diarrhea 
(each in 14.3%), and Cough, Decreased appetite, and Fatigue (each in 10.7%).  
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Among the 13 participants treated at the dose of 170 mg/m2 at Cycle 1 followed by 100 mg/m2 for 
subsequent cycles Q2W, preferred terms reported as TEAEs (all grades) for at least 2 participants 
were: Keratopathy, Keratitis, Asthenia, and Nausea (each reported for 4 participants); Decreased 
appetite, Peripheral sensory neuropathy, Gastroesophageal reflux disease, Proctalgia, Accidental 
overdose, and Dry eye (each reported for 2 participants). Grade 3 keratopathy was reported for 
2 participants. No Grade 4 event was reported. Overall, the safety profile was consistent with what 
is reported in the main escalation phase of the study; refer to the Investigator’s Brochure for 
SAR408701 for details of safety data for study TED13751. 
Other potential risks were observed in a limited number of patients, and clinical pictures were 
consistent with a presentation in patients with underlying relevant risk factors. These potential 
risks include Colitis ([including hemorrhagic], mainly in participants with a known history of 
colitis or gastrointestinal tract conditions), Cardiotoxicity (myocardial or conduction 
abnormalities), Hematologic cytopenias, and Hepatotoxicity, as well as Systemic acute 
hypersensitivity reactions (including anaphylaxis; 1). More detailed information about the known 
and expected benefits and risks and reasonably expected adverse events (AEs) of tusamitamab 
ravtansine may be found in the Investigator’s Brochure.  
Potential risks for tusamitamab ravtansine and mitigation strategies to be employed in the study 
are summarized in Table 2.  
Table 2 - Risk assessment for tusamitab ravtanisine  
Potential risk 
of clinical 
significance 
Summary of data/rationale for risk 
Mitigation strategy 
Study interventions: tusamitamab ravtansine 
Microcystic 
keratopathy 
Nonclinical: Mitotic arrest/single cell necrosis in the cornea 
of the eye in mice and monkeys. In addition, brown 
discoloration of the cornea associated, microscopically, with 
minimal dark pigmentation in cornea epithelial cells in 
monkeys. Findings considered related to the cytotoxic 
properties of DM4. 
Clinical: Main DLT in the dose escalation part of 
study TED13751. In study TED13751 pooled data: among 
the 160 patients treated at a dose level of 100 mg/m2 Q2W, 
51 patients (31.9%) had a corneal TEAE; of these, 
13 patients (8.1%) had events ≥ Grade 3. In study 
TCD15054, of the 6 patients treated at a dose level of 
100 mg/m2 Q2W, 3 patients (50%) reported a corneal TEAE. 
Careful collection of medical history and 
physical examination. 
Assessment of ocular/visual symptoms at 
each visit before IMP administration. 
Specific ocular tests at screening, 
whenever clinically indicated and at EOT. 
Wearing of contact lenses is forbidden. 
Preventive instillation of artificial tears or 
hyaluronic ophthalmic gel drops. 
Curative action: dose delay and 
reduction; artificial tears, corticosteroid 
eye drops and symptomatic treatment; 
ophthalmologist follow-up. 
Peripheral 
neuropathy 
Nonclinical: Nerve fiber degeneration in the peripheral 
nervous system and spinal cord in mice and monkeys. 
Effects attributed to the tubulin binding properties of DM4 and 
inhibition of microtubule assembly. 
Clinical: In study TED13751 at dose level of 100 mg/m2 
Q2W, 43 patients (26.9%) had at least 1 peripheral 
neuropathy TEAE. In study TCD15054, 1 patient (16.7%) had 
peripheral sensory neuropathy. 
Close surveillance of any signs and 
symptoms of peripheral neuropathies. 
This AE is managed by dose 
delay/reduction as well as treatment 
discontinuation in case of Grade 3-4. 
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Potential risk 
of clinical 
significance 
Summary of data/rationale for risk 
Mitigation strategy 
Colitis (including 
hemorrhagic) in 
patients with a 
known history of 
colitis or 
gastrointestinal 
tract conditions 
Preclinical: mitotic arrest/single cell necrosis observed in the 
GI tract (tongue, esophagus, stomach, duodenum, jejunum, 
ileum, cecum, colon and/or rectum). Therefore, degeneration 
and villous atrophy was noted in the intestinal mucosa as 
well as mucosal erosions and/or ulcers. Findings related to 
the cytotoxic properties of DM4. 
Clinical: no cases observed in study TCD15054, and very 
limited occurrence in study TED13751: 
• 
1 patient developed Grade 3 colitis (pooled data 
among the 160 patients treated at 100 mg/m2 
Q2W). 
• 
2 additional patients with colitis in the main dose 
escalation phase at 120 mg/m2 and 150 mg/m2 
dose levels. 
Exclusion criterion (see Section 5.2). 
 
Close surveillance of any diarrhea event 
and further investigation when clinically 
indicated. 
Hematologic 
cytopenias 
Nonclinical: Following a single or a weekly IV administration 
for 5 weeks of tusamitamab ravtansine in mice and/or 
cynomolgus monkeys, transient decreases in RBC and WBC, 
decreases/increases in reticulocytes and 
decreases/increases in platelets. In addition, mitotic 
arrest/single cell necrosis associated with a decreased 
cellularity in the bone marrow and lymphoid tissues. Findings 
considered related to the cytotoxic properties of DM4. 
Clinical: no cases observed in study TCD15054, and very 
limited occurrence in study TED13751: 
• 
Laboratory data showed anemia Grade 3 in 
8 patients (5.1%), platelet count decreased 
Grade 3 in 1 patient (0.6%), and Grade 4 in 
3 patients (1.9%). 
Exclusion criterion (see Section 5.2). 
 
Close surveillance of any signs and 
symptoms. 
 
