Conditions: Metastatic Neoplasm
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 65
Healthy volunteers: no

Brief summary:
Primary Objectives:

* Part 1
* To characterize the safety and tolerability of SAR442720 in combination with pembrolizumab in participants with advanced solid tumors.
* To define the MTD and RP2D for the combination of SAR442720 and pembrolizumab in participants with solid tumors.
* Part 2
* To determine the anti-tumor activity of SAR442720 in combination with pembrolizumab.
* Part 3A
* To define the MTD and RP2D for the combination of SAR442720 and adagrasib in participants with KRAS G12C NSCLC
* To characterize the safety and tolerability of SAR442720 in combination with adagrasib in participants with KRAS G12C NSCLC
* Part 3B
* To determine the anti-tumor activity of SAR442720 in combination with adagrasib in participants with KRAS G12C NSCLC
* Part 4
* To evaluate the impact of food on the PK of SAR442720 when dosed with pembrolizumab.
* To evaluate the impact of the formulations (formulation 1 and formulation 2) on the PK of SAR442720 when dosed with pembrolizumab.

Secondary Objectives:

* Part 1
* To assess the PK of SAR442720 with pembrolizumab, and the PK of pembrolizumab with SAR442720.
* To estimate the anti-tumor effects of SAR442720 with pembrolizumab.
* Part 2
* To assess the safety profile of SAR442720 combined with pembrolizumab.
* To assess other indicators of anti-tumor activity.
* To assess the PK of SAR442720 with pembrolizumab, and the PK of pembrolizumab with SAR442720.
* Part 3A
* To characterize the PK of SAR442720 with adagrasib, and the PK of adagrasib with SAR442720.
* To estimate the anti-tumor effects of SAR442720 with adagrasib
* Part 3B
* To assess the safety profile of SAR442720 with adagrasib in participants with KRAS G12C NSCLC.
* To assess other indicators of anti-tumor activity.
* To assess the PK of SAR442720 with adagrasib, and the PK of adagrasib with SAR442720.
* Part 4
* To assess the safety and tolerability of SAR442720 formulations with pembrolizumab
* To estimate the anti-tumor effects of SAR442720 with pembrolizumab.

Detailed description:
This open label Phase 1 multicenter study was designed to evaluate the safety and maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of SAR442720 in combination with pembrolizumab in participants with solid tumors in Part 1.

In Part 2, in the expansion cohort (Cohort A) we assessed the antitumor activity and safety of SAR442720 combined with pembrolizumab in participants with metastatic 1L lung cancer.

In Part 3, we evaluated the safety, MTD, RP2D and antitumor activity of SAR442720 in combination with adagrasib in participants with lung cancer and KRAS G12C mutation.

In Part 4, we evaluated the impact of the formulations (formulation 1 and formulation 2) and of the food on the PK of SAR442720 when dosed in combination with pembrolizumab. The expected duration of study intervention for participants may vary, based on progression date; median expected duration of study per participant was estimated to be about 10 months in Part 1, Part 3 and Part 4 (up to 1 month for screening, a median of 6 months for treatment, and a median of 3 months for long term follow-up) and in Part 2 16 months (up to 1 month for screening, a median of 12 months for treatment and a median of 3 months for long term follow up.)

Arms:
arm 1: Participants were administered SAR442720 140 milligram (mg) orally twice a week (BIW) on Days 1 and 4 along with pembrolizumab 200 mg via intravenous (IV) infusion once every 3 weeks (Q3W) in 21-day cycles until disease progression, unacceptable adverse events (AEs), or the participant's or investigator's decision to stop the treatment. arm 2: Participants were administered SAR442720 200 mg orally BIW on Days 1 and 2 along with pembrolizumab 200 mg via IV infusion Q3W in 21-day cycles until disease progression, unacceptable AEs, or the participant's or investigator's decision to stop the treatment. arm 3: Participants with programmed death-ligand 1 (PD-L1) tumor proportion score (TPS)\>=50% non-small cell lung cancer (NSCLC) were administered SAR442720 200 mg orally BIW on Days 1 and 2 in 21-day cycles along with an IV infusion of pembrolizumab 200 mg on Q3W (21 days cycle) or 400 mg once in every 6 weeks (Q6W) (42 days cycle) until disease progression, unacceptable AEs, consent withdrawal, or the participant's or investigator's decision to stop the treatment. arm 4: Participants with PDL1 TPS 1% - 49% NSCLC were administered SAR442720 200 mg orally BIW on Days 1 and 2 in 21-day cycles along with an IV infusion of pembrolizumab 200 mg on Q3W (21 days cycle) or 400 mg Q6W (42 days cycle) until disease progression, unacceptable AEs, consent withdrawal, or the participant's or investigator's decision to stop the treatment. arm 5: Participants were administered SAR442720 100 mg orally BIW on Days 1 and 2 along with adagrasib 400 mg orally twice daily (BID) in 21-day cycles until disease progression, unacceptable AEs, consent withdrawal, or the participant's or investigator's decision to stop the treatment. arm 6: Participants were administered SAR442720 200 mg orally BIW on Days 1 and 2 in 21-day cycles (as tablet during the first cycle and as capsule from Cycle 2) along with an IV infusion of pembrolizumab 200 mg Q3W (21-day cycle)or 400 mg Q6W (42-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or the participant's or investigator's decision to stop the treatment.

Interventions: intervention 1: Vociprotafib intervention 2: Pembrolizumab intervention 3: Adagrasib
Intervention descriptions: intervention 1: Pharmaceutical form: Varies Route of administration: Varies intervention 2: Pharmaceutical form:Sterile Lyophilized powder for reconstitution Route of administration: Infusion intervention 3: Pharmaceutical form:Sterile Tablet Route of administration: Oral

Protocol document:
Prot_000.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 
Based on Template: Sanofi OneDocument Version 2.0, dated 14-OCT-2019 
Page 1 
AMENDED CLINICAL TRIAL PROTOCOL 04 
Protocol title: 
A Phase 1/2, open-label, multicenter, dose escalation and 
dose expansion study of SAR442720 in combination with 
other agents in participants with advanced malignancies 
Protocol number: 
TCD16210 
Amendment number: 04 
Compound number 
(INN/Trademark): 
SAR442720 
Study phase: 
Phase 1/2 
Short title: 
Safety and efficacy study of SAR442720 in combination 
with other agents in advanced malignancies  
Sponsor name: 
Sanofi Research and Development 
Legal registered 
address: 
1 avenue Pierre Brossolette 
Chilly Mazarin, 91380 France 
Monitoring Team’s 
Representative Name 
and Contact 
Information 
Regulatory agency identifier number(s): 
IND: 
EudraCT: 
NCT: 
WHO: 
EUDAMED 
Other: 
147102 
2020-000436-22 
NCT04418661  
Not applicable 
Not applicable 
Not applicable 
Date: 
26-Oct-2021
Total number of pages: 178 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES  
DOCUMENT HISTORY 
 
Document 
Country/countries 
impacted by 
amendment 
Date, version 
Amended Clinical Trial Protocol 04 
All 
26-Oct-2021, version 1 (electronic 6.0) 
Amended Clinical Trial Protocol 03 
All 
29-Mar-2021, version 1 (electronic 5.0) 
Amended Clinical Trial Protocol 02 
All 
02-Jul-2020, version 1 (electronic 4.0) 
Amended Clinical Trial Protocol 01 
All 
06-Mar-2020, version 1 (electronic 3.0) 
Original Protocol 
 
27-Jan-2020, version 1 (electronic 1.0) 
Amended protocol 04 (26-Oct-2021) 
This amended protocol (amendment 04) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union because it significantly impacts the safety or physical/mental integrity of 
participants, or the scientific value of the study. 
OVERALL RATIONALE FOR THE AMENDMENT 
The following changes need to be implemented into the protocol of TCD16210 study: 
A new combination cohort with dose escalation and dose expansion parts in participants (NSCLC, 
KRAS G12C mutant) is to be added. Another cohort of 9 evaluable participants is added to assess 
the impact of the formulation and the preliminary impact of food on pharmacokinetic(s) of 
SAR442720 in combination with pembrolizumab. These will result in changes: in the overall 
study design, schedule of assessments, eligibility criteria, treatment duration, sample size, 
statistical considerations, and laboratory assessments etc. The safety sections of the protocol are 
updated in line with the most recent information available. 
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Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Title page 
Study title and short title were updated. 
The study title was updated to 
accommodate the new 
combination of SAR442720 and 
adagrasib (MRTX849). 
Section 1 (Protocol Summary) and 
Synopsis 
Two new cohorts (Part-3 and Part-4) were added in 
the study. 
Section 1 was updated according 
to the new information added 
related to the 2 new cohorts. 
Section 1 (Protocol Summary) – 
Section 1.3 
Tables of schedule of activities, PK time points, and 
pharmacodynamic/biomarker sampling time points 
were added for Part-3; and a table of PK time point 
was added for Part-4. 
Tables related to the new 
combination cohort with dose 
escalation and dose expansion 
parts and another new cohort to 
assess the impact of the 
formulation and the impact of food 
on PK of SAR442720 in 
combination with pembrolizumab 
were added. 
Section 2 (Introduction) 
Section 2.1 (Study Rationale): The purposes of the 
Part-3 and Part-4 were added. 
Section 2.2.2: A new sub-section was added to 
describe the mechanism of action of adagrasib. 
Section 2.2.6: A new sub-section was added to 
describe the rationale for combining SAR442720 
with adagrasib 
Section 2.3: The benefit/risk assessment section 
was updated as per the new adagrasib combination. 
Section 2.3.1.1 (Potential risks of SAR442720): This 
section was updated according to the new 
information added in the most recent Investigator’s 
Brochure (IB). 
Section 2.3.1.2 (Potential risks of pembrolizumab): 
This section was updated according to the new 
information added in the most recent USPI. 
Section 2.3.1.2 (Potential risks of SAR442720 and 
pembrolizumab administration): This section was 
updated according to the most recent IB. 
Section 2.3.1.4 and 2.3.1.5: New subsections were 
added to describe the potential risks of adagrasib 
and its combination with SAR442720. 
Section 2.3.3: Details of Study 849-001 of adagrasib 
were added. 
Section 2.3.4: The benefit and risk conclusion 
statement was updated as per the combination of 
SAR442720 and adagrasib. 
The overall introduction section 
was updated according to the 
requirements of Part-3 and Part-4 
of the study, and the sections 
related to SAR442720 and 
pembrolizumab were updated 
according to new information 
available in the most recent IB 
and USPI, respectively. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 3 (Objectives And 
Endpoints) 
Part-3 and Part-4 related objectives and endpoints 
were added to the table. Disease control rate (DCR) 
is also added as a secondary endpoint to assess 
anti-tumor activity in Part-2 as mentioned in Part-3B 
of the study. 
The overall study objectives and 
endpoints were adjusted to 
accommodate Part-3 and Part-4 
of the study. DCR is also added 
as an endpoint in Part-2, in 
alignment with Part-3B of the 
study. 
Section 4 (Study Design) 
Study design was updated for Part-3 and Part-4 of 
the study. Minor consistency related edits were 
made in the text for Part-2 study design in context to 
the respective SoA table (Section 1.3) of the study.  
Section 4.1.1 (Dose-limiting toxicity criteria): This 
section was updated to accommodate the 
requirements of Part-3A of the study. 
Section 4.1.2 (Dose escalation): This section was 
updated to accommodate the requirements of Part-3 
of the study. 
Section 4.2: The scientific rationale of the study 
design was updated for Part-3 and Part-4 of the 
study. 
Section 4.3: The justification for dose was updated 
for Part-3 and Part-4 of the study. 
The overall study design section 
was updated as per the addition 
of Part-3 and Part-4 of the study. 
Part-2 text updated for 
consistency with the respective 
SoA table. 
Section 5 (Study Population) 
Section 5.1 (Inclusion Criteria): Inclusion criteria, 
I01, I02, I03, I04, I05, I06, I07, and I09 were 
updated to differentiate which criteria belong to 
which part of the study and I12, and I13 for Part-3 
were added. 
Section 5.2 (Exclusion Criteria): E07 was updated to 
‘medically controlled atrial fibrillation >6 month’; 
Exclusion criteria, E08 and E10 were updated to 
differentiate which criteria belong to which part of 
the study; E11 was updated to included “active 
pneumonitis” and “radiation pneumonitis that 
required steroids is not permitted”; E13 updated with 
hepatitis-C virus; E14 updated to include ductal 
carcinoma in situ of the breast carcinoma as an 
exception; E22, E29, E30, and E31 for Part-3 were 
updated/added. 
Inclusion and exclusion criteria of 
the study were updated as per the 
study requirements and the 
addition of Part-3. 
Section 5.3.1 (Meals and Dietary 
Restrictions) 
Instructions for meal consumption for Part-3 and 
Part-4 participants were added. 
The instructions were updated for 
Part-3 and Part-4 participants. 
Section 6 (Study Intervention) 
Details of the new tablet formulation were added in 
Table 16. 
Table 17, a new table with details of adagrasib used 
as a new combination intervention in Part-3 of the 
study was added. 
Section 6.1.1 (Investigational medicinal product): 
the details of adagrasib for Part-3 added of the 
study were. 
Section 6.2: Adagrasib preparation/handling/storage 
details were added. 
The new study intervention of 
adagrasib was added for Part-3 
and the tablet formulation was 
added for Part-4. 
Updates were made for the Part-3 
combination. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 6.4 (Study intervention 
compliance) 
Details of study intervention compliance updated for 
Part-3 and Part-4 of the study. 
Updates were made for the Part-3 
and Part-4 of the study. 
Section 6.4.1 (Missed Dose) 
Instructions were added for participants if they 
missed any dose of adagrasib. 
Updates were made for the for 
Part-3 combination. 
Section 6.5.1 (Prohibited 
Concomitant Therapy) 
Details of the drugs that are prohibited while taking 
adagrasib were added along with exceptions for 
Part-3 of the study. 
Updates were made for the for 
Part-3 combination. 
Section 6.6 (Dose Modification) 
Dose modification and event management details 
for Part-3 and Part-4 were added throughout the 
section. 
The overall section was updated 
for Part-3 and Part-4. 
Section 6.7 (Intervention After the 
End of the Study) 
Details related to study intervention of SAR442720 
and pembrolizumab to be received by the 
participants were updated. 
This information was clarified 
Section 7.1 (Discontinuation of 
Study Intervention) 
Details of adagrasib added. 
This section updated as per 
Part-3 of the study. 
Section 8 (Study Assessments 
And Procedures) 
Section 8.1, Efficacy Assessments: Assessments 
for Part-3A and Part-4 were added. 
Efficacy assessments were 
updated according to the new 
Part-3A and Part-4 of the study. 
Section 8.3.6 (Disease-related 
events and/or disease-related 
outcomes not qualifying as AEs or 
SAEs) 
Section 8.3.6, was deleted. 
This was a correction; this section 
was not applicable to oncology 
studies. 
Section 8.3.7 (Adverse event of 
special interest) 
Section 8.3.7 previously, now as Section 8.3.6, This 
section was updated with the details of adagrasib 
overdose. 
Updated for the Part-3 
combination drug. 
Section 8.5 (Pharmacokinetics) 
Standard text in the section was updated as per the 
new template along with the details for Part-3 and 
Part-4 of the study. 
Updated per the new Sanofi 
protocol template and as per the 
Part-3 and Part-4 of the study. 
Section 8.6 (Pharmacodynamics) 
Details of Part-3 and Part-4 were added, and the 
section was updated according to the study 
requirements. 
Updated as per the Part-3 and 
Part-4 cohorts. 
Section 8.7 (Genetics) 
Standard text about genetics analyses from 
Section 8.5 was moved to this section as per the 
new template 
Updated per the new Sanofi 
protocol template. 
Section 8.8: (Biomarkers) 
The language in this section was updated for better 
presentation. 
Updated for the Part-3 
combination. 
Section 8.9: (Immunogenicity 
Assessments) 
Details of adagrasib were added. 
Updated to clarify applicable parts 
of the study. 
Section 9 (Statistical 
Considerations) 
The statistical hypothesis, sample size 
determination and population, general 
consideration, and efficacy and safety endpoints 
sections were updated 
Statistical considerations were 
updated according to the new 
Part-3 and Part-4 of the study. 
Section 10.2 (Appendix 2) 
Table 22, Protocol-required laboratory assessments 
updated. 
Updated as per the study 
requirements. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 10.3 (Appendix 3) 
Definition of AE was updated. 
Correction of the language used 
for the oncology study. 
Section 10.4 (Appendix 4) 
Duration for using any contraception measures 
(male/female) is updated from 4 months to 6 
months. 
Contraceptive guidance updated 
as per other similar study 
protocols. 
Section 10.5 (appendix 5) 
Tenure of genetic sample retention was updated 
from 10 years to 15 years. 
Updated to be consistent with the 
Sponsor’s other study protocols. 
Section 10.9 (Appendix 9) 
Dose modification guidelines for SAR442720 and 
adagrasib combination were added. 
Updated for the Part-3 
combination. 
Section 101.10 (Appendix 10) 
List of prohibited medications updated as per 
adagrasib addition in Part-3.  
Updated for the Part-3 
combination. 
Section 10.11 (Appendix 11) 
Dose escalations details for Part-3 were added. 
Updated for the Part-3 
combination. 
Section 10.13 (Appendix 13) 
A new appendix for ‘menus and composition for 
food effect study’ was added. 
Two tables (diet plan) were added 
for non-vegan and vegan 
participants in the new Part-4 of 
the study. 
Section 11 (Reference) 
Section 11 was updated with new references. 
Updated to account for the new 
citations added. 
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TABLE OF CONTENTS 
AMENDED CLINICAL TRIAL PROTOCOL 04 .............................................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................... 2 
TABLE OF CONTENTS .................................................................................................................................. 7 
LIST OF TABLES ......................................................................................................................................... 12 
LIST OF FIGURES ........................................................................................................................................ 13 
1 
PROTOCOL SUMMARY ............................................................................................................... 14 
1.1 
SYNOPSIS ..................................................................................................................................... 14 
1.2 
SCHEMA ........................................................................................................................................ 27 
1.3 
SCHEDULE OF ACTIVITIES (SOA) .............................................................................................. 30 
2 
INTRODUCTION ............................................................................................................................ 52 
2.1 
STUDY RATIONALE...................................................................................................................... 52 
2.2 
BACKGROUND ............................................................................................................................. 53 
2.2.1 
Pembrolizumab mechanism of action ............................................................................................ 54 
2.2.2 
Adagrasib mechanism of action ..................................................................................................... 54 
2.2.3 
Rationale for NSCLC...................................................................................................................... 54 
2.2.4 
Current standard of care in NSCLC ............................................................................................... 55 
2.2.5 
Rationale for combining SAR442720 with pembrolizumab ........................................................... 55 
2.2.6 
Rationale for combining SAR442720 with adagrasib .................................................................... 55 
2.3 
BENEFIT/RISK ASSESSMENT ..................................................................................................... 56 
2.3.1 
Risk assessment ............................................................................................................................ 57 
2.3.1.1 
Potential risks of SAR442720 ........................................................................................................ 57 
2.3.1.2 
Potential risks of pembrolizumab ................................................................................................... 61 
2.3.1.3 
Potential risks of SAR442720 and pembrolizumab administration ................................................ 62 
2.3.1.4 
Potential risks of adagrasib ............................................................................................................ 63 
2.3.1.5 
Potential risk for SAR442720 and adagrasib administration ......................................................... 63 
2.3.2 
COVID-19 risk assessment ............................................................................................................ 64 
2.3.3 
Benefit assessment ........................................................................................................................ 64 
2.3.4 
Overall benefit: risk conclusion ...................................................................................................... 65 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................. 66 
3.1 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 69 
4 
STUDY DESIGN ............................................................................................................................ 70 
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4.1 
OVERALL DESIGN ........................................................................................................................ 70 
4.1.1 
Dose-limiting toxicity criteria (Part-1 and Part-3A) ......................................................................... 75 
4.1.2 
Dose escalation .............................................................................................................................. 76 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ......................................................................... 77 
4.2.1 
Dose escalation rationale ............................................................................................................... 78 
4.3 
JUSTIFICATION FOR DOSE ........................................................................................................ 79 
4.4 
END OF STUDY DEFINITION ....................................................................................................... 80 
5 
STUDY POPULATION .................................................................................................................. 81 
5.1 
INCLUSION CRITERIA .................................................................................................................. 81 
5.2 
EXCLUSION CRITERIA ................................................................................................................ 83 
5.3 
LIFESTYLE CONSIDERATIONS ................................................................................................... 87 
5.3.1 
Meals and dietary restrictions ........................................................................................................ 87 
5.4 
SCREEN FAILURES...................................................................................................................... 88 
6 
STUDY INTERVENTION ............................................................................................................... 89 
6.1 
STUDY INTERVENTION(S) ADMINISTERED .............................................................................. 89 
6.1.1 
Investigational medicinal product ................................................................................................... 90 
6.1.2 
Non-investigational medicinal product ........................................................................................... 91 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY....................................................... 91 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ....................................... 92 
6.4 
STUDY INTERVENTION COMPLIANCE ...................................................................................... 92 
6.4.1 
Missed dose ................................................................................................................................... 92 
6.5 
CONCOMITANT THERAPY .......................................................................................................... 93 
6.5.1 
Prohibited concomitant therapy ..................................................................................................... 93 
6.6 
DOSE MODIFICATION .................................................................................................................. 94 
6.6.1 
Dose modification criteria ............................................................................................................... 94 
6.6.1.1 
General guidelines for adagrasib (Part-3) ...................................................................................... 94 
6.6.1.2 
Management of diarrhea ................................................................................................................ 96 
6.6.1.3 
Management of ophthalmologic complications .............................................................................. 97 
6.6.1.4 
Management of hypertension ........................................................................................................ 97 
6.6.1.5 
Management of rhabdomyolysis or symptomatic CPK increase ................................................... 97 
6.6.1.6 
Management of liver function abnormalities and hepatotoxicity .................................................... 98 
6.6.1.7 
Management of decrease in left ventricular ejection fraction ........................................................ 98 
6.6.1.8 
Management of hemorrhage .......................................................................................................... 98 
6.6.1.9 
Management of pyrexia ................................................................................................................. 98 
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6.6.1.10 Management of fatigue .................................................................................................................. 99 
6.6.1.11 Pneumonitis ................................................................................................................................... 99 
6.6.1.12 Management of edema .................................................................................................................. 99 
6.6.1.13 Management of rash ...................................................................................................................... 99 
6.7 
INTERVENTION AFTER THE END OF THE STUDY ................................................................... 99 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ......................................................................................... 100 
7.1 
DISCONTINUATION OF STUDY INTERVENTION .................................................................... 100 
7.1.1 
Definitive discontinuation ............................................................................................................. 100 
7.1.2 
Temporary discontinuation ........................................................................................................... 102 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY ................................ 102 
7.3 
LOST TO FOLLOW UP ............................................................................................................... 103 
8 
STUDY ASSESSMENTS AND PROCEDURES ......................................................................... 104 
8.1 
EFFICACY ASSESSMENTS ....................................................................................................... 104 
8.2 
SAFETY ASSESSMENTS ........................................................................................................... 105 
8.2.1 
Physical examinations ................................................................................................................. 105 
8.2.2 
Vital signs ..................................................................................................................................... 105 
8.2.3 
Weight and height ........................................................................................................................ 105 
8.2.4 
Electrocardiograms ...................................................................................................................... 106 
8.2.5 
Clinical safety laboratory assessments ........................................................................................ 106 
8.2.6 
ECOG performance status ........................................................................................................... 106 
8.2.7 
Retinal examinations .................................................................................................................... 106 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ......................................................... 107 
8.3.1 
Time period and frequency for collecting AE and SAE information ............................................. 107 
8.3.2 
Method of detecting AEs and SAEs ............................................................................................. 107 
8.3.3 
Follow-up of AEs and SAEs ......................................................................................................... 108 
8.3.4 
Regulatory reporting requirements for SAEs ............................................................................... 108 
8.3.5 
Pregnancy .................................................................................................................................... 108 
8.3.6 
Adverse event of special interest ................................................................................................. 109 
8.3.7 
Guidelines for reporting product complaints ................................................................................ 110 
8.4 
TREATMENT OF OVERDOSE .................................................................................................... 110 
8.5 
PHARMACOKINETICS ................................................................................................................ 110 
8.6 
PHARMACODYNAMICS ............................................................................................................. 111 
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8.7 
GENETICS ................................................................................................................................... 112 
8.8 
BIOMARKERS ............................................................................................................................. 112 
8.9 
IMMUNOGENICITY ASSESSMENTS ......................................................................................... 113 
8.10 
HEALTH ECONOMICS OR MEDICAL RESOURCE UTILIZATION AND HEALTH 
ECONOMICS ............................................................................................................................... 113 
8.11 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH .............................. 113 
9 
STATISTICAL CONSIDERATIONS ............................................................................................ 115 
9.1 
STATISTICAL HYPOTHESES ..................................................................................................... 115 
9.2 
SAMPLE SIZE DETERMINATION ............................................................................................... 115 
9.3 
POPULATIONS FOR ANALYSES ............................................................................................... 117 
9.4 
STATISTICAL ANALYSES .......................................................................................................... 117 
9.4.1 
General considerations ................................................................................................................ 117 
9.4.2 
Efficacy endpoint(s)...................................................................................................................... 118 
9.4.3 
Safety endpoint(s) ........................................................................................................................ 119 
9.4.3.1 
Adverse events ............................................................................................................................ 119 
9.4.3.2 
Clinical laboratory evaluations ..................................................................................................... 119 
9.4.4 
Other endpoint(s) ......................................................................................................................... 120 
9.5 
INTERIM ANALYSES .................................................................................................................. 120 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ...................... 121 
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ..... 121 
10.1.1 
Regulatory and ethical considerations ......................................................................................... 121 
10.1.2 
Financial disclosure...................................................................................................................... 122 
10.1.3 
Informed consent process ............................................................................................................ 122 
10.1.4 
Data protection ............................................................................................................................. 123 
10.1.5 
Committees structure ................................................................................................................... 123 
10.1.6 
Dissemination of clinical study data ............................................................................................. 124 
10.1.7 
Data quality assurance ................................................................................................................ 124 
10.1.8 
Source documents ....................................................................................................................... 125 
10.1.9 
Study and site start and closure ................................................................................................... 125 
10.1.10 Publication policy ......................................................................................................................... 126 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS ....................................................................... 126 
10.3 
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING .............................................. 128 
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10.3.1 
Definition of AE ............................................................................................................................ 128 
10.3.2 
Definition of SAE .......................................................................................................................... 129 
10.3.3 
Recording and follow-up of AE and/or SAE ................................................................................. 130 
10.3.4 
Reporting of SAEs........................................................................................................................ 132 
10.4 
APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION ............................................................................................................................ 133 
10.5 
APPENDIX 5: GENETICS ........................................................................................................... 135 
10.6 
APPENDIX 6: COUNTRY-SPECIFIC REQUIREMENTS ............................................................ 136 
10.7 
APPENDIX 7: RESPONSE EVALUATION CRITIERIA IN SOLID TUMORS (RECIST V1.1) ..... 136 
10.8 
APPENDIX 8: EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
PERFORMANCE STATUS SCALE ............................................................................................. 146 
10.9 
APPENDIX 9: GENERAL GUIDELINES FOR THE MANAGEMENT OF ADVERSE 
EVENTS ....................................................................................................................................... 147 
10.10 
APPENDIX 10: MEDICATION CLASSES THAT POTENTIALLY PROLONG QTC, 
STRONG CYP3A INHIBITORS AND/OR INDUCERS, PROTON PUMP INHIBITORS, H-2 
RECEPTOR ANTAGONISTS, STRONG P-GP INHIBITORS AND OTHER PROHIBITED 
MEDICATION CLASSES ............................................................................................................. 152 
10.11 
APPENDIX 11: SIMULATION REPORT – ASSESSMENT OF PERFORMANCE ...................... 154 
10.12 
APPENDIX 12: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY ................................. 162 
10.13 
APPENDIX 13: MENUS AND COMPOSITION FOR FOOD EFFECT STUDY ........................... 163 
10.14 
APPENDIX 14: ABBREVIATIONS ............................................................................................... 164 
10.15 
APPENDIX 15: PROTOCOL AMENDMENT HISTORY .............................................................. 166 
11 
REFERENCES ............................................................................................................................. 175 
 