Routine blood hematology workup, 
Hemoglobin, hematocrit, WBC with 
differential, platelet counts. These tests 
will be performed before IMP 
administration at each visit. During the 
first 2 cycles, they will performed on 
weekly basis. If Grade 4 neutropenia, 
assess ANC every 2 to 3 days until ANC 
≥0.5 x 109/L. 
Cardiotoxicity 
(myocardial or 
conduction 
abnormalities) 
Nonclinical: Occasional minimal or mild 
degeneration/necrosis in the heart observed in single- and 
repeat-dose weekly for 5 weeks toxicity studies in monkeys. 
In the weekly for 5 weeks toxicity study in monkeys, 
compound-related effects on ECG parameters observed in 
some monkeys at the top dose (7 mg/kg/adm) using an 
external telemetric methodology (reversible marked increase 
in HR and non-reversible long-lasting episodes of bundle 
branch block suggesting an alteration in ventricular 
conduction which could nevertheless not be evidenced 
quantitatively (no widening of QRS complex duration) in the 
present experimental conditions. 
Clinical:  
• 
In study TCD15054 no case was observed 
• 
In study TED13751 pooled data, the following AEs 
were each reported for 1 patient: angina pectoris, 
atrioventricu ar block first degree, bundle branch 
block right, Electrocardiogram QT prolonged.  
Exclusion criterion (see Section 5.2). 
Cardiovascular examination. 
Monitoring of potential cardiac 
conduction defects by regular ECG. 
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Potential risk 
of clinical 
significance 
Summary of data/rationale for risk 
Mitigation strategy 
Hepatotoxicity 
Nonclinical: Following a single IV administration of 
tusasmitamab ravtansine in mice and/or cynomolgus 
monkeys, increased aspartate AST, alanine ALT, ALP and/or 
GLDH have been noted. In addition, this was associated with 
mitotic arrest/single cell necrosis observed in the liver. These 
findings are considered related to the cytotoxic properties of 
DM4. 
Clinical:  
• 
In study TED13751 pooled data under 
hepatobiliary disorders SOC, 3 patients (1.9%) had 
hepatocellular injury events including 1 patient 
(1.3%) with Grade 4, 1 patient with a hepatic 
function abnormal event, and 1 patient with 
hypertransaminasaemia. Clinical laboratory data 
showed ALT increased Grade 3 in 2 patients 
(1.3%) and Grade 4 in 2 patients (1.3%); AST 
increased Grade 3 in 6 patients (3.8%) and 
Grade 4 in 3 patients (1.9%); ALP increased 
Grade 3 in 14 patients (8.9%; none with Grade 4), 
and blood bilirubin increased Grade 3 in 6 patients 
(3.8%; none with Grade 4).  
• 
In study TCD15054, AST increased was reported 
for 1 patient (16.7%). 
• 
No “Hy's law" cases have been observed. 
Exclusion criterion (see Section 5.2). 
Close surveillance of any signs and 
symptoms of hepatotoxicities. 
Liver function tests will be performed 
before IMP administration at each visit. 
During the first 2 cycles, they will be 
performed on a weekly basis. 
In case of Grade ≥3 liver function 
abnormal tests, additional tests will be 
repeated every 2-3 days until recovery to 
baseline value. 
Systemic acute 
hypersensitivity 
reactions 
(including 
anaphylaxis) 
Nonclinical: Not observed. 
Clinical:  
• 
in study TED13751 pooled data, 2 patients, 
including 1 patient (0.6%) with Grade 3 
hypersensitivity and 1 patient had Grade 1 infusion-
related reaction. 
• 
in study TCD15054, 1 patient (33.3%) developed 
rash. 
Premedication with histamine H1 
antagonist. 
If a patient has previously experienced 
an infusion-related reaction in a previous 
tusamitamab ravtansine administration, 
premedication will also include 
dexamethasone 10 mg IV for future 
infusions. 
Target infusion time is 1.5 h. In case of 
an IRR, the flow rate can be decreased; 
minimum authorized f ow rate is 33 mL/h. 
Recommended curative action: In case 
of infusion reaction ≥ Grade 2, 
tusamitamab ravtansine administration 
will be interrupted. The infusion may be 
resumed at half of the previous infusion 
rate after the recovery.  
Abrreviations: ALT = alanine aminotransferase; ALP = alkaline phosphatase; ANC = absolute neutrophil count; AST = aspartate 
aminotransferase; DLT = dose-limiting toxicity; ECG = electrocardiogram; EOT = end of treatment; GLDH = glutamate dehydrogenase; 
IMP = investigational medicinal product; IRR = infusion-related reaction; IV = intravenous; SOC = system organ class; TEAE = treatment-
emergent adverse event; Q2W = every 2 weeks; RBC = red blood cell count; WBC = white blood cell count. 
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Ramucirumab  
Ramucirumab, a human IgG1 monoclonal antibody that inhibits VEGFR-2, in combination with 
paclitaxel, has been approved in for the treatment of patients with gastric cancer. Potential and 
identified risks associated with ramucirumab in gastric cancer are summarized here; more detailed 
information about the known and expected benefits and risks and reasonably expected adverse 
effects of ramucirumab and recommended mitigation measures may be found in the US Package 
Insert or Summary of Product Characteristics/SmPC for Cyramza®. 
The most common serious adverse drug reactions (ADRs) associated with ramucirumab were: 
anemia (3.8%) and intestinal obstruction (2.1%).  
The most common ADRs (all grades) observed in ramucirumab-treated patients at a rate of 
≥10% and ≥2% higher than placebo were hypertension and diarrhea (6).  
In Ramucirumab Administered in Combination with Paclitaxel (RAINBOW), the most common 
serious adverse reactions in patients who received ramucirumab with paclitaxel were neutropenia 
(3.7%) and febrile neutropenia (2.4%; 2). The most common adverse reactions (all grades) 
observed in patients who received ramucirumab with paclitaxel at a rate of ≥30% and ≥2% higher 
than placebo with paclitaxel were fatigue/asthenia, neutropenia, diarrhea, and epistaxis. 
Safety profile for the combination  
No overlap in the safety profiles for tusamitamab ravtansine and ramucirumab is anticipated. 
Given the risks of adverse effects including neutropenia, anemia, and infection associated with 
paclitaxel, the combination of tusamitamab ravtansine with ramucirumab may represent a 
treatment regimen with an improved safety profile as compared to the approved combination of 
paclitaxel and ramucirumab.  
2.3.2 Benefit assessment  
Based on the current data obtained in the ongoing monotherapy studies of tusamitamab 
ravtansine (TED13751 and TCD15054), anticipated benefits in the treatment of advanced 
malignancies support the continued clinical development of the agent for treatment in other 
indications. Such indications include GC in which tumor cells express CEACAM5 and are 
known to be sensitive to antitubulin agents, which are associated with significant toxicity. 
Ramucirumab, a human IgG1 monoclonal antibody that inhibits VEGFR-2, is approved in 
combination with paclitaxel for the treatment of patients with advanced or metastatic gastric or 
gastroesophageal cancer with disease progression on or after prior fluoropyrimidine- or 
platinum-containing chemotherapy.  
Nonclinical investigations of the efficacy of combination of tusamitamab ravtansine with a 
surrogate for ramucirumab for use in the murine model context, a rat IgG1 monoclonal antibody 
directed against the murine VEGFR, were performed in gastric cancer PDXs. In a set of 3 gastric 
cancer PDXs, synergy for the combination of tusamitamab ravtansine and anti-VEGFR2 was 
observed in PDXs resistant to paclitaxel (Taxol®) or tusamitamab ravtanisine alone. Efficacy for 
the tusamitamab ravtansine and anti-VEGFR2 combination was the same or better as compared 
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to combination of taxol and anti-VEGFR2, even in PDX resistant to single-agent tusamitamab 
ravtanisine. Additionally, the observed safety profile for the tusamitamab ravtansine and anti-
VEGFR2 combination in PDX mice compared favorably to that observed for the paclitaxel and 
anti-VEGFR2 combination. 
Given the risks of adverse effects including neutropenia, anemia, and infection associated with 
paclitaxel, the combination of tusamitamab ravtansine with ramucirumab may represent a 
treatment regimen with an improved safety profile as compared to the approved combination of 
paclitaxel and ramucirumab. Replacing paclitaxel with tusamitamab ravtansine in combination 
treatment with ramucirumab may improve efficacy in participants with CEACAM5-positive in 
gastric cancer, who represent a patient population with a high unmet need.  
2.3.3 Overall benefit-risk conclusion  
To date, efficacy and safety data from ongoing studies of tusamitamab ravtansine (TED13751, 
and TCD15054) support its continued clinical development. The combination of tusamitamab 
ravtansine with ramucirumab may represent a treatment regimen with improved efficacy and a 
better safety profile as compared to the combination of paclitaxel with ramucirumab approved as 
second-line treatment for gastric or gastroesophageal adenocarcinoma. 
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3 
OBJECTIVES AND ENDPOINTS  
Table 3 - Objectives and endpoints  
Objectives 
Endpoints 
Primary 
• 
Part 1: to confirm the recommended tusamitamab 
ravtansine loading dose Q2W when given in 
combination with ramucirumab in advanced gastric 
or gastroesophageal junction (GEJ) 
adenocarcinoma population 
• 
Part 2: To assess the antitumor activity of 
tusamitamab ravtansine loading dose Q2W in 
combination with ramucirumab in advanced gastric 
or GEJ adenocarcinoma 
• 
Part 1: Incidence of study drug related dose-limiting 
toxicities (DLTs) at Cycle 1 and Cycle 2 (C1D1 to 
C2D14) 
• 
Part 2: Objective response rate (ORR), defined as 
the proportion of participants with confirmed 
complete response (CR) or partial response (PR) as 
best overall response (BOR) per Response 
Evaluation Criteria in Solid Tumors (RECIST) 1.1 
Secondary 
• 
To assess the safety and tolerability of tusamitamab 
ravtansine loading dose Q2W in combination with 
ramucirumab 
• 
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 durability of the response to 
treatment with tusamitamab ravtansine loading 
dose Q2W in combination with ramucirumab 
• 
Duration of response (DOR), defined as the time 
from first documented evidence of CR or PR until 
progressive disease (PD) determined per RECIST 
1.1 or death from any cause, whichever occurs first 
• 
To assess progression-free survival (PFS) of 
tusamitamab ravtansine loading dose Q2W in 
combination with ramucirumab 
• 
Progression-free survival, defined as the time from 
the first investigational medicinal product (IMP) 
administration to the date of the first documented 
disease progression or death due to any cause, 
whichever comes first  
• 
To assess the disease control rate (DCR) of 
tusamitamab ravtansine loading dose Q2W in 
combination with ramucirumab 
• 
Disease control rate, defined as the proportion of 
participants with confirmed CR or PR or SD as BOR 
per RECIST 1.1 
• 
To assess the pharmacokinetics (PK) of 
tusamitamab ravtansine loading dose Q2W and 
ramucirumab when given in combination 
• 
Pharmacokinetic parameters of tusamitamab 
ravtansine and ramucirumab 
• 
To assess the immunogenicity of tusamitamab 
ravtansine loading dose Q2W when given in 
combination with ramucirumab 
• 
Incidence of antitherapeutic antibodies (ATAs) 
against tusamitamab ravtansine 
Exploratory 
• 
To explore circulating carcinoembryonic antigen 
(CEA) as a potential biomarker for activity and to 
evaluate circulating CEA levels at prescreening 
• 
Circulating CEA at prescreening, screening, during 
the treatment period and during the follow-up period 
Abbreviations: ATAs = antitherapeutic antibodies; BOR = best overall response; C1D1 = Cycle 1, Day 1; C2D14 = Cycle 2, Day 14; 
CEA = carcinoembryonic antigen; CR = complete response; CTCAE = Common Terminology Criteria for Adverse Events; DCR = disease control 
rate; DLT = dose-limiting toxicity; DOR = duration of response; GEJ = gastroesophageal junction; IMP = investigational medicinal product; 
NCI = National Cancer Institute; ORR = objective response rate; PD = progressive disease; PFS = progression-free survival; 
PK = pharmacokinetics; PR = partial response; RECIST = Response Evaluation Criteria in Solid Tumors; TEAEs = treatment-emergent adverse 
events, SAEs = serious adverse events. 
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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, single-arm study to confirm the recommended dose, 
safety, efficacy (antitumor activity), and PK of of tusamitamab ravtansine combined with 
ramucirumab in participants previously treated for gastric or gastroesophageal adenocarcinoma 
with CEACAM5-positive tumors. 
In the prescreening phase, patients with gastric or gastroesophageal adenocarnioma will have 
tumor tissue tested centrally to assess proportions of CEACAM5-positive cells and intensity of 
expression, with a prospective analysis of CEACAM5 expression on most recent archival tumor 
tissue. For this analysis, at least 5 fresh-cut slides of formalin-fixed, paraffin embedded (FFPE) 
archival tumor tissue sectioned at a thickness of 4 to 5 µm are required to be sent to the central 
laboratory designated by the Sponsor.  
If less material is available, a participant will be eligible only after discussion with the Sponsor 
confirming that available material is sufficient for key CEACAM5 expression analyses. In case of 
unavailable archival tissue, a fresh biopsy can be considered in participants who have reachable 
lesion that is suitable for biopsy. This prescreening activity can be performed in advance, when a 
participant may be on prior anticancer therapy.  
Once the results for CEACAM5 become available, only participants with positive results (defined 
as CEACAM5 expression of ≥2+ in intensity involving at least 50% of the tumor cell population), 
in archival tumor sample (or if not available fresh biopsy sample) will enter the screening phase. 
During the screening phase, all inclusion/exclusion criteria will be checked to confirm the 
participants’ eligibility for treatment part.  
Treatment allocation will be performed using interactive response technology (IRT). After being 
screened, eligible participants will receive tusamitamab ravtansine combined with ramucirumab 
until documented disease progression, unacceptable toxicity, new anticancer therapy initiation, 
death, or the participant’s or Investigator’s decision to stop the treatment.  
This will be a 2-part study.  
Part 1 (Safety Run-In): 
In Part 1, participants will receive ramucirumab at 8 mg/kg followed by tusamitamab ravtansine 
loading dose at 170 mg/m² (150 mg/ m²) on Day 1 of Cycle 1; and ramucirumab 8 mg/kg 
followed by tusamitamab ravtansine 100 mg/m² every 2 weeks (Q2W) at Cycle 2 and all 
subsequent cycles.  
The DLT observation period is the first 2 cycles (approximately 28 days). A DLT-evaluable 
participant must have completed 2 cycles of treatment or have been discontinued from study 
treatment because of a DLT; DLT nonevaluable participants will be replaced. 
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Part 2: 
In Part 2 of the study, the recommended dose confirmed in Part 1 will be evaluated for activity in 
26 additional participants. Refer to Section 1.1 for an overview of study design, and Section 6 for 
details of administration of study intervention.  
The expected duration of study intervention for participants may vary, based on the disease 
progression date; the median expected duration of the study per participant is estimated as 
34 weeks (up to 4 weeks for screening, a median of 18 weeks for treatment, and a median of 
12 weeks for end-of-treatment assessments and the safety follow-up visit).  
Serious adverse events/AESIs (regardless of relationship with study treatment) and IMP-related 
AEs ongoing at the end of study treatment, and any new IMP-related AEs/SAEs/AESIs will be 
followed until resolution or stabilization (defined as an event ongoing without any change for at 
least 3 months). A safety follow-up visit will be performed 90 days after the last IMP 
administration. If all ongoing IMP related AEs/SAEs/AESIs are resolved or stabilized, no further 
safety follow-up visit will be needed; otherwise, an on-site follow-up visit will be performed 
every 12 weeks. 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN  
The efficacy and the safety of tusamitamab ravtansine is being explored in indications for which 
the tumor expresses CEACAM5 and which are also known to be sensitive to antitubulin agents. 
The prevalence of high CEACAM5 expression (defined as ≥2+ in intensity involving at least 
50% of the tumor cells) is 30% in gastric cancer.  
Assuming a prescreening failure rate of 70% and a screening failure rate of 20%, approximately 
158 participants will be prescreened to achieve up to approximately 38 treated participants in 
whom the safety and antitumor activity of tusamitamab ravtansine in combination with 
ramucirumab can be evaluated in this Phase 2, single-arm study.  
Ramucirumab (an anti-VEGFR2 agent) combined with paclitaxel (an antitubulin agent) leads to 
improved efficacy as compared to single-agent paclitaxel in gastric cancer second-line therapy, 
based on results of the the Phase 3 RAINBOW study (2). Based on nonclinical data (Section 2.1), 
replacing paclitaxel with tusamitumab ravtansine in combination treatment with ramucirumab 
may improve efficacy with an optimized DOR, as well as achieve better safety as compared to the 
combination of paclitaxel with ramucirumab. 
4.3 
JUSTIFICATION FOR DOSE  
The main escalation phase of first-in-human study TED13751 showed that the MTD using a Q2W 
schedule of administration is 100 mg/m². Of 28 DLT-evaluable participants, 5 experienced a DLT 
during the evaluation period: 3 of 8 participants dosed at 120 mg/m², and 2 of 3 participants dosed 
at 150 mg/m². All DLTs were reversible microcystic keratopathies occurring at the end of 
Cycle 2. Confirmed objective response was induced in 2 of 6 participants (1 with colorectal 
cancer and 1 with gastric cancer) treated at the MTD (100 mg/m² Q2W). Additional responses 
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were documented in 2 participants with colorectal cancer treated in the 120 mg/m² cohort after 
having received only 2 infusions at 120 mg/m², followed by a dose delay and reduction to 
100 mg/m² for occurrence of corneal DLT at the end of Cycle 2. Even with dose delay and dose 
reduction, instances of near-maximum tumor shrinkage were documented at the first tumor 
assessment (Cycle 4), indicating that the initial dosing is important. Although a small data set and 
a heterogeneous population does not permit PK/PD correlations to be established, preliminary 
exposure data for tusamitamab ravtansine based on Cmax and AUC0-14d at Cycle 1 suggest 
exposures in participants in whom a response was induced tended to be higher relative to 
nonresponding participants treated in the same cohort. Therefore, increasing the exposure at the 
beginning of the Q2W schedule may permit pharmacologically active concentrations to be 
attained more quickly, potentially increasing the efficacy without increasing the occurrence of 
ocular toxicity. A new “loading dose schedule” cohort was added in order to determine the 
recommended dose and to evaluate the safety.  
At the cut-off date of 17 June 2020, 28 participants were treated in the dose-escalation phase 
using the loading-dose schedule (loading dose at Cycle 1 followed by 100 mg/m² starting at 
Cycle 2). Three participants were treated at the intended loading DL 120 mg/m², 4 participants at 
DL 135 mg/m², 8 participants at DL 150 mg/m², and 13 participants at DL 170 mg/m². No DLT 
was observed at DLs 120, 135, or 150 mg/m². In the first 6 evaluable participants treated at 
170 mg/m², 2 DLTs were reported (in both cases, treatment delay due to keratopathy, Grade 2). 
The 3 following participants treated at 150 mg/m² showed no DLT. The study committee decided 
(supported by the Bayesian modeling) to treat 3 more participants at 170 mg/m², and no DLT was 
reported. The MTD was identified to be 170 mg/m² at Cycle 1 followed by 100 mg/m² starting at 
Cycle 2. Based on supportive PK, clinical data, and the Bayesian model, the Study Committee 
decided 170 mg/m² as the recommended loading dose at Cycle 1 to be followed by 100 mg/m² 
Q2W administration starting at Cycle 2 as a dosing regimen for further studies; thus, this 
recommended loading dose will be used as the starting dose in this study.  
4.4 
END OF STUDY DEFINITION  
The end of the study is defined as the date of the last visit of the last participant in the study or last 
scheduled procedure shown in the Schedule of Activities for the last participant in the trial 
globally. 
A participant is considered to have completed the study if he/she has completed all phases of the 
study including the EOT and the Follow-Up visit approximately 90 days after the last IMP 
administration.  
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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 the following criteria apply: 
Age 
I 01. At least 18 years of age (or the legal age of consent in the jurisdiction in which the study is 
taking place) at the time of signing the informed consent.  
Type of participant and disease characteristics 
I 02. Histologically or cytologically confirmed diagnosis of gastric or GEJ adenocarcinoma. 
I 03. Metastatic disease or locally advanced, unresectable disease.  
I 04. Measurable disease by RECIST 1.1, as determined by the Investigator.  
At least 1 measurable lesion is required. A previously irradiated tumor lesion is considered 
measurable if progression has been demonstrated in the lesion. The lesion must be ≥10 mm 
in the longest diameter (except lymph nodes, which must have a short axis ≥15 mm) as 
imaged in computed tomography (CT; preferred) or magnetic resonance imaging (MRI) 
scans. 
I 05. Documented disease progression during or after first-line therapy containing platinum 
and/or fluoropyrimidine agents, and if appropriate, HER2 therapy.  
No more than 1 previous line of chemotherapy is allowed. Previous treatment with an 
immune checkpoint inhibitor is allowed. Adjuvant/neoadjuvant treatment for a participant 
who had disease progression during or within 6 months of completing platinum and/or 
fluoropyrimidine treatment will be considered as first-line treatment. 
I 06. Expression of CEACAM5 as demonstrated prospectively by a centrally assessed IHC 
assay of ≥2+ in intensity involving at least 50% of the tumor cell population in an archival 
tumor sample (or, if not available, a fresh biopsy sample).  
At least 5 fresh-cut slides of formalin-fixed, paraffin embedded (FFPE) tumor tissue 
sectioned at a thickness of 4 to 5 µm are required. If less material is available, the 
participant could still be considered eligible after discussion with the Sponsor, who may 
assess and confirm that the available material is sufficient for key evaluations. 
I 07. Eastern Cooperative Oncology Group (ECOG) performance status 0-1. 
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Sex, contraceptive/barrier method and pregnancy testing requirements 
I 08. All participants (male and female) 
Contraceptive use by men and women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. 
a) Male participants 
Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least 4 months after the last dose of study intervention: 
• Refrain from donating sperm 
• Plus either:  
- 
Be abstinent from heterosexual or homosexual intercourse as their preferred 
and usual lifestyle (abstinent on a long term and persistent basis) and agree to 
remain abstinent  
OR 
- 
Must agree to use contraception/barrier as detailed below: 
Agree to use male condom when engaging in any activity that allows for 
passage of ejaculate to another person 
b) Female participants 
A female participant is eligible to participate if she is not pregnant or breastfeeding, 
and at least 1 of the following conditions applies: 
• Is not a woman of childbearing potential (WOCBP) 
OR 
• Is a WOCBP and agrees to use a contraceptive method that is highly effective 
(with a failure rate of <1% per year), preferably with low user dependency, as 
described in Appendix 4 of the protocol during the intervention period and for at 
least 7 months after the last dose of study intervention and agrees not to donate 
eggs (ova, oocytes) for the purpose of reproduction during this period. 
A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as 
required by local regulations) before the first dose of study intervention. Additional 
requirements for pregnancy testing during and after study intervention are located 
in Appendix 4 (Section 10.4) of the protocol. The Investigator is responsible for 
review of medical history, menstrual history, and recent sexual activity to decrease 
the risk for inclusion of a woman with an early undetected pregnancy. 
Informed Consent 
I 09. Capable of giving signed informed consent as described in Appendix 1 of the protocol 
which includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol.  
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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. Untreated brain metastases, leptomeningeal disease, or uncontrolled spinal cord 
compression. Participants with previously treated and stable brain metastases may 
participate. The participant must not require any systemic corticosteroids to manage brain 
metastases within 3 weeks prior to the first dose of study intervention. 
E 02. Significant concomitant illness, including any severe medical condition that, in the opinion 
of the investigator or Sponsor, would impair the participant’s participation in the study or 
interpretation of the results. 
E 03. History within the last 3 years of an invasive malignancy other than that treated in this 
study, with the exception of resected/ablated basal or squamous-cell carcinoma of the skin 
or carcinoma in situ of the cervix, or other local tumors considered cured by local 
treatment. 
E 04. Known uncontrolled infection with human immunodeficiency virus (HIV). Participants 
with well controlled HIV infection/disease (Appendix 10; Section 10.10) must be on 
antiretroviral therapy (ART) to be eligible. 
E 05. Active infection with hepatitis A, B (defined as either positive HBs antigen or positive 
hepatitis B viral DNA test above the lower limit of detection of the assay), or C (defined as 
known positive result for antibodies to hepatitis C and known quantitative hepatitis C virus 
[HCV] RNA results greater than the lower limit of detection of the assay).  
E 06. Nonresolution of any prior treatment-related toxicity to < Grade 2 according to NCI 
CTCAE v5.0, with the exception of alopecia, vitiligo, or active thyroiditis controlled with 
hormone replacement therapy (HRT). 
E 07. Unresolved corneal disorder or any previous corneal disorder considered by an 
ophthalmologist to predict higher risk of drug-induced keratopathy.  
E 08. Use of contact lenses that the participant is unwilling to stop for the duration of the study 
intervention. The use of contact lenses is not permitted.  
E 09. Radiographic evidence of major airway or blood vessel invasion or intratumor cavitation, 
regardless of tumor histology. 
E 10. History of uncontrolled hereditary or acquired thrombotic disorder or history of aneurysm. 
E 11. Major surgery within 28 days prior to Day 1/first IMP infusion; subcutaneous venous 
access device placement within 7 days prior to Day 1; or postoperative bleeding 
complications or wound complications from a surgical procedure performed in the last 
2 months. 
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E 12. History of gross hemoptysis (defined as bright red blood or ≥1/2 teaspoon) within 
2 months before the first administration of study intervention. 
E 13. Any arterial thrombotic event, including myocardial infarction, unstable angina, 
cerebrovascular accident, or transient ischemic attack, within 6 months before the first 
administration of study intervention. 
E 14. Uncontrolled arterial hypertension (systolic ≥150 mmHg or diastolic ≥90 mmHg) despite 
standard medical management. A participant with systolic pressure >150 mmHg or 
diastolic pressure >90 mmHg is ineligible for the study. 
E 15. Serious or nonhealing wound, skin ulcer, or bone fracture within 28 days before the first 
administration of study intervention. 
E 16. Gastrointestinal (GI) perforation and/or fistulae within 6 months prior to first 
administration of study intervention. 
E 17. Significant bleeding disorders, vasculitis, or Grade 3-4 gastrointestinal (GI) bleeding 
within 3 months before the first administration of study intervention. 
E 18. Bowel obstruction, history or presence of inflammatory enteropathy or extensive intestinal 
resection Crohn's disease, ulcerative colitis, or chronic diarrhea. 
E 19. Medical condition requiring concomitant administration of a medication with a narrow 
therapeutic window and metabolized by CYP450 (Appendix 11; Section 10.11); and for 
which a dose reduction cannot be considered. 
E 20. Medical conditions requiring concomitant administration of a strong CYP3A inhibitor 
(see Appendix 12; Section 10.12), unless it can be discontinued at least 2 weeks before 
first administration of study intervention. 
Prior/concomitant therapy 
E 21. Any previous systemic therapy with taxane or targeting VEGF or the VEGFR signaling 
pathways (including investigational agents). Other previous targeted therapies are 
permitted, if stopped at least 3 weeks prior to enrollment.  
E 22. Concurrent treatment with any other anticancer therapy. 
E 23. Prior therapy targeting CEACAM5. 
E 24. Prior maytansinoid treatment (DM1 or DM4 ADC). 
E 25. Washout period before the first administration of study intervention of less than 3 weeks or 
less than 5 times the half-life, whichever is shorter, for prior antitumor therapy 
(chemotherapy, targeted agents, immunotherapy and radiotherapy, or any investigational 
treatment). 
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E 26. Poor coagulation as defined by International Normalized Ratio (INR) ≥1.5 or prothrombin 
time (PT) ≥1.5 × upper limit of normal (ULN) and partial thromboplastin time/activated 
partial thromboplastin time (PTT/aPTT) ≥1.5 × ULN, unless the participant is receiving 
anticoagulation therapy. Participants receiving warfarin must be switched to low-
molecular-weight heparin and must achieve a stable coagulation profile prior to the 
first IMP administration. 
Prior/concurrent clinical study experience 
E 27. Previous enrollment in this study, current participation in any other clinical study 
involving an investigational study treatment, or any other type of medical research. 
Diagnostic assessments 
E 28. Poor organ function as defined by any one of the following prior to IMP administration: 
a) Serum creatinine >1.5 × ULN or estimated glomerular filtration rate 
(eGFR) <60 mL/min/1.73 m2 as estimated using a Modification of Diet in Renal 
Disease (MDRD) formula.  
b) Total bilirubin >1.0 × ULN (excluding congenital conjugation disorders [Gilberts], for 
whom total bilirubin ≤3.0 × ULN, with direct bilirubin ≤1.5 × ULN, is allowed). 
or 
aspartate aminotransferase (AST), alanine aminotransferase (ALT) >2.5 × ULN (In 
case of documented liver metastasis, AST, ALT <5 × ULN is allowed).  
c) Neutrophils <1.5 × 109/L, platelet count <100 × 109/L, or hemoglobin <9 g/dL (blood 
infusion-free for at least 2 weeks).  
E 29. Urine dipstick or routine analysis indicating proteinuria of 2+ or higher, unless a 24 hour 
urine collection demonstrates <1000 mg of protein. 
Other exclusions 
E 30. Accommodation in an institution because of regulatory or legal order (eg, prisoners or 
participants who are legally institutionalized). 
E 31. Any country-related specific regulation that would prevent the participant from entering 
the study - see Appendix 8 (Section 10.8) of the protocol (country-specific requirements). 
E 32. Unsuitability for participation, whatever the reason, as judged by the Investigator, 
including medical or clinical conditions, or potential risk for noncompliance with study 
procedures. 
E 33. Employment by the clinical study site or direct involvement in the conduct of the study, or 
having an immediate family member with this status (in conjunction with Section 1.61 of 
the ICH-GCP Ordinance E6). 
E 34. Any specific situation during study implementation/course that may raise ethics concerns. 
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E 35. Sensitivity to any of the study interventions, or components thereof, or drug or other 
allergy that, in the opinion of the Investigator, contraindicates participation in the study. 
5.3 
LIFESTYLE CONSIDERATIONS  
Not applicable. 
5.4 
SCREEN FAILURES  
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently enrolled. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure participants to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure reasons, eligibility criteria, 
and any SAE. 
For individuals who do not meet the criteria for participation in this study (screen failure) and for 
whom resolution of the screen failure may not be expected within a reasonable time frame, the 
screen failure will be recorded.  
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. Rescreened participants should be assigned a participant number different from that 
for 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 reconsent 
(ie, new ICF signed) if the participant finally participates in the trial. However, if the reason for 
the temporary screen failure might have altered the participant’s initial given agreement to 
participate, the Investigator should ask the participant and confirm the participant’s willingness to 
continue or redo some screening procedures and participate in the trial. This oral agreement 
should be documented in the participant’s chart. All the tests outside protocol-specified window 
should be repeated and entered to the additional pages.  
5.5 
CRITERIA FOR TEMPORARILY DELAYING 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 9 (Section 10.9) should be applicable to 
prescreening/screening/enrollment/administration of study treatment. 
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6 
STUDY INTERVENTIONS AND CONCOMITANT THERAPY  
Study intervention is defined as any investigational interventions, marketed products, placebo, or 
medical devices intended to be administered to a study participant according to the study protocol. 
Treatment preparation and administration (including compatible materials), handling, storage and 
accountability will be further detailed in the Pharmacy Manual. 
6.1 
STUDY INTERVENTIONS ADMINISTERED  
Table 4 - Overview of study interventions administered  
Intervention label 
Tusamitamab ravtansine 
Ramucirumab 
Intervention name 
tusamitamab ravtansine 
ramucirumab 
Type 
Drug 
Drug 
Dose formulation 
concentrated solution for IV 
concentrated solution for IV 
Unit dose strength(s) 
5 mg/mL 
10 mg/mL 
Dosage levelsa 
170 (150) mg/m² Cycle 1 then 100 mg/m² 
Q2W 
8 mg/kg Q2W 
Route of administration 
IV infusion 
IV infusion 
Use 
experimental 
experimental 
IMP or NIMP 
IMP 
IMP 
Packaging and labeling 
Supplied in a 30 mL glass vial with a 
white plastic flip-off cap, containing 
125 mg/25 mL tusamitamab ravtansine, 
and labelled with a multilingual booklet 
Supplied in a single-dose vial 
(100 mg/10 mL or 500 mg/50 mL), 
labeled with a multilingual booklet, and 
individually packaged in a carton 
Current/Former names or 
aliases 
tusamitamab ravtansine/SAR408701 
Cyramza® 
Abbreviations: DL -1 = dose level -1; IMP = investigational medicinal product; IV = intravenous; NIMP = noninvestigational medicinal product; 
Q2W = every 2 weeks. 
a The tusamitamab ravtansine starting dose is 170 mg/m²; the dose may be decreased to 150 mg/m2 (DL -1) 
Table 5 - Single arm interventions  
Arm name 
Tusamitamab ravtansine/ramucirumab (single arm) 
Associated interventions 
tusamitamab ravtansine, ramucirumab 
For a regional or national emergency declared by a governmental agency that results in travel 
restrictions, confinement, or restricted site access, contingency measures are included in 
Appendix 9: Contingency Measures for a regional or national emergency that is declared by a 
governmental agency (Section 10.9). 
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Study medication infusion: 
Infusion via a central line is preferred, if available. Prior to dosing, each participant’s dose will be 
individually prepared by the study pharmacist and labeled with protocol number, participant 
number, and treatment description.  
On Day 1 of each treatment cycle, the patient’s BSA will be determined using the most recent 
weight available on the day of the infusion preparation: the weight on the day of the infusion or 
the most recent weight, assuming it was assessed in a reasonable time frame according to 
Investigator assessment. If the infusion is prepared with the most recent weight assessed in a 
reasonable time frame, this will not prevent assessment of weight on D1 of each cycle, which 
must be recorded in the eCRF. The dose needs to be adjusted if change in body weight is >5% of 
weight at the previous cycle. 
Investigational medicinal products: 
Ramucirumab: Ramucirumab should be administered prior to tusamitamab ravtansine infusion. 
Using a controlled infusion pump, ramucirumab will be administered by IV infusion over 1 hour 
on Day 1 of each cycle. If the first infusion is tolerated, all subsequent ramucirumab infusions 
may be administered over 30 minutes. In case of IRR, Grade 1 or 2, the infusion rate of 
ramucirumab will be reduced by 50%.  
Tusamitamab ravtansine: Infusion of tusamitamab ravtansine should be initiated after the end of 
ramucirumab infusion. As IRRs may occur during or following ramucirumab administration, a 
1 hour observation period following the ramucirumab infusion is mandatory prior the initiation of 
tusamitamb ravtansine administration for the first 2 infusions. If the patient shows no evidence of 
an IRR with the first 2 infusions of ramucirumab, no observation period is required for subsequent 
infusions. In the event an IRR occurs thereafter, the 1 hour observation should be reinstituted.  
Using a controlled infusion pump, tusamitamab ravtansine will be administered by IV infusion 
over 1 hour 30 minutes. For a participant with a BSA >2.2 m2, the calculated dose of tusamitamab 
ravtansine will be based on a BSA of 2.2 m2. After the first administration of tusamitamab 
ravtansine, participants should be observed for acute reactions on site for up to 4 hours depending 
on any sign of IRR. In case of a Grade 1-2 IRR, tusamitamab ravtansine must be interrupted and 
may be resumed only after patient recovery, at half of the previous infusion rate, with a minimum 
authorized flow rate at 33 mL/h. Detailed instructions for dilution and administration of the IMP 
is provided in Pharmacy Manual. 
Noninvestigational medicinal products: 
Premedication: 
Both tusamitamab ravtansine and ramucirumab have potential risk of IRR; thus, premedication 
with an IV histamine-1 receptor antagonist (diphenhydramine 50 mg IV or equivalent; 
eg, cetirizine, promethazine, dexchlorpheniramine, according to local approval and availability) 
will be given approximately at least 15 minutes before ramucirumab administration. If a 
participant previously experienced an IRR following a dose of ramucirumab or tusamitamab 
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ravtansine, premedication will also include corticosteroids equivalent to 10 mg IV 
dexamethasone, and acetaminophen/paracetamol for future infusions. All drugs used as 
premedication will be entered on the concomitant premedication page. 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY  
1. The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention and only authorized 
site staff may supply or administer study intervention. All study intervention must be 
stored in a secure, environmentally controlled, and monitored (manual or automated) area 
in accordance with the labeled storage conditions with access limited to the Investigator 
and authorized site staff. 
3. The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records). 
Partially used and used study treatments will be destroyed at the study site according to the 
standard practices of the site after an accurate accountability has been performed and signed by 
the Investigator (or the pharmacist). A detailed treatment log form of the destroyed study 
treatment will be established with the Investigator (or the pharmacist) and countersigned by the 
Investigator and the Monitoring Team. The Investigator must not destroy the unused IMP unless 
Sanofi provides written authorization.  
Further guidance and information for the final disposition of used and unused study interventions 
are provided in the pharmacy manual and/or monitoring plan. 
Any quality issue noticed with the receipt or use of an IMP (deficiency in condition, appearance, 
pertaining documentation, labeling, expiration date, etc) must be promptly reported to the 
Sponsor. Some deficiencies may be recorded through a complaint procedure (see Section 8.3.8). 
A potential defect in the quality of IMP may be subject to initiation of a recall procedure by the 
Sponsor. In this case, the Investigator will be responsible for promptly addressing any request 
made by the Sponsor to recall the IMP and eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP to a third party, allow the IMP to be 
used other than as directed by this clinical trial protocol, or dispose of IMP in any other manner. 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING  
Not applicable; this is a single-arm, nonrandomized, open-label study. 
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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. 
Participants are dosed at the site and will receive study intervention directly from the Investigator 
or designee, under medical supervision. The date and time of eaceh dose administered in the clinic 
will be recorded in the source documents. The dose of study intervention and study participant 
identification will be confirmed at the time of dosing by a member of the study site staff other 
than the person administering the study intervention. 
A record of the quantity of tusamitamab ravtansine and ramucirumab administered to each 
participant must be maintained and reconciled with study intervention and compliance records. 
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.Intervention start and stop dates, including dates for intervention delays 
and/or dose reductions will also be recorded. 
6.5 
DOSE MODIFICATION  
Part 1 (Safety Run-In): 
During Part 1, recommended dose of tusamitamab ravtansine in combination with ramucirumab 
will be determined according to the DLTs observed in participants according to the algorithm 
shown in Figure 1.  
Dose limiting toxicity definition 
All AEs specified in Table 6 occurring during the first 2 cycles of treatment, unless due to disease 
progression or to a cause obviously unrelated to IMP, will be considered DLTs. The duration of 
the DLT observation period will be longer for a participant who delays initiation of Cycle 2 due to 
a treatment-related AE for which the event’s duration would determine whether the AE meets the 
definition of a DLT. The NCI CTCAE Version 5.0 will be used to assess the severity of AEs. 
Causal relationships are to be determined by the Investigator. The DLTs will be confirmed by the 
SC. 
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Table 6 - Dose-limiting toxicities  
Hematological abnormalities 
Grade 4 neutropenia for 7 or more consecutive days. 
Grade 3 to 4 neutropenia complicated by fever (temperature ≥38.5°C on more than 1 occasion) or microbiologically or 
radiographically documented infection 
Grade ≥3 thrombocytopenia associated with clinically significant bleeding requiring clinical intervention 
Nonhematological abnormalities 
Grade 4 non-hematologic AE 
Grade ≥3 keratopathy 
In addition, any other AE that the recruiting Investigators and Sponsor deem to be dose limiting, regardless of its grade, may 
also be considered as DLT. 
Abbreviations: AE = adverse event; DLT = dose-limiting toxicity. 
In the case that it is decided to reduce the initial loading dose of tusamitamab ravtansine to DL -1 
(Table 1), a tusamitamab ravtansine loading dose of 150 mg/m2 will be administered to 
participants on Day 1 of Cycle 1.  
Individual dose adjustment/dose delay: Part 1 and Part 2 
Dose adjustment and/or cycle delay are permitted in case of AEs. In case of toxicity, cycle delays 
and dose modifications should be implemented according Appendix 6 (Section 10.6). Every effort 
will be made to administer the full dose regimen and maximize dose intensity.  
Dose adjustments will be made according to the worst grade of AE observed within a cycle. If a 
participant experiences several adverse events and there are conflicting recommendations, the 
most conservative dose adjustment recommended should be followed.  
Administration of the study treatment will be discontinued in the event of a TEAE that persists 
despite appropriate dose modifications or any other AE that, in the opinion of the Investigator, 
warrants discontinuation.  
Ramucirumab or tusamitamab ravtansine can be discontinued prematurely. The patient will 
remain on study treatment until the last IMP can be discontinued for disease progression, 
unacceptable AE, or the participant’s or investigator’s decision to stop the treatment. The reason 
for premature discontinuation will be captured in the appropriate eCRF page. 
Dose modifications different from those stated in the protocol should be made only in consultation 
with the Sponsor unless required for immediate participant safety.  
All changes to study treatment administration must be recorded in the eCRF. 
In the event of neutropenia or febrile neutropenia, therapeutic G-CSF should be administered 
according to the current American Society of Clinical Oncology (ASCO) guidelines (13); for 
specific recommendations for this study, refer to Appendix 6 (Section 10.6).  
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The acceptable treatment window for tusamitamab ravtansine and ramucirumab administration is 
±2 days. 
See Appendix 6 in Section 10.6 for further guidance for dose modification or discontinuation. 
Approved product labels for ramucirumab should be followed for supportive care and dose 
modification requirement due AEs not listed in Section 10.6. During the conduct of the study, a 
second dose reduction may be needed; such an action must be decided in a case-by-case 
discussion with the Sponsor. In case a dose reduction is necessary for Cycle 2 and subsequent 
cycles, the study intervention will be administered as follows in Table 7. 
Table 7 - Dose modification for toxicity  
Drug name 
Dose 
1st dose reductiona 
2nd dose reductiona 
tusamitamab ravtansine 
100 mg/m2 Q2W 
80 mg/m2 Q2W 
(not permitted) 
ramucirumab  
8 mg/kg Q2W 
6 mg/kg Q2W 
5 mg/kg Q2W 
a Dose modification is applicable from Cycle 2. At Cycle 1 the dose will remain the recommended dose (170 mg/m2 or 150 mg/m2). 
Any participant who requires a tusamitamab ravtansine or ramucirumab dose reduction will 
continue to receive a reduced dose until discontinuation from tusamitamab 
ravtansine/ramucirumab or discontinuation from the study. 
Any patient who has had 1 tusamitamab ravtansine dose reduction or 2 ramucirumab dose 
reductions and who experiences an event that would cause an additional dose reduction must be 
discontinued from tusamitamab ravtansine/ramucirumab. 
If 1 of the 2 drugs (tusamitamab ravtansine or ramucirumab) is prematurely permanently 
discontinued, the other drug can be continued until disease progression. 
Retreatment of a patient requiring a dose delay of more than 1 month will need to be justified by 
an individual case risk-benefit assessment. 
6.5.1 Retreatment criteria: Part 1 and Part 2  
All participants entered into the study will be treated at Day 1. A participant may receive 
additional study interventions if he/she meets retreatment criteria as determined by the 
Investigator and agrees to be retreated.  
At Day 1, the participant must meet all of the following criteria to be eligible for retreatment: 
• Neutrophil 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. 
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• Urine protein: 
- 
<2+ on dipstick or urinalysis for C1D1 
- 
≤2+ on dipstick or urinalysis for subsequent infusions 
OR 
- 
<2 g on 24 hour urine collection. 
• Hypertension is controlled. Every attempt should be made to control blood pressure  
(<150 mmHg systolic and <90 mmHg diastolic). 
• Wound healing: any wound is fully healed. 
6.6 
CONTINUED ACCESS TO INTERVENTION AFTER THE END OF THE STUDY  
Not applicable. 
6.7 
TREATMENT OF OVERDOSE  
For this study, any dose of tusamitamab ravtansine or ramucirumab greater than at least 
30% above the intended administered dose at each cycle, expressed in unit per BSA or weight, 
respectively, will be considered an overdose. 
In the event of an overdose, the Investigator should: 
1. Contact the Sponsor immediately. 
2. Evaluate the participant to determine, in consultation with the Sponsor, whether study 
intervention should be interrupted or whether the dose should be reduced. 
3. Closely monitor the participant for any AE/SAE and laboratory abnormalities.  
4. Obtain a plasma sample for PK analysis if requested by the Sponsor or Sponsor 
representative(s) (determined on a case-by-case basis). 
5. Document appropriately in the CRF. 
6.8 
CONCOMITANT THERAPY  
Any medication or vaccine (including over-the-counter or prescription medicines, recreational 
drugs, vitamins, and/or herbal supplements) that the participant is receiving at the time of 
enrollment or receives during the study must be recorded along with: 
• Reason for use 
• Dates of administration including start and end dates 
The Sponsor should be contacted if there are any questions regarding concomitant or prior 
therapy. 
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Participants must abstain from taking prescription or nonprescription drugs (including vitamins, 
recreational drugs, and dietary or herbal supplements) within 7 days (or 14 days if the drug is a 
potential enzyme inducer) or 5 half-lives (whichever is longer) before the start of study 
intervention until completion of the follow-up visit, unless, in the opinion of the Investigator and 
Sponsor, the medication will not interfere with the study. 
Concomitant medication may be considered on a case-by-case basis by the Investigator, in 
accordance with the following guidelines: 
• Participants with well controlled HIV infection must receive a stable ART regimen 
containing no antiretroviral medication other than the following: abacavir, dolutegravir, 
emtricitabine, lamivudine, raltegravir, rilpivirine, and/or tenofovir. 
• Palliative radiotherapy may be given for control of pain (for palliative intent). If palliative 
radiotherapy is being considered, the Sponsor should be contacted for approval prior to 
initiating treatment, and prior to resuming therapy on the study.  
The irradiated area should be as small as possible and should involve no more than 20% of 
the bone-marrow in any given 3 week period. In all such cases, the possibility of tumor 
progression should be ruled out by physical and radiological assessments of the tumor. 
The irradiated area cannot be used as a parameter for response assessment. If the only 
evaluable lesions are to be irradiated, the participant will stop the study intervention.  
• Any background therapy taken by the participant for concomitant illnesses other than 
cancer (eg, HRT, statin, antihypertensive medication) is allowed. 
• Supportive treatment as medically indicated for the participant's well-being may be 
prescribed at the Investigator's discretion. Every medication or treatment taken by the 
participant during the trial and the reason for its administration must be recorded on the 
eCRF. 
The following treatments are not permitted during this study: 
• Concurrent treatment with other investigational drugs. 
• Concurrent treatment with any other anticancer therapy not specified in the protocol, 
including immunotherapy, hormonal therapy, targeted therapy or biological therapies. 
• The primary prophylactic use of Granulocyte-Colony Stimulating Factor is not allowed 
during the DLT observation period. Secondary prophylaxis or therapeutic administration 
are allowed as detailed in Appendix 6 (Section 10.6). 
• Use of prophylactic erythropoietin during the first 2 cycles. 
• Participants treated or intended to be treated with drugs identified as CYP450 substrates 
with narrow therapeutic range (NTR) should be carefully monitored (See Section 10.11 
[Appendix 11]). 
• Concomitant use of strong CYP3A inhibitors should be avoided from 2 weeks before 
tusamitamab ravtansine administration up to the last tusamitamab ravtansine 
administration (See Section 10.12 [Appendix 12]). 
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• The use of contact lenses will not be permitted during the study treatment period. 
• Participants receiving a stable ART regimen must receive no antiretroviral medication 
other than the following: abacavir, dolutegravir, emtricitabine, lamivudine, raltegravir, 
rilpivirine, and/or tenofovir. 
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7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL  
7.1 
DISCONTINUATION OF STUDY INTERVENTION  
7.1.1 Permanent discontinuation  
If study intervention is permanently discontinued, the participant will remain in the study to be 
evaluated for safety and disease progression status, when applicable. See the SoA (Section 1.3) 
for data to be collected at the time of discontinuation of study intervention and follow-up and for 
any further evaluations that need to be completed. 
Any abnormal laboratory value or ECG parameter will be immediately rechecked for 
confirmation within 1 week before making a decision of permanent discontinuation of the IMP for 
the concerned participant. 
Handling of participants after permanent intervention discontinuation 
Participants will be followed 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, including 
blood samples for PK and immunogenicity assessments.  
All cases of permanent intervention discontinuation must be recorded by the Investigator in the 
appropriate pages of the eCRF when considered as confirmed. 
7.1.2 Temporary discontinuation  
Temporary intervention discontinuation may be considered by the Investigator because of 
suspected AEs or disruption of the clinical trial due to a regional or national emergency declared 
by a governmental agency (Appendix 9: Contingency measures for a regional or national 
emergency that is declared by a governmental agency; Section 10.9). For all temporary 
intervention discontinuations, duration should be recorded by the Investigator in the appropriate 
pages of the eCRF.  
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY  
• A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral or 
compliance reasons. This is expected to be uncommon. 
• At the time of discontinuing from the study, if possible, an early discontinuation visit 
should be conducted, as shown in the SoA. See SoA for data to be collected at the time of 
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study discontinuation and follow-up and for any further evaluations that need to be 
completed. 
• If the participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
• If a participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the Investigator must document this in the site study records. 
If participants no longer wish to take the IMP, they will be encouraged to remain in the study. 
The Investigators should discuss with them key visits to attend. The value of all their study data 
collected during their continued involvement will be emphasized as important to the public health 
value of the study. 
Participants who withdraw from the study intervention should be explicitly asked about the 
contribution of possible AEs to their decision, and any AE information elicited must be 
documented. 
All study withdrawals should be recorded by the Investigator in the appropriate screens of the 
eCRF and in the participant’s medical records. In the medical record, at least the date of the 
withdrawal and the reason should be documented. 
In addition, a participant may withdraw his/her consent to stop participating in the study. 
Withdrawal of consent for intervention should be distinguished from withdrawal of consent for 
follow-up visits and from withdrawal of consent for non-participant contact follow-up, 
eg, medical record checks. The site should document any case of withdrawal of consent. 
Participants who have withdrawn from the study cannot be reallocated (treated) in the study. Their 
inclusion and intervention numbers must not be reused. 
7.3 
LOST TO FOLLOW UP  
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit: 
• The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible 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. 
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• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1 
(Section 10.1). 
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8 
STUDY ASSESSMENTS AND PROCEDURES  
Study procedures and their timing are summarized in the SoA. Protocol waivers or exemptions are 
not allowed. 
• Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The Investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
• Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count, urine tests) and obtained before signing of the ICF may be utilized for screening or 
baseline purposes provided the procedures met the protocol-specified criteria and were 
performed within the time frame defined in the SoA. 
• Tumor CEACAM5 expression, PD-L1 expression status, and circulating CEA will be 
collected during the prescreening visit. 
• In participants who fail prescreening, limited information will be collected as detailed in 
Section 1.3. 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Appendix 9: Contingency measures for a regional or national emergency that is 
declared by a governmental agency (Section 10.9).  
8.1 
EFFICACY ASSESSMENTS  
Planned time points for all efficacy assessments are provided in the SoA. 
The assessment of antitumor activity of tusamitamab ravtansine combined with ramucirumab with 
regard to ORR per RECIST 1.1 is the primary efficacy objective. 
All participants treated must have at least one measurable lesion as per RECIST 1.1 for inclusion 
based on tumor assessment defined in the SOA, Section 1.3. 
Tumor assessment will be made every 6 weeks (±7 day window), and a scheduled assessment 
time point will not be modified in case of a cycle delay. Thoracic-abdominal-pelvic CT-scan or 
MRI and any other examinations as clinically indicated will be performed to assess disease status 
at baseline; then every 6 weeks during the study treatment period until radiological disease 
progression, initiation of further anticancer therapy, death, or study cut-off for secondary 
endpoints, whichever comes first; and at the end of study treatment, except if already done at last 
cycle. Confirmatory radiological evaluation will be performed at least 4 weeks after initial 
documentation of response. After IMP discontinuation, tumor assessment should be performed at 
EOT for patients without imaging performed within past 4 weeks, and every 8 weeks (±7 days) 
after the last tumor assessment until disease progression or initiation of a new anticancer 
treatment, death, or the study cut-off for secondary endpoints, whichever comes first. Brain 
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CT-scan or MRI should be performed at baseline and followed only for patients with brain lesions 
at baseline. Imaging assessments during the on-treatment period are to be scheduled using the 
Cycle 1, Day 1 date as the reference date for all time points, and are not to be scheduled based on 
the date of the previous imaging time point. Delay of an imaging assessment to conform to 
treatment delay is not permitted. The same tumor assessment technique must be used throughout 
the study for a given lesion/participant. 
Secondary efficacy endpoints will include DOR, PFS, and DCR. 
The RECIST 1.1 criteria will be followed for assessment of tumor response; see Appendix 13 
(Section 10.13) for details.  
8.2 
SAFETY ASSESSMENTS  
This section presents safety assessments other than AE assessments (Section 8.3). 
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 major 
body systems, including Cardiovascular, Respiratory, Gastrointestinal and Neurological 
systems. Height (only at screening) and weight will also be measured and recorded. 
• ECOG performance status should be assessed at baseline, before each IMP administration, 
at EOT, and at the follow-up visit. Performance status will be evaluated using ECOG scale 
(14). 
• Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
• Any new finding or worsening of previous finding should be reported as a new AE. 
8.2.2 Specific ocular tests  
Specific complete ocular tests at baseline and EOT will include: assessment of ocular/visual 
symptoms and ocular exams including visual acuity, slit lamp under dilatation, and Schirmer’s 
test. 
Standard specific ocular tests include:  
• Assessment of ocular/visual symptoms, (ie, blurred vision, photophobia, dry eye, etc) at 
each visit before each study intervention. Start and end dates of symptoms will be 
collected. 
• Visual acuity at baseline and whenever clinically indicated. 
• Slit lamp under dilatation at screening and whenever clinically indicated. 
• Schirmer’s test at baseline and whenever clinically indicated. 
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In participants with any ocular/visual symptom (eg, blurred vision, photophobia), complete ocular 
tests will be repeated at the time of the occurrence of the ocular toxicity, if any, regardless of the 
grade. Thereafter, visual acuity, slit lamp examination under dilatation, and Schirmer’s test will be 
repeated once weekly (if not recommended to have less frequent assessment by ophthalmologist 
based on lesion characteristics) until resolution to Grade 1. In case of recurrent ocular toxicity 
observed in subsequent cycles, visual acuity and slit lamp examination under dilatation, and 
Schirmer’s test will be performed at the time of the event onset, then weekly until resolution to 
Grade 1. 
8.2.3 Vital signs  
• Temperature, pulse rate, and blood pressure will be assessed during each physical 
examination. 
• 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). 
• Vital signs (to be taken before blood collection for laboratory tests) will consist of 1 pulse 
and 3 blood pressure measurements (3 consecutive blood pressure readings will be 
recorded at intervals of at least 1 minute). The average of the 3 blood pressure readings 
will be recorded. 
8.2.4 Electrocardiograms  
• Single 12-lead ECGs will be obtained as outlined in the SoA (see Section 1.3) using an 
ECG machine that automatically calculates the heart rate and measures PR, QRS, and QT 
intervals. 
• ECG is required at screening within 7 days prior IMP administration, at baseline before 
starting and after completing the first IMP administration (within 30 minutes after the end 
of tusamitamab ravtansine infusion); before IMP administration at each cycle; and at the 
End of treatment evaluation, 30 (±5) days after last IMP administration. This test can be 
performed on the same day before the study intervention administration, or on the day 
before. An ECG is to be repeated as clinically indicated. 
• ECGs will be interpreted by a qualified physician at the site as soon after the time of ECG 
collection as possible, and ideally while the patient is still present, should additional ECGs 
be performed or for immediate patient management should any clinically relevant findings 
be identified. 
8.2.5 Echocardiogram or MUGA scan  
An echocardiogram or multigated acquisition (MUGA) scan to evaluate left ventricular ejection 
fraction (LVEF) will be evaluated during screening period, and whenever clinically indicated. 
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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 (Section 1.3) for the timing and frequency. These tests will be done at each 
cycle; during the first 2 cycles, hematology and liver function tests will be assessed 
weekly. 
• If Grade 4 neutropenia occurs, assess ANC every 2 to 3 days until ANC ≥0.5 × 109/L.  
• In case of Grade ≥3 abnormal liver function tests, additional tests will be done every 2 to 
3 days until recovery to the baseline value. Additional tests will be performed when 
clinically appropriate. This test can be performed before the study intervention 
administration on the same day or the day before. 
• The Investigator must review the laboratory report, document this review, and record any 
clinically significant changes occurring during the study as an AE. The laboratory reports 
must be filed with the source documents. Abnormal laboratory findings associated with 
the underlying disease are not considered clinically significant, unless judged by the 
Investigator to be more severe than expected for the participant’s condition. 
• All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 30 days after the last dose of study intervention should 
be repeated until the values return to normal or baseline or are no longer considered 
clinically significant by the Investigator. 
- 
If clinically significant values do not return to normal/baseline within a period of time 
judged reasonable by the Investigator, the etiology should be identified and the 
Sponsor notified. 
- 
All protocol-required laboratory tests, as defined in Appendix 2 (Section 10.2), must 
be conducted in accordance with the laboratory manual and the SoA (Section 1.3.). 
- 
If laboratory values from non-protocol-specified laboratory tests performed at the 
institution’s local laboratory require a change in participant management or are 
considered clinically significant by the Investigator (eg, SAE or AE or dose 
modification), then the results must be recorded. 
8.2.7 Guidelines for management of adverse events  
Management of AEs related to tusamitamab ravtansine and ramucirumab is summarized in 
Appendix 6 (Section 10.6); for specific AE related to ramucirumab intake, please refer to the 
current prescribing information leaflet; the most relevant reported events are summarized in this 
section as reminder. 
8.2.7.1 Hypersensitivity reactions  
Premedication treatments provided as prophylactic treatment for hypersensitivity reactions are 
detailed in Section 6.1. 
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In case of an event of hypersensitivity reaction, please refer to the recommended dose 
modification or discontinuation table in Appendix 6 (Section 10.6). 
As with other monoclonal antibodies, IRRs may occur during or following ramucirumab or 
tusamitamab ravtansine administration. Patients should be closely monitored for signs and 
symptoms indicative of an IRR from the initiation of the infusion in an area where resuscitation 
equipment and other agents (such as epinephrine and corticosteroids) are readily available.  
A 1 hour observation period following the ramucirumab infusion is mandatory for the first 
2 infusions. If the patient shows no evidence of an IRR with the first 2 infusions of ramucirumab, 
no observation period is required for subsequent infusions. In the event an IRR occurs thereafter, 
the 1 hour observation should be reinstituted. Symptoms of IRRs include rigors/tremors, back 
pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and 
paresthesia. In severe cases, symptoms include bronchospasm, supraventricular tachycardia, and 
hypotension. If the patient experiences a Grade 1 or Grade 2 IRR, interrupt the infusion and treat 
the patient with anti-allergic medication. If symptoms resolve, resume the infusion at a reduced 
rate (50%). 
8.2.7.2 Ocular toxicity  
It is recommended that topical artificial tears (and/or hyaluronic ophthalmic gel) are used regularly 
in all patients treated with tusamitamab ravtansine during the study treatment period. 
The patient should be asked about ocular/visual symptoms at each visit, and ocular evaluation 
including visual acuity, slit lamp examination under dilatation, and Schirmer’s test should be 
carried on according to Study Procedures (Section 8.2.2). Ocular evaluation will be performed at 
baseline (during the screening period), as required during the treatment (ie, on occurrence of 
ocular symptoms such as blurred vision, photophobia, pain), at the EOT visit, and when relevant 
at follow-up visit(s). The outcome of the examination should be available before infusion of the 
next cycle. If ocular symptoms are present, then a formal ocular examination should be 
performed. In patients with any ocular/visual symptom(s) (eg, blurred vision, photophobia), the 
ocular evaluation should be repeated once weekly, unless less frequent assessment is 
recommended by an ophthalmologist, until resolution to Grade 1. Subsequently, the participant 
should be followed with ocular exam (slit lamp and visual acuity) at each cycle until total 
resolution of the event. 
Photographs of the cornea are recommended to be taken at the site, if possible, when ocular 
findings are first documented, and to follow progression when relevant. Tonometry and additional 
ocular assessment can be performed at discretion of an ophthalmologist when applicable. 
8.2.7.2.1 Keratopathy/keratitis management  
Reversible non-inflammatory, microcystic keratopathy was identified as the DLT during the dose 
escalation process in study TED13751with tusamitamab ravtansine. At slit-lamp examination, it 
presents as lesions consisting of 100s to 1000s microcysts and/or deposits that are initially 
observed at the periphery of the cornea, the limbus being preserved. The lesions have a centripetal 
distribution and evolve towards the center of the corneal upon resolution, following the natural 
keratinocyte regeneration process.  
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For standardization of AE verbatim, keratopathy should be preferred term unless otherwise 
specified by an ophthalmologist due to inflammatory findings on eye exams leading to diagnosis 
of keratitis.  
The potential ocular/visual toxicity symptoms could include, but are not limited to, blurred vision, 
dry eye, and photophobia. Curative treatment may be used as recommended by an 
ophthalmologist.  
No primary prophylaxis other than prevention of dry eye with artificial tears and/or hyaluronic 
ophthalmic gel is recommended; the use of contact lenses is not permitted during the treatment 
period. Corticosteroid-containing ocular drugs are recommended for the management of 
keratopathy/keratitis in the case that ocular symptoms occur, and treatment will be performed 
based on discretion of ophthalmologist. Dose modification and recommendations are further 
described in Appendix 6 (Section 10.6). 
After resuming study treatment, a patient who had Grade ≥2 keratopathy/keratitis should be 
followed with standard ocular exams (ie, slit lamp examination under dilatation and visual acuity) 
every 2 cycles, even if symptoms are no longer reported. If no event recurs during the next 
4 cycles, then regular follow-up (ie, symptom assessment at each visit with standard ocular exam 
in case of any ocular sign/symptom) is applied.  
8.2.7.3 Management of anemia  
Close surveillance of any signs and symptoms is required: a routine blood hematology workup, 
including red blood cell (RBC) counts, hemoglobin, hematocrit, WBC with differential, and 
platelet counts will be done weekly during the first 2 cycles, and thereafter each treatment cycle 
before IMP administration. Patients should not start Cycle 1 treatment if hemoglobin is <9.0 g/dL. 
To be eligible for the study and to receive the first study treatment, the participant must have been 
transfusion-free for 2 weeks. During the treatment period, erythrocyte transfusion can be given, 
upon Investigator decision. Erythropoietin can be given at the discretion of the Investigator, 
except during Screening and the first 2 cycles. Cycle delays or modifications should be compliant 
with Appendix 6 (Section 10.6). 
8.2.7.4 Management of neutropenia  
In patients who experienced either Grade 3 or 4 febrile neutropenia or Grade 4 decreased 
neutrophil count (<500 cells/mm3) for more than 1 week during study intervention, prophylactic 
G-CSF should be implemented per ASCO guidelines (13) to ensure dose intensity (Appendix 6, 
Section 10.6). Doses of tusamitamab ravtansine should be reduced in case of recurrent events even 
after prophylactic G-CSF use. 
If the patient continues to experience these reactions at a lowered dose, the treatment should be 
discontinued (Section 7.1). 
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8.2.7.5 Liver function tests  
Hepatic enzyme increase has been reported with tusamitamab ravtansine administration as 
monotherapy or ramucirumab. Patients should be carefully followed and in case of Grade ≥3 
abnormal liver function tests, additional liver function tests will be done every 2 to 3 days until 
recovery to baseline value. tusamitamab ravtansine should be permanently discontinued in case of 
drug-induced Grade 4 liver enzyme increase. For stopping rules for ramucirumab administration, 
the current product leaflet should be followed. 
Grade ≥3 (ie, >5 × ULN) increased liver enzyme events should be reported as AESIs. 
8.2.7.6 Hypertension  
An increased incidence of severe hypertension (CTCAE Grade 3) has been reported in patients 
receiving ramucirumab as compared with placebo. In most cases, hypertension was controlled 
using standard antihypertensive treatment. Preexisting hypertension should be controlled before 
starting ramucirumab treatment. Monitoring of blood pressure is required during ramucirumab 
therapy. Every attempt should be made to control blood pressure to systolic <140 mmHg and 
diastolic <90 mmHg prior to starting treatment with ramucirumab. Routine clinical and laboratory 
monitoring is required in patients who again develop hypertension or experience a deterioration in 
previous hypertension. 
Withhold ramucirumab for severe hypertension until medically controlled. Permanently 
discontinue ramucirumab for medically significant hypertension that cannot be controlled with 
antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy. 
8.2.7.7 Proteinuria  
Proteinuria is an adverse effect for all therapies targeting the vascular endothelial growth factor 
(VEGF)/VEGFR-2 pathway, including ramucirumab. Proteinuria has been associated with 
ramucirumab in clinical studies; the majority of events were Grade 1 or 2.  
Monitor proteinuria by urine dipstick or routine urinalysis. If the result of the urine dipstick is 2+ 
or greater, perform a 24 hour urine collection for protein measurement.  
Withhold ramucirumab for urine protein levels of 2 or more grams collected over 24 hours. 
Reinitiate ramucirumab at a reduced dose once the urine protein level returns to less than 2 grams 
over 24 hours. Permanently discontinue ramucirumab for urine protein levels greater than 3 grams 
over 24 hours, or in the setting of nephrotic syndrome. 
8.2.7.8 Bleeding/hemorrhage  
Ramucirumab is an antiangiogenic therapy and has the potential to increase the risk of severe 
bleeding. Permanently discontinue ramucirumab in patients who experience severe (Grade 3 or 
Grade 4) bleeding. 
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8.2.7.9 Arterial thromboembolic events  
Serious, sometimes fatal, arterial thromboembolic events (ATEs), including myocardial infarction, 
cardiac arrest, cerebrovascular accident, and cerebral ischemia, occurred across clinical trials. 
Permanently discontinue ramucirumab in patients who experience an ATE. 
8.2.7.10 Peripheral neuropathy  
Participants with a known history of peripheral neuropathies and/or patients having received 
medications known to cause peripheral neuropathies (eg, prior antitubulin, platinum and/or 
taxanes) are at high risk of developing neuropathy. Peripheral neuropathies potentially present as 
signs and symptoms of sensory (paresthesia, dysesthesias, pain, and change in proprioception), 
motor (weakness), and neural dysfunctions. 
There is no further recommendation beyond routine guidance on prevention and treatment of 
peripheral neuropathy. Cycle delays or modifications should be compliant with Appendix 6 
(Section 10.6). 
8.2.7.11 Colitis (including hemorrhagic)  
In study TED13751 evaluating tusamitamab ravtansine in patients with several cancer types, a 
limited number of participants developed colitis. Based on clinical observations, patients with 
known underlying colitis or gastrointestinal tract conditions are noted to be at highest risk for such 
events. The monitoring of patients for GI toxicities will rely on careful evaluation by routine 
history, physical examination, and standard laboratory examination. Close surveillance of any 
signs and symptoms is required, with additional routine hematology workup (hemoglobin, 
hematocrit, and WBC with differential and platelet counts) whenever indicated. As 1 Grade 4 case 
of colitis erosive has been reported, it is recommended to conduct close surveillance of any 
diarrhea event, with further exams when clinically indicated. Treatment is per patient condition, 
based on Investigator discretion. 
8.2.8 Pregnancy testing  
Refer to Section 5.1 for pregnancy testing criteria. The Investigator is responsible for review of 
medical history, menstrual history, and recent sexual activity to decrease the risk of including a 
female participant with an early undetected pregnancy. 
• Pregnancy testing (urine or serum as required by local regulations) should be conducted 
every 4 weeks during intervention (at study visits and if needed, at home in between 
visits). 
• Pregnancy testing (urine or serum as required by local regulations) must be conducted 
corresponding with the time frame for female participant contraception in Section 5.1.  
• Additional serum or urine pregnancy tests may be performed, as determined necessary by 
the Investigator or required by local regulation, to establish the absence of pregnancy at 
any time during the subject’s participation in the study. 
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8.3 
ADVERSE EVENTS (AES), SERIOUS ADVERSE EVENTS (SAES) AND OTHER 
SAFETY REPORTING  
The definitions of adverse events (AEs) and serious adverse events (SAEs) can be found in 
Appendix 3 (Section 10.3). The definition of AESI is provided in Section 8.3.7. 
An AE will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant’s legally authorized representative).  
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue study intervention (see Section 7). 
8.3.1 Time period and frequency for collecting AE and SAE information  
All AEs (serious or nonserious) will be collected from the signing of the ICF until at least 30 days 
after the last study intervention at the time points specified in the SoA (Section 1.3). For a 
participant who was prescreened and had fresh biopsy, only the AEs in the prescreening period 
related to the fresh biopsy procedure itself and within the reporting time frame interval of 1 month 
after fresh biopsy should also be reported in eCRF according to general requirements of AE/SAE. 
All SAEs and AESI will be recorded and reported to the Sponsor or designee immediately and 
under no circumstance should this exceed 24 hours, as indicated in Appendix 3 (Section 10.3). 
The Investigator will submit any updated SAE data to the Sponsor within 24 hours of it being 
available. 
Investigators are not obligated to actively seek information on AEs or SAEs after conclusion of 
the study participation. However, if the Investigator learns of any SAE, including a death, at any 
time after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the Investigator must promptly 
notify the Sponsor. 
8.3.2 Method of detecting AEs and SAEs  
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 8.3.7), will be followed until resolution, stabilization, the 
event is otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). 
Further information on follow-up procedures is provided in Appendix 3 (Section 10.3). 
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8.3.4 Regulatory reporting requirements for SAEs  
• Prompt notification by the Investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met. 
• The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and Investigators. 
• Serious adverse events that are considered expected for tusamitamab ravtansine will be 
specified in the reference safety information in the Investigator Brochure.  
• Suspected unexpected serious adverse reactions (SUSARs) are reported to regulatory 
authorities, Investigators, and IRBs/IECs as follows: 
- 
For SUSARs that are life-threatening or result in death, reporting is no later than 
7 days after first knowledge by the Sponsor, with all relevant follow-up information 
subsequently reported within an additional 8 days. 
 
For SUSARs, other than those that are life-threatening or result in death, reporting is 
no later than 15 days after first knowledge by the Sponsor. 
- 
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 for tusamitamab 
ravtansine and will notify the IRB/IEC, if appropriate according to local requirements. It is 
the responsibility of the Sponsor to assess whether an event meets the criteria for a 
SUSAR, and therefore, is expedited to regulatory authorities. 
8.3.5 Pregnancy  
• Details of all pregnancies in female participants and female partners of male participants 
will be collected after the start of study intervention and until 7 months after the last 
intervention. 
• If a pregnancy is reported, the Investigator will record pregnancy information on the 
appropriate form and submit it to the Sponsor within 24 hours of learning of the 
pregnancy. 
- 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs and will be reported as 
such. 
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• The participant/pregnant female partner will be followed to determine the outcome of the 
pregnancy. The Investigator will collect follow-up information on the participant/pregnant 
female partner and the neonate and the information will be forwarded to the Sponsor. 
• Any post-study pregnancy-related SAE considered reasonably related to the study 
intervention by the Investigator will be reported to the Sponsor as described in 
Section 8.3.4. While the Investigator is not obligated to actively seek this information in 
former study participants' pregnant female partner, he or she may learn of an SAE through 
spontaneous reporting. 
• Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention or be withdrawn from the study. 
Prior to continuation of study intervention following pregnancy, the following must occur: 
• The Sponsor and the relevant IRB/IEC give written approval. 
• The participant gives signed informed consent. 
• The Investigator agrees to monitor the outcome of the pregnancy and the status of the 
participant and her offspring. 
8.3.6 Cardiovascular and death events  
Cardiovascular and death events will be treated as regular events. 
8.3.7 Adverse event of special interest  
An adverse event of special interest (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;  
- 
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). 
• Symptomatic overdose (serious or nonserious) with IMP 
Symptomatic overdose (accidental or intentional) with the IMP is an event suspected by 
the Investigator or spontaneously notified by the participant (not based on systematic pills 
count) and defined as an increase of at least 30% of the dose to be administered in the 
specified duration or if the dose is administered in less than half the recommended 
duration of administration.  
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• Grade ≥3 keratopathy 
• Bundle branch blocks or any conduction defects 
• Grade ≥3 liver enzyme increased (symptomatic or asymptomatic) 
• All protocol-defined DLTs (Section 6.5) 
8.3.8 Guidelines for reporting product complaints  
Any defect in the IMP must be reported as soon as possible by the Investigator to the monitoring 
team that will complete a product complaint form within required timelines. 
Appropriate information (eg, samples, labels or documents like pictures or photocopies) related to 
product identification and to the potential deficiencies may need to be gathered. The Investigator 
will assess whether or not the quality issue has to be reported together with an AE or SAE. 
8.4 
PHARMACOKINETICS  
Blood samples will be collected for the measurement of tusamitamab ravtansine and ramucirumab 
concentrations as described in the PK/ATA flow charts (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. Pharmacokinetic samples could be used for testing analytical method 
performance such as comparability and incurred sample reproducibility. 
8.4.1 Tusamitamab ravtansine  
Data from plasma concentrations of tusamitamab ravtansine 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 concentration-time curve (AUC) will be derived. 
8.4.2 Ramucirumab  
Ramucirumab concentration data will be summarized by descriptive statistics. 
8.5 
GENETICS  
A 20 mL blood sample corresponding to about 10 mL of plasma and an additional 2 mL blood 
sample for germline DNA will be collected for future use at pre-infusion of Cycle 1, Day 1. These 
samples may be used for but not restricted to tumor circulating free deoxyribonucleic acid 
(cfDNA) and germline DNA isolation respectively. Other blood and plasma components as 
circulating proteins or RNA may be also evaluated.  
Participants who do not wish to participate in the genetic research may still participate in the 
study. 
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In case of cfDNA/DNA isolation, samples are planned to be transferred to a central laboratory for 
extraction and mutational profiling of key cancer genes to understand the significance of existing 
mutation during tusamitamab ravtansine treatment. 
Fragmented circulating tumor DNA or cfDNA is released from the tumor in the plasma and can 
readily be extracted and analyzed for mutation of common cancer genes. Subtractive mutation 
analysis will be performed with germline DNA data to identify tumor specific somatic genetic 
aberrations. The list (not exhaustive) of the genes that could be mutated/translocated is: AKT1, 
ALK, BRAF, CDKN1B,CDKN2A, CDKN2D, EGFR, ESR1, FGFR4, HER2, HRAS, KRAS, MDM2, 
MED1, MET, NRAS, PIK3CA, PTEN, RB1, RET, ROS1, and TP53. 
See Appendix 5 (Section 10.5) for information regarding genetic research. Details on processes 
for collection, shipment and destruction of these samples can be found in the study laboratory 
manual. 
As new knowledge is acquired about the disease and/or tusamitamab ravtansine, other techniques 
could be implemented to evaluate other analytes such as circulating proteins or RNA. 
8.6 
BIOMARKERS  
Collection of biological samples for other biomarker research is also part of this study. Samples 
collected for biomarker analyses and their derivatives will be stored for a period of up to 15 years 
after last participant, last visit for potential re-analysis. 
• The following samples for biomarker research are required and will be collected from all 
participants in this study as specified in the SoA: 
- 
Tumor tissue samples will be collected and assayed for CEACAM5 expression to 
determine eligibility for this study. 
The level of CEACAM5 expression in tumor tissues will be determined by a central 
laboratory using a specific anti-CEACAM5 antibody (clone 769). 
- 
Blood samples for circulating CEA will be collected to assess correlation with 
CEACAM5 expression in tumor samples and to explore modulations of circulating 
CEA as a potential pharmacodynamics biomarker of response to tusamitamab 
ravtansine treatment. 
Blood samples for circulating CEA levels will be collected at prescreening for all 
participants, at baseline for screened participants, every 6 weeks during the treatment 
period, at the EOT visit, and in the follow-up period at the time of laboratory assessment 
(as close as possible to and no more than 2 weeks from the tumor assessment) until disease 
progression. Circulating CEA will be assessed using local testing. Venous blood samples 
of approximately 3 mL (volume may change depending on local laboratory assay) will be 
collected for measurement at the local laboratory. 
- 
Blood samples will be collected for measurement of IgG to explore impact of IgG 
level on PK of tusamitamab ravtansine. 
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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, corresponding to 1 mL of serum, will 
be collected. 
- 
Blood and plasma samples will be collected for future analyses (as optional). 
For future use, a 20 mL blood sample corresponding to about 10 mL of plasma and an 
additional 2 mL blood will be collected at baseline. Samples will be stored and analysis 
may be performed for research to develop methods, assays, prognostics and/or 
companion diagnostics related to tusamitamab ravtansine, disease process, pathways 
associated with disease state, and/or mechanism of action of tusamitamab ravtansine. 
Analytes to be evaluated may include but not limited to DNA, RNA, or serum analytes 
to evaluate their association with observed clinical responses to tusamitamab 
ravtansine. 
8.7 
IMMUNOGENICITY ASSESSMENTS  
Blood samples will be collected for assessing the presence of ATA against tusamitamab 
ravtansine in plasma from all participants as described in the PK/ATA flowcharts (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.  
Plasma samples will be screened for antibodies binding to tusamitamab ravtansine and the titer of 
confirmed positive samples will be reported. 
8.8 
HEALTH ECONOMICS OR MEDICAL RESOURCE UTILIZATION  
Health economics or medical resource utilization and health economics parameters are not 
evaluated in this study. 
8.9 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH  
Future research may help further the understanding of disease subtypes, disease biology, related 
conditions, drug response and toxicity, and can help identify new drug targets or biomarkers that 
predict participant response to treatment. Therefore, data and biological samples will be stored 
and used for future research when consented to by participants (see Section 10.1.3) unless 
prohibited by local laws or IRBs/IECs (in such case, consent for future use of sample will not be 
included in the local ICF).  
For participants who consent to the storage and use of their data and remaining and/or extra 
clinical samples, data and samples may be used after the study ends for future research related 
either to the drug, the mechanism of action, and the disease or its associated conditions. Such 
research may include, but is not limited to, performing assessments on DNA, RNA, proteins or 
metabolites. If future research on genetic material is performed, this will also be limited to the 
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purpose of addressing research questions related to the drug, the mechanism of action, the disease 
or its associated conditions. 
In the event future research is conducted for other purposes, the study participants will be 
informed of those purposes and will be given means to object to those research projects. 
Data and samples will be used in compliance with the information provided to participants in the 
ICF Part 2 (future research). 
All study participant data and samples will be coded such that no participant direct identifiers will 
be linked to them. Coded data and samples may be transferred to a Sponsor site (or a 
subcontractor site), which may be located outside of the country where the study is conducted. 
The Sponsor adopts safeguards for protecting participant confidentiality and personal data 
(see Section 10.1.4). 
The samples will be stored for a maximum of 15 years after the end of the study. Any samples 
remaining at the end of retention period will be destroyed. If a participant requests destruction of 
his/her samples before the end of the retention period, the Investigator must notify the Sponsor (or 
its contract organization) in writing. In such case, samples will be destroyed and related coded 
data will be anonymized unless otherwise required by applicable laws. 
Study participant coded data will be stored for future research for up to 25 years after the end of 
the study. If data are still considered of important scientific value after this period, coded data 
already available will be anonymized unless otherwise required by applicable laws (the same will 
apply to the data of a study participant who has requested the destruction of his/her samples). 
Participant’s coded data sets provided to researchers for a specific research project will be 
available to the researchers for a maximum of 2 years after the end of their specific project (end of 
project is defined by publication of the results or finalization of the future research project report). 
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9 
STATISTICAL CONSIDERATIONS  
The safety run-in (Part 1) aims to confirm the recommended dose of tusamitamab ravtansine 
loading dose Q2W in combination with ramucirumab according to DLTs observed. 
Part 2 of this study is designed to obtain preliminary efficacy, safety, and PK data on tusamitamab 
ravtansine loading dose Q2W administered in combination with ramucirumab to participants with 
gastric or GEJ adenocarcinoma. As Part 2 is not intended to explicitly test a hypothesis, 
calculations of power and Type I error were not considered in the study design.  
9.1 
SAMPLE SIZE DETERMINATION  
Assuming a prescreening failure rate of 70% and a study screening failure rate of 20%, 
approximately 158 participants will be prescreened to achieve up to approximately 38 treated 
participants in the safety run-in (Part 1) and Part 2.  
Sample size for the safety run-in (Part 1): 
The actual sample size is expected to vary depending on DLTs observed. It is anticipated that 
around 6 to 12 DLT-evaluable participants will be enrolled in the safety run-in part of the study.  
Sample size for Part 2: 
The initial plan is to treat a total of 32 participants evaluable for activity (at least 1 postbaseline 
evaluable tumor assessment, early clinical progression, or death due to disease progression). The 
6 participants treated at the recommended DL in the safety run-in part will also be evaluable for 
the second part of the study. 
Estimated ORR and 95% exact CIs by number of responders from a sample size of 32 evaluable 
participants for activity are listed in Table 8: 
Table 8 - Estimated objective response rate (ORR) depending on number of responders  
Number of responders 
(N=32) 
Objective response rate in percent (Clopper-Pearson 95% CI) 
Abbreviation: CI = confidence interval 
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9.2 
POPULATIONS FOR ANALYSES  
The following populations for analyses are defined in Table 9:  
Table 9 - 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. 
Enrolled 
Participants from screened population who have been allocated to intervention 
regardless of whether the intervention was received or not. 
All-treated 
All enrolled participants exposed to the study treatment, regardless of the amount of 
treatment administered. This population is the primary population for all efficacy 
parameters. 
DLT-Evaluable (Part1) 
All enrolled participants who received 2 cycles with at least 80% of the intended 
dose for both tusamitamab ravtansine and ramucirumab at each of the first 
2 infusions unless they discontinued the study intervention before the end of 
Cycle 2 due to a DLT. 
Activity 
All treated participants who have measurable disease at study entry and at least 
1 postbaseline evaluable tumor assessment. Participants with no postbaseline 
evaluable tumor assessment but with an early clinical progression or who died from 
disease progression will also be included in this set. This population is the 
secondary population for all efficacy parameters. 
PK 
All participants from the all-treated population with at least 1 postbaseline PK 
concentration (whatever the cycle and even if dosing is incomplete) with adequate 
documentation of dosing and sampling dates and times.  
ATA 
All participants from the all-treated population with at least 1 postbaseline ATA 
result (negative, positive or inconclusive). 
Abbreviations: ATA = antitherapeutic antibody; CEACAM5 = carcinoembryonic antigen-related cell adhesion molecule 5; DLT = dose-limiting 
toxicity; PK = pharmacokinetic. 
Participants exposed to study intervention before or without being enrolled will not be considered 
enrolled and will not be included in any analysis population. The safety experience of these 
participants will be reported separately.  
Enrolled participants for whom it is unclear whether they took the study intervention will be 
considered as exposed and will be included in the safety population. 
For any participant enrolled more than once, only the data associated with the first enrollment will 
be used in any analysis population. The safety experience associated with any later enrollment 
will be reported separately. 
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9.3 
STATISTICAL ANALYSES  
The statistical analysis plan will include a more technical and detailed description of the statistical 
analyses described in this section. This section is a summary of the planned statistical analyses of 
the most important endpoints including primary and key secondary endpoints. 
9.3.1 General considerations  
This study is not intended to explicitly test a hypothesis. For primary and secondary efficacy 
endpoints, 95% CIs will be provided. 
All efficacy endpoints based on radiological assessments of tumor burden (ie, ORR, DOR, PFS, 
and DCR) will be derived using the local radiologist’s/Investigator’s assessment. 
In general, continuous data will be summarized using the number of observations available, mean, 
standard deviation, median, Q1, Q3, minimum, and maximum. Categorical and ordinal data will 
be summarized using the count and percentage of participants. 
The baseline value is defined as the last available value before the first dose of investigational 
medicinal product (IMP). 
The study cut-off for analysis of the primary endpoint for the study, ORR, corresponds to the date 
on which all evaluable treated participants have had at least 2 postbaseline tumor assessments, 
experienced confirmed objective response, or have discontinued the study for any reason. This 
study cut-off can be up to approximately 16 weeks (12 weeks for 2 tumor assessments and 
4 weeks for confirmation of response, if needed) after the last participant’s first IMP 
administration. 
The final study cut-off date for analysis of the secondary efficacy endpoints, which include DOR 
and PFS, will be 4 months after the cut-off date for the primary analysis. At that time, the primary 
analysis of ORR and DCR will also be updated. 
Observation period 
The observation period will be divided into 4 segments:  
• The pretreatment period is defined as the period up to first IMP administration. 
- 
The prescreening period is defined as the period from the prescreening 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 (TE) period) is defined as the period 
from the first IMP administration to the last IMP administration +30 days. 
• The posttreatment period is defined as the period from the end of the on-treatment 
period. 
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9.3.2 Primary endpoints  
As it is a 2-part study, there are 2 primary endpoints: incidence of study-drug related DLTs at 
Cycle 1 and Cycle 2 in Part 1 and ORR as per RECIST 1.1 in Part 2. 
9.3.2.1 Incidence of study-drug related DLT at Cycle 1 and Cycle 2  
The primary safety analysis will be based on a principal stratum estimand defined according to the 
following attributes: 
• The primary safety endpoint is study-drug related DLT during the DLT observation period 
(ie, from Cycle 1 Day 1 to Cycle 2 Day 14). 
• The treatment condition of interest is tusamitamab ravtansine loading dose Q2W in 
combination with ramucirumab, by DL (if applicable). 
• The analysis population is the DLT-evaluable population (defined in Section 9.2 
Populations for analyses). 
• There is no defined strategy for handling intercurrent events due to the definition of the 
analysis population. Indeed, participants from the DLT-evaluable population will not 
experience any anticipated intercurrent events (intervention discontinuation, study 
discontinuation, start of an anticancer therapy and death) before experiencing a DLT at 
Cycle 1 or Cycle 2, or before completing the Cycle 2, whichever is earlier. 
• The population-level summary will include the incidence of DLTs at Cycle 1 and Cycle 2, 
defined as number and percentage of participants experiencing at least 1 study-
drug-related DLT. There will be no missing data in the analysis population. 
9.3.2.2 Objective response rate  
The primary efficacy analysis will be based on a treatment policy and composite variable 
estimand defined according to the following attributes: 
• The primary efficacy endpoint is confirmed objective response (confirmed CR or PR as 
BOR) as per RECIST 1.1. The BOR will be derived according to RECIST 1.1 definitions 
based on the investigator’s assessment. The BOR is the best overall response observed 
from the date of the first administration of IMP until documented disease progression, 
death, start of an anticancer therapy, or analysis cut-off date, whichever occurs first. 
• The treatment condition of interest is tusamitamab ravtansine loading dose Q2W in 
combination with ramucirumab. 
• The analysis population is the subgroup of participants from all-treated population 
(defined in Section 9.2 Populations for analyses) treated at the recommended dose of 
tusamitamab ravtansine loading dose Q2W (ie, excluding participants treated at the 
starting dose if this differs from the recommended dose). 
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• Intercurrent events: 
- 
The study intervention discontinuation intercurrent event will be handled with the 
treatment policy strategy. Confirmed objective response will be assessed based on 
tumor assessments regardless of study intervention discontinuation. 
- 
The other anticipated intercurrent events will be handled with the composite strategy. 
Participants who discontinue the study, start an anticancer therapy, experience PD, or 
die prior to a confirmed objective response will be considered nonresponders. 
• The population-level summary will be the ORR, defined as the rate of participants with 
confirmed objective response and 2-sided 95% CIs using the Clopper-Pearson method. In 
the absence of confirmed objective response, participants will be considered as 
nonresponders, whatever the reason (including participants with missing or nonevaluable 
BOR). 
As a supplementary analysis, ORR as per RECIST 1.1 will also be summarized on the 
subgroup of participants from activity population (defined in Section 9.2 Populations for 
analyses) treated at the recommended dose for tusamitamab ravtansine in a loading-dose 
Q2W regimen (ie, excluding participants treated at the starting dose if this differs from the 
recommended dose). The same analytical approach as described above will be used. 
9.3.3 Secondary endpoints  
The secondary efficacy endpoints detailed in this section are DOR, PFS, and DCR. Analyses of 
other secondary endpoints are described separately with other safety analyses (adverse events and 
laboratory variables, vital signs and electrocardiograms) or other analyses (pharmacokinetic, 
immunogenicity). 
9.3.3.1 Duration of response  
Analysis of the DOR will be based on a treatment policy and composite variable estimand defined 
according to the following attributes: 
• The endpoint is DOR, defined as the time from the date of first initial occurrence of the 
confirmed CR or PR to the date of first radiological documentation of PD according to 
RECIST 1.1 or death due to any cause, whichever occurs first. 
In the absence of disease progression or death before the analysis cut-off date, DOR will 
be censored at the date of the last evaluable tumor assessment (not showing documented 
disease progression) performed before the analysis cut-off date. 
• The treatment condition of interest is tusamitamab ravtansine loading dose Q2W in 
combination with ramucirumab. 
• The analysis population is the subgroup of participants from all-treated population 
(defined in Section 9.2 Populations for analyses) treated at the recommended dose of 
tusamitamab ravtansine in a loading-dose Q2W regimen (ie, excluding participants treated 
at the starting dose if this differs from the recommended dose) who achieved a confirmed 
objective response (PR or CR). 
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• Intercurrent events: 
- 
The study intervention discontinuation intercurrent event will be handled with the 
treatment policy strategy. DOR will be assessed based on tumor assessments 
regardless of study intervention discontinuation. 
- 
The other anticipated intercurrent events will be handled with the composite strategy. 
For participants who discontinue the study or start an anticancer therapy prior to 
observing PD or death, DOR will be censored at the date of the last evaluable tumor 
assessment (not showing PD) performed prior to the intercurrent event. 
• The population-level summary will include the median DOR and associated 95% CI using 
Kaplan-Meier methods. In the absence of confirmed objective response, DOR will not be 
derived. 
9.3.3.2 Progression-free survival  
Analysis of the PFS will be based on a treatment policy and composite variable estimand defined 
according to the following attributes: 
• The endpoint is PFS, defined as the time from the date of the first administration of IMP to 
the first documentation of objective PD according to RECIST 1.1 definitions or death due 
to any cause, whichever comes first. 
If progression or death is not observed before the analysis cut-off date, then PFS will be 
censored at the date of the last evaluable tumor assessment performed before the analysis 
cut-off date. A participant without PFS event (death or documented disease progression) 
and without any evaluable postbaseline tumor assessment will be censored at the date of 
the first administration of IMP (Day 1). 
• The treatment condition of interest is tusamitamab ravtansine loading dose Q2W in 
combination with ramucirumab. 
• The analysis population is the subgroup of participants from all-treated population 
(defined in Section 9.2 Populations for analyses) treated at the recommended dose of a 
tusamitamab ravtansine loading-dose Q2W regimen (ie, excluding participants treated at 
the starting dose, if this differs from the recommended dose). 
• Intercurrent events: 
- 
The study intervention discontinuation intercurrent event will be handled with the 
treatment policy strategy. PFS will be assessed based on tumor assessments regardless 
of study intervention discontinuation. 
- 
The other anticipated intercurrent events will be handled with the composite strategy. 
For participants who discontinue the study or start an anticancer therapy prior to 
observing a PFS event (death or documented disease progression), PFS will be 
censored at the date of the last evaluable tumor assessment (not showing PD) 
performed prior to observing the intercurrent event. A participant without a PFS event 
and without any evaluable postbaseline tumor assessment will be censored at the date 
of the first administration of IMP (Day 1). 
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• The population-level summary will include: 
- 
Kaplan-Meier estimates of the 25th, 50th, and 75th percentiles and their associated 
95% CIs. The method of Brookmeyer and Crowley and a log-log transformation of the 
survival function will be used to construct 95% CIs. 
- 
Number (%) of participants at risk as well as the probabilities of being event-free at 
least at 2, 4, 6, 8, and 10 months with 95% CIs using the Kaplan-Meier method and a 
log-log approach based on a normal approximation following Greenwood’s formula. 
- 
Kaplan-Meier curves including the number of participants at risk at key time points. 
- 
Number (%) of participants with an event and the type of event (documented disease 
progression or death). 
- 
Number (%) of censored participants and reason for censoring (no baseline tumor 
assessment, no evaluable postbaseline tumor assessment, ongoing without documented 
progression, event occurred after 2 or more non-evaluable tumor assessments or 
initiation of further anticancer therapy). 
9.3.3.3 Disease control rate  
Analysis of the DCR will be based on a treatment policy and composite variable estimand defined 
according to the following attributes: 
• The endpoint is disease control response (confirmed CR or PR, or SD as BOR) as per 
RECIST 1.1. 
• The treatment condition of interest is tusamitamab ravtansine loading dose Q2W in 
combination with ramucirumab. 
• The analysis population is the subgroup of participants from all-treated population 
(defined in Section 9.2 Population for analyses) treated at the recommended dose of 
tusamitamab ravtansine in a loading-dose Q2W regimen (ie, excluding participants treated 
at the starting dose, if this differs from the recommended dose). 
• Intercurrent events: 
- 
The study intervention discontinuation intercurrent event will be handled with the 
treatment policy strategy. Disease control response will be assessed based on tumor 
assessments regardless of study intervention discontinuation. 
- 
The other anticipated intercurrent events will be handled with the composite strategy. 
Participants who discontinue the study, start an anticancer therapy, experience PD, or 
die prior to observing a disease control response will be considered nonresponders. 
• The population-level summary will be the disease control rate (DCR), defined as the rate 
of participants with disease control response and two-sided 95% CIs using the Clopper-
Pearson method. In the absence of a disease control response, participants will be 
considered as nonresponders, whatever the reason (including participants with missing or 
nonevaluable BOR). 
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As a supplementary analysis, DCR as per RECIST 1.1 will also be summarized on the 
subgroup of participants from activity population (defined in Section 9.2 Population for 
analyses) treated at the recommended dose of tusamitamab ravtansine in a loading-dose 
Q2W regimen (ie, excluding participants treated at the starting dose if this differs from the 
recommended dose). The same analytical approach as described above will be used. 
9.3.4 Exploratory endpoints  
Analyses of circulating CEA will be described in the SAP. 
9.3.5 Other safety analyses  
Except if otherwise mentioned, all safety analyses will be conducted in the all-treated population. 
9.3.5.1 Adverse events  
General common rules for adverse events 
The AEs will be analyzed in the following 3 categories: 
• Pretreatment AEs: AEs that developed, worsened or became serious during the 
pretreatment period. 
• TEAEs: AEs that developed, worsened or became serious during the treatment-emergent 
period. 
• Posttreatment AEs: AEs that developed, worsened or became serious during the 
posttreatment period.  
Similarly, the deaths will be analyzed in the pretreatment, treatment-emergent and posttreatment 
periods.  
Summaries will be provided for all grades combined and for Grade ≥3 (including Grade 5). 
Missing grades, if any, will be included in the “all grades” category.  
Analysis of all adverse events 
Adverse event incidence table will be provided for all types of TEAEs: all TEAEs, all treatment-
emergent AESI (defined with a preferred term or a prespecified grouping), all treatment-emergent 
SAEs, all TEAEs related to IMP, all TEAEs leading to permanent full/partial intervention 
discontinuation and all TEAEs leading to dose modification or dose interruption. 
The AE summaries will be generated with number (%) of participants experiencing at least one 
event.  
Deaths will also be analyzed. 
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9.3.5.2 Laboratory variables, vital signs and electrocardiograms (ECGs)  
Quantitative analyses 
For vital signs and ECG variables, descriptive statistics for results and changes from baseline will 
be provided for each planned visit, and the worst value (minimum and/or maximum value 
depending on the parameter) during the on-treatment period. These analyses will be performed 
using local measurements. 
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, 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 v5.0. 
• 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 ECG, the incidence of participants with at least one abnormal ECG during the treatment-
emergent period will be summarized regardless of the baseline level and according to the 
following baseline status categories:  
• Normal/missing 
• Abnormal 
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9.3.6 Other analyses  
Pharmacokinetic 
The population PK analyses will be described in a specific document and the results will be 
presented separately from the clinical study report. 
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. 
Other 
For a regional or national emergency declared by a governmental agency (eg, COVID-19), 
contingency measures are included in Section 10.9.  
9.4 
INTERIM ANALYSES  
No interim analysis is planned. 
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10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS  
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS  
10.1.1 Regulatory and ethical considerations  
• This study will be conducted in accordance with the protocol and with the following: 
- 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and the applicable amendments and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical Guidelines 
- 
Applicable ICH Good Clinical Practice (GCP) Guidelines 
- 
Applicable laws and regulations (eg, data protection law as General Data Protection 
Regulation - GDPR) 
• The protocol, protocol amendments, ICF, Investigator Brochure, [IDFU] and other 
relevant documents (eg, advertisements) must be submitted to an IRB/IEC by the 
Investigator and reviewed and approved by the IRB/IEC before the study is initiated. 
• Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 
• Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate hazard 
to study participants. 
• The Investigator will be responsible for the following: 
- 
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC.  
- 
Determining whether an incidental finding (as per Sanofi policy) should be returned to 
a participant and, if it meets the appropriate criteria, to ensure the finding is returned 
(an incidental finding is a previously undiagnosed medical condition that is discovered 
unintentionally and is unrelated to the aims of the study for which the tests are being 
performed). The following should be considered when determining the return of an 
incidental finding. 
• The return of such information to the study participant (and/or his/her designated 
healthcare professional, if so designated by the participant) is consistent with all applicable 
national, state, or regional laws and regulations in the country where the study is being 
conducted, and 
• The finding reveals a substantial risk of a serious health condition or has reproductive 
importance, AND has analytical validity, AND has clinical validity.  
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• The participant in a clinical study has the right to opt out of being notified by the 
Investigator of such incidental findings. In the event that the participant has opted out of 
being notified and the finding has consequences for other individuals, eg, the finding 
relates to a communicable disease, Investigators should seek independent ethical advice 
before determining next steps. 
• In case the participant has decided to opt out, the Investigator must record in the site 
medical files that she/he does not want to know about such findings. 
- 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures. 
- 
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies (if applicable), European Medical Device Regulation 
2017/745 for clinical device research (if applicable), and all other applicable local 
regulations. 
As applicable, according to Directive 2001/20/EC, the Sponsor will be responsible for obtaining 
approval from the Competent Authorities of the EU Member States and/or Ethics Committees, as 
appropriate, for any amendments to the clinical trial that are deemed as “substantial” (ie, changes 
which are likely to have a significant impact on the safety or physical or mental integrity of the 
clinical trial participants or on the scientific value of the trial) prior to their implementation. 
10.1.2 Financial disclosure  
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate, financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
10.1.3 Informed consent process  
• The Investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding 
the study.  
• Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representative will be required to sign a statement of informed consent 
that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Health 
Insurance Portability and Accountability Act (HIPAA) requirements, where applicable, 
and the IRB/IEC or study center.  
• The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF. 
• In case of ICF amendment while the participants are still included in the study, they must 
be re-consented to the most current version of the ICF(s) during their participation in the 
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study. Where participants are not in the study anymore, teams in charge of the amendment 
must define if those participants must or not re-consent or be informed of the amendment 
(eg, if the processing of personal data is modified, if the Sponsor changes, etc). 
• A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative.  
• A participant who requires prolongation of the screening period (temporary screen failure) 
is not required to sign another ICF. However, if the reason for the temporary screen failure 
is a reason that might have altered the participant’s initial given agreement to participate, 
the Investigator should ask the participant to confirm willingness to continue or repeat 
some screening procedures and to participate in the trial. This oral agreement should be 
documented in the participant’s chart. Participants who screen failed and then rescreen 
need to re-sign a new screening ICF. 
• A participant who has CEACAM5 results available from a prior study must sign an 
addendum to the informed consent; no additional prescreening informed consent will be 
required. 
The ICF contains 2 separate sections that addresses the use for research of participants’ data 
and/or samples (remaining mandatory ones or new extra samples collected for optional research). 
Optional exploratory research must be detailed in the section “Optional tests/procedures” and 
future research is to be defined in Core Study Informed Consent Form (CSICF) Part 2. Each 
option is subject to an independent consent and must be confirmed by ticking a checkbox in 
CSICF Part 3. The Investigator or authorized designee will explain to each participant the 
objectives of the exploratory research and why data and samples are important for future research. 
Participants will be told that they are free to refuse to participate and may withdraw their consent 
at any time and for any reason during the storage period. 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Appendix 9 (Section 10.9). 
10.1.4 Data protection  
All personal data collected and/or processed in relation to this study will be handled in 
compliance with all applicable Privacy & Data Protection 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 Investigators, nurses, experts, service 
providers, Ethics Committee members, etc.  
When archiving or processing personal data pertaining to the Investigator and/or to the 
participants, the Sponsor takes all appropriate measures to safeguard and prevent access to this 
data by any unauthorized third party. 
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Protection of participant data 
Data collected must be adequate, relevant and not excessive, in relation to the purposes for which 
they are collected. Each category of data must be properly justified and in line with the study 
objective. 
Participant race and ethnicity will be collected in this study because they are expected to modify 
the drug response/because they are required by regulatory agencies (eg, on African American 
population for the FDA or on Japanese population for the Pharmaceuticals and Medical Devices 
Agency in Japan). They will not be collected in the countries where this is prohibited by local 
regulation. 
• Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor or its service providers will be identifiable only 
by the unique identifier; participant names or any information which would make the 
participant identifiable will not be transferred to the Sponsor.  
• The participant must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with applicable data protection laws. The level of disclosure 
must also be explained to the participant as described in the informed consent.  
• The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
• Participants must be informed that their study-related data will be used for the whole “drug 
development program”, ie, for this trial as well as for the following steps necessary for the 
development of the investigational product, including to support negotiations with payers 
and publication of results. 
Protection of data related to professionals involved in the study  
• Personal data (eg, contact details, affiliation(s) details, job title and related professional 
information, role in the study, professional resume, training records) are necessary to 
allow Sanofi to manage involvement in the study and/or the related contractual or pre-
contractual relationship. They may be communicated to any company of the Sanofi group 
(“Sanofi”) or to Sanofi service providers, where needed. 
• Personal data can be processed for other studies and projects. At any time, objection to 
processing can be made by contacting the Sanofi Data Protection Officer (link available at 
Sanofi.com).  
• In case of refusal to the processing of personal data by or on behalf of Sanofi, it will be 
impossible to involve the professionals in any Sanofi study. In case the professionals have 
already been involved in a Sanofi study, they will not be able to object to the processing of 
their personal data as long as they are required to be processed by applicable regulations. 
The same rule applies in case the professionals are listed on a regulatory agencies 
disqualification list. 
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• 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 
email, visit https://www.sanofi.com/en/our-responsibility/sanofi-global-privacy-
policy/contact). 
10.1.5 Committees structure  
10.1.5.1 
Study committee  
The SC includes the Investigators or designees and Sponsor team members and, when 
appropriate, ad hoc experts. Decisions to continue the enrollment at a DL or to reduce the dose to 
be tested will be made after the appropriate data are collected and reviewed by the SC. The SC 
will convene regularly (eg, every 2 weeks) during Part 1 of the study (run-in); and may meet 
ad hoc for specific discussions. Meeting minutes will be documented. 
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10.1.6 Dissemination of clinical study data  
Study participants 
Sanofi shares information about clinical trials and results on publicly accessible websites, based 
on company commitments, international and local legal and regulatory requirements, and other 
clinical trial disclosure commitments established by pharmaceutical industry associations. These 
websites include clinicaltrials.gov, EU clinicaltrialregister (eu.ctr), and sanofi.com, as well as 
some national registries. 
In addition, results from clinical trials in patients are required to be submitted to peer-reviewed 
journals following internal company review for accuracy, fair balance and intellectual property. 
For those journals that request sharing of the analyzable data sets that are reported in the 
publication, interested researchers are directed to submit their request to 
clinicalstudydatarequest.com. 
Individual participant data and supporting clinical documents are available for request at 
clinicalstudydatarequest.com. While making information available we continue to protect the 
privacy of participants in our clinical trials. Details on data sharing criteria and process for 
requesting access can be found at this web address: clinicalstudydatarequest.com. 
Professionals involved in the study or in the drug development program 
Sanofi may publicly disclose, and communicate to relevant authorities/institutions, the funding, 
including payments and transfers of value, direct or indirect, made to healthcare organizations and 
professionals and/or any direct or indirect advantages and/or any related information or document 
if required by applicable law, by regulation or by a code of conduct such as the “EFPIA Code on 
Disclosure of Transfers of Value from Pharmaceutical Companies to Healthcare Professionals and 
Healthcare Organisations”. 
10.1.7 Data quality assurance  
• All participant data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the Sponsor or designee electronically (eg, laboratory data). The 
Investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 
• Guidance on completion of CRFs will be provided in the CRF completion instructions. 
• The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• Quality tolerance limits (QTLs) will be predefined in the list of predefined potential 
deviations to identify systematic issues that can impact participant safety and/or reliability 
of study results. These predefined parameters will be monitored during the study and 
important deviations from the QTLs and remedial actions taken will be summarized in the 
clinical study report. 
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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). 
• Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator for 25 years after the signature of the final study 
report unless local regulations or institutional policies require a longer retention period. No 
records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor. 
10.1.8 Source documents  
• Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the Investigator’s site. 
• Data 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. 
• Definition of what constitutes source data can be found in the eCRF completion 
instructions. 
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
• Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements. 
10.1.9 Study and site start and closure  
First act of recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The first act of recruitment is the first site open and will be the study start date. 
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Study/Site termination 
The Sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for study termination by the Sponsor, as well as reasons for the early closure of a study 
site by the Sponsor or Investigator may include but are not limited to: 
• For study termination: 
- 
Information on the product leads to doubt as to the benefit/risk ratio 
- 
Discontinuation of further study intervention development 
• For site termination: 
- 
Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor’s procedures, or GCP guidelines 
- 
Inadequate or no recruitment (evaluated after a reasonable amount of time) of 
participants by the Investigator 
- 
Total number of participants included earlier than expected 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The Investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up. 
10.1.10 
Publication policy  
• The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor 
before submission. This allows the Sponsor to protect proprietary information and to 
provide comments. 
• The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data. In 
this case, a coordinating Investigator will be designated by mutual agreement. 
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
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10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS  
• The tests detailed in Table 10 will be performed by the local laboratory. 
• Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol. 
• Additional tests may be performed at any time during the study as determined necessary by 
the Investigator or required by local regulations. 
• Pregnancy testing will be performed in all WOCBP at baseline, at End of treatment visit, 
and the 3 month follow-up, as detailed in the SOA (Section 1.3). Women of childbearing 
potential must have a negative serum pregnancy test result within 7 days prior to the initial 
intervention; at the End of treatment evaluation (30 ±5 days after the last IMP 
administration); and at the Follow-up (90 ±7 days after the last IMP administration). 
Additionally, during the treatment period, serum/urine pregnancy tests will be performed 
at the beginning of the visit every 4 weeks (ie, every 2 cycles/every other cycle). 
• Investigators must document their review of each laboratory safety report. 
Table 10 - Protocol-required safety laboratory assessments  
Laboratory assessments 
Parameters 
Hematology 
Platelet count 
 