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LIST OF TABLES  
Table 1 - Dose escalation for Part-1 .............................................................................................................. 19 
Table 2 - Schedule of activities (SOA) for Part-1 and Part-4 ........................................................................ 30 
Table 3 - Schedule of activities for Part-2 ..................................................................................................... 37 
Table 4 - Schedule of activities for Part-3 ..................................................................................................... 43 
Table 5 - PK time points for Part-1 and Part-2 .............................................................................................. 47 
Table 6 - PK time points (Part-3A dose escalation) ...................................................................................... 48 
Table 7 - PK time points (Part-3B Dose Expansion) ..................................................................................... 49 
Table 8 - PK time points for Part-4 ................................................................................................................ 50 
Table 9 - Pharmacodynamic/biomarker sampling time points (Part-1 and Part-2) ....................................... 51 
Table 10 - Pharmacodynamic/Biomarker sampling time points for Part-3 .................................................... 51 
Table 11 - Potential risks of SAR442720 ...................................................................................................... 59 
Table 12 - Objectives and endpoints ............................................................................................................. 66 
Table 13 - Dose escalation for Part-1 ............................................................................................................ 71 
Table 14 - Dose escalation for Part-3A ......................................................................................................... 73 
Table 15 - Dose escalation rule of the modified toxicity probability interval-2 method ................................. 79 
Table 16 - Overview of study interventions administered in Part-1, -2, and -4 ............................................. 89 
Table 17 - Overview of study interventions administered in Part-3 ............................................................... 90 
Table 18 - Estimated objective response rate (ORR) and 90% CI in Part-2 ............................................... 115 
Table 19 - Estimated objective response rate (ORR) and 90% CI in Part-3B ............................................ 116 
Table 20 - Populations for analyses ............................................................................................................ 117 
Table 21 - Summary of efficacy endpoints .................................................................................................. 118 
Table 22 - Protocol-required laboratory assessments ................................................................................ 127 
Table 23 - Time point response: Participants with target lesions (with or without nontarget lesions) ........ 144 
Table 24 - Time point response: Participants with nontarget lesions only .................................................. 144 
Table 25 - Best overall response when confirmation is required ................................................................ 145 
Table 26 - General guidelines ..................................................................................................................... 147 
Table 27 - Dose modification guidelines for combination regimens (SAR442720 and pembrolizumab 
combination or SAR442720 and adagrasib combination) ........................................................................... 148 
Table 28 - Option 1: Moderate-Calorie, Moderate-Fat Breakfast, Non-Vegan ........................................... 163 
Table 29 - Moderate-Calorie, Moderate-Fat Breakfast, Vegan ................................................................... 163 
 
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LIST OF FIGURES  
Figure 1 - Graphical study design of SAR442720 administered BIW and pembrolizumab 
every 3 weeks for Part-1................................................................................................................................ 27 
Figure 2 - Graphical study design of SAR442720 and pembrolizumab for Part-2 ........................................ 28 
Figure 3 - Graphical study design of SAR442720 and adagrasib for Part-3 ................................................. 29 
Figure 4 - Graphical study design of SAR442720 and pembrolizumab for Part-4 ........................................ 29 
Figure 5 - The RAS-MAPK pathway demonstrating the convergence nodal position of SHP2 in the 
pathway ......................................................................................................................................................... 54 
Figure 6 - DLT simulation scenarios ............................................................................................................ 156 
Figure 7 - Probability of a dose level selected as MTD for mTPI2 .............................................................. 158 
Figure 8 - Probability of a dose level selected as MTD for 3+3 .................................................................. 159 
Figure 9 - Mean number of participants per dose level for mTPI2 .............................................................. 160 
Figure 10 - Mean number of participants per dose level for 3+3 ................................................................ 161 
 
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1 
PROTOCOL SUMMARY  
1.1 
SYNOPSIS  
Protocol title: A Phase 1/2, open-label, multicenter, dose escalation and dose expansion study of 
SAR442720 in combination with other agents in participants with advanced 
malignancies.  
Short title: 
Safety and efficacy study of SAR442720 in combination with other agents in 
advanced malignancies 
Rationale: 
SAR442720 (also known as RMC-4630) is a potent, selective, and orally bioavailable Src 
Homology region 2 domain−containing protein tyrosine phosphatase 2 (SHP2) allosteric inhibitor. 
SHP2 is a positive regulator of RAS activation. SHP2 is also involved in signaling in T-cells. It 
binds with programmed cell death protein 1 (PD-1) following programmed death-ligand 1 
(PD-L1) stimulation and inhibits T cell activation. Therefore, targeting SHP2 may restore or even 
enhance T-cell functions. The costimulatory receptor CD-28, and to some extent the T-cell 
receptor, are dephosphorylated and de-activate some critical components of the interferon gamma 
(IFNγ) signaling cascade. Defects in this cascade have been described as a key component of 
resistance to anti-PD1 therapy. SHP2 inhibition may increase the efficacy of PD1 inhibitors in 
patients with high PD-L1 expression but may also sensitize patients with low PD-L1 expression to 
a PD1 inhibitor (1, 2).  
Immune Checkpoint Inhibitor (ICI) in combination with standard of care (SoC) 
chemotherapy/platinum doublet has significantly improved overall survival (OS) in non-small cell 
lung cancer (NSCLC). In dose escalation (Part-1), the aim of this study is to evaluate the safety, 
maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of SAR442720 in 
combination with ICI, pembrolizumab, in participants with solid tumors including 
advanced/metastatic NSCLC or colorectal cancer (CRC). In addition, expansion part (Part-2) of 
the study seeks preliminary clinical efficacy of SAR442720 in combination with pembrolizumab 
in participants with advanced solid tumors. 
As a positive downstream regulator of receptor tyrosine kinases and upstream regulator of RAS 
activation, SHP2 is an important target for tumors with active RAS cycling. The RAS family of 
oncogenes is frequently activated by mutations in human cancers, while KRAS G12C is the most 
frequent mutation in lung cancer. Targeted inhibition of the KRAS G12C mutation has been 
shown to be clinically effective for this previously intractable cancer (3, 4). Part-3 of this study 
will evaluate the safety, recommended Phase 2 dose (RP2D) and anti-tumor effect of SAR442720 
in combination with a KRAS G12C inhibitor, adagrasib (MRTX849), in participants with 
advanced NSCLC and KRAS G12C mutation. 
To evaluate the effect of food on the pharmacokinetic(s) (PK) of SAR442720 tablet and to assess 
the relative bioavailability of SAR442720 tablet formulation (test) compared to the SAR442720 
capsule formulation (reference) when dosed in combination with pembrolizumab in participants 
with advanced malignancies, the Sponsor is conducting Part-4 of the study. 
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Part-1 Dose Escalation (SAR442720 and pembrolizumab) 
Objectives 
Endpoints 
Primary 
• 
To characterize the safety and tolerability of 
SAR442720 in combination with pembrolizumab in 
participants with advanced solid tumors including 
non-small cell lung cancer (NSCLC) who 
progressed on anti-PD1/PD-L1 containing therapy 
and advanced CRC after progression to all standard 
of care (SoC) therapy. 
• 
Incidence, nature, and severity of 
treatment-emergent adverse events (AEs) and 
serious adverse events (SAEs), graded according to 
the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE) v5.0 for 
the combination of SAR442720 and 
pembrolizumab. 
• 
To define the MTD and RP2D for the combination of 
SAR442720 and pembrolizumab in participants with 
solid tumors. 
• 
Incidence of study drug-related dose limiting 
toxicities (DLTs) in Cycle 1. 
Secondary 
 
• 
To assess the pharmacokinetic(s) (PK) of 
SAR442720 in combination with pembrolizumab, 
and to assess the PK of pembrolizumab in 
combination with SAR442720. 
• 
Plasma concentrations of SAR442720 
• 
Serum concentrations of pembrolizumab 
• 
To estimate the anti-tumor effects of SAR442720 in 
combination with pembrolizumab in all participants. 
• 
Objective response rate (ORR) and duration of 
response (DoR) of SAR442720 and pembrolizumab 
in all participants. ORR of combination therapy with 
SAR442720 and pembrolizumab will be based on 
Response Evaluation Criteria in Solid Tumors 
(RECIST) v1.1. 
Part-2 Dose Expansion (SAR442720 and pembrolizumab) 
Objectives 
Endpoints 
Primary 
• 
To determine the anti-tumor activity of SAR442720 
in combination with pembrolizumab.  
• 
Objective response rate defined as the proportion of 
participants who have a confirmed complete 
response (CR) or partial response (PR) determined 
by the Investigator, per RECIST v1.1 
Secondary 
• 
To assess the safety profile of SAR442720 in 
combination with pembrolizumab. 
• 
Incidence of treatment-emergent adverse events 
(TEAEs), serious adverse events (SAEs), laboratory 
abnormalities according to National Cancer Institute 
Common Terminology Criteria for Adverse Events 
(NCI CTCAE) v5.0. 
• 
To assess other indicators of anti-tumor activity. 
• 
Time to response (TTR) defined as the time from 
the first administration of investigational medicinal 
product (IMP) to the first documented evidence of 
PR or CR determined by the Investigator per 
RECIST v1.1 (for NSCLC). 
• 
DoR, defined as the time from first documented 
evidence of CR or PR until progressive disease 
(PD) determined by the Investigator per 
RECIST v1.1 or death from any cause, whichever 
occurs first. 
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Objectives 
Endpoints 
• 
Clinical benefit rate (CBR) including confirmed CR 
or PR at any time or stable disease (SD) of at least 
6 months determined by the Investigator per 
RECIST v1.1. 
• 
Disease control rate (DCR) including confirmed CR 
or PR or SD as determined by the Investigator per 
RECIST v1.1. 
• 
Progression free survival (PFS), defined as the time 
from the date of first IMP administration to the date 
of the first documented disease progression 
determined by the Investigator as per RECIST v1.1 
or death due to any cause, whichever occurs first. 
• 
To assess the PK of SAR442720 in combination 
with pembrolizumab, and to assess the PK of 
pembrolizumab in combination with SAR442720. 
• 
Plasma concentrations of SAR442720. 
• 
Serum concentration of pembrolizumab. 
Part-3A Dose Escalation (SAR442720 and adagrasib) 
Objectives 
Endpoints 
Primary 
• 
To define the MTD and RP2D for the combination of 
SAR442720 and adagrasib in participants with 
NSCLC and KRAS G12C mutation. 
• 
To characterize the safety and tolerability of 
SAR442720 in combination with adagrasib in 
participants with NSCLC and KRAS G12C mutation. 
• 
Incidence of study drug-related DLTs in Cycle 1. 
 