Red blood cell (RBC) count 
 
Hemoglobin 
 
Hematocrit 
 
White blood cell (WBC) count with differential: 
 
Neutrophils 
 
Lymphocytes 
 
Monocytes 
 
Eosinophils 
 
Basophils 
Clinical blood chemistrya 
Urea/blood urea nitrogen (BUN) 
 
Creatinine 
 
Glucose 
 
Potassium 
 
Sodium 
 
Calcium 
 
Aspartate aminotransferase (AST)/Serum glutamic-oxaloacetic transaminase (SGOT) 
 
Alanine aminotransferase (ALT)/Serum glutamic-pyruvic transaminase (SGPT) 
 
Alkaline phosphatase 
 
Total and conjugated bilirubin 
 
Total protein 
 
Albumin 
 
LDH 
Coagulation 
Coagulation parameters (INR, aPTT)  
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Laboratory assessments 
Parameters 
Urinalysis 
Urine dipstick or routine urinalysis 
If urine dipstick or routine urinalysis inticates proteinuria ≥2+, a 24 hour urine collection for 
protein measurement must be obtained. 
Serum/urine pregnancyb 
 
Serologyc 
human immunodeficiency virus (HIV) 
 
hepatitis B virus surface antigen (HBsAg) 
 
hepatitis C virus (HCV) 
Abbreviations: aPTT = activated partial thromboplastin time; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
BUN = blood urea nitrogen; HBsAg = hepatitis B virus surface antigen; HCV = hepatitis C virus; HIV = human immunodeficiency virus; 
INR = International Normalized Ratio; LDH = tactate dehydrogenase; RBC = red blood cell count; SGOT = serum glutamic-oxaloacetic 
transaminase (AST); SGPT = serum glutamic-pyruvic transaminase (ALT); WBC = white blood cell count. 
NOTES: 
a Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or monitoring event are 
given in Appendix 6 (Section 10.6) All events of Grade 4 AST/ALT increase must be reported as an SAE. Investigators must document 
their review of each laboratory safety report. 
b Only for WOCBP. 
c Serological testing for specific viral infections may not be required at all sites. Local authorities may require testing for human 
immunodeficiency virus (HIV), hepatitis B viral antigen (HBsAg), and/or hepatitis C virus (HCV); please refer to Appendix 8 (Section 10.8) 
for details of any locally required testing for these or other viruses. 
10.3 
APPENDIX 3: AES AND SAES: DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING  
10.3.1 Definition of AE  
AE definition 
• An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered related 
to the study intervention. 
• NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention. 
Definition of unsolicited and solicited AE 
• An unsolicited adverse event is an adverse event that was not solicited using a participant 
diary and that is communicated by a participant who has signed the informed consent. 
Unsolicited AEs include serious and non-serious AEs. 
• Potential unsolicited AEs may be medically attended (ie, symptoms or illnesses requiring a 
hospitalisation, or emergency room visit, or visit to/by a health care provider). The 
participant will be instructed to contact the site as soon as possible to report medically 
attended event(s), as well as any events that, though not medically attended, are of 
participant concern. Detailed information about reported unsolicited AEs will be collected 
by qualified site personnel and documented in the participant’s records. 
• Unsolicited AEs that are not medically attended nor perceived as a concern by participant 
will be collected during interview with participant and by review of available medical 
records at the next visit. 
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• Solicited AEs are pre-defined local and systemic events for which the participant is 
specifically questioned, and which are noted by the participants in their diary. 
Events meeting the AE definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the Investigator (ie, not related to progression of underlying 
disease), eg: 
- 
Leading to IMP discontinuation or modification of dosing, and/or  
- 
Fulfilling a seriousness criterion, and/or  
- 
Defined as an AESI 
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study intervention administration even though 
it may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. 
• "Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy assessments. 
However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy 
will be reported as AE or SAE if they fulfill the definition of an AE or SAE. 
• The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfill the definition of an AE or SAE. Also, "lack of 
efficacy" or "failure of expected pharmacological action" also constitutes an AE or SAE. 
Events NOT meeting the AE definition 
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the participant’s condition. 
• The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
• Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
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10.3.2 Definition of SAE  
An SAE is defined as any adverse event 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 admitted (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the 
AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE. 
d) Results in persistent or significant disability/incapacity 
- 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
- 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
e) Is a congenital anomaly/birth defect 
f) Is a suspected transmission of any infectious agent via an authorized medicinal 
product 
g) Other situations: 
- 
Medical or scientific judgment should be exercised by the Investigator in deciding 
whether SAE reporting is appropriate in other situations such as significant 
medical events that may jeopardize the participant or may require medical or 
surgical intervention to prevent one of the other outcomes listed in the above 
definition. These events should usually be considered serious. 
- 
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.  
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10.3.3 Recording and follow-up of AE and/or SAE  
AE and SAE recording 
• When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
• The Investigator will then record all relevant AE/SAE information. 
• It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to the Sponsor’s representative in lieu of completion of the required form. 
• There may be instances when copies of medical records for certain cases are requested by 
the Sponsor’s representative. In this case, all participant identifiers, with the exception of 
the participant number, will be redacted on the copies of the medical records before 
submission to the Sponsor’s representative. 
• The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported during the 
study and assign it to 1 of the following categories: 
• Mild: An event that is easily tolerated by the participant, causing minimal discomfort and 
not interfering with everyday activities. 
• Moderate: An event that causes sufficient discomfort to interfere with normal everyday 
activities. 
• Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. “Severe” is a category used for rating the 
intensity of an event; and both AEs and SAEs can be assessed as severe. 
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as described 
in the definition of an SAE, NOT when it is rated as severe. 
Assessment of causality 
• The Investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. 
• A "reasonable possibility" of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than that a relationship cannot be ruled 
out. 
• The Investigator will use clinical judgment to determine the relationship. 
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• Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
• The Investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment. 
• For each AE/SAE, the Investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• There may be situations in which an SAE has occurred and the Investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the Investigator always make an assessment of causality for every event before 
the initial transmission of the SAE data to the monotoring team. 
• The Investigator may change his/her opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment. 
• The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
Follow-up of AEs and SAEs 
• The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the Sponsor’s 
representative to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
• If a participant dies during participation in the study or during a recognized follow-up 
period, the Investigator will provide the Sponsor with a copy of any post-mortem findings 
including histopathology. 
• New or updated information will be recorded in the originally submitted documents. 
• The Investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information. 
10.3.4 Reporting of SAEs  
SAE reporting to the Sponsor via an electronic data collection tool 
• The primary mechanism for reporting an SAE to the Sponsor’s representative will be the 
electronic data collection tool. 
• If the electronic system is unavailable, then the site will use the paper SAE data collection 
tool (see next section) to report the event within 24 hours. 
• The site will enter the SAE data into the electronic system as soon as it becomes available. 
• After the study is completed at a given site, the electronic data collection tool will be taken 
off-line to prevent the entry of new data or changes to existing data. 
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• If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken off-
line, then the site can report this information on a paper SAE form (see next section) or to 
the Sponsor’s representative by telephone. 
• Contacts for SAE reporting can be found in the Investigator study file. 
SAE reporting to the Sponsor via paper data collection tool 
• Facsimile transmission of the SAE paper data collection tool is the preferred method to 
transmit this information to the Sponsor’s representative. 
• In rare circumstances and in the absence of facsimile equipment, notification by telephone 
is acceptable with a copy of the SAE data collection tool sent by overnight mail or courier 
service. 
• Initial notification via telephone does not replace the need for the Investigator to complete 
and sign the SAE CRF pages within the designated reporting time frames. 
• Contacts for SAE reporting can be found in the Investigator study file. 
10.4 
APPENDIX 4: CONTRACEPTIVE AND BARRIER GUIDANCE  
10.4.1 Definitions  
A woman is considered WOCBP (fertile) from the time of menarche until becoming 
postmenopausal (see below) unless permanently sterile (see below). 
• A postmenopausal state is defined as the period of time after a woman has experienced no 
menses for 12 consecutive months without an alternative medical cause. 
• A high follicle-stimulating hormone (FSH) level in the postmenopausal range may be used 
to confirm a postmenopausal state in women not using hormonal contraception or HRT.  
• Females on HRT and whose menopausal status is in doubt will be required to use one of 
the non-estrogen hormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation 
of postmenopausal status before study enrollment. 
Permanent sterilization methods include: 
• Documented hysterectomy 
• Documented bilateral salpingectomy 
• Documented bilateral oophorectomy 
• For individuals with permanent infertility due to an alternate medical cause other than the 
above, (eg, Mullerian agenesis, androgen insensitivity, gonadal dysgenesis), Investigator 
discretion should be applied to determining study entry eligibility. 
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Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first administration of study intervention, additional evaluation should be 
considered. 
10.4.2 Contraception guidance  
 
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
Highly Effective Methodsb That Have Low User Dependency Failure rate of <1% per year when used 
consistently and correctly. 
• 
Implantable progestogen-only hormone contraception associated with inhibition of ovulationc 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS)c 
• 
Bilateral tubal occlusion 
• 
Azoospermic partner (vasectomized or due to a medical cause) 
Azoospermia is a highly effective contraceptive method provided that the partner is the sole sexual partner of the 
woman of childbearing potential and the absence of sperm has been confirmed. If not, an additional highly effective 
method of contraception should be used. 
Note: documentation of azoospermia for a male participant can come from the site personnel’s review of the 
participant’s medical records, medical examination, or medical history interview. 
Highly Effective Methodsb That Are User Dependent Failure rate of <1% per year when used 
consistently and correctly. 
• 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulationc 
- 
oral 
- 
intravaginal 
- 
transdermal 
- 
injectable 
• 
Progestogen-only hormone contraception associated with inhibition of ovulationc 
- 
oral 
- 
injectable 
• 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse 
during the entire period of risk associated with the study intervention. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the study and the preferred and usual lifestyle of the participant. 
a Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive methods for those 
participating in clinical studies.  
b Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those when used consistently and 
correctly. 
c If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable contraceptive methods are limited to 
those which inhibit ovulation as the primary mode of action. 
Note: Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational 
amenorrhoea method (LAM) are not acceptable methods of contraception for this study. Male condom and female condom should not be used 
together (due to risk of failure with friction) 
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10.4.3 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. 
10.5 
APPENDIX 5: GENETICS  
Use/Analysis of DNA 
• Genetic variation may impact a participant’s response to study intervention, susceptibility 
to, and severity and progression of disease. Variable response to study intervention may be 
due to genetic determinants that impact drug absorption, distribution, metabolism, and 
excretion; mechanism of action of the drug; disease etiology; and/or molecular subtype of 
the disease being treated. Therefore, where local regulations and IRB/IEC allow, a blood 
sample will be collected for DNA/RNA analysis from consenting participants. 
• DNA samples will be used for research related to tusamitamab ravtansine or advanced 
solid tumors and related diseases. They may also be used to develop tests/assays including 
diagnostic tests related to CEACAM5-targeting drugs and advanced solid tumors. Genetic 
research may consist of the analysis of one or more candidate genes or the analysis of 
genetic markers throughout the genome or analysis of the entire genome (as appropriate). 
• DNA samples will be analyzed for determination of tumor mutation profiles of plasma 
cfDNA and tumor DNA. Subtractive mutation analysis will be performed with germline 
DNA data to identify tumor-specific somatic genetic aberrations. Additional analyses such 
as RNA analysis may be conducted if it is hypothesized that these may help further 
explain the clinical data. 
• The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to tusamitamab ravtansine or study interventions of this class to 
understand study disease or related conditions. 
• The results of genetic analyses may be reported in the clinical study report (CSR) or in a 
separate study summary. 
• The Sponsor will store the DNA samples in a secure storage space with adequate measures 
to protect confidentiality. 
• The samples may be retained while research on tusamitamab ravtansine or advanced solid 
tumors and related diseases continues, but no longer than 15 years or other period, as per 
local requirements. 
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10.6 
APPENDIX 6: RECOMMENDED SUPPORTIVE CARE AND/OR DOSE MODIFICATION GUIDELINES FOR DRUG-RELATED ADVERSE 
EVENTS  
Event 
Symptoms severity (Nadir)  
(NCI CTCAE v5) 
Management of IMP 
dosing (ramucirumab) 
Management of IMP dosing 
(tusamitamab ravtansine) 
Supportive care guidelines 
Infusion-related reactions  
Grade 1-2 
Mild-moderate 
Eg, Grade ≤2 nausea, headache, 
tachycardia, hypotension, rash, shortness of 
breath. 
Interrupt ramucirumab infusion and 
start appropriate treatment.  
 
Reduce infusion rate by 50% 
Interrupt tusamitamab ravtansine infusion. 
Tusamitamab ravtansine may be resumed only 
after patient recovery, at half the previous infusion 
ratea. 
Give diphenhydramine 50 mg IV and/or 
dexamethasone 10 mg IV. ramucirumab label 
should be followed 
Dexamethasone can be added as premedication 
for upcoming cycles for tusamitamab ravtansine 
 
Grade 3-4 
Severe 
Eg, symptomatic bronchospasm, urticaria 
lesions covering >30% BSA, hypotension, 
angioedema. 
Interrupt ramucirumab infusion and 
definitively discontinue 
ramucirumab 
Interrupt tusamitamab ravtansine infusion and 
definitively discontinue tusamitamab ravtansine 
and consider infusion delay. 
Give diphenhydramine 50 mg IV and/or 
dexamethasone 10 mg IV and/or epinephrine and 
any required treatment per investigator 
judgement. 
Ocular toxicity:  
Keratopathy/keratitisb 
associated with 
tusamitamab ravtansine 
Grade 1 - Asymptomatic 
Corneal lesions only observed on routine 
ocular examination and not requiring topical 
treatment. 
Administer ramucirumab at same 
dose, and same day as 
tusamitamab ravtansine 
Next infusion of tusamitamab ravtansine at the 
same dose, with or without cycle delay, depending 
on the recommendation from the ophthalmologist 
(nature and extent of the lesion). 
Standard ocular examination is planned as 
recommended by the ophthalmologist. 
 
Grade 2 
Symptomatic or requiring topical treatment 
(curative) or limiting instrumental activity of 
daily life. 
Moderate decrease in visual acuity (best 
corrected visual acuity 20/40 and better or 
3 lines or less decreased vision from known 
baseline) 
Administer ramucirumab at same 
dose, and same day as 
tusamitamab ravtansine or 
administer ramucirumab as 
planned if definitive discontinuation 
of tusamitamab ravtansine 
1st episode: Omit tusamitamab ravtansine until 
resolution to Grade 1 (asymptomatic) and restart 
tusamitamab ravtansine at the same dose. 
2nd episode: Omit tusamitamab ravtansine until 
resolution to Grade 1 (asymptomatic) and 
tusamitamab ravtansine dose reduction. 
3rd episode: depending on benefit risk, definitive 
discontinuation of tusamitamab ravtansine may be 
envisaged 
 
Standard ocular examination weekly until 
resolutionc, d. 
Start curative treatment per ophthalmologist 
recommendation.  
After resuming study treatment, participant 
should be followed with standard ocular 
examination every 2 cycles, even if asymptomatic 
during next 4 cycles. If no recurrence is 
observed, the standard process with follow-up of 
the ocular symptom should be resumed.  
Management of study drug upon recurrence to be 
discussed according to Grade of the event at 
recurrence, clinical benefit from study drug and 
recommendation from the ophthalmologist. 
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Event 
Symptoms severity (Nadir)  
(NCI CTCAE v5) 
Management of IMP 
dosing (ramucirumab) 
Management of IMP dosing 
(tusamitamab ravtansine) 
Supportive care guidelines 
Ocular toxicity (continued) 
Grade 3 
Symptomatic with marked decrease in visual 
acuity (best corrected visual acuity worse 
than 20/40 or more than 3 lines of 
decreased vision from known baseline, up to 
20/200); corneal ulcer; limiting selfcare 
activity of daily life 
Administer ramucirumab at same 
dose, and same day as 
tusamitamab ravtansine or 
administer ramucirumab as 
planned if definitive discontinuation 
of tusamitamab ravtansine 
1st episode: Omit tusamitamab ravtansine until 
resolution (asymptomatic), and restart 
tusamitamab ravtansine with dose reduction. 
2nd episode: definitive discontinuation of 
tusamitamab ravtansine.  
 
Standard ocular examination weekly until 
resolutionc, d 
Start curative treatment per ophthalmologist 
recommendation.  
After resuming study treatment, participant 
should be followed with standard ocular 
examination by every 2 cycles, e en 
asymptomatic during next four cycles. If no 
recurrence, standard process with follow-up with 
ocular symptom is resumed  
Management of study drug upon recurrence to be 
discussed according to Grade of the event at 
recurrence, clinical benefit from study drug and 
recommendation from the ophthalmologist 
 
Grade 4 
Perforation or best corrected visual acuity of 
20/200 or worse in the affected eye. 
Administer ramucirumab as 
planned.  
Definitive discontinuation of tusamitamab 
ravtansine. 
 
Complete the corneal examination as 
recommended by ophthalmologist. Repeat the 
standard ocular examination weeklyc until 
resolutiond. 
Start curative treatment per ophthalmologist 
recommendation.  
Conduction disorder 
associated with 
tusamitamab ravtansine 
Grade 1 
Mild symptoms 
Administer ramucirumab as 
planned.  
tusamitamab ravtansine administration to be 
continued upon decision by the Investigator and 
Sponsor, depending on the nature of the 
conduction disorder. 
ECG performed once weekly until event 
resolution. 
Additional evaluations such as LVEF and Holter 
monitoring should be performed when relevant. 
 
Grade ≥2 
Administer ramucirumab as 
planned.  
Definitive discontinuation of tusamitamab 
ravtansine. 
 
ECG to be repeated twice weekly until event 
resolution. 
Prompt cardiology consultation 
Additional evaluations such LVEF and Holter 
monitoring should be performed when relevant. 
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Event 
Symptoms severity (Nadir)  
(NCI CTCAE v5) 
Management of IMP 
dosing (ramucirumab) 
Management of IMP dosing 
(tusamitamab ravtansine) 
Supportive care guidelines 
Peripheral neuropathy 
Grade 1:  
Asymptomatic 
Administer ramucirumab as 
planned. 
Administer tusamitamab ravtansine as planned, 
Patient who has ongoing Grade 1 neuropathy 
has high risk of worsening of his/her symptoms 
and should be closely followed.  
 
Grade 2:  
Moderate symptoms; limiting instrumental 
Activities of Daily Living 
Delay cycle until recovery to 
≤ Grade 1; at next cycle, 
administer ramucirumab the same 
day as tusamitamab ravtansine 
Delay cycle until recovery to ≤ Grade 1 and dose 
reduction if no improvement with dose delay 
Grade 3:  
Severe symptoms; limiting self care 
Activities of Daily Living 
Administer ramucirumab as 
planned. 
Definitive discontinuation of tusamitamab 
ravtansine 
Grade 4: 
Life-threatening consequences; urgent 
intervention indicated 
Administer ramucirumab as 
planned. 
Definitive discontinuation of tusamitamab 
ravtansine 
Neutrophil count decreased Grade 1 
<LLN - 1500/mm3 ; <LLN - 1.5 × 109/L 
No change in IMPs administration. No change in IMPs administration  
No intervention. 
 
Grade 2 
<1500 - 1000/mm3; <1.5 - 1.0 × 109/L 
Delay the cycle until recovery of 
absolute neutrophil count 
>1500/mm3. 
Restart at the same dose. 
Delay the cycle until recovery of absolute 
neutrophil count >1500/mm3. 
Restart at the same dose. 
No intervention. 
 
Grade 3 
<1000 - 500/mm3; <1.0 - 0.5 × 109/L 
Or 
Grade 4 
<500/mm3; <0.5 × 109/L 
Delay the cycle until recovery of 
absolute neutrophil count 
>1500/mm3. 
Restart when absolute neutrophil 
count >1500/mm3 at the same 
dose. Prophylactic G-CSF can be 
considered in all subsequent 
cycles 
Delay the cycle. 
Restart the treatment when absolute neutrophil 
count >1500/mm3 at the same dose; prophylactic 
G-CSF can be considered in all subsequent cycles  
Follow ASCO guidelines on usage of G-CSF and 
antibiotherapy (13). Repeat test every 3 days.  
 
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Event 
Symptoms severity (Nadir)  
(NCI CTCAE v5) 
Management of IMP 
dosing (ramucirumab) 
Management of IMP dosing 
(tusamitamab ravtansine) 
Supportive care guidelines 
Neutrophil count decreased 
(continued) 
Grade 4 >7 days 
<500/mm3; <0.5 × 109/L 
Delay the cycle until absolute 
neutrophil count >1500/mm3. 
1st episode administer next cycle 
with ramucirumab at the same 
dose and administer growth factors 
2nd episode: administer 
ramucirumab at the same dose 
3rd episode: definitive 
discontinuation of IMPs 
Delay the cycle until absolute neutrophil count 
>1500/mm3. 
1st episode administer tusamitamab ravtansine 
next cycle at the same dose and administer 
growth factors 
2nd episode: administer tusamitamab ravtansine at 
reduced dose 
3rd episode: definitive discontinuation 
Follow ASCO guidelines on G-CSF usage and 
antibiotherapy (13). Repeat 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 
ramucirumab at reduce dose 
3rd episode: definitive 
discontinuation  
Delay cycle until absolute neutrophil count 
>1500/mm3. 
1st episode administer next cycle at the same dose 
and administer G-CSF 
2nd episode: administer tusamitamab ravtansine at 
reduce dose 
3rd episode: definitive discontinuation  
To ensure relative dose intensity, G-CSF is 
recommended as secondary prophylaxis in all 
patients with Grade 3 febrile neutropenia  
ASCO guideline is recommended for supportive 
treatment if there are no defined clinical 
standards (13). 
 
Grade 4 
Life-threatening consequences 
Administration changes to be 
decided at the Investigator’s 
discretion per product label 
Administration changes to be decided at the 
Investigator’s discretion. 
1st episode: administer next cycle at reduced dose 
and administer G-CSF 
2nd episode: definitive discontinuation 
 
Hypertension 
Grade 3 
Severe hypertension 
Withhold ramucirumab until 
controlled with medical 
management, and restart at same 
dose 
Administer tusamitamab ravtansine the same day 
as ramucirumab 
 
Grade 4 
Severe hypertension that cannot be 
controlled with antihypertensive therapy 
Definitively discontinue 
ramucirumab 
Administer tusamitamab ravtansine as planned 
 
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Event 
Symptoms severity (Nadir)  
(NCI CTCAE v5) 
Management of IMP 
dosing (ramucirumab) 
Management of IMP dosing 
(tusamitamab ravtansine) 
Supportive care guidelines 
Proteinuria 
First occurrence of increased urine protein 
levels greater than or equal to 2 g per 
24 hours 
Omit ramucirumab until urine 
protein level is <2 g per 24 hours; 
then resume ramucirumab at a 
reduced dose of 6 mg/kg 
Administer tusamitamab ravtansine as planned 
 
Reoccurrence of urine protein level greater 
than 2 g per 24 hours following initial dose 
reduction 
Omit ramucirumab until protein 
level is <2 g per 24 hours; then 
resume ramucirumab at a reduced 
dose of 5 mg/kg) 
Administer tusamitamab ravtansine as planned 
 
Urine protein level greater than 3 g per 
24 hours or in the setting of nephrotic 
syndrome 
Definitvely discontinue 
ramucirumab 
Consider benefit/risk for the patient to continue or 
delay tusamitamab ravtansine infusion 
 
Hemorrhage 
Grade 3 or 4 
Definitively discontinue 
ramucirumab 
Definitive discontinuation of tusamitamab 
ravtansine 
 
Gastrointestinal Perforation 
All Grades 
Definitively discontinue 
ramucirumab 
Consider benefit/risk for the patient to continue or 
delay tusamitamab ravtansine infusion 
 
Arterial Thromboembolic 
Events 
All Grades 
Definitively discontinue 
ramucirumab 
Administer tusamitamab ravtansine as planned 
 
Wound Healing 
Complications 
All Grades 
Definitively discontinue 
ramucirumab for wound healing 
complications requiring medical 
intervention 
Consider benefit/risk for the patient to continue or 
delay tusamitamab ravtansine infusion 
 
a Tusamitamab ravtansine is stable at least 7.5 hours in the infusion bag at room temperature. If necessary, a new infusion should be prepared with the remaining dose to be administered. 
b The NCI CTCAE V5.0 grading is to be applied to keratopathy. 
c Standard ocular examination per protocol includes visual acuity, slit lamp examination, Schirmer’s test, and enquiring for ocular/visual symptoms. 
d When possible at the site, photographs should be done when findings are first documented and to follow progression when relevant. Any additional relevant ocular examination can be done if indicated. 
Abbreviations: ASCO = American Society of Clinical Oncology, ASOCT = Anterior segment optical coherence, BSA = Body surface area, ECG = Electrocardiogram, G-CSF = Granulocyte colony-stimulating factor, 
Hb = Hemoglobin, IMP = Investigational medicinal product, IV = Intravenous; LLN = Lower limit of normal, LVEF = Left ventricular ejection fraction, NCI CTCAE = National Cancer Institute Common Terminology 
Criteria for Adverse Events, RBC = Red blood cell. 
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10.7 
APPENDIX 7: AES, ADES, SAES, SADES, USADES AND DEVICE DEFICIENCIES: 
DEFINITIONS AND PROCEDURES FOR RECORDING, EVALUATING, FOLLOW-UP, 
AND REPORTING IN MEDICAL DEVICE STUDIES  
Not applicable. 
10.8 
APPENDIX 8: COUNTRY-SPECIFIC REQUIREMENTS  
Serology for HBsAg, HCV, or HIV will be performed at screening only if required at the country 
level. 
10.9 
APPENDIX 9: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY  
Continuation of the study in the event of a regional or national emergency declared by a 
governmental agency: 
A regional or national emergency declared by a governmental agency (eg, public health 
emergency, natural disaster, pandemic, and terrorist attack) may prevent access to the clinical trial 
site. 
Contingency procedures are suggested below for an emergency that prevents access to the study 
site, to ensure the safety of the participants, to consider continuity of the clinical study conduct, 
protect trial integrity, and assist in maintaining compliance with GCP in Conduct of Clinical 
Trials Guidance. Sponsor agreement MUST be obtained prior to the implementation of these 
procedures for the duration of the emergency. 
During the emergency, if the site will be unable to adequately follow protocol mandated 
procedures, alternative treatment outside the clinical trial should be proposed, and 
prescreening/screening/enrollment/administration of study intervention may be temporarily 
delayed/halted. 
Attempts should be made to perform all assessments in accordance with the approved protocol to 
the extent possible. In case this is not possible due to a temporary disruption caused by an 
emergency, focus should be given to assessments necessary to ensure the safety of participants 
and those important to preserving the main scientific value of the study.  
Contingencies implemented due to emergency will be documented. 
10.9.1 Remote prescreening process  
If there is no other way to conduct prescreening procedures during a regional or national 
emergency declared by a governmental agency (eg, due to a COVID-19 pandemic), the site may 
consider implementing a remote prescreening ICF process compliant with country/site 
requirements for only those participants who have sufficient archival samples.  
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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 pre-screening, the Investigator/delegate should send the pre-
screening ICF via e-mail to the participant’s personal e-mail address (as allowed by local 
regulation) or by postal mail. The Investigator/delegate should provide an overview of the 
study (eg, tusamitamab ravtansine mechanism of action; design of the study in terms of 
treatment groups, visits, and pre-screening procedures; and rationale for assessment of 
CEACAM5 expression). The Investigator/delegate should respond to any question raised 
by a participant, and this correspondence should be documented in detail in the 
participant’s source file. 
• If a participant agrees to participate in the pre-screening phase, the participant should print 
out, sign, and date 2 copies of the ICF. A scan of a signed ICF should be sent via secured 
e-mail (if available), and 1 of the signed original ICFs to be filed in the Investigator Study 
File should be sent via postal mail. 
• The Investigator/delegate should review each received signed ICF (or a printout of an 
electronically submitted, scanned copy), sign and date it, and archive it in the Investigator 
Study File. It is mandatory for the Investigator to ensure the collection of the original 
signed ICF sent by mail; the signed original should be attached to any previously filed 
signed printout of an electronically submitted signed ICF. After properly documenting this 
consent process, the site may proceed to prepare and send the slides for CEACAM5 
assessment. 
10.9.2 Screening procedures  
The Investigator/site should assess the site’s capacity to conduct study procedures throughout the 
study for each participant before starting any screening procedure. If the site cannot guarantee an 
accurate follow-up in the context of the trial, alternative treatment outside the clinical trial should 
be proposed. This assessment, per the Investigator’s medical judgement and depending on the 
country/site status, should be communicated to the participant. The participant should satisfy all 
eligibility criteria before enrolling to the study; and no protocol waiver is acceptable. Remote 
signature of main study ICF is not acceptable in any circumstance.  
10.9.3 Study intervention  
During a regional or national emergency declared by a governmental agency, all contingency 
plans should be implemented to ensure compliance to study treatment, based on a case-by-case 
benefit-risk assessment. Administration (or, in case of temporary interruption, reinitiation) of the 
IMP can occur only once the Investigator has determined, according to his/her best judgement, 
that the contribution of the IMP(s) to the occurrence of the epidemic event (eg, COVID-19) was 
unlikely. 
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Any further safety measure (eg, interim laboratory assessment such as neutrophil count 
monitoring; regular contact with site staff) to follow the safety of patients during the regional or 
national emergency period can be considered.  
10.9.4 Study procedures  
All efforts should be made to ensure that measurements of key parameters for efficacy endpoints 
can be performed at the site. If the Investigator is unable to guarantee that the protocol-required 
efficacy assessments can be conducted, no participant should be screened until the site confirms 
its capacity to perform the assessments.  
As part of a site’s contingency plan, a back-up site should be identified in advance in the case that 
the site delegated to perform the radiological tumor assessment is prevented from performing the 
assessment by a regional or national emergency situation (eg, COVID-19 outbreak). The 
Investigator should ensure that the back-up site conducts the RECIST assessment in same manner 
as that used for baseline tumor assessments.  
In the case that the primary tumor assessment site is incapacitated, ongoing patients would then be 
referred to the back-up site for tumor assessment. The Investigator/delegate should ensure the 
information on baseline assessment methods is shared with the back-up site’s radiologist to ensure 
same method is followed for scans. 
Depending on site status, if needed, Cycle 1 and Cycle 2 weekly safety laboratory assessment 
(hematology [hemoglobin, hematocrit, RBC, WBC with differential, and platelet counts] and liver 
function tests [AST, ALT, total and conjugated bilirubin, ALP]) can be arranged to be performed 
either at a laboratory certified to perform these tests that is close to the patient’s home, or via 
sampling at the patient’s home.  
10.9.5 Informed consent process  
For a regional or national emergency declared by a governmental agency, contingency procedures 
may be implemented for the duration of the emergency. The participant or legally authorized 
representative should be informed verbally prior to initiating any change that is to be implemented 
for the duration of the emergency (eg, study visit delays, use of back-up sites for safety laboratory 
or tumor assessment). 
 
10.10 APPENDIX 10: DEFINITION OF WELL CONTROLLED HUMAN IMMUNODEFICIENCY 
VIRUS INFECTION  
Well controlled HIV infection is defined as meeting all of the following criteria: 
• CD4+ T-cell count >350 cells/mm3 at time of screening.  
• Virologic suppression, defined as confirmed HIV RNA level <50 copies/mL or the lower 
limit of quantification (below the limit of detection) using a locally available assay, 
achieved and maintained for at least 12 weeks prior to screening. 
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• On a stable ART regimen, without changes in drugs or dose modification, for at least 
4 weeks prior to study entry (Day 1).  
• On a combination ART regimen containing no antiretroviral medication other than the 
following: abacavir, dolutegravir, emtricitabine, lamivudine, raltegravir, rilpivirine, and/or 
tenofovir. 
10.11 APPENDIX 11: CYP450 SUBSTRATES WITH NARROW THERAPEUTIC INDICES  
Table 11 - List of CYP substrates with narrow therapeutic range  
In vivo CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A Narrow Therapeutic Range 
(NTR) Substrates 
CYP enzyme 
NTR Substratesa 
CYP1A2 
Theophylline, tizanidine 
CYP2C8 
Paclitaxel 
CYP2C9 
Warfarin, phenytoin 
CYP2C19 
S-mephenytoin 
CYP2D6 
Thioridazine 
CYP3A 
Alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, quinidine, sirolimus, 
tacrolimus, cisapride, astemizole, terfenadine, pimozide 
a CYP Substrates with a Narrow Therapeutic Range - drugs with an exposure-response relationship that indicates that relatively small 
increases in their exposure levels by co-administered CYP inhibitors may lead to safety concerns 
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10.12 APPENDIX 12: STRONG CYP3A INHIBITORS  
Table 12 - List of strong CYP3A inhibitors  
CYP3A 
inhibitors 
Precipitant Therapeutic 
Class 
Victim (oral, unless otherwise 
specified) 
AUC Ratio 
Potent CYP3A Inhibitors (yielding substrate AUC ratio >5) 
VIEKIRA PAK 
Antivirals 
Tacrolimus 
55.76 
Telaprevir 
Antivirals 
Midazolam 
13.5 
Indinavir/RIT 
Protease inhibitors 
Alfentanil 
36.50 
Tipranavir/RIT 
Protease inhibitors 
Midazolam 
26.91 
Ritonavir 
Protease inhibitors 
Midazolam 
26.41 
Cobicistat (GS-9350) none 
Midazolam 
19.03 
Indinavir 
Protease inhibitors 
Vardenafil 
9.67 
Ketoconazole 
Antifungals 
Midazolam 
17.08 
Troleandomycin 
Antibiotics 
Midazolam 
14.80 
Saquinavir/RIT 
Protease inhibitors 
Midazolam 
12.48 
Itraconazole 
Antifungals 
Midazolam 
10.80 
Voriconazole 
Antifungals 
Midazolam 
9.63 
Mibefradil 
Calcium Channel Blockers 
Midazolam 
8.86 
Clarithromycin 
Antibiotics 
Midazolam 
8.39 
Danoprevir/RIT 
Antivirals 
Midazolam 
13.42 
Lopinavir/RIT 
Protease inhibitors 
Alfentanil 
11.47 
Elvitegravir/RIT 
Treatments of AIDS 
Midazolam 
12.8 
Posaconazole 
Antifungals 
Midazolam 
6.23 
Telithromycin 
Antibiotics 
Midazolam 
6.2 
Conivaptan 
Diuretics 
Midazolam 
5.76 
Nefazodone 
Antidepressants 
Midazolam 
5.44 
Nelfinavir 
Protease inhibitors 
Midazolam 
5.29 
Saquinavir 
Protease inhibitors 
Midazolam 
5.18 
Boceprevir 
Antivirals 
Midazolam 
5.05 
Idelalisib 
Kinase inhibitors 
Midazolam 
5.15 
LCL161 
Cancer treatments 
Midazolam 
8.80 
Mifepristone 
Antiprogestins 
Simvastatin 
9.55  
Ceritinib 
Kinase Inhibitors 
Midazolam 
5.84 
Ribociclib 
Kinase Inhibitors 
Midazolam 
5.17 
Josamycin 
Antibiotics 
Ivabradine 
7.70 
Tucatinib 
Kinase Inhibitors 
Midazolam 
5.74 
Abbreviations: AIDS = Acquired immune deficiency syndrome; AUC = Area under the curve; CYP = Cytochrome P450; RIT = Ritonavir. 
List extracted from the Drug Interaction Database from the University of Washington, updated January 2021 
(https://didb.druginteractionsolutions.org/resources/list-of-substrates-inhibitors-and-inducers/?Oid=1130) and from FDA, updated June 2020 
(https://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/ucm093664.htm). 
 