 
• 
Incidence, nature, and severity of TEAEs and SAEs 
graded according to NCI CTCAE v5.0 for the 
combination of SAR442720 and adagrasib. 
Secondary 
• 
To characterize the PK of SAR442720 in 
combination with adagrasib, and to characterize the 
PK of adagrasib in combination with SAR442720. 
• 
PK parameters of SAR442720 (Cmax, Tmax, 
AUC0-last). 
• 
PK parameters of adagrasib (Cmax, Tmax, AUC0-last). 
• 
To estimate the anti-tumor effects of SAR442720 in 
combination with adagrasib in all participants. 
• 
ORR and DoR of SAR442720 and adagrasib in all 
participants. ORR of combination therapy with 
SAR442720 and adagrasib will be based on 
RECIST v1.1. 
Part-3B Dose Expansion (SAR442720 and adagrasib) 
Objectives 
Endpoints 
Primary 
• 
To determine the anti-tumor activity of SAR442720 
in combination with adagrasib in participants with 
NSCLC and KRAS G12C mutation. 
• 
ORR defined as the proportion of participants who 
have a confirmed CR or PR determined by the 
Investigator per RECIST v1.1. 
Secondary 
Objectives 
Endpoints 
• 
To assess the safety profile of SAR442720 when 
combined with adagrasib in participants with 
NSCLC and KRAS G12C mutation. 
• 
Incidence of TEAEs, SAEs, and laboratory 
abnormalities according to NCI CTCAE v5.0. 
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Objectives 
Endpoints 
• 
To assess other indicators of anti-tumor activity. 
• 
TTR defined as the time from the first administration 
of investigational medicinal product (IMP) to the first 
documented evidence of PR or CR determined by 
the Investigator per RECIST 1.1 (for NSCLC). 
• 
DoR, defined as the time from first documented 
evidence of CR or PR until progressive disease 
(PD) determined by the Investigator per 
RECIST 1.1 or death from any cause, whichever 
occurs first. 
• 
CBR including confirmed CR or PR at any time or 
SD of at least 6 months (determined by the 
Investigator per RECIST v1.1. 
• 
 DCR including confirmed CR or PR or SD as 
determined by the Investigator per RECIST v1.1. 
• 
PFS, defined as the time from the date of first IMP 
administration to the date of the first documented 
disease progression determined by the Investigator 
as per RECIST v1.1 or death due to any cause, 
whichever occurs first. 
• 
To assess the PK of SAR442720 in combination 
with adagrasib, and to assess the PK of adagrasib 
in combination with SAR442720. 
• 
Plasma concentrations of SAR442720 and 
adagrasib. 
Part-4 (SAR442720 and pembrolizumab) 
Objectives 
Endpoints 
Primary 
• 
To evaluate the impact of food on the PK of 
SAR442720 when dosed in combination with 
pembrolizumab. 
 
• 
To evaluate the impact of the formulation (tablets 
vs. capsules) on the PK of SAR442720 when dosed 
in combination with pembrolizumab. 
• 
Plasma PK parameters of SAR442720 following 
oral administration of SA442720 tablets in 
combination with pembrolizumab under fed and 
fasted states (eg. Cmax, Tmax, AUC0-last). 
• 
Plasma PK parameters of SAR442720 following 
oral administration of SAR442720 tablets (test 
formulation) and capsules (reference formulation) in 
combination with pembrolizumab under fasted state 
(eg, Cmax, Tmax, AUC0-last). 
Secondary 
• 
To assess the safety and tolerability of SAR442720 
under fasted and fed conditions in combination with 
pembrolizumab through the cycles, when dosing 
with capsule and tablet formulations in combination 
with pembrolizumab. 
• 
To estimate the anti-tumor effects of SAR442720 in 
combination with pembrolizumab in all participants. 
• 
Incidence, nature, and severity of TEAEs and 
SAEs, graded according to the NCI CTCAE v5.0 for 
SAR442720 in combination with pembrolizumab 
• 
ORR and DoR of SAR442720 and pembrolizumab 
in all participants. ORR of combination therapy with 
SAR442720 and pembrolizumab will be based on 
RECIST v1.1. 
 
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Overall design: 
This is a Phase 1/2 open-label, multi-center, safety, preliminary efficacy, and PK study of 
SAR442720 in combination with other agents in participants with advanced malignancies. 
Part-1 of the study is to characterize the safety and tolerability of SAR442720 in combination 
with pembrolizumab and to confirm the RP2D. Participants with either NSCLC or advanced CRC 
will be enrolled in the study. 
SAR442720 will be administered orally on a continuous basis. The starting dose (DL1) of 
SAR442720 is 140 mg Day 1 and Day 4 twice weekly (BIW) with pembrolizumab given at 
200 mg intravenous (IV) once every 3 weeks (Q3W). During the study, alternative BIW dose 
schedules, such as Day 1 and Day 2 of each week, or any other emergent dose schedule from the 
ongoing Phase 1 monotherapy escalation study can be explored after agreement of the Study 
Committee. The dose of SAR442720 will be escalated or de-escalated depending on the emerging 
safety data of the combination. 
One of the BIW 
dose schedules will be tested, based on the safety and tolerability data from the ongoing Phase 1 
monotherapy escalation study. The decision to initiate alternative dose levels will be made by the 
Study Committee after careful evaluation of safety and/or PK data from the ongoing Phase 1 
monotherapy escalation study and data generated in this combination study. Overall safety 
monitoring will be performed throughout the conduct of the study. Additional dose levels and/or 
additional schedules of administration could be tested based on emerging PK and safety data.  
The DLT () observation period is 1 cycle (21 days). All the adverse events (AEs) occurring during 
treatment, unless due to disease progression or to a cause obviously unrelated to investigational 
medicinal product (IMP), will be taken into consideration by the Sponsor and recruiting 
Investigators for the determination of the MTD and RP2D for the SAR442720 and 
pembrolizumab combination. The Study Committee will review the overall safety, PK/PDy and 
activity data and in agreement with the Sponsor’s Study Medical Manager will decide the 
recommended dose for the expansion phase. 
The Study Committee will be comprised of the Principal Investigator from each site involved in 
the dose escalation phase, clinical team members from the Sponsor (including at least the Study 
Medical Manager, Global Study Manager, and experts when appropriate such as Global Safety 
Officer, pharmacokineticists, biostatisticians). 
The Study Committee will review clinical data on a regular basis, with a review being performed 
at least at the end of each DL cohort, before the enrollment of new participants at the next DL, and 
at the end of the dose escalation phase of the study. The Study Committee in agreement with the 
Sponsor’s Study Medical Manager will decide on whether to escalate or de-escalate to the next 
DL or to add alternative dose levels during Study Committee meetings based on current safety 
profile and tolerability, available PK information, and statistical design recommendation. 
Decisions regarding participant treatment and cohort expansion will be discussed and clearly 
documented in the discussion minutes. The Study Committee in agreement with the Sponsor’s 
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Study Medical Manager may permit the evaluation of additional DL and/or additional schedules 
of administration of SAR442720, depending upon the observed safety and DLT at each DL, and 
the safety and/or PK data observed in the ongoing Phase 1 monotherapy escalation study. 
Table 1 - Dose escalation for Part-1 
Dose Level (DL) 
SAR442720 
Pembrolizumab 
DL1  
140 mg BIW 
200 mg Q3W 
DL2 
200 mg BIW 
200 mg Q3W 
DL-1 
100 mg BIW 
200 mg Q3W 
BIW = Day 1 and Day 2 of each week, Day 1 and Day 4 of each week, or any other emergent dose schedule from the ongoing Phase 1 
monotherapy escalation study; Q3W = once every 3 weeks 
The National Cancer Institute Common Terminology Criteria for Adverse Events NCI CTCAE 
Version 5.0 will be used to assess the severity of AEs. Causal relationships are to be determined 
by the Investigator. The potential DLTs will be confirmed by the Sponsor and recruiting 
Investigators. 
Part-2 
The expansion cohort (Part-2), un-controlled, non-randomized, open-label will assess the 
anti-tumor activity and safety of SAR442720 combined with pembrolizumab in participants with 
NSCLC.  
Part-2 will assess the anti-tumor efficacy and safety of adding SAR442720 to pembrolizumab as 
1L NSCLC therapy.  
• Cohort A1: participants with PD-L1 tumor proportion score (TPS) ≥50% NSCLC to 
receive SAR442720 + pembrolizumab as 1L therapy.  
• Cohort A2: participants with PD-L1 TPS 1%-49% NSCLC to receive 
SAR442720 + pembrolizumab as 1L therapy. 
Part-2 of the study will start once RP2D for SAR442720 from Part-1 is confirmed. The 
SAR442720 dose will be 200 mg BIW, Day 1 and Day 2 of each week, administered orally 
(21 days per cycle). This dose emerged as the safe dose of SAR442720 from the escalation part 
(Part-1) of this study. Pembrolizumab will be administered as a dose of 200 mg using a 
30 minutes IV infusion on Day 1 every 3 weeks (21 days cycle) or a dose of 400 mg using 
30 minutes IV infusion on Day 1 and every 6 weeks (42 days cycle).  
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Part-3 
Part-3 of this open-label, multi-center, un-controlled, non-randomized study, will assess the 
safety, (RP2D, anti-tumor activity, and PK of SAR442720 in combination with adagrasib in 
participants with NSCLC harboring KRAS G12C mutation. 
Part-3A 
SAR442720 and adagrasib will be administered orally on a continuous basis. The starting dose 
(DL1) of SAR442720 will be 100 mg on Day 1 and Day 2 BIW with adagrasib given at 400 mg 
twice daily (BID) orally. The dose escalation will follow the modified toxicity probability 
interval 2 (mTPI2) design with a minimum of 3 participants evaluable for DLT for each dose 
level. Participants will be DLT-evaluable if they have taken at least 80% of the scheduled Cycle 1 
dose of both drugs in the first 21 days of treatment. The same mTPI-2 design as that used in Part-1 
will be used in Part-3A.  
The dose of SAR442720 will be escalated or de-escalated depending on the emerging safety data 
of the combination. The starting dose (DL1) of SAR442720 will be 100 mg BIW, which is 50% 
of the highest cleared dose in the ongoing Phase 1 monotherapy dose escalation study 
(https://clinicaltrials.gov; NCT03634982). Dose Level 2 (DL2) (140 mg BIW) and dose level 3 
(DL3) (200 mg BIW) for SAR442720 have been cleared in the ongoing Phase 1 monotherapy 
dose escalation study. The adagrasib starting dose (DL1) will be 400 mg BID orally, which is 
1 dose level below the RP2D in monotherapy (3). The design of the study assumes 5 combination 
dose levels with 3 to 6 participants per dose level. At least 6 participants need to be treated at the 
MTD and RP2D. In Part-3A approximately 15 to 30 DLT-evaluable participants are expected to 
be enrolled during the dose escalation part.  
Part-3B 
The Part-3B dose expansion will assess the anti-tumor activity and safety of SAR442720 
combined with adagrasib in participants with NSCLC harboring KRAS G12C mutation.  
The Part-3B dose expansion of the study will start once RP2D for SAR442720 and adagrasib 
from the Part-3A dose escalation is confirmed.  
Approximately 40 participants will be enrolled in Part-3B dose expansion and treated at the RP2D 
identified in Part-3A. 
Part-4 
The Part-4 of this Phase 1/2, open-label, multi-center, non-randomized study will assess the effect 
of food on the PK of SAR442720 tablet, when dosed in combination with pembrolizumab in 
participants with advanced malignancies. It will also evaluate the relative bioavailability of 
SAR442720 tablet formulation (test) compared to the SAR442720 capsule formulation (reference) 
when dosed in combination with pembrolizumab in participants with advanced malignancies. 
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SAR442720 and pembrolizumab will be administered on a continuous basis, with SAR442720 
administered orally at the RP2D determined from Part-1, and pembrolizumab administered 
intravenously at 200 mg Q3W or 400 mg Q6W. The SAR442720 tablet formulation (test) will be 
administered during the first cycle (21 days), and starting from C2D1, SAR442720 capsule 
formulation (reference) will be administered until the end of treatment (EOT). On C1D1, each 
participant will receive SAR442720 tablet in combination with pembrolizumab with a moderate-
calorie moderate-fat breakfast after an overnight fast of 10 hours. The breakfast should be 
consumed within 0.5 hour, and there should be another 4 hour fast after the completion of 
breakfast. On C1D15, each participant will receive SAR442720 tablet after a 10 hour overnight 
fast prior to dosing on C1D15, followed by a 4 hour fast postdose. On C2D1, each participant will 
receive SAR442720 capsule in combination with pembrolizumab after a 10 hour overnight fast 
prior to dosing on C2D1, followed by a 4 hour fast postdose. For all other days (except for C1D1, 
C1D15, and C2D1), participants will be fasted for 1 hour prior and 1 hour after each SAR442720 
dose. Water will be permitted ad lib for participants in either fasted or fed state, except for 1 hour 
before and 1 hour after the administration of SAR442720. Participants will be instructed to take 
SAR442720 with 240 mL of water. 
Disclosure Statement: This is a non-randomized study with SAR442720 in combination with 
other agents (pembrolizumab or adagrasib) with no masking in participants with advanced 
malignancies.  
Number of participants: 
Approximately 18 to 24 DLT evaluable participants are expected to be enrolled during the Dose 
Escalation and mini-expansion cohort (Part-1). It assumes 3 combination dose levels (as shown 
above) with 3 to 6 participants per dose level. At least 6 participants need to be treated at the 
MTD. After the MTD is identified, another 6 participants will be treated at the MTD to confirm 
the decision and determine the RP2D. The actual sample size will vary depending on DLTs 
observed and the number of dose levels explored. 
In Part-2 approximately 40 participants will be enrolled and treated at RP2D determined from 
Part-1. It is planned to enroll 20 participants with PD-L1 TPS ≥50% (Cohort A1) and 20 
participants with PD-L1 TPS in 1-49% (Cohort A2). 
In Part-3A, approximately 15-30 DLT evaluable participants are expected to be enrolled. In 
Part-3B, approximately 40 participants at the RP2D determined from Part-3A will be enrolled.  
In Part-4, up to approximately 12 participants will be enrolled. 
“Note: Enrolled participants are all participants from screened participants who have been 
allocated to an intervention regardless of whether the intervention was received or not”. 
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Intervention groups and study duration: 
Part-1 and Part-4 
The duration of the study for a participant will include a period for screening of up to 28 days. 
Participants will be evaluated for safety and tolerability. Once successfully screened, enrolled 
participants may receive study intervention until disease progression, unacceptable AE, or the 
participant’s or investigator’s decision to stop the treatment. Each cycle of treatment will have 
duration of 21 days. After discontinuing study intervention, participants will return to the study 
site approximately 30 days after the last IMP administration or before the participant receives 
another anti-cancer therapy, whichever is earlier, for end-of-treatment assessments. Participants 
without documented disease progression at the end of a treatment visit who have not yet started 
treatment with another anti-cancer therapy will proceed with 3 months follow-up visits until 
initiation of another anti-cancer therapy, disease progression, death, or study cutoff date 
(whichever comes first). The expected duration of study intervention for participants may vary, 
based on progression date; median expected duration of study per participant is estimated to be 
10 months (up to 1 month for screening, a median of 6 months for treatment, and a median of 
3 months for long term follow-up).  
Part-2 and Part-3 
The duration of the study for a participant will include: 
• Screening period: up to 28 days. 
• Treatment Period: enrolled participants will receive continuous treatment until PD, 
unacceptable AE, and other full permanent discontinuation criteria as described in 
Section 7.1. 
• End of treatment and Follow-up: EOT visit will occur 30 days ±5 days from last IMP 
administration or prior to initiation of further therapy. Participants will then enter the 
follow up (not applicable to Part-3) and will be followed differently depending on the 
reason leading to EOT: 
- 
Participants who discontinue study treatment with radiological or clinical progressive 
disease (PD) (per [Response Evaluation Criteria in Solid Tumors (RECIST)] v1.1) or 
iCPD (per iRECIST) will be followed in the Follow-Up Visit 1 occurring 3 months 
±5 days from last IMP administration, or until start of new anticancer therapy or cohort 
cut-off, whichever comes first, before moving to the Survival Phone Call Follow-Up 
Period. 
For Part-2 and Part-3B, the primary endpoint (objective response rate [ORR]) analyses is 
performed when all participants have at least 2 post baseline tumor assessments with response 
durability demonstrated or discontinue study treatment (whichever occurs first). 
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Study intervention(s) 
Investigational medicinal products 
SAR442720 capsules 
• Formulation: SAR442720 capsules are supplied as powder-in-capsule drug products of 
20 mg and 100 mg. The capsules are packaged in high-density polyethylene (HDPE) 
bottles.  
• Route of administration: Oral with water after 1 hour fast; no food or drink (other than 
water) allowed for 1 hour after administration (C1D1, C1D15 and C2D1 in Part-4 are 
exceptions). 
• Dose regimen: SAR442720 capsules will be administered orally BIW (Day 1 and Day 2 of 
each week or, Day 1 and Day 4 of each week, or any other emergent dose schedule from 
the ongoing Phase 1 monotherapy escalation study). The starting dose is 140 mg on Day 1 
and Day 4 each week in Part-1 and 100 mg BIW, Day 1 and Day 2 in Part-3A. The dosing 
regimen of Part-2 and Part-4 is 200 mg on Day 1 and Day 2 BIW. 
SAR442720 tablets 
• Formulation: SAR442720 tablets are supplied as film-coated tablets drug products of 
20 mg and 100 mg. The tablets are packaged in Aclar blisters containing 8 tablets.  
• Route of administration: Oral with water after 1 hour fast; no food or drink (other than 
water) is allowed for 1 hour after administration (C1D1, C1D15, and C2D1 in Part-4 are 
exceptions). 
• Dose regimen: SAR442720 tablets will be administered orally BIW (Day 1 and Day 2 of 
each week or, Day 1 and Day 4 of each week, or any other emergent dose schedule from 
the ongoing Phase 1 monotherapy escalation study). The dosing regimen of Part-4 is 
200 mg on Day 1 and Day 2 BIW.  
Pembrolizumab 
• Formulation: 50 mg lyophilized powder in single-dose vial for reconstitution or 
100 mg/4 mL (25 mg/mL) solution in a single-dose vial 
• Route of administration: IV infusion  
• Dose regimen: Pembrolizumab will be administered at 200 mg via IV infusion over 
30 minutes Q3W or 400 mg via IV infusion over 30 minutes Q6W (for Part-2 and Part-4) 
in accordance with the label as mentioned in Section 6.1.1. 
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Adagrasib (Part-3 only) 
• Formulation: MRTX849 is supplied as immediate release film-coated tablets of 200 mg. 
The tablets are packaged in HDPE bottles. 
• Route of administration: Oral with at least 240 mL (8 ounces) of water; may be taken with 
or without food. When co-administered with SAR442720, adagrasib should be taken 
without food (as SAR442720). 
• Dose regimen: Adagrasib will be administered orally BID (two times a day) each day. The 
starting dose is 400 mg BID each day; this should be at 12-hour intervals to the extent 
possible. 
Statistical considerations: 
Part-1 
• Primary endpoint: The primary endpoints in the Part-1 are incidence, nature, and severity 
of DLTs, AEs, and SAEs. The treatment-emergent adverse event (TEAE) period is defined 
as the time from the first dose of study interventions up to 30 days after last dose of study 
interventions. The number and percentage of participants experiencing TEAEs by primary 
system organ class and preferred term (PT) will be summarized by NCI CTCAE Version 
5.0 grade (all grades and Grade ≥3). Similar tables will be prepared for treatment-related 
TEAEs, adverse event of special interest (AESIs), TEAEs leading to treatment 
discontinuation, TEAEs leading to dose modification, delay or omission, serious TEAEs 
and TEAEs with fatal outcome. 
• Main secondary endpoints: Secondary endpoints include laboratory results, ORR, 
duration of response (DoR), and PK concentrations. 
Clinical laboratory test results will be graded according to NCI CTCAE Version 5.0, when 
applicable. Number (%) of participants with laboratory abnormalities (ie, all grades and 
Grade ≥3) using the worst grade during the TEAE period will be provided for all-treated 
population.  
The ORR per RECIST v1.1 will be summarized with descriptive statistics with a 90% 
2-sided confidence interval (CI). DoR will be analyzed using Kaplan-Meier method. 
PK concentrations of SAR442720 and pembrolizumab will be summarized with 
descriptive statistics. 
Part-2 
• Primary endpoint: The primary endpoint in the Part-2 is ORR. The ORR per 
RECIST v1.1 will be summarized with descriptive statistics with a 90% 2-sided CI.  
• Main secondary endpoints: Secondary endpoints include AEs, laboratory results, DoR, 
progression free survival (PFS), time to response (TTR) and clinical benefit rate (CBR), 
disease control rate (DCR), and PK concentrations. 
Incidence and severity of AEs and SAEs will be summarized. The number and percentage 
of participants experiencing TEAEs by primary system organ class and PT will be 
summarized by NCI CTCAE Version 5.0 grade (all grades and Grade ≥3). Similar tables 
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will be prepared for treatment-related TEAEs, adverse event of special interest (AESIs), 
TEAEs leading to treatment discontinuation, TEAEs leading to dose modification, delay 
or omission, serious TEAEs and TEAEs with fatal outcome. 
Clinical laboratory test results will be graded according to NCI CTCAE Version 5.0, when 
applicable. Number (%) of participants with laboratory abnormalities (ie, all grades and 
Grade ≥3) using the worst grade during the TEAE period will be provided for all-treated 
population.  
The DoR and PFS will be analyzed using Kaplan-Meier method. 
The PK concentrations of SAR442720 and pembrolizumab will be summarized with 
descriptive statistics. 
Part-3A 
• Primary endpoint: The primary endpoints in the Part-3A are incidence, nature, and 
severity of DLTs, AEs, and SAEs. The TEAE period is defined as the time from the first 
dose of study interventions up to 30 days after last dose of study interventions. The 
number and percentage of participants experiencing TEAEs by primary system organ class 
and PT will be summarized by NCI CTCAE Version 5.0 grade (all grades and Grade ≥3). 
Similar tables will be prepared for treatment-related TEAEs, AESIs, TEAEs leading to 
treatment discontinuation, TEAEs leading to dose modification, delay or omission, serious 
TEAEs and TEAEs with fatal outcome. 
• Main secondary endpoints: The secondary endpoints include laboratory results, ORR, 
DoR, PFS, TTR, CBR, and PK. 
Clinical laboratory test results will be graded according to NCI CTCAE Version 5.0, when 
applicable. Number (%) of participants with laboratory abnormalities (ie, all grades and 
Grade ≥3) using the worst grade during the TEAE period will be provided for all-treated 
population.  
The DoR and PFS will be analyzed using Kaplan-Meier method. 
The PK parameters of SAR442720 and adagrasib will be summarized with descriptive 
statistics. 
Part-3B 
• Primary endpoint: The primary endpoint in Part-3B is ORR. The ORR per RECIST v1.1 
will be summarized with descriptive statistics with a 90% 2-sided CI.  
• Main secondary endpoints: The secondary endpoints include AEs, laboratory results, 
DoR, PFS, TTR CBR, DCR, and PK. 
The incidence and severity of AEs and SAEs will be summarized. The number and 
percentage of participants experiencing TEAEs by primary system organ class and PT will 
be summarized by NCI CTCAE Version 5.0 grade (all grades and Grade ≥3). Similar 
tables will be prepared for treatment-related TEAEs, AESIs, TEAEs leading to treatment 
discontinuation, TEAEs leading to dose modification, delay or omission, serious TEAEs, 
and TEAEs with fatal outcome. 
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Clinical laboratory test results will be graded according to NCI CTCAE Version 5.0, when 
applicable. Number (%) of participants with laboratory abnormalities (ie, all grades and 
Grade ≥3) using the worst grade during the TEAE period will be provided for the 
all-treated population.  
The DoR and PFS will be analyzed using Kaplan-Meier method. 
The PK concentrations of SAR442720 and adagrasib will be summarized with descriptive 
statistics. 
Part-4 
• Primary endpoint: The PK parameters of SAR442720 will be estimated with 
non-compartmental analysis and summarized using descriptive statistics. The geometric 
mean ratios and 90% confidence intervals of AUC and Cmax will be computed for 
SAR442720 between fed and fasted states of tablet formulation (C1D1 to C1D15) and 
between the tablet (test) and capsule (reference) formulations (C1D15 to C2D1). In 
addition, the PK parameters in Part-4 will be analyzed using a mixed effect model, which 
will be provided in SAP. 
• Secondary endpoints: The secondary endpoints include AEs, ORR, and DoR. 
The incidence and severity of AEs and SAEs will be summarized. The number and 
percentage of participants experiencing TEAEs by primary system organ class and PT will 
be summarized by NCI CTCAE Version 5.0 grade (all grades and Grade ≥3). Similar 
tables will be prepared for treatment-related TEAEs, AESIs, TEAEs leading to treatment 
discontinuation, TEAEs leading to dose modification, delay or omission, serious TEAEs, 
and TEAEs with fatal outcome. 
The ORR per RECIST v1.1 will be summarized with descriptive statistics with a 90% 
2-sided confidence interval. 
The DoR will be analyzed using the Kaplan-Meier method. 
Data Monitoring Committee:  
No DMC was appointed.  
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1.2 
SCHEMA  
Figure 1 - Graphical study design of SAR442720 administered BIW and pembrolizumab every 3 weeks for Part-1  
 