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10.13 APPENDIX 13: RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
VERSION 1.1  
Details provided in bibliographic reference (15). 
10.13.1 
Measurability of tumor at baseline  
At baseline, tumor lesions/lymph nodes will be categorized as measurable or non-measurable as 
follows. 
Measurable lesions must be accurately measured in at least 1 dimension (longest diameter in the 
plane of the measurement to be recorded) with a minimum size of: 
• 10 mm by CT-scan (CT-scan slice thickness no greater than 5 mm). 
• 10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable). 
• 20 mm by chest X-ray. 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node 
must be ≥15 mm in the short axis when assessed by CT-scan (CT-scan slice thickness 
recommended to be no greater than 5 mm). At baseline and at follow-up, only the short axis will 
be measured and followed. 
Non-measurable lesions are all other lesions, including small lesions (longest diameter <10 mm or 
pathological lymph nodes with ≥10 to <15 mm short axis), as well as truly non-measurable 
lesions. Lesions considered non-measurable include: leptomeningeal disease, ascites, pleural or 
pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, and 
abdominal masses/abdominal organomegaly identified by physical exam that is not measurable by 
reproducible imaging techniques. 
10.13.2 
Special considerations regarding lesion measurability  
• Bone lesions: 
1. Bone scan, positron emission tomography scan or plain films are not considered adequate 
imaging techniques to measure bone lesions. However, these techniques can be used to 
confirm the presence or disappearance of bone lesions. 
2. Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross-sectional imaging techniques such as CT or MRI can be 
considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above. 
3. Blastic bone lesions are non-measurable. 
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• Cystic lesions: 
1. Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, 
by definition, simple cysts. 
2. “Cystic lesions” thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same participant, these are preferred for selection as target 
lesions. 
• Lesions with prior local treatment: 
1. Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-
regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion. 
Method of assessment 
All measurements should be recorded in metric notation, using calipers if clinically assessed. All 
baseline evaluations should be performed as close as possible to the treatment start and never 
more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation should 
always be performed rather than clinical examination unless the lesion(s) being followed cannot 
be imaged but are assessable by clinical examination. 
• Clinical lesions: Clinical lesions will only be considered measurable when they are 
superficial and ≥10 mm diameter as assessed using calipers. For the case of skin lesions, 
documentation by color photography including a ruler to estimate the size of the lesion is 
suggested. As noted above, when lesions can be evaluated by both clinical exam and 
imaging, imaging evaluation should be undertaken since it is more objective and may be 
reviewed at the end of the study. 
• Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new 
lesions. However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung. 
• CT, MRI: CT is the best currently available and reproducible method to measure lesions 
selected for response assessment. Measurability of lesions on CT-scan is based on the 
assumption that CT slice thickness is 5 mm or less. When CT-scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion should be twice the slice 
thickness. 
• Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement. If new lesions are identified by ultrasound in the course of 
the study, confirmation by CT or MRI is advised. 
• Endoscopy, laparoscopy: The utilization of these techniques for objective tumor 
evaluation is not advised. 
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• Tumor markers: Tumor markers alone cannot be used to assess objective tumor 
response. 
• Cytology, histology: These techniques can be used to differentiate between PR and CR in 
rare cases if required by protocol. 
Baseline documentation of “target” and “non-target” lesions 
When more than 1 measurable lesion is present at baseline all lesions up to a maximum of 
5 lesions total (and a maximum of 2 lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline. 
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, and should lend themselves to reproducible repeated 
measurements. 
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
≥15 mm by CT-scan. Only the short axis of these nodes will contribute to the baseline sum. All 
other pathological nodes (those with short axis ≥10 mm but <15 mm) should not be considered 
non-target lesions. Nodes that have a short axis <10 mm are considered non-pathological and 
should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. The baseline sum diameters 
will be used as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required and 
these lesions should be followed as “present”, “absent”, or “unequivocal progression”. In addition, 
it is possible to record multiple non-target lesions involving the same organ as a single item on the 
case (eg, “multiple enlarged pelvic lymph nodes” or “multiple liver metastases”). 
Response criteria 
Response criteria are described in Table 13. 
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Table 13 - Response criteria  
Response criteria 
Evaluation of target lesions 
CR 
Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-
target) must have reduction in short axis to <10 mm. 
PR 
At least a 30% decrease in the sum of diameters of target lesions, taking as reference the 
baseline sum of diameters. 
PD 
At least a 20% increase in the sum of diameters of target lesions, taking as reference the 
smallest sum on study (this includes the baseline sum if that is the smallest on study). In 
addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm. (Note: the appearance of 1 or more new lesions is also 
considered progression). 
SD 
Neither sufficient shrinkage from the baseline study to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum of diameters while on study. 
Abbreviations: CR = complete response; PD = progressive disease; PR = partial response; SD = stable disease. 
Special notes on the assessment of target lesions 
Lymph nodes identified as target lesions should always have the actual short axis measurement 
recorded and should be measured in the same anatomical plane as the baseline examination, even 
if the nodes regress to <10 mm on study. This means that when lymph nodes are included as 
target lesions, the “sum” of lesions may not be zero even if CR criteria are met, since a normal 
lymph node is defined as having a short axis of <10 mm. For PR, SD and PD, the actual short axis 
measurement of the nodes is to be included in the sum of target lesions. 
Target lesions that become “too small to measure”: All lesions (nodal and non-nodal) recorded at 
baseline should have their actual measurements recorded at each subsequent evaluation, even 
when very small (eg, 2 mm). However, sometimes lesions or lymph nodes which are recorded as 
target lesions at baseline become so faint on CT-scan that the radiologist may not feel comfortable 
assigning an exact measure and may report them as being “too small to measure”. When this 
occurs it is important that a value be recorded on the CRF. If it is the opinion of the radiologist 
that the lesion has likely disappeared, the measurement should be recorded as 0 mm. If the lesion 
is believed to be present and is faintly seen but too small to measure, a default value of 5 mm 
should be assigned. 
When non-nodal lesions “fragment”, the longest diameters of the fragmented portions should be 
added together to calculate the target lesion sum. Similarly, as lesions coalesce, a plane between 
them may be maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion. If the lesions have truly coalesced such that they are no longer separable, the 
vector of the longest diameter in this instance should be the maximal longest diameter for the 
“coalesced lesion”. 
Evaluation of non-target lesions 
While some non-target lesions may actually be measurable, they need not be measured and 
instead should be assessed only qualitatively at the time points specified in the protocol. 
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• CR: Disappearance of all non-target lesions and normalization of tumor marker level. All 
lymph nodes must be non-pathological in size (<10 mm short axis). 
• Non-CR/Non-PD: Persistence of 1 or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits. 
• Progressive Disease: Unequivocal progression of existing non-target lesions. (Note: the 
appearance of 1 or more new lesions is also considered progression). 
The concept of progression of non-target disease requires additional explanation as follows: 
When the participant also has measurable disease; in this setting, to achieve “unequivocal 
progression” on the basis of the non-target disease, there must be an overall level of substantial 
worsening in non-target disease such that, even in presence of SD or PR in target disease, the 
overall tumor burden has increased sufficiently to merit discontinuation of therapy. A modest 
“increase” in the size of 1 or more non-target lesions is usually not sufficient to qualify for 
unequivocal progression status. 
When the participant has only non-measurable disease; to achieve “unequivocal progression” on 
the basis of the non-target disease, there must be an overall level of substantial worsening such 
that the overall tumor burden has increased sufficiently to merit discontinuation of therapy. A 
modest “increase” in the size of 1 or more non-target lesions is usually not sufficient to qualify for 
unequivocal progression status. Because worsening in non-target disease cannot be easily 
quantified (by definition: if all lesions are truly non-measurable) a useful test that can be applied 
when assessing participants for unequivocal progression is to consider if the increase in overall 
disease burden based on the change in non-measurable disease is comparable in magnitude to the 
increase that would be required to declare PD for measurable disease: ie, an increase in tumor 
burden representing an additional 73% increase in “volume” (which is equivalent to a 
20% increase diameter in a measurable lesion). Examples include an increase in a pleural effusion 
from “trace” to “large”, an increase in lymphangitic disease from localized to widespread, or may 
be described in protocols as “sufficient to require a change in therapy”. If “unequivocal 
progression” is seen, the participant should be considered to have had overall PD at that point. 
New lesions 
The appearance of new malignant lesions denotes disease progression. The finding of a new 
lesion should be unequivocal: ie, not attributable to differences in scanning technique, change in 
imaging modality or findings thought to represent something other than tumor (for example, some 
“new” bone lesions may be simply healing or flare of pre-existing lesions). This is particularly 
important when the participant’s baseline lesions show PR or CR. For example, necrosis of a liver 
lesion may be reported on a CT-scan report as a “new” cystic lesion, which it is not. 
A lesion identified on a follow-up study in an anatomical location that was not scanned at baseline 
is considered a new lesion and will indicate disease progression. An example of this is the 
participant who has visceral disease at baseline and while on study has a CT or MRI brain ordered 
which reveals metastases. The participant’s brain metastases are considered to be constitute PD 
even if he/she did not have brain imaging at baseline. 
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If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents new disease. If repeat scans confirm that there is a 
new lesion, then progression should be declared using the date of the initial scan. 
While fluorodeoxyglucose-positron emission tomography (FDG-PET) response assessments need 
additional study, it is sometimes reasonable to incorporate the use of FDG-PET scanning to 
complement CT-scanning in assessment of progression (particularly possible “new” disease). 
New lesions on the basis of FDG-PET imaging can be identified according to the following 
algorithm: 
1. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
2. No FDG-PET at baseline and a positive FDG-PET at follow-up. 
If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this 
is PD. 
If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional 
follow-up CT-scans are needed to determine if there is truly progression occurring at that site (if 
so, the date of PD will be the date of the initial abnormal FDG-PET scan). If the positive 
FDG-PET at follow-up corresponds to a pre-existing site of disease on CT that is not progressing 
on the basis of the anatomic images, this is not PD. 
Evaluation of best overall response 
Time point response: At each protocol-specified time point, a response assessment should occur. 
Table 14 provides a summary of the overall response status calculation at each time point for 
participants who have measurable disease at baseline. 
Table 14 - Response in participants with target disease  
Target lesions 
Non-target lesions 
New lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
Inevaluable 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response; PD = progressive disease; PR = partial response; SD = stable disease.  
When participants have non-measurable (therefore non-target) disease only, Table 15 is to be 
used. 
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Table 15 - Response in participants with non-target disease only  
Non-target lesions 
New lesions 
Overall response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD 
Not all evaluated 
No 
Inevaluable  
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
CR = complete response; PD = progressive disease. 
Missing assessments and inevaluable designation: When no imaging/measurement is done at all at 
a particular time point, the participant is not evaluable (NE) at that time point. 
If only a subset of lesion measurements are made at an assessment, usually the case is also 
considered NE at that time point, unless a convincing argument can be made that the contribution 
of the individual missing lesion(s) would not change the assigned time point response. This would 
be most likely to happen in the case of PD. 
Special notes on response assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to “normal” 
size (<10 mm), they may still have a measurement reported on scans. This measurement should be 
recorded even though the nodes are normal in order not to overstate progression should it be based 
on increase in size of the nodes. As noted earlier, this means that participants with CR may not 
have a total sum of “zero” on the CRF. 
In trials where confirmation of response is required, repeated “NE” time point assessments may 
complicate best response determination. The analysis plan for the trial must address how missing 
data/assessments will be addressed in determination of response and progression. For example, in 
most trials it is reasonable to consider a participant with time point responses of PR-NE-PR as a 
confirmed response. 
Participants with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as “symptomatic 
deterioration”. Every effort should be made to document objective progression even after 
discontinuation of treatment. Symptomatic deterioration is not a descriptor of an objective 
response: it is a reason for stopping study therapy. 
The objective response status of such participants is to be determined by evaluation of target and 
non-target disease. For equivocal findings of progression (eg, very small and uncertain new 
lesions; cystic changes or necrosis in existing lesions), treatment may continue until the next 
scheduled assessment. If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected. 
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Duration of response 
The duration of overall response is measured from the time measurement criteria are first met for 
CR/PR (whichever is first recorded) until the first date that recurrent or PD is objectively 
documented (taking as reference for PD the smallest measurements recorded on study). 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that recurrent disease is objectively documented. 
Duration of stable disease 
Stable disease is measured from the start of the treatment until the criteria for progression are met, 
taking as reference the smallest sum on study (if the baseline sum is the smallest, this is the 
reference for calculation of PD). 
Reproduced from:  
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response 
evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1). Eur J Cancer. 
2009;45:228-47. 
10.14 APPENDIX 14: ABBREVIATIONS AND DEFINITIONS  
 
ADC: 
antibody-drug conjugate 
ADR: 
adverse drug reaction 
AESI: 
adverse event of special interest 
ALT: 
alanine aminotransferase (SGPT) 
ANC: 
absolute neutrophil count 
aPTT: 
activated partial thromboplastin time 
ART: 
antiretroviral therapy 
AST: 
aspartate aminotransferase (SGOT) 
ATA: 
antitherapeutic antibody 
ATE: 
arterial thromboembolic event 
BOR: 
best overall response 
BSA: 
body surface area 
BSC: 
best supportive care 
CEACAM5: 
carcinoembryonic antigen cell adhesion molecule 5 
CI: 
confidence interval 
CR: 
complete response 
CSICF: 
Core Study Informed Consent Form 
CT: 
computed tomography 
CTCAE: 
Common Terminology Criteria for Adverse Events 
DCR: 
disease control rate 
DL: 
dose level 
DLT: 
dose limiting toxicity 
DOR: 
duration of response 
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ECOG: 
Eastern Cooperative Oncology Group 
eGFR: 
estimated glomerular filtration rate 
FDA: 
United States Food and Drug Administration 
FDG-PET: 
fluorodeoxyglucose-positron emission tomography 
FFPE: 
formalin-fixed, paraffin embedded 
FIH: 
first-in-human 
GC: 
gastric cancer 
GEJ: 
gastroesophageal junction 
HBsAg: 
hepatitis B virus surface antigen 
HCV: 
hepatitis C virus 
HIV: 
human immunodeficiency virus 
HR: 
hazard ratio 
HRT: 
hormone replacement therapy 
ICF: 
informed consent form 
IEC: 
independent ethics committee 
IHC: 
immunohistochemistry 
IMP: 
investigational medicinal product 
INR: 
International Normalized Ratio 
IRB: 
institutional review boards 
IRR: 
infusion-related reaction 
IRT: 
interactive response technology 
IV: 
intravenous 
MRI: 
magnetic resonance imaging 
MTD: 
maximum tolerated dose 
NCI: 
National Cancer Institute 
NE: 
not evaluable 
NSQ NSCLC: 
nonsquamous, non‑small-cell lung cancer 
NTR: 
narrow therapeutic range 
ORR: 
objective response rate 
PCSA: 
potentially clinically significant abnormalities 
PD: 
progressive disease 
PDX: 
patient-derived xenograft 
PFS: 
progression-free survival 
PK: 
pharmacokinetic 
PR: 
partial response 
PT: 
prothrombin time 
PTT: 
partial thromboplastin time 
Q2W: 
every 2 weeks 
RD: 
Recommended Dose 
RECIST: 
Response Evaluation Criteria in Solid Tumors 
SAE: 
serious adverse event 
SD: 
stable disease 
SUSAR: 
suspected unexpected serious adverse reaction 
TEAE: 
treatment-emergent adverse event 
ULN: 
upper limit of normal 
VEGF: 
vascular endothelial growth factor  
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VEGFR2: 
vascular endothelial growth factor 2 
WOCBP: 
woman of childbearing potential 
 
10.15 APPENDIX 15: PROTOCOL AMENDMENT HISTORY  
Not applicable. 
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11 
REFERENCES  
1. Gazzah A, Ricordel C, Cousin S, Cho BC, Calvo E, Kim TM, et al. Efficacy and safety of the 
antibody-drug conjugate (ADC) SAR408701 in patients (pts) with non-squamous non-small 
cell lung cancer (NSQ NSCLC) expressing carcinoembryonic antigen-related cell adhesion 
molecule 5 (CEACAM5). Proceedings of the ASCO 2020 Annual Virtual Meeting. 
2. Wilke H, Muro K, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, et al. Ramucirumab plus 
paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric 
or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised 
phase 3 trial. Lancet Oncol. 2014;15(11):1224-35. 
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 gene family 
members. Tumor Biol. 1995;16(1):10-6. 
5. Hammarstrom S. The carcinoembryonic antigen (CEA) family: structures, suggested functions 
and expression in normal and malignant tissues. Semin Cancer Biol. 1999;9(2):67-81. 
6. Fuchs CS, Tomasek J, Yong CJ, Dumitru F, Passalacqua R, Goswami C, et al. Ramucirumab 
monotherapy for previously treated advanced gastric or gastro-oesophageal junction 
adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, 
phase 3 trial. Lancet. 2014;383(9911):31-9. 
7. Arnold M, Ferlay J, van Berge Henegouwen MI, Soerjomataram I. Global burden of 
oesophageal and gastric cancer by histology and subsite in 2018. Gut. 2020;69(9):1564-71. 
8. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 
2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 
countries. CA Cancer J Clin. 2018;68(6):394-424. 
9. International Agency for Research on Cancer. 2021. Cancer Fact Sheets: Stomach Cancer. 
[online] Available at: <https://gco.iarc.fr/today/data/pdf/fact-sheets/cancers/cancer-fact-sheets-
5.pdf> [Accessed 19 April 2021]. 
10. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence 
and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J 
Cancer. 2015;136(5):E359-86. 
11. Jemal A, Siegel R, Ward E, Murray T, Xu J, Smigal C, et al. Cancer statistics, 2006. CA: a 
cancer journal for clinicians 2006;56(2):106-30. 
12. Wagner AD, Grothe W, Haerting J, Kleber G, Grothey A, Fleig W. Chemotherapy in 
advanced gastric cancer: A systematic review and meta-analysis based on aggregate data. J 
Clin Oncol. 2006;24(18):2903-9. 
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13. 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. 
14. 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. 
15. Eisenhauer EA, Therasse P, Bogaerts J Schwartz LH, Sargent D, Ford R, et al. New response 
evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer. 
2009;45(2):228-47. 
 
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VV-CLIN-0608487 2.0

SAP_001.pdf: 
 
 
 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive 
property of Sanofi (or any of its affiliated companies). The use of such confidential information must be restricted to the 
recipient for the agreed purpose and must not be disclosed, published or otherwise communicated to any unauthorized 
persons, for any reason, in any form whatsoever without the prior written consent of Sanofi (or the concerned affiliated 
company); ‘affiliated company’ means any corporation, partnership or other entity which at the date of communication 
or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ 
meaning direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, 
partnership or other entity 
 
According to template: Sanofi eSAP Version 2.0, dated 20-OCT-2021 
 Page 1 
STATISTICAL ANALYSIS PLAN  
Protocol title: 
Open-label study of tusamitamab ravtansine (SAR408701) in 
combination with ramucirumab in participants previously 
treated for advanced gastric or gastroesophageal junction 
(GEJ) adenocarcinoma with CEACAM5-positive tumors 
Protocol number: 
ACT16444 
Compound number 
(INN/Trademark): 
SAR408701 
tusamitamab ravtansine/Not applicable 
Study phase: 
Phase 2 
Short Title: 
Tusamitamab ravtansine (SAR408701) in combination with 
ramucirumab in pretreated participants with gastric cancer 
CARMEN-GC01 
Statistician: 
 
Statistical project leader: 
 
Date of issue: 
17-Jul-2023 
Regulatory agency identifier number(s): 
IND: 
Not applicable 
EudraCT: 
2021-001967-26 
NCT: 
Not applicable 
WHO: 
Not applicable 
EUDAMED: 
Not applicable 
Other: 
Not applicable 
 
Date: 
17-Jul-2023 
Total number of pages: 46 
 
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Statistical Analysis Plan  
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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ................................................................................................................... 1 
TABLE OF CONTENTS .................................................................................................................................. 2 
LIST OF TABLES ........................................................................................................................................... 4 
VERSION HISTORY ....................................................................................................................................... 5 
1 
INTRODUCTION .............................................................................................................................. 6 
1.1 
STUDY DESIGN .............................................................................................................................. 6 
1.2 
OBJECTIVES AND ENDPOINTS .................................................................................................... 7 
1.2.1 
Estimands ........................................................................................................................................ 8 
2 
ANALYSIS POPULATIONS .......................................................................................................... 10 
3 
STATISTICAL ANALYSES ........................................................................................................... 12 
3.1 
GENERAL CONSIDERATIONS .................................................................................................... 12 
3.2 
PRIMARY ENDPOINT(S) ANALYSIS ............................................................................................ 12 
3.2.1 
Definition of endpoint(s) ................................................................................................................. 13 
3.2.1.1 
Study-drug related DLT at Cycle 1 and Cycle 2 ............................................................................ 13 
3.2.1.2 
Confirmed objective response ....................................................................................................... 13 
3.2.2 
Main analytical approach ............................................................................................................... 13 
3.2.2.1 
Confirmed objective response ....................................................................................................... 13 
3.2.3 
Sensitivity analysis ......................................................................................................................... 14 
3.2.4 
Supplementary analyses ................................................................................................................ 14 
3.3 
SECONDARY ENDPOINT(S) ANALYSIS ..................................................................................... 14 
3.3.1 
Key/Confirmatory secondary endpoint(s) ...................................................................................... 14 
3.3.2 
Supportive secondary endpoint(s) ................................................................................................. 15 
3.3.2.1 
Definition of endpoints ................................................................................................................... 15 
3.3.2.2 
Main analytical approach ............................................................................................................... 15 
3.4 
TERTIARY/EXPLORATORY ENDPOINT(S) ANALYSIS .............................................................. 18 
3.5 
MULTIPLICITY ISSUES ................................................................................................................ 18 
3.6 
OTHER SAFETY ANALYSES ....................................................................................................... 18 
3.6.1 
Extent of exposure ......................................................................................................................... 18 
3.6.1.1 
Overall exposure ............................................................................................................................ 18 
3.6.1.2 
Tusamitamab ravtansine exposure ................................................................................................ 19 
3.6.1.3 
Ramucirumab exposure ................................................................................................................. 21 
3.6.2 
Adverse events .............................................................................................................................. 22 
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3.6.3 
Additional safety assessments ....................................................................................................... 28 
3.6.3.1 
Laboratory variables, vital signs and electrocardiograms (ECGs) ................................................. 28 
3.6.3.2 
Ophthalmological examinations ..................................................................................................... 30 
3.7 
OTHER ANALYSES....................................................................................................................... 31 
3.7.1 
Other variables and/or parameters ................................................................................................ 31 
3.7.1.1 
PK analyses ................................................................................................................................... 31 
3.7.1.2 
Immunogenicity analyses ............................................................................................................... 32 
3.7.1.3 
Biomarker analyses........................................................................................................................ 34 
3.7.1.4 
Analyses of pharmacokinetic/pharmacodynamic ........................................................................... 35 
3.7.2 
Subgroup analyses ........................................................................................................................ 35 
3.8 
INTERIM ANALYSES .................................................................................................................... 36 
4 
SAMPLE SIZE DETERMINATION ................................................................................................ 38 
5 
SUPPORTING DOCUMENTATION .............................................................................................. 39 
5.1 
APPENDIX 1 LIST OF ABBREVIATIONS ..................................................................................... 39 
5.2 
APPENDIX 2 PARTICIPANT DISPOSITIONS .............................................................................. 40 
5.3 
APPENDIX 3 DEMOGRAPHICS AND BASELINE CHARACTERISTICS, PRIOR OR 
CONCOMITANT MEDICATIONS .................................................................................................. 41 
5.4 
APPENDIX 4 DATA HANDLING CONVENTIONS ........................................................................ 44 
5.5 
APPENDIX 5 SANOFI SPONSOR GENERIC RANGES FOR HEMATOLOGICAL AND 
BIOCHEMISTRY PARAMETERS .................................................................................................. 45 
6 
REFERENCES ............................................................................................................................... 46 
 
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LIST OF TABLES  
Table 1 - Dose levels in safety run-in part ....................................................................................................... 6 
Table 2 - Objectives and endpoints ................................................................................................................. 7 
Table 3 - Summary of primary estimand for primary efficacy endpoint ........................................................... 9 
Table 4 - Populations for analyses ................................................................................................................ 10 
Table 5 - Tusamitamab ravtansine dose reduction criteria ........................................................................... 20 
Table 6 - Ramucirumab dose reduction criteria ............................................................................................ 22 
Table 7 - Sorting of AE tables ....................................................................................................................... 23 
Table 8 - Analyses of adverse events ........................................................................................................... 24 
Table 9 - Selections for AESIs and other AEs of interest .............................................................................. 26 
Table 10 - Estimated objective response rate (ORR) depending on number of responders ........................ 38 
Table 11 - Generic ranges for hematological and coagulation parameters .................................................. 45 
Table 12 - Generic ranges for biochemistry parameters ............................................................................... 45 
 
 
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VERSION HISTORY  
This statistical analysis plan (SAP) for Study ACT16444 is based on the protocol dated  
19-Apr-2021. The first participant was enrolled in the dose escalation part on 21-Nov-2021. This 
SAP is approved before the primary analysis of Objective Response Rate (ORR).  
Major changes in statistical analysis plan 
SAP Version 
Approval Date 
Changes 
Rationale 
1 
17-Jul-2023 
Estimands attributes have been updated for 
efficacy endpoints. 
Corrections to align with ICH 
E9 (R1) definitions. 
 
 
Definition of DLT-evaluable population (for Part 1) 
has been updated. 
Clarification on the definition. 
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1 
INTRODUCTION  
1.1 
STUDY DESIGN  
This is a Phase 2, open-label, multicenter, single-arm study to confirm the recommended dose, 
safety, efficacy (antitumor activity), and pharmacokinetics (PK) of tusamitamab ravtansine 
combined with ramucirumab in participants previously treated for gastric or gastroesophageal 
adenocarcinoma with CEACAM5-positive tumors. 
The study will comprise 2 parts: Part 1 (Safety run-in) to assess the tolerability and to confirm the 
recommended dose (RD) of tusamitamab ravtansine in combination with ramucirumab; and 
Part 2, to assess the antitumor activity of tusamitamab ravtansine in combination with ramucirumab. 
The screening phase will be performed only in prescreened participants determined to be 
CEACAM5-positive by immunohistochemistry (IHC) assessment.  
Approximately 32 to 38 participants will be treated from approximately 21 sites to achieve a total 
of 32 participants treated at the RD and evaluable for activity. 
The cycle duration is 14 days. The median expected duration of study per participant is estimated 
at 34 weeks (up to 4 weeks for screening, a median of 18 weeks for study intervention 
administration, a median of 12 weeks for end-of-treatment (EOT) assessments, and the safety 
follow-up visit).  
Treatment allocation will be performed using interactive response technology (IRT). After being 
screened, eligible participants will receive tusamitamab ravtansine combined with ramucirumab 
until documented disease progression, unacceptable toxicity, new anticancer therapy initiation, 
death, or the participant’s or Investigator’s decision to stop the treatment.  
This will be a 2-part study.  
• Part 1 (safety run-in): participants will receive ramucirumab 8 mg/kg followed by 
tusamitamab ravtansine at 170 mg/m² at Day 1 Cycle 1, and ramucirumab 8 mg/kg 
followed by tusamitamab ravtansine 100 mg/m² at Cycle 2 Q2W in all subsequent cycles. 
In the case that it is decided to reduce the initial loading dose of tusamitamab ravtansine to 
Dose Level (DL)-1 (Table 1), a tusamitamab ravtansine loading dose of 150 mg/m² will be 
administered to participants at Day 1 of Cycle 1. 
Table 1 - Dose levels in safety run-in part  
Dose Level (DL) 
Tusamitamab revtansine 
Ramucirumab 
Starting dose 
170 mg/m² Q2W Cycle 1; 
100 mg/m² Q2W Cycle 2 and thereafter 
8 mg/kg Q2W 
Minus -1 (DL-1) 
150 mg/m² Q2W Cycle 1; 
100 mg/m² Q2W Cycle 2 and thereafter 
8 mg/kg Q2W 
DL-1 = dose level -1; Q2W = every 2 weeks 
 
• Part 2: Participants enrolled in the dose expansion part will receive SAR408701 at the RD 
determined at the end of the safety run-in (Part 1).  
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1.2 
OBJECTIVES AND ENDPOINTS  
Table 2 - Objectives and endpoints  
Objectives 
Endpoints 
Primary 
• 
Part 1: to confirm the recommended tusamitamab 
ravtansine loading dose Q2W when given in 
combination with ramucirumab in advanced gastric 
or gastroesophageal junction (GEJ) 
adenocarcinoma population 
• 
Part 1: Incidence of study drug related dose-limiting 
toxicities (DLTs) at Cycle 1 and Cycle 2 (C1D1 to 
C2D14) 
 
• 
Part 2: To assess the antitumor activity of 
tusamitamab ravtansine loading dose Q2W in 
combination with ramucirumab in advanced gastric 
or GEJ adenocarcinoma 
• 
Part 2: Objective response rate (ORR), defined as 
the proportion of participants with confirmed 
complete response (CR) or partial response (PR) as 
best overall response (BOR) per Response 
Evaluation Criteria in Solid Tumors (RECIST) 1.1 
Secondary 
• 
To assess the safety and tolerability of tusamitamab 
ravtansine loading dose Q2W in combination with 
ramucirumab 
 
• 
Incidence of treatment-emergent adverse events 
(TEAEs), serious adverse event (SAEs), and 
laboratory abnormalities according to the National 
Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE) V5.0 
• 
To assess the durability of the response to 
treatment with tusamitamab ravtansine loading 
dose Q2W in combination with ramucirumab 
 
• 
Duration of response (DOR), defined as the time 
from first documented evidence of CR or PR until 
progressive disease (PD) determined per RECIST 
1.1 or death from any cause, whichever occurs first 
• 
To assess progression-free survival (PFS) of 
tusamitamab ravtansine loading dose Q2W in 
combination with ramucirumab 
 
• 
Progression-free survival, defined as the time from 
the first investigational medicinal product (IMP) 
administration to the date of the first documented 
disease progression or death due to any cause, 
whichever comes first 
• 
To assess the disease control rate (DCR) of 
tusamitamab ravtansine loading dose Q2W in 
combination with ramucirumab 
 
• 
Disease control rate, defined as the proportion of 
participants with confirmed CR or PR or stable 
disease (SD) as BOR per RECIST 1.1 
• 
To assess the PK of tusamitamab ravtansine 
loading dose Q2W and ramucirumab when given in 
combination 
• 
Pharmacokinetic parameters of tusamitamab 
ravtansine and ramucirumab 
• 
To assess the immunogenicity of tusamitamab 
ravtansine loading dose Q2W when given in 
combination with ramucirumab 
• 
Incidence of antitherapeutic antibodies (ATAs) 
against tusamitamab ravtansine 
Exploratory 
• 
To explore the circulating carcinoembryonic antigen 
(CEA) as a potential biomarker for activity and to 
evaluate circulating CEA levels at prescreening 
• 
Circulating CEA at prescreening, screening, during 
the treatment period and during the follow-up period 
 
 
Abbreviations: ATAs = antitherapeutic antibodies; BOR = best overall response; C1D1 = Cycle 1, Day 1; C2D14 = Cycle 2, Day 14;  
CEA = carcinoembryonic antigen; CR = complete response; CTCAE = Common Terminology Criteria for Adverse Events; DCR = disease control 
rate; DLT = dose-limiting toxicity; DOR = duration of response; GEJ = gastroesophageal junction; IMP = investigational medicinal product;  
NCI = National Cancer Institute; ORR = objective response rate; PD = progressive disease; PFS = progression-free survival;  
PK = pharmacokinetics; PR = partial response; RECIST = Response Evaluation Criteria in Solid Tumors; TEAEs = treatment-emergent adverse 
events, SAEs = serious adverse events. 
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1.2.1 Estimands  
The primary estimand defined for the primary efficacy endpoint is summarized in Table 3. More 
details are provided in Section 3.  
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Table 3 - Summary of primary estimand for primary efficacy endpoint  
Endpoint 
Category 
(estimand) 
Estimands 
Endpoint 
Population 
Intercurrent event(s) handling strategy 
Population-level summary  
(Analysis and missing data handling) 
Primary efficacy objective: To assess the antitumor activity of tusamitamab ravtansine loading dose Q2W in combination with ramucirumab in advanced gastric or GEJ 
adenocarcinoma 
Primary endpoint 
(primary estimand for 
Part 2) 
Confirmed objective 
response (confirmed CR 
or PR as BOR) as per 
RECIST 1.1 
All-treated population 
at the recommended 
tusamitamab 
ravtansine loading 
dose 
Regardless of IMP discontinuation (treatment policy 
strategy) 
“While not initiating further systemic anticancer 
therapy” strategy) 
ORR, defined as the rate of participants with 
confirmed objective response, and 2-sided 95% 
confidence interval (CI) using the Clopper-Pearson 
method. 
In the absence of confirmed objective response, 
participants will be considered as nonresponders, 
whatever the reason (including participants with 
nonevaluable BOR). 
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2 
ANALYSIS POPULATIONS  
The following populations for analyses are defined:  
Table 4 - 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 the screening informed consent for study participation. 
Enrolled 
Participants from screened population who have been allocated to intervention regardless of 
whether the intervention was received or not. 
All-treated 
All enrolled participants exposed to the study treatment, regardless of the amount of 
treatment administered. All safety analyses will be performed on this population, which is 
also the primary population for analysis of all efficacy parameters.  
DLT-evaluable (Part 1) 
All enrolled participants who received 2 cycles with at least 80% of the intended dose for 
both tusamitamab ravtansine and ramucirumab at each of the first 2 infusions. Any 
participant who experienced a DLT during that period will also be DLT-evaluable. 
Activity 
All-treated participants who have measurable disease at study entry and at least 
1 postbaseline evaluable tumor assessment. Participants with no postbaseline evaluable 
tumor assessment but with an early clinical progression or who died from disease 
progression will also be included in this set. This population is the secondary population for 
analysis of efficacy parameters. 
Pharmacokinetic (PK) 
All participants from the all-treated population with at least 1 postbaseline PK concentration 
(whatever the cycle and even if dosing is incomplete) with adequate documentation of 
dosing and sampling dates and times. 
ATA 
All participants from the all-treated population with at least 1 postbaseline ATA result 
(negative, positive, or inconclusive). 
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 treatment due to COVID-19  
• 
and who did not permanently discontinue study due to COVID-19. 
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 “Yes” in the “Completion of 
screening phase” e-CRF page. 
In practice, a participant will be included in the DLT-evaluable population (applicable to Part 1 
only) if a “Dose Limiting Toxicities” e-CRF page has been filled in at the end of Cycle 1 and at 
the end of Cycle 2 (or Cycle 1 only if participant did not receive Cycle 2 because of a DLT). This 
includes any participant followed up to the end of the DLT observation period, or having 
experienced a DLT before the end of the DLT observation period and validated by the Study 
Committee. A participant with an overdose (defined as a dose received at least 30% above the 
intended dose) of tusamitamab ravtansine or ramucirumab at any of the 2 first infusions will be 
excluded from the DLT-evaluable population.  
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Participants exposed to study intervention before or without being enrolled will not be considered 
enrolled and will not be included in any analysis population. The safety experience of these 
participants will be reported separately. Enrolled participants for whom it is unclear whether they 
took the study intervention will be considered as exposed and will be included in the all-treated 
population. 
For any participant enrolled more than once, only the data associated with the first enrollment will 
be used in any analysis population. The safety experience associated with any later enrollment 
will be reported separately. 
In practice, participants whose BOR is nonevaluable due to minimum criteria for SD duration not 
met (ie, overall response of SD and the minimum duration, defined as 0.75 x duration between the 
first IMP intake and the first planned tumor assessment is not met) and there is no subsequent 
evaluable tumor assessment, or documented PD after two or more non-evaluable tumor 
assessments (ie, overall response of PD and the time between the date of first IMP intake and the 
documentation of PD is greater than the theoretical planned date of the second tumor assessment) 
will be considered as not evaluable for the activity population.  
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3 
STATISTICAL ANALYSES  
3.1 
GENERAL CONSIDERATIONS  
This study is not intended to explicitly test a hypothesis. For primary and secondary efficacy 
endpoints, 95% CIs will be provided. 
All efficacy endpoints based on radiological assessments of tumor burden (ie, ORR, DOR, PFS, 
and DCR) will be derived using the local radiologist’s/Investigator’s assessment. 
In general, continuous data will be summarized using the number of observations available, mean, 
standard deviation, median, Q1, Q3, minimum, and maximum. Categorical and ordinal data will 
be summarized using the count and percentage of participants. 
The baseline value is defined as the last available value before the first dose IMP.  
The study cut-off for analysis of the primary endpoint for the Part 2 of the study, ORR, 
corresponds to the date on which all evaluable treated participants have had at least 2 postbaseline 
tumor assessments, experienced confirmed objective response, or have discontinued the study for 
any reason. This study cut-off can be up to approximately 16 weeks (12 weeks for 2 tumor 
assessments and 4 weeks for confirmation of response, if needed) after the last participant’s 
first IMP administration. 
The final study cut-off date for analysis of the secondary efficacy endpoints, which include DOR 
and PFS, will be 4 months after the cut-off date for the primary analysis. At that time, the primary 
analysis of ORR and DCR will also be updated. 
Observation period  
The observation period will be divided into 4 segments:  
• The pre-treatment period is defined as the period up to first IMP administration. 
• The on-treatment period (ie, treatment-emergent (TE) period) is defined as the period 
from the first IMP administration to the last IMP administration +30 days. 
• The post-treatment period is defined as the period from the end of the on-treatment 
period. 
3.2 
PRIMARY ENDPOINT(S) ANALYSIS  
As it is a 2-part study, there are 2 primary endpoints: study-drug related DLTs at Cycle 1 and 
Cycle 2 in Part 1, and confirmed objective response as per RECIST 1.1 in Part 2.  
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3.2.1 Definition of endpoint(s)  
3.2.1.1 Study-drug related DLT at Cycle 1 and Cycle 2  
The primary safety endpoint is study-drug related DLTs during the DLT observation period 
(ie, from Cycle 1 Day 1 to Cycle 2 Day 14). The list of DLTs to be considered for the study is 
defined in Table 6 of the protocol. For analysis purposes, DLTs will be identified based on the 
Adverse Events (AEs) reported on the e-CRF DLT page during observation period in Part 1. 
Statistical analysis for DLTs is described in Section 3.6.2. 
3.2.1.2 Confirmed objective response  
The primary efficacy endpoint is confirmed objective response determined according to 
RECIST 1.1. A confirmed objective response is defined as a confirmed CR or PR as 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.  
3.2.2 Main analytical approach  
3.2.2.1 Confirmed objective response  
The primary efficacy analysis is based on the primary estimand for part 2 introduced in 
Section 1.2.1. This primary estimand is defined according to the following attributes: 
• The primary efficacy endpoint is confirmed objective response (confirmed CR or PR as 
BOR) as per RECIST 1.1. based on the investigator’s assessment as defined in 
Section 3.2.1.2.  
• The treatment condition of interest is tusamitamab ravtansine loading dose Q2W in 
combination with ramucirumab. 
• The analysis population is the participants from all-treated population (defined in 
Section 2) treated at the RD of tusamitamab ravtansine loading dose Q2W regimen 
(ie, excluding participants treated at the starting dose, if this differs from the RD).  
• 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 done up to the time of initiation of further anticancer therapy.  
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• The population-level summary will be the ORR, defined as the rate of participants with 
confirmed objective response and 2-sided 95% CIs using the Clopper-Pearson method.  
In the absence of confirmed objective response before the analysis cut-off date (taking into 
account the intercurrent event handling strategies), participants will be considered as non-
responders, whatever the reason (including participants with missing or non-evaluable BOR).  
3.2.3 Sensitivity analysis  
No sensitivity analysis is planned in this study. 
3.2.4 Supplementary analyses  
Number (%) of participants within each BOR category, including not evaluable as per 
RECIST 1.1 and reason for being not evaluable will be provided on the subgroup of participants 
from the all-treated population treated at the RD (ie, excluding participants treated at the starting 
dose if this differs from the RD).  
As a supplementary analysis, confirmed objective response as per RECIST 1.1 will also be 
summarized on the subgroup of participants from activity population (defined in Section 2) 
treated at the RD for tusamitamab ravtansine in a loading-dose Q2W regimen (ie, excluding 
participants treated at the starting dose if this differs from the RD). The same analytical approach 
as described above will be used.  
In addition, the best relative tumor change from baseline, defined as the smallest relative tumor 
change from baseline (where tumor change at time t is the difference between sum of the longest 
diameters of the target lesions at time t and baseline, resulting in a negative value in case of 
decrease), will be summarized using a waterfall plot on the participants on the all-treated 
population treated at the RD (ie, excluding participants treated at the starting dose if this differs 
from the RD). A swimmer plot will also be provided reporting the duration of treatment for all 
participants with their overall response and some baseline characteristics. This plot will 
differentiate responders from non-responders. In addition, a spider plot will also be provided 
reporting the tumor change from baseline over the time. 
3.3 
SECONDARY ENDPOINT(S) ANALYSIS  
The secondary endpoints detailed in this section are the duration of response, the progression-free 
survival and the disease control rate. Other secondary endpoints analyses are defined in 
Section 3.6.2 (AE, SAE), Section 3.6.3.1 (laboratory abnormalities), Section 3.7.1.1 (PK) and 
Section 3.7.1.2 (immunogenicity).  
3.3.1 Key/Confirmatory secondary endpoint(s)  
No key/confirmatory endpoint is defined. 
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3.3.2 Supportive secondary endpoint(s)  
3.3.2.1 Definition of endpoints  
3.3.2.1.1 Duration of response  
DOR is defined as the time from the date of first initial occurrence of the confirmed CR or PR to 
the date of first documentation of objective progressive disease according to RECIST 1.1 (1, 2) or 
death due to any cause, whichever occurs first. 
3.3.2.1.2 Progression-free survival  
PFS is defined as the time from the date of the first administration of IMP to the date of the 
first documentation of objective progressive disease according to RECIST 1.1 (1, 2) or death due 
to any cause, whichever occurs first. 
3.3.2.1.3 Disease control rate  
The DCR is estimated by dividing the number of participants with confirmed objective response 
or SD (CR or PR or SD as BOR), determined according to RECIST 1.1, by the number of 
participants from the analysis population.  
3.3.2.2 Main analytical approach  
3.3.2.2.1 Duration of response  
DOR analysis is based on an estimand defined according to the following attributes: 
• The endpoint is duration of response as defined in Section 3.3.2.1. 
• The treatment condition of interest is tusamitamab ravtansine loading dose Q2W in 
combination with ramucirumab. 
• The analysis population is the participants from the all-treated population (defined in 
Section 2) treated at the RD of tusamitamab ravtansine in a loading-dose Q2W regimen 
(ie, excluding participants treated at the starting dose if this differs from the RD) limited to 
participants who achieved a confirmed objective response. 
• Intercurrent events: 
- 
The study intervention discontinuation will be handled with the treatment policy 
strategy. DOR will be assessed based on tumor assessments regardless of study 
intervention discontinuation. 
- 
The further anticancer therapy (including further systemic anticancer therapies) 
intercurrent event will be handled with the hypothetical strategy. DOR will be assessed 
based on tumor assessments had a further anticancer therapy not been taken. DOR will 
be assessed based on tumor assessments up to the time of initiation of further 
anticancer therapy. 
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Two or more consecutive missing/unevaluable tumor assessments immediately before 
documented PD or death will be handled with the hypothetical strategy. DOR will be 
assessed based on tumor assessments had 2 consecutive tumor assessments not been 
missed immediately before documented PD or death. DOR will be assessed based on 
tumor assessments up to the last evaluable tumor assessment documenting no 
progression. 
• The population-level summary will include the median DOR and associated 95% CI from 
Kaplan-Meier methods.  
In the absence of documented disease progression or death before the analysis cut-off date (taking 
into account the intercurrent event handling strategies), DOR will be censored at the date of the 
last evaluable tumor assessment (not showing documented disease progression) performed before 
the analysis cut-off date.  
3.3.2.2.2 Progression-free survival  
PFS analysis is based on an estimand defined according to the following attributes: 
• The endpoint is progression-free survival. 
• The treatment condition of interest is tusamitamab ravtansine loading dose Q2W in 
combination with ramucirumab. 
•  The analysis population is the participants from the all-treated population (defined in 
Section 2) treated at the RD of tusamitamab ravtansine in a loading-dose Q2W regimen 
(ie, excluding participants treated at the starting dose if this differs from the RD). 
• Intercurrent events: 
- 
The study intervention discontinuation will be handled with the treatment policy 
strategy. PFS will be assessed based on tumor assessments regardless of study 
intervention discontinuation. 
- 
The further anticancer therapy (including further systemic anticancer therapies) 
intercurrent event will be handled with the hypothetical strategy. PFS will be assessed 
based on tumor assessments had a further anticancer therapy not been taken. PFS will 
be assessed based on tumor assessments up to the time of initiation of further 
anticancer therapy. 
- 
Two or more consecutive missing/unevaluable tumor assessments immediately before 
documented PD or death will be handled with the hypothetical strategy. PFS will be 
assessed based on tumor assessments had 2 consecutive tumor assessments not been 
missed immediately before documented PD or death. PFS will be assessed based on 
tumor assessments up to the last evaluable tumor assessment documenting no 
progression. 
• The population-level summary will include: 
- 
Kaplan-Meier estimates of the 25th, 50th, and 75th percentiles and their associated 
95% CIs using a log-log transformation of the survival function and the method of 
Brookmeyer and Crowley. 
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Number (%) of participants at risk as well as the probabilities of being event-free at 
least at 3, 6, 9, and 12 months with 95% CIs using the Kaplan-Meier method and 
a log-log approach based on a normal approximation following the Greenwood’s 
formula.  
- 
Kaplan-Meier curve including the number of participants at risk at key time points. 
In addition, the number (%) of participants with an event and the type of event (documented 
disease progression or death without documented disease progression) and the number (%) of 
censored participants and reason for censoring (no baseline tumor assessment, no evaluable post-
baseline tumor assessments, alive without documented disease progression, event occurred after 
two or more non-evaluable tumor assessments, or initiation of further anticancer therapy) will be 
analyzed.  
In the absence of documented disease progression or death before the analysis cut-off date (taking 
into account the intercurrent event handling strategies), PFS will be censored at the date of the 
last evaluable tumor assessment (not showing documented disease progression) performed before 
the analysis cut-off date, or at the date of the first administration of IMP (Day 1) if no PFS event 
(documented disease progression or death) and no baseline tumor assessment or no evaluable 
postbaseline tumor assessment has been done.  
3.3.2.2.3 Disease control rate  
DCR analysis is based on an estimand defined according to the following attributes: 
• The endpoint is disease control response (confirmed CR or PR or SD as BOR) as per 
RECIST 1.1. 
• The treatment condition of interest is tusamitamab ravtansine loading dose Q2W in 
combination with ramucirumab. 
• The analysis population is the participants from all-treated population (defined in 
Section 2) treated at the RD of tusamitamab ravtansine loading-dose Q2W regimen 
(ie, excluding participants treated at the starting dose if this differs from the RD). 
• Intercurrent events: 
- 
The study intervention discontinuation will be handled with the treatment policy 
strategy. Disease control response will be assessed based on tumor assessments 
regardless of study intervention discontinuation. 
- 
The further anticancer therapy (defined as all further systemic anti-cancer therapies) 
intercurrent event will be handled with the “while not initiating further anticancer 
therapy” strategy. Disease control response will be assessed based on tumor 
assessments done up to the initiation of further anticancer therapy. 
• The population-level summary will include the disease control rate, defined as the rate of 
participants with disease control response and 2-sided 95% CIs using the Clopper-Pearson 
method.  
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In the absence of confirmed objective response and SD before the analysis cut-off date (taking 
into account the intercurrent event handling strategies), participants will be considered as non-
DCR, whatever the reason (including participants with non-evaluable BOR). 
Disease control rate will also be summarized on the activity population as a supplementary 
analysis. 
3.4 
TERTIARY/EXPLORATORY ENDPOINT(S) ANALYSIS  
Analyses of tertiary/exploratory endpoints (eg, biomarkers) are defined in Section 3.7.1.3. 
3.5 
MULTIPLICITY ISSUES  
No multiplicity issues are handled in this study. 
3.6 
OTHER SAFETY ANALYSES  
All safety analyses will be performed on the all-treated population as defined in Section 2, 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. 
3.6.1 Extent of exposure  
3.6.1.1 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 interventions is administered. 
• Duration of overall exposure (in weeks) is defined as (Last day of exposure – first day of 
exposure +1)/7. 
- 
The first day of exposure is defined as the first administration date with non-zero dose 
for at least one of the IMP (tusamitamab ravtansine or ramucirumab).  
- 
The last day of exposure is the day before the theoretical date of the next 
administration (after the last administration), defined as the last administration date of 
at least one IMP + 14 days – 1 (tusamitamab ravtansine and ramucirumab). 
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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 – 14 days – 
start date of the previous cycle is >2 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 3 and 7 days (using 
maximum delay across all cycles)  
- 
Number (%) of participants with a cycle delayed between 8 and 14 days (using 
maximum delay across all cycles) 
- 
Number (%) of participants with a cycle delayed >14 days (using maximum delay 
across all cycles) 
• Number (%) of cycles delayed 
- 
Number (%) of cycles delayed between 3 and 7 days 
- 
Number (%) of cycles delayed between 8 and 14 days 
- 
Number (%) of cycles delayed >14 days 
3.6.1.2 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 + number of theoretical days until the next 
administration – 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 (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). 
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• Planned dose intensity (PDI in mg/m²/week): corresponds to the planned dose at C1D1 + 
planned dose at subsequent cycles multiplied by the theoretical total number of doses 
started and divided by the theoretical cycle duration expressed in weeks (ie, 2 weeks per 
cycle started). Note: Theoretical total number of doses started is derived based on cycles 
where at least one IMP is administered (even in case of dose omission), up to the end of 
treatment of tusamitamab ravtansine. 
• 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 (loading dose) and second administration 
(first 100 mg/m² infusion) will not be counted as a dose reduction. For the third 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. 
Table 5 - Tusamitamab ravtansine dose reduction criteria  
Actual dose level 
Dose level interval 
Starting dose (100 mg/m²) 
>90 mg/m²  
Dose level -1 (80 mg/m²)  
>72.5 mg/m² and ≤90 mg/m²  
Low dose 
>0 mg/m² and ≤72.5 mg/m²  
• Dose delay: A dose will be considered as delayed if the tusamitamab ravtansine 
administration date of the current cycle – 14 days – tusamitamab ravtansine administration 
date of the previous cycle is >2 days. Dose delay is not defined for the first cycle. 
• Dose omission is defined as a dose not administered at the scheduled visit but 
administered afterwards. 
• Dose interruption: A dose will be considered as interrupted if the tusamitamab ravtansine 
administration is stopped during an infusion regardless of whether it is restarted or not.  
Dose modifications and dose interruptions will be analyzed by participant and cycle as follows:  
• Participant (number of participants treated will be used as denominator) 
- 
Number (%) of participants with at least 1 dose modification 
- 
Number (%) of participants with at least 1 dose delayed 
- 
Number (%) of participants with at least 1 dose reduction 
- 
Number (%) of participants with at least 1 dose omission 
- 
Number (%) of participants with a least 1 dose interruption  
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• Cycle (number of cycles started will be used as denominator) 
- 
Number (%) of cycles with at least 1 dose modification 
- 
Number (%) of cycles with at least 1 cycle delayed 
- 
Number (%) of cycles with at least 1 dose reduction 
- 
Number (%) of cycles with at least 1 dose omission 
- 
Number (%) of cycles with at least 1 dose interruption 
3.6.1.3 Ramucirumab exposure  
The dose information will be assessed by the following: 
• Total number of cycles started. 
• Number of cycles started per participant. 
• Duration of ramucirumab exposure (in weeks) is defined by date of last administration of 
ramucirumab + number of theoretical days until the next administration – date of 
first administration of ramucirumab/7. 
• Actual dose (in mg/kg). In case of dose interruption, actual dose will be the sum of the 
actual doses administered before and after the dose interruption. 
• Cumulative dose (mg/kg): the cumulative dose is the sum of all actual doses of 
ramucirumab, given from first to last administration. 
• Actual dose intensity (ADI in mg/kg/week): defined as the cumulative dose divided by the 
duration of ramucirumab exposure (in weeks). 
• Planned dose intensity (PDI in mg/kg/week): corresponds to the planned dose multiplied 
by the theoretical total number of doses started and divided by the theoretical cycle 
duration expressed in weeks (ie, 2 weeks per cycle started). Note: Theoretical total number 
of doses started is derived based on cycles where at least one IMP is administered (even in 
case of dose omission), up to the end of treatment of ramucirumab. 
• Relative dose intensity (RDI, in %):100 ×
ADI (mg/kg/week) 
PDI (mg/kg/week). 
The total number of cycles started, number of cycles started by participant will be summarized as 
a quantitative variable and by category (number [%] of participants receiving at least 1 cycle, at 
least 2 cycles, etc). Duration of ramucirumab 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 ramucirumab 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 - Ramucirumab dose reduction criteria  
Actual dose level 
Dose level interval 
Starting dose (8 mg/kg) 
>7 mg/kg  
Dose level -1 (6 mg/kg)  
>5.5 mg/kg and ≤7 mg/kg  
Dose level -2 (5 mg/kg) 
> 4 mg/kg and ≤5.5 mg/kg 
Low dose 
>0 mg/kg and ≤4 mg/kg  
• Dose delay: A dose will be considered as delayed if the ramucirumab administration date 
of the current cycle – 14 days – ramucirumab administration date of the previous cycle is 
>2 days. Dose delay is not defined for the first cycle. 
• Dose omission is defined as a dose not administered at the scheduled visit but 
administered afterwards. 
• Dose interruption: A dose will be considered as interrupted if the ramucirumab 
administration is stopped during an infusion regardless of whether it is restarted or not.  
Dose modifications and dose interruptions will be analyzed by participant and cycle as follows:  
• Participant (number of participants treated will be used as denominator) 
- 
Number (%) of participants with at least 1 dose modification 
- 
Number (%) of participants with at least 1 dose delayed 
- 
Number (%) of participants with at least 1 dose reduction 
- 
Number (%) of participants with at least 1 dose omission 
- 
Number (%) of participants with a least 1 dose interruption  
• Cycle (number of cycles started will be used as denominator) 
- 
Number (%) of cycles with at least 1 dose modification 
- 
Number (%) of cycles with at least 1 cycle delayed 
- 
Number (%) of cycles with at least 1 dose reduction 
- 
Number (%) of cycles with at least 1 dose omission 
- 
Number (%) of cycles with at least 1 dose interruption 
3.6.2 Adverse events  
General common rules for adverse events 
All AEs will be graded according to 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.  
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The AEs will be analyzed in the following 3 categories: 
• Pre-treatment AEs: AEs that developed, worsened, or became serious during the pre-
treatment period. 
• TEAEs: AEs that developed, worsened, or became serious during the treatment-emergent 
period 
• Post-treatment AEs: AEs that developed, worsened, or became serious during the post-
treatment period  
Similarly, the deaths will be analyzed in the pre-treatment, treatment-emergent, and post-
treatment periods.  
The primary AE analyses will be on TEAEs. Pre-treatment and post-treatment AEs will be 
described separately.  
An AE with incomplete or missing date/time of onset (occurrence, worsening, or becoming 
serious) will be classified as a TEAE unless there is definitive information to determine it is a pre-
treatment or a post-treatment AE.  
If the assessment of the relationship to IMP is missing for an AE, this AE will be assumed as 
related to IMP. A 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 7.  
Table 7 - 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 
PT 
By decreasing frequency of PTsa 
a Sorting will be based on the SAR408701 overall incidence 
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 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)  
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• Any treatment-emergent SAE 
• Any treatment-emergent adverse event of special interest (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 ramucirumab 
• Any TEAE related to IMP 
• Any Grade ≥3 TEAE related to IMP 
• Any serious TEAE related to IMP 
• Any treatment-emergent corneal event (CMQ “Corneal events compound level”) 
• Any treatment-emergent peripheral neuropathy event TEAE (SMQ “Peripheral 
neuropathy” [Narrow and Broad]) 
• Any ocular/visual symptoms TEAE (CMQ “Eye disorders exclude corneal disorders”) 
The AE summaries of Table 8 will be generated with number (%) of participants experiencing at 
least 1 event. The analyses will be performed for all grades combined and for Grade ≥3. 
Table 8 - 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 ramucirumab 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 ramucirumab 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 ramucirumab 
Primary SOC and PT 
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Type of AE 
MedDRA levels 
TEAE leading to deathb 
Primary SOC and PT 
TEAE related to tusamitamab ravtansine and leading to deathb 
Primary SOC and PT 
TEAE related to ramucirumab and leading to deathb 
 
AE leading to deathb 
 
- In context of disease progressionc 
 
- In context other than disease progressiond 
 
Pretreatment AE 
Overviewa 
 
Primary SOC and PT 
Pre-treatment SAE 
Primary SOC and PT 
Post-treatment AE 
Overviewa 
 
Primary SOC and PT 
Post-treatment SAE 
Primary SOC and PT 
TEAE leading to dose modification of tusamitamab ravtansine 
(including dose delay, dose reduction and dose omission) 
Primary SOC and PT 
TEAE leading to dose modification of ramucirumab (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 ramucirumab 
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 study 
intervention discontinuation (except for pretreatment) 
b Death as an outcome of the AE as reported by the Investigator in the AE page 
c Death within 30 days from last IMP administration and the cause of death is disease progression 
d Death within 30 days from last IMP administration and for whom cause of death is not disease progression or the death occurred more 
than 30 days from last IMP administration and the cause of death is AE 
Analysis of deaths 
In addition to the analyses of deaths included in Table 8 the number (%) of participants in the 
following categories will be provided: 
• Deaths during the treatment-emergent and post-treatment periods by study period and 
reason for death 
• 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 period,  
- 
Any Grade TEAE with a fatal outcome during the posttreatment 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 
AESIs and other AEs of interest will be selected for analyses as indicated in Table 9. Number (%) 
of participants experiencing at least 1 TEAE will be provided overall for AESIs, and for each 
other event of interest, by SOC and PT (if applicable). DLT observed during the DLT observation 
period will be listed in the DLT-evaluable population. Tables will be sorted as indicated in 
Table 7.  
Table 9 - 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 
defect 
e-CRF AESI specific tick box on the AE page. It could include events with PTs 
from SMQ “Conduction defects” (Narrow) 
Grade ≥3 liver enzyme increased 
(symptomatic or asymptomatic) 
e-CRF AESI specific tick box on the AE page. It could include Grade ≥3 PTs 
from the SMQ “Hepatic disorders” (Narrow and Broad) 
Symptomatic overdose (serious or 
nonserious) with IMP/NIMP 
e-CRF symptomatic overdose specific tick box on the Overdose page. 
Pregnancy of a female participant entered in 
a study as well as pregnancy occurring in a 
female partner of a male participant entered 
in a study with IMP/NIMP 
e-CRF specific tick box for AE linked to pregnancy on the Pregnancy page. 
DLT during DLT observation period 
e-CRF specific DLT page 
Other AEs of interest 
 