Abbreviations: BIW = twice a week, C = Cycle, D = Day; DLT = dose-limiting toxicities, ICF = informed consent form, W = Week. 
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Figure 2 - Graphical study design of SAR442720 and pembrolizumab for Part-2  
 
Abbreviations: D = day, DL = dose level, IV = intravenous, NSCLS = non-small cell lung cancer, PD1 = programmed cell death protein 1, PD-L1 = programmed death-ligand 1; Pembro = pembrolizumab, 
RP2D = recommended Phase 2 dose, TPS = Tumor Proportion Score. 
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Figure 3 - Graphical study design of SAR442720 and adagrasib for Part-3  
 
Abbreviations: D = day, BID = twice daily, BIW = twice a week, DL = dose level, DLT = dose-limiting toxicity, NSCLS = non-small cell lung cancer, RP2D = recommended Phase 2 dose. 
Figure 4 - Graphical study design of SAR442720 and pembrolizumab for Part-4  
 
Abbreviations: C= cycle, D = day, PK = pharmacokinetics. 
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1.3 
SCHEDULE OF ACTIVITIES (SOA)  
Table 2 - Schedule of activities (SOA) for Part-1 and Part-4 
Procedure  
(Part-1 and 
Part-4) 
Screeninga 
Cycle 1 (21-day cycle) 
Cycles 2+  
(21-day cycle) 
EOT 
(within  
30 ±5d of 
last dose)b 
LTFU (every 
3 months 
±2 wks)c 
Notes 
E/D=Early Discontinuation 
Day  
-1 to  
-28 
-1 to  
-14 
1 
8 
(±1 d) 
15 
(±1 d) 
1 
(±2 d) 
15 
(±2 d) 
Clinical Assessments 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
Obtain written informed consent from the participant 
before any protocol required procedures and 
assessments are performed. Standard of care 
evaluations performed as part of the participant’s 
routine treatment prior to signing consent may be used 
if they were done in the timeframe required for 
screening. 
Inclusion and 
exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
Recheck clinical status before 1st dose of study 
intervention. 
Demography 
X 
 
 
 
 
 
 
 
 
Demographic information includes: age, gender, race, 
and ethnicity. 
Full physical 
examination  
 
X 
X 
X 
X 
X 
 
X 
 
Complete physical examination should be performed 
during screening, D1, D8, D15 of C1 and D1 of each 
cycle starting at C2, and at EOT. See Section 8.2.1 for 
details 
Medical history 
X 
 
 
 
 
 
 
 
 
Prior cancer history includes: (i) date of diagnosis, 
(ii) staging, (iii) all previous therapies (ie, 
chemotherapy, immunotherapy, biologic or targeted 
agents, experimental therapies, radiotherapy, and 
surgery), (iv) previous therapy details (ie, regimen, start 
and stop dates), (v) best response for each regimen, 
and (vi) date of relapse or disease progression. 
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Procedure  
(Part-1 and 
Part-4) 
Screeninga 
Cycle 1 (21-day cycle) 
Cycles 2+  
(21-day cycle) 
EOT 
(within  
30 ±5d of 
last dose)b 
LTFU (every 
3 months 
±2 wks)c 
Notes 
E/D=Early Discontinuation 
Day  
-1 to  
-28 
-1 to  
-14 
1 
8 
(±1 d) 
15 
(±1 d) 
1 
(±2 d) 
15 
(±2 d) 
Past and 
current medical 
conditions  
X 
 
 
 
 
 
 
 
 
 
Documentation 
of tumor 
genotypic 
mutations 
X 
 
 
 
 
 
 
 
 
Documentation of at least one of the following 
genotypic mutations is required: KRAS amplification or 
mutations of KRASG12, NF1 LOF, or BRAF Class 3 
mutations. See inclusion criteria for specific 
genotype/histotype requirement. 
ECOG 
performance 
status 
 
X 
X 
 
 
X 
 
X 
 
ECOG performance status to be assessed at 
screening, C1D1, and D1 of each subsequent cycle 
beginning at C2, and at EOT. 
Vital signs 
 
X 
X 
X 
X 
X 
X 
X 
 
Vital signs should be taken prior to administration of 
study intervention. See Section 8.2.2 for details. 
Body weight 
and height 
 
 
X 
 
X 
X 
 
X 
 
Baseline height is required. Weight should be 
measured at baseline (predose C1D1), C1D15, D1 of 
each subsequent cycle, and at EOT.  
Ophthalmic 
examination 
including retinal 
examination 
with OCT 
X 
 
 
 
 
X 
 
X 
 
Ophthalmic examination should be performed by an 
ophthalmologist during screening, between C2D1 to 
D7, then every 3 cycles, and EOT. See Section 8.2.7 
for details. 
Head MRI 
X 
 
 
 
 
 
 
 
 
Required within 4 weeks of C1D1 for participants with 
previous history of brain metastases. See Section 5.2, 
E 03. 
Pregnancy test 
(WOCBP only) 
 
X 
X 
 
 
X 
 
X 
 
For females of childbearing potential (including tubal 
ligation), perform a blood pregnancy test at screening 
and a urine/blood pregnancy test predose on D1 of 
each cycle, as well as at the EOT. See Section 10.2 for 
details. 
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Procedure  
(Part-1 and 
Part-4) 
Screeninga 
Cycle 1 (21-day cycle) 
Cycles 2+  
(21-day cycle) 
EOT 
(within  
30 ±5d of 
last dose)b 
LTFU (every 
3 months 
±2 wks)c 
Notes 
E/D=Early Discontinuation 
Day  
-1 to  
-28 
-1 to  
-14 
1 
8 
(±1 d) 
15 
(±1 d) 
1 
(±2 d) 
15 
(±2 d) 
Coagulation 
tests 
 
X 
X 
 
 
C3D1 
then 
QO 
cycle 
 
X 
 
C1D1 hematology, chemistry, and coagulation samples 
are not required, if they were obtained within the 
previous 72 hours as part of screening. Participants 
receiving anticoagulation in which PT/aPTT (or partial 
thromboplastin time [PTT]) may be affected, should 
undergo additional monitoring on D1 at least every 
other cycle starting with C3D1 and then at EOT. 
Additional testing may be performed as clinically 
indicated. See Section 10.2 for details. 
Laboratory 
assessments 
(including liver 
chemistries)  
 
X 
X 
X 
X 
X 
X 
X 
 
C1D1 hematology, chemistry, and coagulation samples 
are not required, if they were obtained within the 
previous 72 hours as part of screening. 
Testing must be performed and reviewed before dosing 
on C1D1. See Section 10.2 for details. C2+Day 15 
laboratory assessments could be done remotely if 
needed and after discussion with the Study Medical 
Manager.  
12-lead ECG 
 
X 
X 
 
X 
C3D1 
then 
QO 
cycle 
 
X 
 
A single pre dose ECG should be obtained on C1D1 
and C1D15 and then D1 of every 2 cycles starting at C3 
(eg, C3D1, C5D1, etc) and at EOT See Section 8.2.4. 
Hepatitis B and 
C 
X 
 
 
 
 
 
 
 
 
See Section 10.2. 
Urinalysis 
 
X 
X 
 
 
X 
 
 
 
See Section 10.2. 
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Procedure  
(Part-1 and 
Part-4) 
Screeninga 
Cycle 1 (21-day cycle) 
Cycles 2+  
(21-day cycle) 
EOT 
(within  
30 ±5d of 
last dose)b 
LTFU (every 
3 months 
±2 wks)c 
Notes 
E/D=Early Discontinuation 
Day  
-1 to  
-28 
-1 to  
-14 
1 
8 
(±1 d) 
15 
(±1 d) 
1 
(±2 d) 
15 
(±2 d) 
ECHO/MUGA 
X 
 
 
 
 
C2 D1-
D7 then 
Q3 
cycle 
 
X 
 
ECHO is the preferred methodology to measure LVEF. 
MUGA scan may be used if ECHO is not available or 
not technically feasible. However, the same 
methodology should be used throughout the study. 
Assessments should be performed during screening, 
C2 D1-7, every 3 cycles thereafter, and EOT, and as 
clinically indicated. If a participant does not complete 
2 cycles of study intervention, the EOT assessment of 
LVEF is not required unless clinical signs or symptoms 
warrant an examination. Images will be collected and 
stored for possible central review. 
CPK (total and 
MB isoenzyme) 
 
 
X 
 
 
X 
 
X 
 
CPK levels should be obtained at C1D1, D1 of each 
cycle, EOT and as clinically indicated. 
Telephone 
contact for 
survival 
follow-upc 
 
 
 
 
 
 
 
 
X 
 
Tumor assessments 
CT/MRI scan 
X 
 
 
 
 
C3 D1, C5 D1, 
C7D1, then every 3 
cycles 
X 
 
See Section 8.1. 
RECIST tumor 
response 
assessment 
X 
 
 
 
 
C3 D1, C5 D1, 
C7D1, then every 3 
cycles 
 
 
See Section 8.1. 
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Procedure  
(Part-1 and 
Part-4) 
Screeninga 
Cycle 1 (21-day cycle) 
Cycles 2+  
(21-day cycle) 
EOT 
(within  
30 ±5d of 
last dose)b 
LTFU (every 
3 months 
±2 wks)c 
Notes 
E/D=Early Discontinuation 
Day  
-1 to  
-28 
-1 to  
-14 
1 
8 
(±1 d) 
15 
(±1 d) 
1 
(±2 d) 
15 
(±2 d) 
PDy and biomarker assessments (only for Part-1) 
Archival tumor 
tissue (baseline 
tumor tissue is 
required, 
on-treatment 
and EOT biopsy 
is optional') 
X 
 
 
In case fresh tumor biopsy cannot be collected as 
required, archival tumor tissue should be available to be 
submitted between screening and end of treatment: 
a) 1 H&E slide and 10 x 10-micron slides (minimum 
30% viable tumor volume), or b) 1 H&E slide and  
20 × 4-micron slides (with minimum 30% viable tumor 
volume). FFPE blocks, with sufficient tissue to allow the 
required slides to be sectioned, can be provided. 
Fresh tumor 
biopsy 
 
 
X 
 
 
 
X 
X 
 
Fresh tumor biopsies (applicable to Part-1 only) 
pre-treatment and C2D15 will be mandatory for 
participants enrolled in the study, unless the 
investigator determines that the tumor site is not 
amenable to biopsy and poses a significant risk to 
participant safety. The Sponsor will evaluate this 
requirement on a case-by-case basis, and archival 
tumor tissue should not be used to replace fresh tumor 
biopsy in more than 6 participants. Pre-treatment 
biopsy may be a biopsy which was completed within 
6 months prior to C1D1 without any anti-cancer 
treatment administered in such timeframe. The on-
treatment biopsy may be obtained at C2D15 with a 
window of ±7 days. Pre-treatment and on-treatment 
biopsy (C2D15 with a window of ±7 days) should be 
collected from the same lesion. An EOT biopsy will be 
requested but is not mandatory. See Section 8.6. 
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Procedure  
(Part-1 and 
Part-4) 
Screeninga 
Cycle 1 (21-day cycle) 
Cycles 2+  
(21-day cycle) 
EOT 
(within  
30 ±5d of 
last dose)b 
LTFU (every 
3 months 
±2 wks)c 
Notes 
E/D=Early Discontinuation 
Day  
-1 to  
-28 
-1 to  
-14 
1 
8 
(±1 d) 
15 
(±1 d) 
1 
(±2 d) 
15 
(±2 d) 
Blood for 
immune cell 
profiling, 
cytokines, RNA 
and ctDNA 
biomarker 
 
 
See Table 9 below (Part-1 only) 
 
 
 
Study intervention 
SAR442720 
dosing 
 
 
Continuous dosing (twice weekly) 
 
 
SAR442720 is administrated orally at home or at the 
hospital. See Section 6.1. 
Pembrolizumab 
dosing 
 
 
Continuous dosing Q3W (Part-1 and Part-4) or Q6W 
(Part-4 only) 
 
 
Pembrolizumab is administrated in IV infusion at the 
hospital. See Section 6.1. 
Assessment 
and 
documentation 
of study 
compliance 
 
 
=============================→ 
 
 
Participants should be instructed to bring their pills and 
diary to every visit.  
AE review 
 
X 
=============================→ 
X 
 
C1D1 predose and See Section 8.3.  
SAE review 
 
X 
=============================→ 
X 
 
C1D1 predose and See Section 8.3. 
Concomitant 
medication 
review 
 
X 
=============================→ 
X 
 
Record all concomitant medications including any 
prescription medications, over-the-counter 
preparations, and transfusions received by participant 
from 7 days preceding C1D1 through EOT. 
PK assessments 
Plasma 
samples 
 
 
See Table 5 (Part-1) and Table 8 (Part-4) below 
 
 
Blood samples (1.5 mL/sample) will be collected and 
processed into plasma for SAR442720 PK analysis at 
the time points listed in Table 5 (Part-1) and Table 8 
(Part-4). 
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Procedure  
(Part-1 and 
Part-4) 
Screeninga 
Cycle 1 (21-day cycle) 
Cycles 2+  
(21-day cycle) 
EOT 
(within  
30 ±5d of 
last dose)b 
LTFU (every 
3 months 
±2 wks)c 
Notes 
E/D=Early Discontinuation 
Day  
-1 to  
-28 
-1 to  
-14 
1 
8 
(±1 d) 
15 
(±1 d) 
1 
(±2 d) 
15 
(±2 d) 
Serum samples 
 