Any AE meeting DLT criteria beyond DLT 
observation period 
AEs reported on the e-CRF specific DLT page outside the DLT observation 
period 
Corneal events (reported as AEs) 
CMQ “Corneal events compound level” containing the PTs included in both 
SOC “Eye disorders” and SMQ “Corneal disorders” (Narrow) 
Ocular/visual adverse events (excluding 
corneal disorders) 
CMQ “Eye disorders exclude corneal disorders” containing the 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) 
Colitis events (excluding infective) 
CMQ “Colitis (excluding infective)” containing PTs included in HLT “Colitis 
(excl infective)”) 
Hypersensitivity events  
SMQ “Hypersensitivity” (Narrow) and adverse event occurring on the day or 
the day after the infusion 
Hepatic disorders adverse events 
SMQ “Hepatic disorders” (Narrow and Broad) 
Hematological adverse events 
SMQ “Haematopoietic cytopenias” (Narrow and Broad) 
AE related to COVID-19 illness 
SMQ “COVID-19” (Narrow) 
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An overview of corneal TEAEs will be provided with the following AE categories: any corneal 
TEAEs, Grade ≥3 corneal TEAEs, treatment-emergent corneal SAEs, corneal TEAEs related to 
IMP, Grade ≥3 corneal TEAEs related to IMP, corneal TEAEs leading to permanent full 
intervention discontinuation, corneal TEAEs leading to permanent partial discontinuation of 
tusamitamab ravtansine, and corneal TEAEs leading to dose modification (cycle delay, dose 
reduction, or dose omission) of tusamitamab ravtansine. 
A summary of treatment-emergent corneal events will be provided. 
• Cycle of first occurrence regardless of the grade 
• Cycle of first occurrence of the worst grade 
• Number (%) of participants by worst grade 
• Relationship to study intervention: in case of multiple occurrences in a single participant 
with different relationships, if any event is related, then the relationship will be considered 
as related for that participant 
• Action taken with the study intervention: in case of multiple occurrences with different 
actions in a single participant, the most severe action taken will be tabulated and selected 
according to the following order of severity: drug withdrawn, dose reduced, drug 
interrupted, dose not changed 
• Outcome: in case of multiple occurrences with different outcomes in a single participant, 
the most severe outcome will be tabulated and selected according to the following order of 
severity: fatal, not recovered or resolved, recovering and resolving, recovered and resolved 
with sequelae, recovered and resolved, unknown. 
In addition, analyses on occurrence and recurrence of corneal events will be provided. 
An occurrence of a corneal event will be defined as 1 or a group of concomitant corneal events. 
A recurrence will be defined as any occurrence of corneal event starting after a previously 
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 1 recovered or resolved occurrence of a corneal event (with or without 
sequelae), considering the longest duration among all occurrence 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.  
Beside the AE categorized as ocular/visual adverse events, all ocular symptoms (coded term) 
recorded in e-CRF will be reported as descriptive analysis. Same descriptive analysis will be done 
separately for ocular/visual symptoms associated to treatment-emergent corneal events (CMQ). 
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3.6.3 Additional safety assessments  
3.6.3.1  Laboratory variables, vital signs and electrocardiograms (ECGs)  
The following laboratory variables, vital signs and electrocardiogram (ECG) variables will be 
analyzed. They will be converted into standard international units. 
• Hematology and coagulation:  
- 
Red blood cells, platelets and coagulation: hemoglobin, hematocrit, red blood cell 
count, platelet count, prothrombin time (expressed as international normalized ratio 
[INR]) and activated partial thromboplastin time (aPTT). 
- 
White blood cells: white blood cell (WBC) count, neutrophils, lymphocytes, 
monocytes, basophils, eosinophils.  
• Clinical chemistry: 
- 
Metabolism: glucose, total protein and albumin. 
- 
Electrolytes: sodium, potassium, 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 × (4.0 – [serum albumin (g/L) × 0.1]), where 4.0 represents the 
average albumin level.  
- 
Renal function: creatinine, blood urea nitrogen (BUN), urea, estimated glomerular 
filtration rate (eGFR) by the Modification of Diet in Renal Disease (MDRD method. 
- 
Liver function: alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
alkaline phosphatase (ALP), lactate dehydrogenase (LDH), total and direct bilirubin. 
• Urinalysis: 
- 
Urinalysis dipstick: proteins, red blood cell count, white blood cell count, glucose, pH. 
- 
Urinalysis: protein assessed on 24 hour urine collection. 
• Vital signs: temperature, pulse rate, systolic and diastolic blood pressure, weight and 
Eastern Cooperative Oncology Group (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 biochemistry parameters, local normal ranges (LLN, ULN) will 
be used for grading. 
Quantitative analyses 
For vital signs and ECG variables above, descriptive statistics for results and changes from 
baseline will be provided for each planned visit, and the worst value (minimum and/or maximum 
value depending on the parameter) during the on-treatment period. These analyses will be 
performed using local measurements.   
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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 an 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 on-treatment period, using all measurements (either local or central, either scheduled, 
nonscheduled, or repeated). 
QTcF prolongation will be graded according to NCI-CTCAE Version 5.0. The frequency of 
participants in each grade of QTcF prolongation during the on-treatment period will be 
summarized. For participants with multiple occurrences of QTcF prolongation during the 
treatment, the maximum grade per participant will be used. 
For laboratory variables, vital signs and ECG variables above, the incidence of participants with at 
least 1 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 
The number (%) of participants with QTcF abnormality worsening during the on-treatment period 
(worst value per participant) according to baseline value will be displayed. 
For laboratory variables graded by NCI-CTCAE, 
• The number (%) of participants with abnormal laboratory tests at baseline will be 
presented by grade.  
• The number (%) of participants with abnormal laboratory tests during the treatment-
emergent period will be summarized by grade. When appropriate, the number (%) of 
participants with abnormality of any grade and with Grade 3-4 abnormalities will be 
provided.  
• For liver function, baseline status will be provided according to multiples of ULN.  
For laboratory variables not graded by NCI-CTCAE nor by PCSA, the number (%) of participants 
with laboratory tests outside normal ranges will be provided.  
For ECOG PS, the number (%) of participants in each grade (considering the worst grade during 
the TE period) will be provided according to baseline. 
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Additional analyses for drug-induced liver injury 
The following additional analyses will be performed for drug-induced liver injury:  
• For each liver function test (eg, ALT), participants having experienced a PCSA will be 
summarized considering worst on-treatment value. 
• An e-DISH-like plot of peak bilirubin/ULN versus peak alanine aminotransferase or 
aspartate aminotransferase (worst value)/ULN will be provided. The graph will be divided 
into 4 quadrants with a vertical line corresponding to 3 ULN for ALT/AST and 
a horizontal line corresponding to 2 ULN for total bilirubin.  
• For each liver function test (eg, ALT), participants having experienced a PCSA (eg, ALT 
>5 x 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 x ULN). 
3.6.3.2 Ophthalmological examinations  
Schirmer test 
Participants reported Schirmer’s test will be classified into 3 classes at baseline: normal 
(≥10 mm), moderate (<10 and >5 mm), severe (≤5 mm) (3). The worst classification between the 
laterality will be considered. A frequency table of the baseline status with and without 
anaesthetics will be provided for the participants with corneal events (CMQ) during the treatment-
emergent period and for the participants without an event.  
Visual acuity test 
Analyses are done on the best corrected visual acuity (BCVA) assessed using Snellen Chart 
method. 
Frequency tables on BCVA measured during the on-treatment period will be performed separately 
on all participants and on participants who experienced at least one treatment-emergent corneal 
event: 
• On the worst change from baseline: No worsening versus baseline (no line decrease), 
Worsening versus baseline (1 to 3 lines decrease versus baseline, or >3 lines decrease 
versus baseline). 
• On the worst absolute value: No change versus baseline, Worsening versus baseline 
(BCVA equals to 20/40 or better, BCVA worse than 20/40 up to 20/200, BCVA 20/200 or 
worse). 
• On the CTCAE worst vision decrease: BCVA equals to 20/40 or better or 1 to 3 lines 
decrease versus baseline, BCVA worse than 20/40 up to 20/200 or >3 lines decrease 
versus baseline, BCVA 20/200 or worse. 
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• For participants who had worsening versus baseline (at least one line decrease) on BCVA, 
the worst outcome on the last BCVA will be displayed: Recovered to baseline, Not 
recovered to baseline, Lost to follow-up or dead with ongoing corneal events. 
A participant will be considered as lost to follow-up if the participant discontinued the study and 
did not perform any follow-up visit.  
A shift table of the category of the last BCVA value (Normal (20/20 or better), worse than 20/20 
up to 20/40, worse than 20/40 up to 20/200 or 20/200 or worse) versus the category of the worst 
BCVA value (20/40 or better, worse than 20/40 up to 20/200, 20/200 or worse) will be performed 
for participants who experienced at least one treatment-emergent corneal event.  
For the summary table on participants who experienced at least one treatment-emergent corneal 
event, the worst value and the worst change from baseline are measured during any of the 
treatment-emergent corneal events experienced by the participant (between start date and end date 
of the corneal events). For summary table on all participants, all on-treatment BCVA values are 
considered. 
The worst classification between the laterality will be considered for the worst absolute value, the 
worst change from baseline and the last value separately even if not measured on the same eye. If 
the worst absolute value is the same for both eyes, then the eye with the worst change from 
baseline is considered, and if identical, then the eye with the worst last value is considered. 
Participants whose baseline visual acuity had been reported in naked eye instead of BCVA 
(ie, whenever the baseline value was worse than the values reported during the treatment 
period/treatment-emergent corneal event) will be excluded from this analysis. 
Slit lamp examination 
Descriptive statistics of slit lamp examination will be provided separately at baseline and at the 
time of first abnormal slit lamp after occurrence of a treatment-emergent corneal event, and at the 
time of the worst BCVA value during a treatment-emergent corneal event for participants 
experiencing treatment-emergent corneal events (CMQ). The outcome (normal, abnormal), and 
for abnormal findings, the type of lesions and the distribution will be described by laterality 
(unilateral, bilateral, all).  
3.7 
OTHER ANALYSES  
3.7.1 Other variables and/or parameters  
3.7.1.1 PK analyses  
All concentration values below the LLOQ will be treated as zero in individual listing and 
respective descriptive statistics. Geometric mean will not be computed in case at least 
one concentration is below LLOQ. 
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Individual observed predose concentrations (Ctrough) and concentrations observed at end of 
infusion (Ceoi, Ceoi+1h if any) of tusamitamab ravtansine and ramucirumab will be listed and 
summarized with standard descriptive statistics (such as the number of observations, arithmetic 
and geometric means, median, standard deviation, coefficient of variation, minimum, and 
maximum) by visit and by dose level (if applicable).  
For the descriptive statistics, Ctrough following any dose modification (delay or reduction as 
defined in Section 3.6.1.2) will be excluded. Ceoi and Ceoi+1h will be excluded following dose 
reduction.  
A graphical representation of mean Ctrough (±SD) profile over time, by drug in separate figure and 
by dose level superimposed in the same figure (if applicable), will be provided throughout the 
course of treatment. 
3.7.1.1.1 Population PK analyses  
The population PK analyses will be described in a specific document and the results will be 
presented separately from the clinical study report.  
3.7.1.1.2 IgG  
In the all-treated population, the level of IgG in blood at pre-infusion of Cycle 1 Day 1 will be 
summarized with standard descriptive statistics (such as the number of observations, arithmetic 
and geometric means, median, standard deviation, coefficient of variation, minimum and 
maximum) for tusamitamab ravtansine. A listing will also be provided. 
3.7.1.2 Immunogenicity analyses  
Participant’s ATA status, response variable, and kinetics of ATA responses (see definitions 
below) will be summarized on the ATA population.  
Kinetics of ATA responses will be described for participants with treatment-induced ATA and for 
participants with treatment-boosted ATA, separately. Time to ATA onset and duration of ATA 
will be described with minimum, Q1, median, Q3, and maximum statistics. 
Peak titer will be described with minimum, Q1, median, Q3, and maximum statistics for 
participants with treatment-induced ATA and for participants with treatment-boosted ATA, 
separately. 
Sample status (negative, positive, inconclusive) and titers will also be described overtime using 
descriptive statistics.  
The impact of positive immune response on efficacy, PK, and safety variables may be further 
explored, depending on ATA incidence. 
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Participant’s ATA status 
• Participants with pre-existing ATAs correspond to participants with ATAs present in 
samples drawn before first administration of intervention. Participants with missing ATA 
sample at baseline will be considered as without pre-existing ATA. 
• Participants with treatment-emergent ATA correspond to participants with at least 
1 treatment-induced/boosted ATA. 
- 
Participants with treatment-induced ATAs correspond to participants with ATAs that 
developed at any time after first IMP administration and without pre-existing ATA 
(including participants without pre-treatment samples). 
- 
Participants with treatment-boosted ATAs correspond to participants with pre-
existing ATAs that are boosted at any time after first IMP administration to a 
significant higher titer than the baseline. A 2-fold serial dilution schema is used during 
titration, so at least a 4-fold increase will be considered as significant.  
• Participants with unclassified ATA correspond to participants with pre-existing ATAs 
that cannot be classified as treatment-boosted ATA because of missing titer(s) 
(ie, a positive ATA sample at any time after first IMP administration in a participant with 
pre-existing ATA but with missing titer at this sample or at baseline). 
• Participants without treatment-emergent ATA correspond to participants without 
treatment-induced/boosted ATA and without any inconclusive sample nor unclassified 
ATA at any time after first IMP administration. 
• Participants with inconclusive ATA are defined as participants which cannot irrefutably 
be classified as with or without treatment-emergent ATA. 
Kinetics of ATA response 
Kinetics of ATA response will be derived for participants with treatment-induced/boosted ATA. 
• Time to onset of ATA response is defined as the time period between the first IMP 
administration and the first treatment-induced/boosted ATA.  
• Duration of ATA response is defined as the time between the first treatment-induced/ 
boosted ATA and the last treatment-induced/boosted ATA, irrespective of negative 
samples or positive samples not reaching the boosted threshold in-between. ATA duration 
will be summarized only for participants with persistent ATA response.  
• Persistent ATA response is defined by treatment-induced/boosted ATA with a duration 
of ATA response of at least 16 weeks.  
• Transient ATA response is defined by treatment-induced/boosted ATA with a duration 
of ATA response of less than 16 weeks and the last sample is not treatment-
induced/boosted.  
• Indeterminate ATA response is defined by treatment-induced/boosted ATA that are 
neither persistent nor transient. 
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ATA response variable: 
• ATA incidence is defined as the proportion of participants found to have seroconverted 
(treatment-induced ATAs) or boosted their pre-existing ATA response (treatment-boosted 
ATAs) at any time after first IMP administration. 
3.7.1.3 Biomarker analyses  
Several exploratory objectives related to pharmacodynamic endpoints will be considered in this 
study. 
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. 
3.7.1.3.1 Circulating CEA levels before IMP and CEACAM5 IHC  
In the pre-screened population, the CEACAM5 IHC expression status (negative (0%), moderate 
(1-49%) and high expressers (≥50%) based on the % of cells expressing CEACAM5 at the 
membrane with intensity >= 2+) and the H-score will be described using descriptive statistics. 
Circulating CEA levels before IMP will be correlated with IHC CEACAM5 expression status (for 
prescreened participants). To this end, the closest circulating CEA assessment to biopsy (or the 
oldest value before IMP if the date of the biopsy is missing) will be considered. The circulating 
CEA levels (quantitative and by thresholds) will be presented using descriptive statistics by IHC 
CEACAM5 expression status (negative, moderate and high CEACAM5 expressers) and overall. 
The correlation between the circulating CEA levels (quantitative) and the IHC CEACAM5 
expression will be also assessed, and graphically visualized. To this end, Pearson correlation, 
Spearman’s rank, or Kendall’s tau coefficient will be considered depending on the nature of the 
data. The time between the tumor biopsy specimen collection date and the date of the considered 
circulating CEA assessment will also be described and investigated in the correlation. 
To evaluate the variability of circulating CEA values before IMP, an intraclass correlation 
coefficient will be calculated between circulating CEA values (when two values are available). 
A graphical visualization may be provided to observe the degree of concordance.  
3.7.1.3.2 Circulating CEA levels at baseline and clinical response  
Circulating CEA levels before IMP administration will be correlated with confirmed objective 
response (for all treated participants). To this end, the last circulating CEA assessment before 
(closest to) IMP administration will be considered and reported as the baseline value.  
Baseline circulating CEA values will be presented using descriptive statistics by response status 
and overall. The confirmed objective response rate and two-sided 95% CIs using the Clopper-
Pearson method will be presented for each circulating CEA subgroups (base on the predefined 
thresholds).  
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The correlation between the circulating CEA levels (quantitative) and the tumor burden at 
baseline will be also assessed and visualized graphically. To this end, Pearson correlation, 
Spearman’s rank, or Kendall’s tau coefficient will be considered depending on the nature of the 
data. 
3.7.1.3.3 Modulations of circulating CEA as a potential PD biomarker of response to 
tusamitamab ravtansine treatment  
A graphic visualization (spaghetti plot) will show the relative change from baseline of circulating 
CEA values for each participant, and will be annotated with the BOR. 
3.7.1.3.4  Mutational profiling   
Genomic alterations locally assessed and entered in the eCRF at prescreening as per protocol will 
be presented. For each gene, participants will be grouped into two groups: “altered” 
(ie, participants with at least one alteration for the gene) and “wild-type” (ie, participants without 
alteration for the gene) and described using descriptive statistics by IHC CEACAM5 expression 
and overall. The confirmed objective response rate and two-sided 95% CIs using the Clopper-
Pearson method will be presented for each gene in the all-treated population. 
Circulating-free DNA (cfDNA) centrally assessed may be also generated and will be analyzed in 
the same way as genomic alterations entered locally in the eCRF. 
3.7.1.4 Analyses of pharmacokinetic/pharmacodynamic  
Efficacy endpoints for PK/PD analysis include response status, tumor shrinkage (eg, best relative 
tumor shrinkage or best tumor shrinkage). The relationship between those endpoints and PK will 
be assessed through descriptive statistics and plots.  
The relationship between response status and the prognostic PK parameters may be analyzed by 
fitting a logistic regression model if a sufficient number of responses is observed. Moreover, if 
relevant, the relationship between best relative tumor shrinkage and the prognostic PK parameters 
may be analyzed by fitting a linear regression model. 
3.7.2 Subgroup analyses  
To assess the homogeneity of the treatment effect across various subgroups, analyses will be 
performed on the primary efficacy endpoint (defined in Section 3.2.1.2) across the following 
subgroups (categories with fewer than 5 participants may be combined with other categories): 
• Race (White, Black or African American, Asian, Other) 
• Age group (<65, ≥65 years)  
• Sex (Male, Female) 
• ECOG PS at baseline (0, 1) 
• PD-L1 expression (<1%, ≥1%; <5%, ≥5%) 
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• Circulating CEA at baseline (<100, ≥100 μg/L; <80, ≥80 μg/L and <50, ≥50 μg/L) 
• Prior ICI treatment administration (Sequential, Combination with chemotherapy, no ICI) 
• Time from initial diagnosis (<12 months, ≥12 months) 
• Number of organs involved (excluding primary tumor location) (<3, ≥3) 
• Tumor burden at baseline, ie, sum of the longest diameters of the target lesions (<100 mm, 
≥100 mm) 
• Primary tumor (Gastric, GEJ) 
• Previous treatment (doublet [FOLFOX or XELOX], triplet [other Chemotherapy+FOLFOX 
or other Chemotherapy+XELOX]) 
• Histology types (Intestinal, Diffuse, Mixed, Other) 
• Peritoneal metastases (Yes, No) 
• Previous gastrectomy (Partial, Total, No) 
• Presence of ascites (Yes, No) 
• Time to PD on first-line: <6 months; ≥6 months 
• Region (Europe, East Asia, Other region) 
• Prior treatment with a HER2 therapy (Yes, No) 
If a sufficient number of responses is observed tables/plots will be provided, otherwise subgroup 
information will be displayed in listings only. For tables, objective response rate estimate and the 
corresponding 95% CI will be provided for each subgroup using the same method as applied to 
the primary analysis. Forest plots will be provided. 
3.8 
INTERIM ANALYSES  
No formal interim analysis is planned in this study. 
The study analysis will be conducted in 2 steps. 
The first analysis step will be conducted when all evaluable 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 approximatively 16 weeks 
after the date of the first IMP administration of the last participant: 12 weeks for 2 tumor 
assessment, and 4 weeks if a confirmation of response is needed. 
The second analysis step will be based on the study cut-off date for analysis of the secondary 
efficacy endpoints, which include DOR and PFS, 4 months after the study cut-off date for the 
primary analysis. At that time, the primary analysis of ORR and DCR will also be updated. 
The final analysis will be conducted at the end of the study. Only safety analyses will be updated 
at this time. 
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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 analysis step and second analysis step). 
Analyses methods and conventions described in the other sections of this SAP will be applied for 
all analyses if applicable. The following additional rules will apply at the first analysis step and 
second analysis step: 
• Participants without end of treatment status performed at the time of the analysis cut-off 
date will be considered as ongoing. Therefore: 
- 
Participants who did not discontinue the study intervention at the analysis cut-off date 
will be analyzed as “ongoing” in the disposition summary. 
- 
Their TE period and concomitant medication period will end at the analysis cut-off 
date. 
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4 
SAMPLE SIZE DETERMINATION 
The safety run-in (Part 1) aims to confirm the recommended dose of tusamitamab ravtansine 
loading dose Q2W in combination with ramucirumab according to DLTs observed. 
Part 2 of this study is designed to obtain preliminary efficacy, safety, and PK data on tusamitamab 
ravtansine loading dose Q2W administered in combination with ramucirumab to participants with 
gastric or GEJ adenocarcinoma. As Part 2 is not intended to explicitly test a hypothesis, 
calculations of power and Type I error were not considered in the study design. 
Assuming a prescreening failure rate of 70% and a study screen failure rate of 20%, 
approximatively 158 participants will be prescreened to achieve up to approximatively 38 treated 
participants in the safety run-in (Part 1) and Part 2.  
Sample size for the safety run-in (Part 1): 
The actual sample size is expected to vary depending on DLTs observed. It is anticipated that 
around 6 to 12 DLT-evaluable participants will be enrolled in the safety run-in part of the study. 
Sample size for Part 2: 
The initial plan is to treat a total of 32 participants evaluable for activity (at least 1 postbaseline 
evaluable tumor assessment, early clinical progression, or death due to disease progression). The 
6 participants treated at the recommended DL in the safety run-in part will also be evaluable for 
the second part of the study.  
Estimated ORR and 95% exact CIs by number of responders from a sample size of 32 evaluable 
participants for activity are listed in Table 10: 
Table 10 - Estimated objective response rate (ORR) depending on number of responders 
Number of responders 
(N=32) 
Objective response rate in % 
(95% Clopper-Pearson CI) 
Abbreviation: CI = confidence interval 
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5 
SUPPORTING DOCUMENTATION  
5.1 
APPENDIX 1 LIST OF ABBREVIATIONS  
 
ADI: 
actual dose intensity 
AEs: 
adverse events 
AESI: 
adverse event of special interest 
ALP: 
alkaline phosphatase 
ALT: 
alanine aminotransferase 
AST: 
aspartate aminotransferase 
ATA: 
antitherapeutic antibody 
BCVA: 
best corrected visual acuity 
BOR: 
best overall response 
BUN: 
blood urea nitrogen 
CEA: 
carcinoembryonic antigen 
CEACAM5: 
carcinoembryonic antigen related cell adhesion molecule 5 
cfDNA: 
circulating-free deoxyribonucleic acid 
CI: 
confidence interval 
CMQ: 
company MedDRA queries 
COVID-19: 
coronavirus disease 2019 
CR: 
complete response 
CTCAE: 
common terminology criteria for adverse events 
DCR: 
disease control rate 
DL: 
dose level 
DLT: 
dose-limiting toxicity 
DOR: 
duration of response 
ECG: 
electrocardiogram 
ECOG: 
Eastern Cooperative Oncology Group 
eGFR: 
estimated glomerular filtration rate 
EOT: 
end of treatment 
GEJ: 
gastroesphageal junction 
HLGT: 
high level group term 
HLT: 
high-level term 
IHC: 
ImmunoHistoChemistry 
IMP: 
investigational medicinal product 
INR: 
international normalized ratio 
IRT: 
interactive response technology 
ITT: 
intent-to-treat 
LDH: 
lactate dehydrogenase 
LLN: 
lower limit of normal 
LLOQ: 
lower limit of quantification 
LLT: 
lower-level term 
MDRD: 
modification of diet in renal disease 
MedDRA: 
Medical Dictionary for Regulatory Activities 
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NCI: 
National Cancer Institute 
ORR: 
objective response rate 
PCSA: 
potentially clinically significant abnormalities 
PD: 
progressive disease 
PDI: 
planned dose intensity 
PFS: 
progression-free survival 
PK: 
pharmacokinetic 
PR: 
partial response 
PS: 
performance status 
PT: 
preferred term 
RD: 
recommended dose 
RDI: 
relative dose intensity 
RECIST: 
response evaluation criteria in solid tumors 
SAEs: 
serious adverse events 
SAP: 
statistical analysis plan 
SD: 
stable disease 
SOC: 
system organ class 
TE: 
treatment-emergent 
TEAE: 
treatment-emergent adverse event 
ULN: 
upper limit of normal 
ULOQ: 
upper limit of quantification 
WHO-DD: 
World Health Organization-drug dictionary 
 
5.2 
APPENDIX 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. 
Prescreen failures are defined as participants who consent to participate in the prescreening phase 
of the study but are not subsequently screened. The number (%) of prescreen failures and reasons 
for prescreen failures will be provided in the prescreened population. 
Screen failures are defined as participants who consent to participate in the study but are not 
subsequently enrolled. The number (%) of screen failures and reasons for screen failures will be 
provided in the screened population. 
Regarding intervention discontinuation, the following definitions will be used: 
• Permanent partial intervention discontinuation is defined as the discontinuation of 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 
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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 
study 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 ramucirumab 
• Participants who discontinued the study, and main reason for study discontinuation  
Reasons for permanent full/partial study intervention and study discontinuation such as “adverse 
event” and “other reasons” will be split as related versus not related to COVID-19 (if applicable). 
Any treated and not enrolled participants will also be listed.  
In addition, the number (%) of participants pre-screened, pre-screened failed, screened, screened-
failed, enrolled, enrolled and treated, with permanent full intervention discontinuation and with 
early study discontinuation will be provided by country and site.  
For all categories of participants (except for prescreened, screened, and nonenrolled categories), 
the percentage 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). 
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. 
Demographic and baseline characteristics  
• Age in years as quantitative variable and in categories (<65, 65 to <75, ≥75) 
• Sex (Male, Female) 
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• Race (American Indian or Alaska Native, Asian, Black or African American, Native 
Hawaiian or Other Pacific Islander, White, Not reported, Unknown) 
• Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not reported, Unknown) 
• Region (Europe [Belgium, Russian and Spain], East Asia [Japan, Korea], other region 
[Turkey]) 
• ECOG PS (0,1) 
• Weight in kg as a quantitative variable 
• BSA in m² as a 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 (gastric, GEJ), histopathology type, staging, 
Siewert-Stein classification, histology type, time from initial diagnosis to first administration of 
IMP (in months). 
Specific disease status at study entry includes extend of diseases, number (both excluding and 
including primary tumor location) and type of organs involved (including primary tumor 
location), ascites presence, PD-L1 expression (<1%, ≥1% and <5%, ≥5%), Peritoneal metastases 
(Yes, No).  
CEACAM5 expression, circulating CEA (<100 µg/L, ≥100 µg/L, <80 µg/L, ≥80 µg/L, <50 µg/L, 
≥50 µg/L, <5 µg/L, ≥5 µg/L and <3 µg/L, ≥3 µg/L) and type of tumor biopsy (archival /fresh) will 
also be described.  
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 taken 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 for 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 the Section 6.1 of the study protocol, participants receive premedications prior to 
ramucirumab administration to prevent from infusion related allergic reactions to tusamitamab 
ravtansine and/or ramucirumab. Premedications are defined as non-investigational medicinal 
products and are reported on a specific e-CRF page.  
Anticancer therapies  
Prior anticancer therapies include anticancer treatment, surgery related to gastric cancer and 
radiotherapy.  
• Number (%) of prior anticancer therapies including neoadjuvant, adjuvant and advanced 
regimen 
• Number of participants with intent: 
- 
Neoadjuvant and adjuvant and advanced 
- 
Neoadjuvant or adjuvant and advanced 
- 
Neoadjuvant or adjuvant only 
- 
Advanced only 
• Number (%) of prior anticancer therapies in the advanced setting 
• Type of prior anticancer treatment including neoadjuvant, adjuvant and advanced 
regimens: 
- 
Biologics and small molecules 
- 
Tyrosine kinase inhibitor (TKI): EGFR inhibitors, antiangiogenics, BRAF kinase 
inhibitors, ALK inhibitors, RAS/RAF/MEK/ERK signaling pathway inhibitors, 
ROS1 inhibitors 
- 
Immune checkpoint inhibitor (ICI) 
- 
Anti-VEGF/VEGFR 
- 
Targeted therapies (HER2 therapy, Other) 
- 
Others 
- 
Chemotherapy: Doublet (FOLFOX or XELOX), Triplet (other 
Chemotherapy+FOLFOX or other Chemotherapy+XELOX), Other Chemotherapy 
(Chemotherapy+HER2, Chemotherapy + ICI, Chemotherapy+HER2+ICI) 
- 
Antibody drug conjugate (ADC) 
- 
Others 
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• Summary of last anticancer therapy: 
- 
Time from completion of last regimen to first administration of IMP (in months) 
- 
Time to disease progression on first-line <6 months; ≥6 months 
- 
Main treatments of last regimen 
- 
Doublet (FOLFOX or XELOX) 
- 
Triplet (other Chemotherapy+FOLFOX or other Chemotherapy+XELOX) 
- 
Other Chemotherapy (Chemotherapy+HER2, Chemotherapy + ICI, 
Chemotherap+HER2+ICI) 
- 
Best response to the last regimen 
- 
Reason for discontinuation of the last line of therapy 
• Prior surgery: number (%) of participants with any prior surgery related to gastric cancer, 
type of surgery (total and partial gastrectomy), and time from the last surgery to the 
first administration of IMP (in years) 
• Prior radiotherapy: number (%) of participants with any prior radiotherapy related to 
gastric cancer, intent, analgesic intent (if palliative), and time from last dose of 
radiotherapy to first administration of IMP (in years) 
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. 
Corrected QT formula 
The QTc parameter will be derived following the Fridericia method: 
QTcF = QT/RR0.33 
Where RR interval (in seconds) is 60 divided by heart rate. 
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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 (4) are provided in tables below. 
Table 11 - 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 
Fraction of 1 
0.41 
0.53 
Hematocrit 
F 
Fraction of 1 
0.36 
0.46 
Hemoglobin 
M 
g/L 
135 
175 
Hemoglobin 
F 
g/L 
120 
160 
Leukocytes (WBC) count 
 
10^9/L 
4.5 
11 
Lymphocytes 
 
10^9/L 
1 
2 
Monocytes 
 
10^9/L 
0.18 
0.5 
Neutrophils 
 
10^9/L 
1.8 
3.15 
Platelets count 
 
10^9/L 
150 
350 
Prothrombin time 
 
INR 
0.8 
1.2 
Table 12 - 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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Statistical Analysis Plan 
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SAR408701-ACT16444 - tusamitamab ravtansine 
Version number: 1 
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6 
REFERENCES  
 
 
1. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New 
guidelines to evaluate the response to treatment in solid tumors. European Organization for 
Research and Treatment of Cancer, National Cancer Institute of the United States, National 
Cancer Institute of Canada. 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. Akpek EK, Amescua G, Farid M, Garcia-Ferrer FJ, Lin A, Rhee MK, et al. Dry Eye 
Syndrome Preferred Practice Pattern®. Ophthalmology. 2019;126(1):P286-334. 
4. Kratz A, Ferraro M, Sluss PM, Lewandrowski KB. Laboratory reference values. New England 
Journal of Medicine. 2004;351(15):1548-63. 
 
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