 
See Table 5 (Part-1) and Table 8 (Part-4) below 
 
 
Blood samples (1.5 mL/sample) will be collected and 
processed into serum for pembrolizumab PK analysis at 
the time points listed in Table 5 (Part-1) and Table 8 
(Part-4). 
Abbreviations: AE = adverse event, aPTT = activated partial thromboplastin time, C = cycle, CPK = creatine phosphokinase, CT = computed tomography, ctDNA = circulating tumor DNA, D or d = day, 
ECG = electrocardiogram, ECHO = echocardiogram, ECOG = Eastern Cooperative Oncology Group, EOT = end of treatment, FFPE = formalin-fixed paraffin-embedded, H&E = hematoxylin and eosin, 
IV = intravenous LTFU = long-term follow-up, LVEF = left ventricular ejection fraction, MRI = magnetic resonance imaging, MUGA = multigated acquisition, NF1 = neurofibromin 1; OCT = optical coherence 
tomography, PD = pharmacodynamics, PK = pharmacokinetic(s), PT = prothrombin time, PTT = partial thromboplastin time, Q3W = once every 3 weeks, Q6W = once every 6 weeks QO = every other, 
RECIST = Response Evaluation Criteria in Solid Tumours, SAE = serious adverse event, WOCBP = women of child bearing potential. 
a Screening window is 14 days unless otherwise specified. Informed consent as well as participant demographics, medical history including documentation of tumor genotypic mutations, screening hepatitis tests, 
CT/MRI scan, ECHO/MUGA scan, and ophthalmic examination may be obtained 28 days before C1D1. 
b Participants who discontinue study treatment should complete the safety follow-up or EOT visit within 30 days (±5 days) after the last dose, or prior to new treatment, whichever is earlier. Participants who wish to 
withdraw from study intervention treatment should be encouraged to complete the EOT. If a participant chooses to withdraw from the study completely, the reason for withdrawal should be documented.  
c Post-study follow-up for disease status: Participants who discontinue study intervention treatment with radiological or clinical PD at the end of a treatment visit who have not yet started treatment with another 
anti-cancer therapy will proceed with 3 months follow-up visits until initiation of another anti-cancer therapy, disease progression, death, or study cutoff date (whichever comes first).  
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Table 3 - Schedule of activities for Part-2  
Procedure  
(Part-2) 
Screeninga 
Cycle 1 (21-day cycle) 
Cycles 2+ (21-day 
cycle) 
EOT 
(within  
30 ±5d of 
last dose)b 
LTFU (every 
3 months ±2 wks)c 
Notes 
 
Day  
-1 to 
-28 
-1 to  
-14 
1 
8 
(±1 d) 
15 
(±1 d) 
1 (±2 d) 
15 
(±2 d) 
Clinical Assessments 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
Obtain written informed consent from the 
participant before any protocol required 
procedures and assessments are 
performed. Standard of care evaluations 
performed as part of the participant’s 
routine treatment prior to signing 
consent may be used if they were done 
in the timeframe required for screening. 
Inclusion and 
exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
Recheck clinical status before 1st dose 
of study intervention. 
Demography 
X 
 
 
 
 
 
 
 
 
Demographic information includes: age, 
gender, race, and ethnicity. 
Full physical 
examination  
 
X 
X 
 
 
X 
 
X 
 
Complete physical examination should 
be performed during screening, D1 of 
Cycle 1 and D1 of each cycle starting at 
C2, and at EOT. See Section 8.2.1 for 
details 
Medical history 
X 
 
 
 
 
 
 
 
 
Prior cancer history includes: (i) date of 
diagnosis, (ii) staging, (iii) all previous 
therapies (ie, chemotherapy, 
immunotherapy, biologic or targeted 
agents, experimental therapies, 
radiotherapy, and surgery), (iv) previous 
therapy details (ie, regimen, start and 
stop dates), (v) best response for each 
regimen, and (vi) date of relapse or 
disease progression. 
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Procedure  
(Part-2) 
Screeninga 
Cycle 1 (21-day cycle) 
Cycles 2+ (21-day 
cycle) 
EOT 
(within  
30 ±5d of 
last dose)b 
LTFU (every 
3 months ±2 wks)c 
Notes 
 
Day  
-1 to 
-28 
-1 to  
-14 
1 
8 
(±1 d) 
15 
(±1 d) 
1 (±2 d) 
15 
(±2 d) 
Past and 
current medical 
conditions  
X 
 
 
 
 
 
 
 
 
 
Documentation 
of tumor 
genotypic 
mutations 
X 
 
 
 
 
 
 
 
 
Documentation of lack of known SHP2 
inhibition resistant mutations is required. 
See exclusion criteria E 29. 
ECOG 
performance 
status 
 
X 
X 
 
 
X 
 
X 
 
ECOG performance status to be 
assessed at screening, C1D1, and D1 of 
each subsequent cycle beginning at C2, 
and at EOT. 
Vital signs 
 
X 
X 
X 
X 
X 
X 
X 
 
Vital signs should be taken prior to 
administration of study intervention. See 
Section 8.2.2 for details. 
Body weight 
and height 
 
 
X 
 
 
X 
 
X 
 
Baseline height is required. Weight 
should be measured at baseline 
(predose C1D1), C1D1, C1D15, D1 of 
each subsequent cycle, and at EOT.  
Ophthalmic 
examination 
including retinal 
examination 
with OCT 
X 
 
 
 
 
X 
 
X 
 
Ophthalmic examination should be 
performed by an ophthalmologist during 
screening, between C2D1 to D7, then 
every 3 cycles and EOT. See 
Section 8.2.7 for details. Unscheduled 
ophthalmology consultation 
recommended per Investigator’s 
discretion as clinically indicated 
Head MRI 
X 
 
 
 
 
 
 
 
 
Required within 4 weeks of C1D1 for 
participants with previous history of brain 
metastases. See Section 5.2, E 03. 
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Procedure  
(Part-2) 
Screeninga 
Cycle 1 (21-day cycle) 
Cycles 2+ (21-day 
cycle) 
EOT 
(within  
30 ±5d of 
last dose)b 
LTFU (every 
3 months ±2 wks)c 
Notes 
 
Day  
-1 to 
-28 
-1 to  
-14 
1 
8 
(±1 d) 
15 
(±1 d) 
1 (±2 d) 
15 
(±2 d) 
Pregnancy test 
(WOCBP only) 
 
X 
X 
 
 
X 
 
X 
 
For females of childbearing potential 
(including tubal ligation), perform a blood 
pregnancy test at screening and a 
urine/blood pregnancy test predose on 
D1 of each cycle, as well as at the EOT. 
See Section 10.2 for details. 
Coagulation 
tests 
 
X 
X 
 
 
C3D1 then 
QO cycle 
 
X 
 
C1D1 hematology, chemistry, and 
coagulation samples are not required, if 
they were obtained within the previous 
72 hours as part of screening. 
Participants receiving anticoagulation in 
which PT/aPTT (or partial thromboplastin 
time [PTT]) may be affected, should 
undergo additional monitoring on D1 at 
least every other cycle starting with 
C3D1 and then at EOT. Additional 
testing may be performed as clinically 
indicated. See Section 10.2 for details. 
Laboratory 
assessments 
(including liver 
chemistries)  
 
X 
X 
X 
X 
X 
X 
X 
 
C1D1 hematology, chemistry, and 
coagulation samples are not required, if 
they were obtained within the previous 
72 hours as part of screening. 
Testing must be performed and 
reviewed before dosing on C1D1. See 
Section 10.2 for details. C2+Day 15 
laboratory assessments could be done 
remotely if needed and after discussion 
with the Study Medical Manager. 
12-lead ECG 
 
X 
X 
 
X 
C3D1 then 
QO cycle 
 
X 
 
A single pre dose ECG should be 
obtained on C1D1 and C1D15 and then 
D1 of every 2 cycles starting at C3 (eg, 
C3D1, C5D1, etc) and at EOT See 
Section 8.2.4. 
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Procedure  
(Part-2) 
Screeninga 
Cycle 1 (21-day cycle) 
Cycles 2+ (21-day 
cycle) 
EOT 
(within  
30 ±5d of 
last dose)b 
LTFU (every 
3 months ±2 wks)c 
Notes 
 
Day  
-1 to 
-28 
-1 to  
-14 
1 
8 
(±1 d) 
15 
(±1 d) 
1 (±2 d) 
15 
(±2 d) 
Hepatitis B and 
C 
X 
 
 
 
 
 
 
 
 
See Section 10.2. 
Urinalysis 
 
X 
X 
 
 
X 
 
 
 
See Section 10.2. 
ECHO/MUGA 
X 
 
 
 
 
C2 D1-D7 
then Q3 
cycle 
 
X 
 
ECHO is the preferred methodology to 
measure LVEF. MUGA scan may be 
used if ECHO is not available or not 
technically feasible. However, the same 
methodology should be used throughout 
the study. Assessments should be 
performed during screening, C2 D1-7, 
every 3 cycles thereafter, and EOT, and 
as clinically indicated. If a participant 
does not complete 2 cycles of study 
intervention, the EOT assessment of 
LVEF is not required unless clinical 
signs or symptoms warrant an 
examination. Images will be collected 
and stored for possible central review. 
CPK (total and 
MB isoenzyme) 
 
 
X 
 
 
X 
 
X 
 
CPK levels should be obtained at C1D1, 
D1 of each cycle, EOT and as clinically 
indicated. 
Telephone 
contact for 
survival 
follow-upc 
 
 
 
 
 
 
 
 
X 
 
Tumor assessments 
CT/MRI scan 
X 
 
 
 
 
Every 9 weeks  
(+/- 7 days) 
X 
 
RECIST tumor response assessment will 
be performed at the time of each scan. 
See Section 8.1. 
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Procedure  
(Part-2) 
Screeninga 
Cycle 1 (21-day cycle) 
Cycles 2+ (21-day 
cycle) 
EOT 
(within  
30 ±5d of 
last dose)b 
LTFU (every 
3 months ±2 wks)c 
Notes 
 
Day  
-1 to 
-28 
-1 to  
-14 
1 
8 
(±1 d) 
15 
(±1 d) 
1 (±2 d) 
15 
(±2 d) 
PDy and biomarker assessments 
Archival tumor 
tissue 
X 
 
 
In case fresh tumor biopsy cannot be 
collected as required, archival tumor 
tissue should be obtained from biopsies 
done within 6 months to be submitted 
between screening and C2D15:  
a) 1 H&E slide 1 H&E slide and minimum 
10 × 4-micron slides (with minimum 30% 
viable tumor volume). FFPE blocks, with 
sufficient tissue to allow the required 
slides to be sectioned, can be provided. 
Fresh tumor 
biopsy 
 
 
X 
 
 
 
X 
X 
 
Fresh tumor biopsies are required per 
inclusion criteria. The on-treatment 
biopsy may be obtained at C2D15 with a 
window of ±7 days. On treatment and 
EOT biopsy are optional and should be 
collected from the same lesion as 
baseline. See Section 8.6. 
Blood for 
immune cell 
profiling, 
cytokines, RNA 
and ctDNA 
biomarker 
 
 
See Table 9 below 
 
 
 
Study intervention 
SAR442720 
dosing 
 
 
Continuous dosing (twice weekly) 
 
 
SAR442720 is administrated orally at 
home or at the hospital. See Section 6.1. 
Pembrolizumab 
dosing 
 
 
Continuous dosing 200mg Q3W (or 400 mg Q6W) 
 
 
Pembrolizumab is administrated in IV 
infusion at the hospital. See Section 6.1. 
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Procedure  
(Part-2) 
Screeninga 
Cycle 1 (21-day cycle) 
Cycles 2+ (21-day 
cycle) 
EOT 
(within  
30 ±5d of 
last dose)b 
LTFU (every 
3 months ±2 wks)c 
Notes 
 
Day  
-1 to 
-28 
-1 to  
-14 
1 
8 
(±1 d) 
15 
(±1 d) 
1 (±2 d) 
15 
(±2 d) 
Assessment 
and 
documentation 
of study 
compliance 
 
 
=============================→ 
 
 
Participants should be instructed to bring 
their pills and diary to every visit.  
AE review 
 
X 
=============================→ 
X 
 
Predose on C1D1 also see Section 8.3. 
SAE review 
 
X 
=============================→ 
X 
 
Predose on C1D1 also see Section 8.3. 
Concomitant 
medication 
review 
 
X 
=============================→ 
X 
 
Record all concomitant medications 
including any prescription medications, 
over-the-counter preparations, and 
transfusions received by participant from 
7 days preceding C1D1 through EOT. 
PK assessments 
Plasma 
samples 
 
 
See Table 5 below 
 
 
Blood samples (1.5 mL/sample) will be 
collected and processed into plasma for 
SAR442720 PK analysis at the time 
points listed in Table 5. 
Serum samples 
 
 
See Table 5 below 
 
 
Blood samples (1.5 mL/sample) will be 
collected and processed into serum for 
pembrolizumab PK analysis at the time 
points listed in Table 5. 
Abbreviations: AE = adverse event, aPTT = activated partial thromboplastin time, C = cycle, CPK = creatine phosphokinase, CT = computed tomography, ctDNA = circulating tumor DNA, D or d = day, 
ECG = electrocardiogram, ECHO = echocardiogram, ECOG = Eastern Cooperative Oncology Group, EOT = end of treatment, FFPE = formalin-fixed paraffin-embedded, H&E = hematoxylin and eosin, 
IV = intravenous, LTFU = long-term follow-up, LVEF = left ventricular ejection fraction, MRI = magnetic resonance imaging, MUGA = multigated acquisition, OCT = optical coherence tomography, 
PD = pharmacodynamics, PK = pharmacokinetic(s), PT = prothrombin time, PTT = partial thromboplastin time, Q3W = once every 3weeks, Q3W = once every 3weeks, QO = every other,  
RECIST = Response Evaluation Criteria in Solid Tumours, SAE = serious adverse event, SHP2 = Src Homology region 2 domain-containing protein tyrosine phosphatase 2. 
WOCBP = women of child bearing potential. 
a Screening window is 14 days unless otherwise specified. Informed consent should be signed before any study specific procedures; it can be signed more than 28 days prior to initiating study treatment. Participant 
demographics, medical history including documentation of tumor genotypic mutations, screening hepatitis tests, CT/MRI scan, ECHO/MUGA scan, and ophthalmic examination may be obtained 28 days before 
C1D1. 
b Participants who discontinue study treatment should complete the safety follow-up or EOT visit within 30 days (±5 days) after the last dose, or prior to new treatment, whichever is earlier. Participants who wish to 
withdraw from study intervention treatment should be encouraged to complete the EOT. If a participant chooses to withdraw from the study completely, the reason for withdrawal should be documented.  
c Post-study follow-up for disease status: Participants who discontinue study treatment with radiological or clinical PD at the end of a treatment visit who have not yet started treatment with another anti-cancer 
therapy will proceed with 3 months follow-up visits until initiation of another anti-cancer therapy, disease progression, death, or study cutoff date (whichever comes first). 
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Table 4 - Schedule of activities for Part-3  
Procedure  
(Part-3) 
Screeninga 
Cycle 1 (21-day cycle) 
Cycles 2+  
(21-day cycle) 
EOT (within 30 ±5d of 
last dose)b 
 
Notes 
 
Day  
-1 to 
-28 
-1 to  
-14 
1 
8 
(±1 d) 
15 (±1 d) 
1 (±2 d) 
15 
(±2 d) 
Clinical Assessments 
Informed consent 
X 
 
 
 
 
 
 
 
Obtain written informed consent from the participant 
before any protocol required procedures and 
assessments are performed. Standard of care 
evaluations performed as part of the participant’s routine 
treatment prior to signing consent may be used if they 
were done in the timeframe required for screening. 
Inclusion and 
exclusion criteria 
X 
 
 
 
 
 
 
 
Recheck clinical status before 1st dose of study 
intervention. 
Demography 
X 
 
 
 
 
 
 
 
Demographic information includes: age, gender, race, 
and ethnicity. 
Full physical 
examination  
 
X 
X 
 
 
X 
 
X 
Complete physical examination should be performed 
during screening, D1 of Cycle 1 and D1 of each cycle 
starting at C2, and at EOT.  
Medical history 
X 
 
 
 
 
 
 
 
Prior cancer history includes: (i) date of diagnosis, 
(ii) staging, (iii) all previous therapies (ie, chemotherapy, 
immunotherapy, biologic or targeted agents, 
experimental therapies, radiotherapy, and surgery), 
(iv) previous therapy details (ie, regimen, start and stop 
dates), (v) best response for each regimen, and (vi) date 
of relapse or disease progression. 
Past and current 
medical conditions  
X 
 
 
 
 
 
 
 
 
Documentation of 
tumor genotypic 
mutations 
X 
 
 
 
 
 
 
 
 
ECOG 
performance 
status 
 
X 
X 
 
 
X 
 
X 
ECOG performance status to be assessed at screening, 
C1D1, and D1 of each subsequent cycle beginning at 
C2, and at EOT. 
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Procedure  
(Part-3) 
Screeninga 
Cycle 1 (21-day cycle) 
Cycles 2+  
(21-day cycle) 
EOT (within 30 ±5d of 
last dose)b 
 
Notes 
 
Day  
-1 to 
-28 
-1 to  
-14 
1 
8 
(±1 d) 
15 (±1 d) 
1 (±2 d) 
15 
(±2 d) 
Vital signs 
 
X 
X 
X 
X 
X 
X 
X 
Vital signs should be taken prior to administration of 
study intervention. See protocol for details. 
Body weight and 
height 
 
 
X 
 
X 
X 
 
X 
Baseline height is required. Weight should be measured 
at baseline (predose C1D1), C1D15, D1 of each 
subsequent cycle, and at EOT.  
Ophthalmic 
examination 
including retinal 
examination with 
OCT 
X 
 
 
 
 
X 
 
X 
Ophthalmic examination should be performed by an 
ophthalmologist during screening, and EOT. 
Unscheduled ophthalmology consultation recommended 
per Investigator’s discretion as clinically indicated 
Head MRI 
X 
 
 
 
 
 
 
 
Required within 4 weeks of C1D1 for participants with 
previous history of brain metastases.  
Pregnancy test 
(WOCBP only) 
 
X 
X 
 
 
X 
 
X 
For females of childbearing potential (including tubal 
ligation), perform a blood pregnancy test at screening 
and a urine/blood pregnancy test predose on D1 of each 
cycle, as well as at the EOT. 
Coagulation tests 
 
X 
X 
 
 
C3D1 
then QO 
cycle 
 
X 
Additional testing may be performed as clinically 
indicated. 
Laboratory 
assessments 
(including liver 
chemistries)  
 
X 
X 
X 
X 
X 
X 
X 
C1D1 hematology, chemistry, and coagulation samples 
are not required, if they were obtained within the 
previous 72 hours as part of screening. 
Testing must be performed and reviewed before dosing 
on C1D1. C2+Day 15 laboratory assessments could be 
done remotely if needed and after discussion with the 
Study Medical Manager.  
12-lead ECG 
 
X 
X 
 
X 
C3D1 
then QO 
cycle 
 
X 
A single pre dose ECG should be obtained on C1D1 and 
C1D15 and then D1 of every 2 cycles starting at C3 (eg, 
C3D1, C5D1, etc) and at EOT. Unscheduled ECGs to be 
obtained in case of signs and symptoms, and as per 
Investigator’s assessment. 
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Procedure  
(Part-3) 
Screeninga 
Cycle 1 (21-day cycle) 
Cycles 2+  
(21-day cycle) 
EOT (within 30 ±5d of 
last dose)b 
 
Notes 
 
Day  
-1 to 
-28 
-1 to  
-14 
1 
8 
(±1 d) 
15 (±1 d) 
1 (±2 d) 
15 
(±2 d) 
Hepatitis B and C 
X 
 
 
 
 
 
 
 
 
Urinalysis 
 
X 
X 
 
 
X 
 
 
 
ECHO/MUGA 
X 
 
 
 
 
C2 D1-7 
then Q3 
cycle 
 
X 
ECHO is the preferred methodology to measure LVEF. 
MUGA scan may be used if ECHO is not available or not 
technically feasible. However, the same methodology 
should be used throughout the study. Assessments 
should be performed during screening, C2 D1-7, every 
3 cycles thereafter, and EOT, and as clinically indicated.  
CPK (total and 
MB isoenzyme) 
 
 
X 
 
 
X 
 
X 
CPK levels should be obtained at C1D1, D1 of each 
cycle, EOT and as clinically indicated. 
Tumor assessments 
CT/MRI scan 
X 
 
 
 
 
Every 6 weeks  
(+/- 7 days) 
X 
RECIST tumor response assessment will be performed 
at the time of each scan.  
PDy and biomarker assessments 
Archival tumor 
tissue 
X 
 
In case fresh tumor biopsy cannot be collected as 
required, archival tumor tissue should be obtained from 
biopsies done within 6 months to be submitted between 
screening and C2D15. 
Fresh tumor 
biopsy 
 
 
X 
 
X 
 
 
X 
Fresh tumor biopsy is optional in dose escalation 
(Part-3A). Fresh tumor biopsy is required in dose 
expansion (Part-3B). The on-treatment and EOT 
biopsies are optional, on-treatment biopsy may be 
obtained at C1D15 with a window of +7 days. On 
treatment and EOT biopsy should be collected from the 
same lesion as baseline.  
ctDNA biomarker 
 
 
See Table 10 below 
 
 
Study intervention 
SAR442720 
dosing 
 
 
Continuous dosing (twice weekly) 
 
SAR442720 is administrated orally at home or at the 
hospital.  
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Procedure  
(Part-3) 
Screeninga 
Cycle 1 (21-day cycle) 
Cycles 2+  
(21-day cycle) 
EOT (within 30 ±5d of 
last dose)b 
 
Notes 
 
Day  
-1 to 
-28 
-1 to  
-14 
1 
8 
(±1 d) 
15 (±1 d) 
1 (±2 d) 
15 
(±2 d) 
Adagrasib 
 
 
Continuous dosing (twice daily) 
 
Adagrasib is administrated orally at home or at the 
hospital.  
Assessment and 
documentation of 
study compliance 
 
 
=============================→ 
 
Participants should be instructed to bring their pills and 
diary to every visit.  
AE review 
 
X 
=============================→ 
X 
Predose on C1D1 also See Section 8.3 
SAE review 
 
X 
=============================→ 
X 
Predose on C1D1 also See Section 8.3 
Concomitant 
medication review 
 
X 
=============================→ 
X 
Record all concomitant medications including any 
prescription medications, over the counter preparations, 
and transfusions received by participant from 7 days 
preceding C1D1 through EOT. 
SAR442720 PK 
samples 
 
 
See Table 6 below 
 
Blood samples (1.5 mL/sample) will be collected and 
processed into plasma for SAR442720 PK analysis at 
the time points listed in Table 6 and Table 7. 
Adagrasib PK 
samples 
 
 
See Table 7 below 
 
Blood samples (1.5 mL/sample) will be collected and 
processed into plasma for adagrasib PK analysis at the 
time points listed in Table 6 and Table 7. 
Abbreviations: AE = adverse event, C = cycle, CPK = creatine phosphokinase, CT = computed tomography, ctDNA = circulating tumor DNA, D or d = day, ECG = electrocardiogram, ECHO = echocardiogram, 
ECOG = Eastern Cooperative Oncology Group, EOT = end of treatment, IV = intravenous, LVEF = left ventricular ejection fraction, MRI = magnetic resonance imaging, MUGA = multigated acquisition, OCT = optical 
coherence tomography, PK = pharmacokinetic(s), QO = every other, RECIST = Response Evaluation Criteria in Solid Tumours, SAE = serious adverse event, WOCBP = women of child bearing potential. 
a Screening window is 14 days unless otherwise specified. Informed consent should be signed before any study specific procedures, it can be signed more than 28 days prior to initiating study treatment. Participant 
demographics, medical history including documentation of tumor genotypic mutations, screening hepatitis tests, CT/MRI scan, ECHO/MUGA scan, and ophthalmic examination may be obtained 28 days before 
C1D1. 
b Participants who discontinue study treatment should complete the safety follow-up or EOT visit within 30 days (±5 days) after the last dose, or prior to new treatment, whichever is earlier. Participants who wish to 
withdraw from study intervention treatment should be encouraged to complete the EOT. If a participant chooses to withdraw from the study completely, the reason for withdrawal should be documented.  
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Table 5 - PK time points for Part-1 and Part-2 
SAR442720 
Pembrolizumab 
Study Day 
PK Time pointsa 
Windowb 
Study Day 
PK Time pointsa 
Windowb 
Cycle 1 
Day 1 
Predosec 
Within 1 hour before Day 1 dose 
Day 1 
Predosec 
Within 1 hour before Day 1 dose 
  
2 hours 
±10 minutes 
 
Postdose 
 <30 min after end of infusion 
  
8 hourse 
±30 minutes 
 
 
  
Day 8d 
Predose 
Within 1 hour before Day 8 dose 
 
 
 
Day 15 
Predose 
Within 1 hour before Day 15 dose 
  
  
  
Cycle 2  
Day 1 
Predosec  
Within 1 hour before Day 1 dose 
Day 1 
Predosec 
Within 1 hour before Day 1 dose 
  
2 hours 
±10 minutes 
 
 
  
  
8 hourse 
±30 minutes 
 
 
  
Day 2d 
2 hourse 
±10 minutes 
 
 
 
Cycle 6  
 Day 1 
Predosec 
Within 1 hour before Day 1 dose 
Day 1 
Predosec 
Within 1 hour before Day 1 dose 
EOT 
X 
Any time during visit 
 
 
 
Abbreviations: EOT = end of treatment; PK = pharmacokinetic(s). 
a PK samples = one 1.5 mL sample required per time point. 
b Windows are relative to the nominal time point. 
c PK samples for SAR442720 and pembrolizumab will be collected at the same time points. 
d Only for Day 1, Day 2 of each weekly dosing schedule 
e Only collected during Part-1. 
 
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Table 6 - PK time points (Part-3A dose escalation)  
SAR442720 
Adagrasib 
Study Day 
PK Time pointsa 
Windowb 
PK Time pointsa 
Windowb 
Cycle 1 
 
Day 1 
  
  
Predose 
0.5 hourc 
1 hour 
2 hours 
4 hours 
6 hours 
  
Within 1 hour before Day 1 dose 
±10 minutes 
±10 minutes 
±10 minutes 
±10 minutes 
±30 minutes 
  
Predose 
1 hour 
2 hours 
4 hours 
6 hours 
8 hoursd 
12 hoursd 
Within 1 hour before Day 1 morning dose 
±10 minutes 
±10 minutes 
±10 minutes 
±30 minutes 
±30 minutes 
Within 1 hour before D1 evening dose 
Day 2 
24 hours after D1 dose 
Within 1 hour before Day 2 dose 
12 hours after D1 evening dose  
Within 1 hour before D2 morning dose 
Day 8 
Predose 
Within 1 hour before Day 8 dose 
Predose 
Within 1 hour before Day 8 morning dose 
Day 15 
Predose 
0.5 hourc 
1 hour 
2 hours 
4 hours 
6 hours 
Within 1 hour before Day 15 dose 
±10 minutes 
±10 minutes 
±10 minutes 
±10 minutes 
±30 minutes 
Predose 
1 hour 
2 hours 
4 hours 
6 hours 
8 hoursd 
Within 1 hour before Day 15 morning dose 
±10 minutes 
±10 minutes 
±10 minutes 
±30 minutes 
±30 minutes 
Day 16 
24 hours after D15 dose 
2 hoursc 
Within 1 hour before Day 16 dose 
±10 minutes 
12 hours after D15 evening dose 
- 
Within 1 hour before Day 16 morning dose 
- 
Cycle 2, 3 and Cycle 4  
 
 Day 1 
Predose 
Within 1 hour before Day 1 dose 
Predose 
Within 1 hour before Day 1 dose 
EOT 
X 
Any time during visit 
X 
Any time during visit 
Abbreviations: EOT = end of treatment, PK = pharmacokinetic(s). 
a For samples where both SAR442720 and adagrasib are collected, they could be collected at the same time points. 
b Windows are relative to the nominal time point. 
c SAR442720 only PK samples. 
d Adagrasib only PK sample, 12-hour sample on Day 1 is optional to collect. 
 
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Table 7 - PK time points (Part-3B Dose Expansion)  
SAR442720 
Adagrasib 
Study Day 
PK Time pointsa 
Windowb 
PK Time pointsa 
Windowb 
Cycle 1 
 
Day 1 
  
  
Predose 
2 hoursc 
6 hours 
 
Within 1 hour before Day 1 dose 
±10 minutes 
±30 minutes 
 
Predose 
- 
6 hours  
Within 1 hour before Day 1 morning dose 
- 
±30 minutes 
Day 8 
Predose 
Within 1 hour before Day 8 dose 
Predose 
Within 1 hour before Day 8 morning dose 
Day 15 
Predose 
2 hoursc 
6 hours 
Within 1 hour before Day 15 dose 
±10 minutes 
±30 minutes 
Predose 
- 
6 hours 
Within 1 hour before Day 15 morning dose 
- 
±30 minutes 
Cycle 2, 3 and 4 
 
 Day 1 
Predose 
Within 1 hour before Day 1 dose 
Predose 
Within 1 hour before Day 1 dose 
EOT 
X 
Any time during visit 
X 
Any time during visit 
Abbreviations: EOT = end of treatment, PK = pharmacokinetic(s). 
a 
For samples collected for both SAR442720 and adagrasib can be collected at the same time points. 
b 
Windows are relative to the nominal time point. 
c 
SAR442720 only PK samples. 
 
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Table 8 - PK time points for Part-4  
SAR442720 
Pembrolizumab 
Study Day 
PK Time 
pointsa 
Windowb 
Study Day 
PK Time 
pointsa 
Windowb 
Cycle 1 
Day 1 
Predosec 
0.5 hour 
1 hour 
2 hours 
4 hours 
8 hours 
Within 1 hour before Day 1 dose 
±5 minutes 
±10 minutes 
±10 minutes 
±30 minutes 
±30 minutes 
Day 1 
Predosec 
 
Postdose 
Within 1 hour before 
Day 1 dose 
<30 min after end of 
infusion 
Day 2 
24 hours post 
Day 1 dose 
Within 1 hour before Day 2 dose 
- 
- 
- 
Day 8 
Predose 
Within 1 hour before Day 8 dose 
- 
- 
- 
Day 15 
Predosec 
0.5 hour 
1 hour 
2 hours 
4 hours 
8 hours 
Within 1 hour before Day 1 dose 
±5 minutes 
±10 minutes 
±10 minutes 
±30 minutes 
±30 minutes  
- 
- 
- 
Day 16 
24 hours post 
Day 15 dose 
Within 1 hour before Day 16 dose 
- 
- 
- 
Cycle 2 
Day 1 
Predosec 
0.5 hour 
1 hour 
2 hours 
4 hours 
8 hours 
Within 1 hour before Day 1 dose 
±5 minutes 
±10 minutes 
±10 minutes 
±30 minutes 
±30 minutes  
Day 1 
Predosec 
Within 1 hour before 
Day 1 dose 
Day 2 
24 hours post 
Day 1 dose 
Within 1 hour before Day 2 dose 
- 
- 
- 
Cycle 6 
Day 1 
Predosec 
Within 1 hour before Day 1 dose 
Day 1  
Predosec 
Within 1 hour before 
Day 1 dose 
EOT 
X 
Any time during visit 
- 
- 
- 
Abbreviations: EOT = end of treatment,; PK = pharmacokinetic(s). 
a PK samples = one 1.5 mL sample is required per time point. 
b Windows are relative to the nominal time point. 
c PK samples for SAR442720 and pembrolizumab will be collected at the same time points. 
 
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Table 9 - Pharmacodynamic/biomarker sampling time points (Part-1 and Part-2)  
Study Day 
RNABiomarker 
Time pointsa 
Blood 
germline 
testingsb 
ctDNA 
Biomarker 
Time 
pointsc 
Immune 
cell 
profiling 
time 
pointsd 
Cytokines 
time 
pointse 
Windowf 
Cycle 1 
 
 
 
 
 
 
Day 1 
Predose 
Predose 
Predose 
Predose 
Predose 
Within 1 hour 
before Day 1 
dose 
Day 15 
Trough 
- 
- 
- 
- 
 
Trough 
- 
- 
- 
- 
Trough 
- 
- 
- 
- 
Trough 
- 
- 
- 
- 
Within 1 hour 
before 
Day 15 dose  
Cycles 2, 3, and 4 
Day 1 
Predose 
 
Predose 
Predose 
Predose 
Within 1 hour 
before dose 
EOT 
X 
 
X 
X 
X 
Any time 
during visit 
Abbreviations: C = cycle, ctDNA = circulating tumor DNA, D = day, EOT = end of treatment 
a RNA biomarkers: 3 mL sample is required per time point.  
b Blood sample collected at baseline will be used as the germline control from consenting participants. 
c ctDNA biomarkers: 10 mL sample required per time point. Baseline or C1D1 predose of ctDNA biomarker will be collected from all 
participants. On-treatment of ctDNA biomarker (From C1D15 to EOT) will only be collected from participants in the dose-expansion 
cohorts. 
d Immune cell profiling biomarkers: 8 mL sample is required per time point. 
e Cytokine biomarkers: 4mL sample is required per time point.  
f 
Windows are relative to the nominal time point. 
Table 10 - Pharmacodynamic/Biomarker sampling time points for Part-3  
Study Day 
ctDNA Biomarker Time pointsa 
Windowb 
Cycle 1 
 
 
Day 1 
Predose 
Within 1 hour before Day 1 dose 
Day 15 
Trough 
Within 1 hour before Day 15 dose  
Cycles 2, 3, and 4 
 
 
Day 1 
Predose 
Within 1 hour before dose 
EOT 
X 
Any time during visit 
Abbreviations: C = cycle, ctDNA = circulating tumor DNA, D = day; EOT = end of treatment. 
a ctDNA biomarkers: 10 mL sample required per time point. Baseline or C1D1 predose of ctDNA biomarker will be collected from all 
participants. On-treatment of ctDNA biomarker (From C1D15 to EOT) will only be collected from participants in the dose-expansion 
cohorts. 
b Windows are relative to the nominal time point. 
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2 
INTRODUCTION  
SAR442720 (also known as RMC-4630) is a potent, selective, and orally bioavailable SHP2 
allosteric inhibitor that is being developed for participants with tumors harboring certain 
activating mutations or other genotypic aberrations in the RAS–mitogen-activated protein kinase 
(MAPK) pathway, including upstream mutations in receptor tyrosine kinases (RTKs). 
2.1 
STUDY RATIONALE  
The RAS-MAPK pathway is frequently dysregulated in human cancers, typically as a result of 
genomic alterations that lead to hyperactivation (5). These alterations can occur at 3 levels: 
upstream of RAS in RTKs, directly within mediators of the RAS catalytic cycle (RAS isoforms 
and RAS GTPase activating proteins [GAPs], such as neurofibromin 1 [NF1]), or in downstream 
effector kinases, such as BRAF or MEK (6). 
SAR442720 is a potent, selective, and orally bioavailable SHP2 allosteric inhibitor. SHP2 is a 
positive upstream regulator of RAS activation, and thus, presents a suitable therapeutic target for 
patients whose tumors harbor oncogenic mutations that remain dependent on active RAS cycling 
between GTP- and GDP-bound state. Examples of these include subsets of KRASG12, NF1 LOF 
mutations, class 3 type mutations in BRAF (7, 8) or amplification of wild-type KRAS (9).  
SHP2 is also involved in signaling in T-cells. It binds with PD-1 following PD-L1 stimulation and 
inhibits T-cell activation. Therefore, targeting SHP2 may restore or even enhance T-cell 
functions. The costimulatory receptor CD-28, and to some extent the T-cell receptor, are 
dephosphorylated and de-activate some critical components of the interferon gamma (IFNγ) 
signaling cascade, defects in which have been described as a key component of resistance to 
anti-PD1 therapy. SHP2 inhibition may increase the efficacy of PD1 inhibitors in patients with 
high PD-L1 expression but may also sensitize patients with low PD-L1 expression to a PD1 
inhibitor (1, 2).  
SHP2 is expressed in immune cells and plays a role in signal transduction downstream of 
regulatory immunoreceptors, including PD-1 (10). Preclinical studies have demonstrated a role for 
SHP2 in tumor immunity through modulation of both innate and adaptive mechanisms. In 
particular, allosteric inhibition of SHP2 has been shown to increase CD8+T cell tumor infiltrates 
and to deplete pro-tumorigenic tumor associated macrophages through attenuation of CSF-1 
receptor signaling (11). Consistent with a pleiotropic effect on the immune system, SHP2 
inhibition has been shown to attenuate tumor growth in syngeneic models of mouse tumors that 
are apparently insensitive to a direct, cell intrinsic effect of SHP2 inhibition (12, 13, 14). Given 
the potential complementary mechanisms of action, SAR442720 plus anti-PD-1 represents a 
rational combination which was evaluated in preclinical models.  
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Preclinical testing confirms that SHP2 inhibition does not confer sensitivity to PD1 refractory 
tumors (11). In addition, the preliminary observations from patients receiving single agent 
SAR442720 suggest increased T-cell infiltration and activation of innate immune system in 
tumors during SHP2i treatment. Considering that SHP2 plays vital roles in tumor growth and 
tumor immunity, so combination of SAR442720 with anti-PD1 therapy would provide a 
promising therapeutic strategy. 
The purpose of the escalation part (Part-1) is to evaluate the safety, PK, and preliminary efficacy 
of escalating doses of SAR442720 in combination with pembrolizumab in adult participants with 
relapsed/refractory solid tumors with specific mutations/rearrangements that result in 
hyperactivation of the RAS-MAPK pathway and to identify the RP2D for this combination. 
The purpose of the expansion part (Part-2) is to evaluate the anti-tumor activity and safety of 
SAR442720 combined with pembrolizumab in first-line treatment of participants with advanced 
NSCLC.  
The purpose of Part-3 (Part-3A: dose escalation and Part-3B: dose expansion) of this study is to 
evaluate the safety, recommended Phase 2 dose (RP2D), anti-tumor effect, and PK of SAR442720 
in combination with KRAS G12C inhibitor, adagrasib in participants with NSCLC harboring 
KRAS G12C mutations. 
The purpose of Part-4 of this study is to evaluate the effect of food on the PK of SAR442720 
tablet and the relative bioavailability of SAR442720 tablet formulation (test) compared to the 
SAR442720 capsule formulation (reference), when dosed in combination with pembrolizumab to 
participants with advanced malignancies. 
2.2 
BACKGROUND  
SHP2 is a non-receptor protein tyrosine phosphatase and scaffold protein that functions 
downstream of multiple RTKs, integrating cell surface growth factor signals to promote RAS 
activation (Figure 5). SAR442720 was designed as a potent and selective SHP2 allosteric inhibitor 
that suppresses RAS activation and the proliferation in cancers that, distinct from those dependent 
on oncogenic RTKs, are driven by nucleotide cycling oncogenic point mutations (eg, 
KRAS G12C) and wild-type amplification of KRAS and other RAS-GTP dependent downstream 
mutations, eg, NF1 LOF, or RAS-GTP dependent oncogenic BRAF Class 3 (9, 15). 
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2.2.1 Pembrolizumab mechanism of action  
Pembrolizumab is a human PD-1-blocking monoclonal antibody that binds to the PD-1 receptor 
and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of 
the immune response, including the anti-tumor immune response. 
Figure 5 - The RAS-MAPK pathway demonstrating the convergence nodal position of SHP2 in the 
pathway  
 
2.2.2 Adagrasib mechanism of action  
Adagrasib (MRTX849) is an orally available small molecule that elicits anti-tumor activity through 
selective, covalent binding to and inhibition of the KRAS G12C mutant variant. Adagrasib 
effectively inhibits KRAS signaling and demonstrates cytoreductive anti-tumor activity in KRAS 
G12C-mutant models. Adagrasib demonstrated potent inhibition of KRAS-dependent signal 
transduction and cancer cell viability, and selectivity of > 1000 × for KRAS G12C compared with 
KRAS wild-type. Adagrasib inhibited tumor cell growth and viability in cells harboring KRAS 
G12C mutations, but not in cells with wild-type KRAS or other KRAS mutations. Adagrasib 
demonstrated broad-spectrum anti-tumor activity across a panel of KRAS G12C-positive patient- or 
cell-derived tumor models implanted in mice at well-tolerated dose levels including complete tumor 
responses in a subset of models (16). Collectively, these results support the evaluation of adagrasib 
in patients with malignancies having KRAS G12C mutations.  
2.2.3 Rationale for NSCLC  
Worldwide, lung cancer remains the leading cause of cancer incidence and its mortality is 
projected to reach 2.45 million worldwide by 2030, a 39% increase in just over a decade (17). 
NSCLC accounts for approximately 85% of all lung cancer cases, with 2 broad histologic 
subtypes, squamous cell carcinoma and non-squamous cell carcinoma (majority is 
adenocarcinoma) (18). 
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2.2.4 Current standard of care in NSCLC  
Prominent adaptive anti-tumor immune responses have been documented by direct analysis of 
immune cell populations and indirectly by measuring tumor PD-L1 expression, interferon 
gamma–related signatures, or multimarker transcriptomic profiles (19, 20, 21, 22). Using 
immunohistochemistry (IHC), PD-L1 expression in greater than or equal to 1% of tumor cells has 
been reported in approximately 60% of advanced NSCLC and with high levels (eg, ≥50% of 
tumor cells) in 25% to 30% of cases (23, 24).  
The KEYNOTE 024 trial reported a significant improvement in overall survival (OS) for 
pembrolizumab monotherapy in an equally selected population, mostly generated in the subgroup 
of patients with high PD-L1 expression (≥50%) (25). In the KEYNOTE 042 trial, a significant 
benefit with 1L pembrolizumab compared with platinum-based chemotherapy was revealed by 
using a lower selection threshold, PD-L1 ≥1% (26). The KEYNOTE 021 trial was the 
first Phase 2 randomized study reporting improved outcome (ORR: 56.7% versus 30.2%; 
PFS: 24.0 months versus 9.3 months; and OS: not reached versus 21.1 months) with upfront 
pembrolizumab-chemotherapy combinations in unselected patients with non-squamous advanced 
NSCLC compared with chemotherapy alone (platinum plus pemetrexed) (27). These results were 
confirmed by the Phase 3 KEYNOTE 189 trial in all PD-L1 subsets, even PD-L1-negative tumors 
(28). Pembrolizumab is therefore approved in combination with platinum and pemetrexed as the 
first line therapy for non-squamous NSCLC in both the European Union (EU) (29) and the US 
(30). Pembrolizumab monotherapy is also approved as the first-line therapy to treat patients with 
TPS ≥1% NSCLC in the US, and to treat patients with NSCLC TPS ≥50% in the EU. 
2.2.5 Rationale for combining SAR442720 with pembrolizumab  
The anti-tumor activity observed in in-vitro studies and in vivo mouse studies of SAR442720 in 
the presence of an anti-PD1 antibody is described in Section 2.1. 
Both preclinical studies and preliminary clinical biomarker data suggest SAR442720 could 
modulate tumor immune microenvironment, characterized by an increase in CD8+T cell 
infiltration and selective decrease of pro-tumorigenic macrophages in tumor tissue. The immune 
permissive tumor microenvironment modulation by SAR442720 could synergize with 
pembrolizumab to enhance anti-tumor activity (11). 
Therefore, this expansion part, Cohort A1 and Cohort A2, will further assess the potential 
synergistic activity of SAR442720 with pembrolizumab in first-line treatment in different cohorts 
of participants with advanced NSCLC, from an anti-tumor activity and safety standpoint. 
2.2.6 Rationale for combining SAR442720 with adagrasib  
Nonclinical and clinical studies observations with RAF inhibitors have suggested that inhibition 
of RAS signaling may be transient due to feedback activation. Mechanistic studies have shown 
that such adaptive resistance may be mediated by SHP2 (31), and clinical trial observations have 
implicated RTK signaling (32, 33). 
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The combination of SAR442720 and adagrasib may augment anti-tumor activity through 
inhibition of feedback activation and consequently prevent resistance. Although inhibitors of 
KRAS G12C covalently bind to mutant cysteine in KRAS G12C in its GDP-bound state (34, 35), 
KRAS G12C continues to cycle between GTP and GDP states, and KRAS G12C retains the 
ability to transduce upstream activation into downstream signaling (36, 37). Thus, the addition 
SAR442720 to adagrasib may promote anti-tumor activity by inhibiting the cycling to GTP-bound 
KRAS for both mutant and wild type KRAS species, therefore theoretically preventing resistance.  
In vivo experiments were conducted with MRTX849 and the SHP2 inhibitor RMC-4550 to 
evaluate the anti-tumor activity of the combination in five KRAS G12C-mutant human tumor 
xenograft models grown in immunocompromised mice. RMC-4550 was selected as a prototype 
SHP2 inhibitor for proof-of-concept nonclinical combination studies as it is the most active and 
best characterized of all SHP2 inhibitors reported to date (37). As RMC-4550 was reported to be 
highly selective for SHP2 and demonstrated clear target-mediated activity in nonclinical studies, it 
is proposed as a suitable surrogate prototype SHP2 target class inhibitor for proof-of-concept 
combination anti-tumor efficacy studies. The combination of MRTX849 and RMC-4550 elicited 
significant anti-tumor activity compared to single agent treatment in all five models. The effect of 
the combination compared to the single agent effect was pronounced in some models. For 
example, in the KYSE-410 model, treatment with either single agent resulted in stable disease 
whereas the combination elicited near complete response. In addition, the KYSE-410 and 
SW1573 models were two of the xenograft models least sensitive to MRTX849 single agent 
treatment in a previous survey of models (16), suggesting SHP2 inhibition may address 
mechanisms that limit the effectiveness of single agent MRTX849 treatment. The increased 
combination anti-tumor activity was observed in tumor models derived from multiple cancer types 
suggesting the combination of MRTX849 and a SHP2 inhibitor may be broadly active in multiple 
cancer types. In summary, the combination of MRTX849 and a SHP2 inhibitor exhibited 
increased anti-tumor activity in multiple in vivo models compared to single agent treatment and 
these data provide rationale for combining these agents for the treatment of cancer. 
The KRAS G12C mutation occurs frequently in NSCLC (14%) and effective targeted therapies 
for cancers with KRAS mutations remain an unmet medical need. KRAS G12C mutant NSCLC 
patients showed a variable and submaximal response to KRAS G12C inhibitors; objective 
response rate (ORR) to sotorasib, another KRAS G12C inhibitor that was granted accelerated 
approval for NSCLC patients, was 37% (4) and ORR to adagrasib was 45% (3). In addition, it was 
shown in mouse model that treatment with MRTX849 remodeled the tumor immune 
microenvironment and was able to produce sustained complete response when combined with 
check point inhibitors in immune competent animals but not in T-cell deficient mice (38). These 
data suggest that SHP2 inhibition in combination with KRAS G12C inhibitor has potential to 
enhance the anti-tumor activity by blocking the receptor tyrosine kinase resistance mechanisms as 
well as by contributing to immune permissive tumor microenvironment. 
2.3 
BENEFIT/RISK ASSESSMENT  
Most patients with mutations/rearrangements that confer hyperactivation of the RAS-MAPK 
pathway have a poor prognosis. The combination of SHP2 inhibition together with anti-PD1 
inhibition provides a potentially novel targeted treatment for these patients with advanced solid 
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tumors harboring mutations resulting in hyperactivation of the RAS-MAPK pathway. RAS family 
oncogenes are frequently activated by mutations in human cancers and KRAS G12C is the 
predominant mutation in NSCLC (39). Therapies specifically targeting the mutant KRAS G12C, 
shown to be clinically effective in these previously intractable cancers. Mechanism of action and 
preclinical data suggest that the anticancer activity of KRAS G12C inhibitors deepened when 
combined with SHP2 inhibition. 
SAR442720 is currently being administered to humans in a Phase 1 dose-escalation and 
dose-expansion monotherapy study, Protocol RMC 4630 01, (https://clinicaltrials.gov; 
NCT03634982) evaluating its safety, tolerability, preliminary efficacy, MTD, and RP2D, PK, and 
PDy profiles. More detailed information about the expected benefits and risks and reasonably 
expected AEs of SAR442720 based on clinical and pre-clinical data and class of drugs may be 
found in the SAR442720 Investigator’s Brochure (IB). 
Pembrolizumab is a PD-1-blocking antibody indicated for several indications including 
melanoma, NSCLC, Head and Neck Squamous Cell Cancer (HNSCC), Classical Hodgkin 
Lymphoma (cHL), Primary Mediastinal Large B-Cell Lymphoma (PMBCL), Urothelial 
Carcinoma, Microsatellite Instability-High Cancer, Gastric Cancer, Cervical Cancer, 
Hepatocellular Carcinoma (HCC), Merkel Cell Carcinoma (MCC), Renal Cell Carcinoma (RCC). 
Pembrolizumab has been administered in clinical trials as a single-agent and in combination with 
a variety of compounds and therapies. Further information can be found in the current version of 
the pembrolizumab US package insert. 
The Phase 2 part of the adagrasib clinical study 849-001 is evaluating the clinical activity of 
MRTX849 in cohorts of patients who have tumors with the KRAS G12C mutation. As of 
30 August 2020, clinical activity data have been reported for patients with NSCLC administered 
MRTX849 at the Phase 2 dose of 600 mg BID in Phase 1/1b or Phase 2 cohorts. 
2.3.1 Risk assessment  
2.3.1.1 Potential risks of SAR442720  
Given the limited clinical experience to date, the potential risks are based on the combinations of 
emerging clinical safety data, pre-clinical data and class effects. Until the cut-off date of the most 
recent IB (17-July-2021), cumulatively 242 participants have been exposed to the drug, 
113 participants in the monotherapy trial (RMC 4630-01), 112 participants in the RMC 4630-02 
(cobimetinib and osimertinib combination study) and 17 participants in the pembrolizumab study 
(TCD16210). Based on the emerging safety data in the aforementioned studies, especially data 
coming from the monotherapy trial, the following potential risks have been identified: edema, 
diarrhea, anemia and thrombocytopenia, which are summarized in Table 11.  
Most AEs observed in RMC-4630-01, RMC-4630-02, and TCD16210 are low grade in severity, 
primarily Grade 1 or 2, and are managed adequately in the clinic.  
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The safety and tolerability profiles of SAR442720 were consistent with the mechanism of action 
and RAS pathway inhibition. Frequently reported treatment-emergent AEs of any grade regardless 
of relationship to study drug by PT or group of clinically associated PTs included edema includes 
hemodynamic edema, effusions, and fluid overload events (48.7%), diarrhea (48.7%), anemia and 
fatigue, and thrombocytopenia (32.7% each), dyspnea (31.9%), nausea (21.2%), and aspartate 
aminotransferase increase (20.4%). Grade ≥3 TEAEs by PT or group of clinically associated PTs 
included anemia (16.8%), thrombocytopenia (15.0%), dyspnea (12.4%), edema (9.7%), and 
pneumonia (6.7%). The most frequently reported treatment-related AEs, as assessed by the 
Investigator, of any grade, by PT or group of clinically associated PTs were diarrhea (35.4%), 
thrombocytopenia (30.1%), edema (28.3%), fatigue (28.3%), and anemia (27.4%). Grade ≥3 
related AEs reported included thrombocytopenia (13.3%), anemia (11.5%), hypertension and 
diarrhea (4.4% each). Data on the intermittent schedule suggest that it may be better tolerated than 
the daily schedule. For further detailed safety profile and incidence of TEAEs please refer to the 
most recent IB.  
Potential risks of SAR442720 have been determined based on the emerging clinical safety data 
and are listed in Table 11. Amongst the potential risks associated with SAR442720, diarrhea is 
managed using Imodium and Lomotil in the majority of participants, thrombocytopenia is 
primarily managed with dose interruptions, Grade 3 anemia is managed with blood transfusions 
with or without dose interruptions, and edema is managed with diuretics such as Lasix or 
spironolactone. 
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Table 11 - Potential risks of SAR442720  
Potential Risk 
Descriptions and Guidance for the Investigator 
Edema* 
Edema of any grade was reported in 48.7% (55/113) of participants in study RMC-4630-01. 
Grade ≥3 edema was reported in 11 participants (9.7%) in study RMC-4630-01. The median time to 
first onset of edema was 17 days, with a median duration of 14.5 days for the resolved events. 
Guidance to the Investigators:  
Observe for early signs of edema and investigate for potential other clinical causes including medications. 
Follow institutional guidelines to manage edema including cessation of other medications known to be 
associated with the development of edema, if clinically indicated. 
Follow protocol dose modification guidelines in the event of observing edema. 
Thrombocytopenia* Thrombocytopenia AEs, of any grade, were reported in all dosing cohorts, including RP2DS of 200 mg 
(D1D2) in RMC-4630-01 study. The overall incidence was 33% (37/113) including 15.0% (17/113) 
Grade 3-4 events. No Grade 3-4 bleeding events in conjunction with thrombocytopenia have been reported 
as of data cutoff date. Median time to onset of thrombocytopenia** was 15 days from the start of study 
treatment and median duration was 24.0 days. 
Guidance to the Investigators: 
These recommendations refer only to the management of uncomplicated thrombocytopenia, ie, decrease in 
platelet counts without any accompanying clinical events of bleeding/significant bruising or other known risk 
factors for bleeding. 
For Grade 1-2 events (platelet level 50 000 to <100 000 [entry criteria]), continue treatment at current dose 
level and frequency and monitor closely. 
For Grade 3-4 events (platelet level <50 000), manage per institutional guidelines and interrupt dosing until 
patient recovers to Grade 1 or better (platelet level >75 000). If recovery occurs, the Investigator may 
resume dosing at the same dose level and frequency, if clinically appropriate. If Grade 3-4 events recur, 
hold dose until recovery to Grade 1 or better and consider re-introducing study drug at reduced frequency, 
or withdrawing patient from study therapy. 
For thrombocytopenia associated bleeding event or in participants with significant additional risk factors for 
bleeding, the general dose modification guidelines should be considered. The Investigator may interrupt or 
discontinue study treatment as deemed medically appropriate. 
Diarrhea 
Diarrhea AEs, of any grade, were reported in 48.7% (55/113) participants in the RMC-4630-01 study. 
Grade ≥3 AEs were reported in 5.3% (6/113) participants. Median time to onset of diarrhea was 9.0 days 
from the start of study treatment and median duration was 4.0 days. 
Guidance to the Investigators: 
Evaluate for other or concomitant causes, including medications (eg, stool softeners, laxatives, antacids), 
infection including Clostridium difficile, malabsorption/lactose intolerance, fecal impaction, and dietary 
supplements high in fiber. 
For Grade 1 or 2 diarrhea, dietary modifications should be considered including cessation of 
lactose-containing products, eats small meals, and adequate hydration. Consumption of the BRAT (banana, 
rice, apples, toast) diet may be helpful. In addition, loperamide or codeine may be used or alternatives in 
refractory cases such as octreotide and budesonide. 
For >Grade 2 diarrhea, consider hospitalization for fluid and electrolyte replacement and antibiotics, 
particularly if accompanied by fever or Grade 3-4 neutropenia. 
Consultation with a gastroenterologist should be considered, particularly for severe or refractory events. 
Anemia* 
Anemia AEs of any grade were reported in 37.2% (42/113) participants in the RMC-4630-01 study.  
Grade ≥3 AEs were reported in 16.8% (19/113) participants. Median time for onset of anemia*** was 
21.5 days and median duration was 21.5 days. 
Guidance to the Investigators: 
Monitor closely and provide supportive care according to institutional standards. 
Interrupt study treatment as clinically appropriate. 
Dose interruption or discontinuation may not be required depending on baseline hemoglobin and transfusion 
history. 
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.* Includes edema peripheral, pleural effusion, periorbital edema, face edema, pericardial effusion, localized edema, peripheral swelling, ascites, 
generalized edema, eyelid edema, fluid retention, joint swelling, lip edema, and pulmonary edema; thrombocytopenia includes 
thrombocytopenia and platelet count decreased, anemia includes anemia, anemia macrocytic, hemoglobin decreased, and normocytic anemia 
** Time to and duration of thrombocytopenia was calculated using laboratory data. 
*** Time to and duration of anemia was calculated using laboratory data. 
Thromboembolic events: 
• There was one participant (1/17) who experienced a Grade 3 pulmonary embolism in the 
TCD16210 study (pembrolizumab combination study, in the 200 mg cohort) approximately 
40 days after the start of study medication, which was assessed as related to SAR442720. 
The thromboembolic reports were heavily confounded by pre-existing risk factors and thrombosis 
is a known risk with higher incidence in cancer participants. Lung cancer participants may be at 
particularly high risk as 9/14 monotherapy participants and 5/9 SAR442720-cobimetanib arm 
participants with a thromboembolic event had NSCLC. 
Pneumonitis: 
Several drug-induced pneumonitis (including two fatal) cases have been reported in study 
RMC-4630-02 with cobimetinib and osimertinib combination regimens. Drug-induced 
pneumonitis is a known risk for both cobimetinib and osimertinib according to their labels. 
Pneumonitis was reported for adagrasib during clinical studies; however, there is not sufficient 
data to support a relationship at this time. Similarly, SAR442720 monotherapy is not associated 
with a higher risk of pneumonitis, whereas pembrolizumab may be associated with rare events of 
drug-induced pneumonitis therefore the Investigators should make all efforts to exclude 
pneumonitis/interstitial lung disease in case of respiratory symptoms (please refer to the IB for 
more details on the incidence of pneumonitis in each study).  
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Reactivation of autoimmune disorders is a possible adverse reaction given the published 
preclinical study reports that show SHP2 can bind to phosphorylated immunoreceptor tyrosine 
based inhibition and activation motifs (ITIM and ITAM) domains on immune regulatory receptors 
and SHP2 can transduce signals downstream of PD-1 (40, 41, 42, 43, 44). As such, an exclusion 
criterion around patient history of prior autoimmune disease has been included for Part-1 and 
Part-2. 
 Soft tissue mineralization is considered clinically monitorable 
with calcium and phosphate levels since the increase in inorganic phosphorous levels precedes the 
soft tissue mineralization as published (45). 
. 
From non-clinical studies, SAR442720 is considered non-mutagenic, non-clastogenic/aneugenic, 
and non-phototoxic. 
 
Please refer to the SAR442720 IB for more details regarding the safety profile. 
2.3.1.2 Potential risks of pembrolizumab  
Pembrolizumab is a PD-1 blocking antibody indicated in more than 12 different tumors and lines 
of treatment (including NSCLC and CRC).  
The Warning and precautions for pembrolizumab include immune-mediated reactions which may 
be severe or fatal, can occur in any organ system or tissue, including the following: 
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immune-mediated pneumonitis, colitis, hepatitis, endocrinopathies, nephritis with renal 
dysfunction, dermatologic adverse reactions including Stevens Johnson syndrome and toxic 
epidermal necrolysis and solid organ transplant rejection. It includes infusion related reaction, 
embryofetal toxicity and complications of allogeneic hematopoietic stem cell transplantation 
(HSCT). Treatment of patients with multiple myeloma (MM) with a PD-1 or PD-L1 in 
combination with a thalidomide analogue plus dexamethasone is not recommended outside of 
controlled clinical trials.  
The most common adverse reactions (reported in ≥20% of patients) are for pembrolizumab as 
single agent: fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, 
pyrexia, cough, dyspnea, constipation, pain, and abdominal pain. For pembrolizumab in 
combination with chemotherapy are: fatigue/asthenia, nausea, constipation, diarrhea, decreased 
appetite, rash, vomiting, cough, dyspnea, pyrexia, alopecia, and peripheral neuropathy and for 
pembrolizumab in combination with axitinib are: diarrhea, fatigue/asthenia, hypertension, 
hepatotoxicity, hypothyroidism, decreased appetite, palmar-plantar erythrodysesthesia, nausea, 
stomatitis/mucosal inflammation, dysphonia, rash, cough, and constipation. 
Pembrolizumab has been approved for use at an additional recommended dosage of 400 mg every 
6 weeks for all approved adult indications. Based on the modeling of dose/exposure efficacy and 
safety relationships and observed pharmacokinetic data from an interim analysis of 41 patients 
with melanoma treated with pembrolizumab 400 mg every 6 weeks, there are no anticipated 
clinically significant differences in efficacy and safety between pembrolizumab doses of 200 mg 
or 2 mg/kg every 3 weeks or 400 mg every 6 weeks. 
Refer to Pembrolizumab US Package Insert and summary of product characteristics (SmPC) for 
details and the most recent information. 
2.3.1.3 Potential risks of SAR442720 and pembrolizumab administration  
The individual drugs have distinct mechanisms of action and safety profiles. Based on the 
available pre-clinical and clinical data from each individual drug, no potentially overlapping 
serious adverse drug reactions are anticipated with the SAR442720 and pembrolizumab 
combination. There is a possibility that combination of the two drugs can potentiate or alleviate 
the side effects that has been observed individually in monotherapy. There is also a possibility of 
new safety issues which are distinct from the known safety profiles of each individual drug. 
The potential of drug-drug interaction between SAR442720 and pembrolizumab is low. Given 
pembrolizumab is a therapeutic monoclonal antibody, it is expected to be catabolized into amino 
acids by general protein degradation process, which is not expected to be affected by SAR442720. 
As pembrolizumab is not considered a cytokine modulator, it is unlikely to have an effect on drug 
metabolizing enzymes or transporters in terms of inhibition or induction, thus PK of SAR442720 
is not expected to be affected by pembrolizumab as well. 
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2.3.1.4 Potential risks of adagrasib  
Adagrasib is being evaluated as monotherapy and in combination with selected cancer therapies in 
various clinical studies.  
As of 27-November-2020, a total of 439 subjects, including 259 patients and 180 other subjects 
(healthy volunteers or special populations), have been treated with adagrasib. Among enrolled 
patients, 67% had a primary diagnosis of NSCLC, and 20% had a primary diagnosis of CRC. A 
total of 202 (78%) treated patients received MRTX849 as monotherapy, while 57 (22%) patients 
received adagrasib in combination with another agent. 
The most commonly reported TEAEs attributed to adagrasib by the investigator across all patients 
(irrespective of causality to any combination agents) were nausea (49.4%), diarrhea (49.0%), 
vomiting (36.7%), fatigue (27.8%), alanine aminotransferase (ALT) increased (16.2%),AST 
increased (14.7%), blood creatinine increased (12.7%), decreased appetite (12.4%), and ECG QT 
prolonged (10.8%). 
The most commonly reported treatment-emergent SAEs of any cause reported in patient trials of 
adagrasib include pneumonia (4.6%), dyspnea (3.5%), hyponatremia (3.1%), malignant neoplasm 
progression (2.7%), dehydration (2.3%), lung infection (2.3%), acute kidney injury (1.9%), 
anemia (1.9%), blood creatinine increased (1.9%), hypoxia (1.9%), pleural effusion (1.9%), 
hypotension (1.5%), muscular weakness (1.5%), nausea (1.5%), pulmonary embolism (1.5%), 
pyrexia (1.5%), sepsis (1.5%), and vomiting (1.5%).Apart from the above listed common AEs, 
pneumonitis was reported for adagrasib during clinical studies, however there is not sufficient 
data to support relationship at this time. 
Please refer to adagrasib IB for more details regarding the safety profile. 
2.3.1.5 Potential risk for SAR442720 and adagrasib administration  
SAR442720 is identified as a CYP3A and P-gp substrate, with CYP3A contributing to 
approximately 45% of total hepatocyte metabolism. Adagrasib is a strong inhibitor of CYP3A and 
a weak inhibitor of P-gp, which may increase SAR22720 exposure by up to 2-fold (mainly due to 
CYP3A inhibition). Starting dose of SAR442720 was reduced to 50% of its RP2D from 
monotherapy and Part-1 of this study. In addition, adagrasib will be started at the lower dose 
(400 mg BID rather than 600 mg RP2D). 
SAR442720 is not anticipated to alter the PK of adagrasib, because SAR442720 has no effect on 
CYPs and transporters. Overlapping toxicities such as gastrointestinal toxicities are anticipated 
between the 2 drugs, hence such toxicities may occur more frequently than in the monotherapy 
settings. It is not known whether QT prolongation may occur more frequently with the 
combination therapy, however this cannot be excluded at this stage. 
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2.3.2 COVID-19 risk assessment  
It is not yet known whether SAR442720 will pose additional risk for patients in the context of the 
current COVID-19 pandemic. However, the risk of exposure to infected people cannot be 
completely excluded as the participants/subjects may need to expose to public area (eg, commute 
to the site and at the site) (Section 10.12). 
Risk mitigation for COVID-19 
• Continued risk monitoring before starting the study and while on study  
• Sites must follow local practice in deciding if patients need to be tested for COVID-19 
• Closely monitor symptom and signs for COVID-19 
• Reduce the public exposure while ambulatory, as feasible 
2.3.3 Benefit assessment  
SHP2 is a novel mechanism and PD-1 is proven effective in many histologyies including NSCLC. 
Participants in late disease setting as in Part-1 with limited or not clinically meaningful treatment 
options can therefore potentially benefit from novel combination approaches such as the 
one proposed in this study. 
NSCLC is a tumor types that is benefiting from ICI treatment. The compound ICI (anti-PD1) 
pembrolizumab to be combined with SAR442720 in this study is approved to treat various disease 
settings of NSCLC, and few other anti-PD1/PD-L1 (eg, nivolumab and atezolizumab) are 
approved for the treatment of similar disease settings of NSCLC. 
 
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The combination regimen with adagrasib proposed to be evaluated in this study protocol 
amendment is anticipated to bring further benefit to participants with NSCLC. The addition of 
SAR442720 to adagrasib may promote anti-tumor activity by inhibiting cycling to GTP-bound 
KRAS in both mutant and wild-type KRAS species, therefore theoretically preventing resistance. 
The Phase 2 segment of Study 849-001 is evaluating the clinical activity of MRTX849 (adagrasib) 
in cohorts of patients having tumors with the KRAS G12C mutation. As of 30 August 2020, 
clinical activity data have been reported for patients with NSCLC administered MRTX849 at the 
Phase 2 dose of 600 mg BID in Phase 1/1b or Phase 2 cohorts. 
Among patients with NSCLC with the KRAS G12C mutation with measurable disease and at least 
1 on-study assessment, 23/51 patients (45%) experienced a partial response in accordance with 
RECIST 1.1 based on the Investigator’s assessment (3). Unconfirmed responses were initially 
documented among 5/23 responders, all of which were confirmed during continued study 
treatment. The disease control rate (PR plus stable disease) was 96.1% (49/51 of patients). Based 
on the clinical efficacy results described above and the preclinical efficacy data described in detail 
in Section 2.2.6, adding SAR442720 to adagrasib treatment may further increase clinical benefit 
in patients with NSCLC and KRAS G12C mutation.  
2.3.4 Overall benefit: risk conclusion  
Overall, the anticipated benefit/risk ratio of SAR442720 in combination with either 
pembrolizumab or adagrasib supports the conduct of study TCD16210 in participants with 
advanced solid tumors. 
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3 
OBJECTIVES AND ENDPOINTS  
Table 12 - Objectives and endpoints  
Part-1 Dose Escalation (SAR442720 and pembrolizumab) 
Objectives 
Endpoints 
Primary 
• 
To characterize the safety and tolerability of 
SAR442720 in combination with pembrolizumab 
in participants with advanced solid tumors 
including non-small cell lung cancer (NSCLC) 
who progressed on anti-PD-1/PD-L1 containing 
therapy and advanced CRC after progression to 
all standard of care (SoC) therapy. 
• 
Incidence, nature, and severity of treatment-emergent 
AEs and SAEs, graded according to the National 
Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE) v5.0 for the combination 
of SAR442720 and pembrolizumab. 
• 
To define the MTD and RP2D for the 
combination of SAR442720 and pembrolizumab 
in participants with solid tumors. 
• 
Incidence of study drug-related dose-limiting toxicities 
(DLTs) in Cycle 1. 
Secondary 
• 
To assess the pharmacokinetic(s) (PK) of 
SAR442720 in combination with pembrolizumab, 
and to assess the PK of pembrolizumab in 
combination with SAR442720. 
• 
Plasma concentrations of SAR442720. 
• 
Serum concentrations of pembrolizumab. 
• 
To estimate the anti-tumor effects of SAR442720 
in combination with pembrolizumab in all 
participants. 
• 
Objective response rate (ORR) and duration of 
response (DoR) of SAR442720 and pembrolizumab in 
all participants. ORR of combination therapy with 
SAR442720 and pembrolizumab will be based on 
Response Evaluation Criteria in Solid Tumors 
(RECIST) v1.1. 
 
Part-2 Dose Expansion (SAR442720 and pembrolizumab) 
Objectives 
Endpoints 
Primary 
• 
To determine the anti-tumor activity of 
SAR442720 in combination with pembrolizumab. 
• 
Objective response rate defined as the proportion of 
participants who have a confirmed complete response 
(CR) or partial response (PR) determined by the 
Investigator, per RECIST v1.1. 
Secondary 
• 
To assess the safety profile of SAR442720 when 
combined with pembrolizumab. 
• 
Incidence of treatment-emergent adverse events 
(TEAEs), serious adverse events (SAEs), laboratory 
abnormalities according to NCI CTCAE v5.0. 
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Objectives 
Endpoints 
• 
To assess other indicators of anti-tumor activity. 
• 
Time to response (TTR) defined as the time from the 
first administration of investigational medicinal product 
(IMP) to the first documented evidence of PR or CR 
determined by the Investigator per RECIST v1.1 
(for NSCLC). 
• 
DoR, defined as the time from first documented 
evidence of CR or PR until progressive disease (PD) 
determined by the Investigator per RECIST v1.1 or 
death from any cause, whichever occurs first. 
• 
Clinical benefit rate (CBR) including confirmed CR or 
PR at any time or stable disease (SD) of at least 
6 months (determined by the Investigator per 
RECIST v1.1. 
• 
Disease control rate (DCR) including confirmed CR or 
PR or SD as determined by the Investigator per 
RECIST v1.1. 
• 
Progression free survival (PFS), defined as the time 
from the date of first IMP administration to the date of 
the first documented disease progression determined 
by the Investigator as per RECIST v1.1 or death due to 
any cause, whichever occurs first. 
• 
To assess the pharmacokinetic (PK) of 
SAR442720 in combination with pembrolizumab, 
and to assess the PK of pembrolizumab in 
combination with SAR442720. 
• 
Plasma concentrations of SAR442720. 
• 
Serum concentration of pembrolizumab. 
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Part-3A Dose Escalation (SAR442720 and adagrasib) 
Objectives 
Endpoints 
Primary 
• 
To define the MTD and RP2D for the 
combination of SAR442720 and adagrasib in 
participants with NSCLC and KRAS G12C 
mutation. 
• 
To characterize the safety and tolerability of 
SAR442720 in combination with adagrasib in 
participants with NSCLC and KRAS G12C mutation 
• 
Incidence of study drug-related DLTs in Cycle 1. 
 
 
 
• 
Incidence, nature, and severity of TEAEs and SAEs, 
graded according to NCI CTCAEv5.0 for the 
combination of SAR442720 and adagrasib. 
Secondary 
• 
To characterize the PK of SAR442720 in 
combination with adagrasib, and to characterize the 
PK of adagrasib in combination with SAR442720. 
• 
PK parameters of SAR442720 (Cmax, Tmax, AUC0-last) 
• 
PK parameters of adagrasib (Cmax, Tmax, AUC0-last) 
• 
To estimate the anti-tumor effects of SAR442720 
in combination with adagrasib in all participants 
• 
ORR and DoR of SAR442720 and adagrasib in all 
participants. ORR of combination therapy with 
SAR442720 and adagrasib will be based on 
RECIST v1.1. 
Part-3B Dose Expansion (SAR442720 and adagrasib) 
Objectives 
Endpoints 
Primary 
• 
To determine the anti-tumor activity of SAR442720 
in combination with adagrasib in participants with 
NSCLC and KRAS G12C mutation. 
• 
ORR defined as the proportion of participants who 
have a confirmed CR or PR determined by the 
Investigator per RECIST v1.1. 
Secondary 
• 
To assess the safety profile of SAR442720 when 
combined with adagrasib in participants with 
NSCLC and KRAS G12C mutation. 
• 
Incidence of TEAEs, SAEs, and laboratory 
abnormalities according to NCI CTCAE v5.0. 
• 
To assess other indicators of anti-tumor activity. 
• 
TTR defined as the time from the first administration of 
investigational medicinal product (IMP) to the first 
documented evidence of PR or CR determined by the 
Investigator per RECIST v1.1 (for NSCLC). 
• 
DoR, defined as the time from first documented 
evidence of CR or PR until PD determined by the 
Investigator per RECIST v1.1 or death from any 
cause, whichever occurs first. 
• 
CBR including confirmed CR or PR at any time or SD 
of at least 6 months determined by the Investigator per 
RECIST v1.1. 
• 
DCR including confirmed CR or PR or SD as 
determined by the Investigator per RECIST v1.1. 
• 
PFS, defined as the time from the date of first IMP 
administration to the date of the first documented 
disease progression determined by the Investigator as 
per RECIST v1.1 or death due to any cause, 
whichever occurs first. 
• 
To assess the PK of SAR442720 in combination 
with adagrasib, and to assess the PK of 
adagrasib in combination with SAR442720. 
• 
Plasma concentrations of SAR442720 and adagrasib. 
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Part-3A and Part-3B (SAR442720 and adagrasib) 
Objectives 
Endpoints 
Part-4 (SAR442720 and pembrolizumab) 
 
Objectives 
Endpoints 
Primary 
• 
To evaluate the impact of food on the PK of 
SAR442720 when dosed in combination with 
pembrolizumab. 
 
• 
To evaluate the impact of the formulation (tablets 
vs. capsules) on the PK of SAR442720 when 
dosed in combination with pembrolizumab. 
• 
Plasma PK parameters of SAR442720 following oral 
administration of SA442720 tablets in combination 
with pembrolizumab under fed and fasted states 
(eg, Cmax, Tmax, AUC0-last). 
• 
Plasma PK parameters of SAR442720 following oral 
administration of SAR442720 tablets (test formulation) 
and capsules (reference formulation) in combination 
with pembrolizumab under fasted state (eg, Cmax, Tmax, 
AUC0-last). 
Secondary 
• 
To assess the safety and tolerability of 
SAR442720 under fasted and fed conditions in 
combination with pembrolizumab through the 
cycles, when dosing with capsule and tablet 
formulations in combination with pembrolizumab. 
• 
To estimate the anti-tumor effects of SAR442720 
in combination with pembrolizumab in all 
participants. 
• 
Incidence, nature, and severity of TEAEs and SAEs, 
graded according to the NCI CTCAE v5.0 for 
SAR442720 in combination with pembrolizumab. 
 
 
• 
ORR and DoR of SAR442720 and pembrolizumab in 
all participants. ORR of combination therapy with 
SAR442720 and pembrolizumab will be based on 
RECIST v1.1. 
3.1 
APPROPRIATENESS OF MEASUREMENTS  
The efficacy and safety measurements used in this study are standard for the evaluation of therapy 
in participants with advanced solid tumors. 
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4 
STUDY DESIGN  
This is a Phase 1/2 open-label, multi-center, safety, preliminary efficacy, and PK study of 
SAR442720 in combination with other agents in participants with advanced malignancies. 
4.1 
OVERALL DESIGN  
Part-1 
Part-1 of the study is to characterize the safety and tolerability of SAR442720 in combination 
with pembrolizumab and to confirm the RP2D. Participants with either NSCLC or advanced CRC 
will be enrolled in the study. There is no minimum participant number requirement for either 
tumor type. 
Prior to enrollment, all participants will undergo screening to determine study eligibility. 
Questions regarding eligible mutations may be addressed to the Sponsor. Information on tumor 
genotype will be collected on all participants. Participants must have one or more of the following 
molecular aberrations:  
• KRASG12C mutations (NSCLC, CRC and any other histotype) 
• KRASG12A, KRASG12D, KRASG12S, KRASG12V mutations (NSCLC) 
• KRASG12A, KRASG12D, KRASG12S, KRASG12V and/or MSI-H or dMMR (CRC) 
• KRAS amplification (any histotype) 
• NF1 LOF (any histotype) 
• BRAF Class 3 mutations (any histotype) 
The presence of one or more of these tumor genotypes is required for enrollment. Eligibility will 
be assessed based on prior genomic testing using a clinically validated or qualified assay of tumor 
samples. Circulating tumor DNA (ctDNA) mutational analysis using a clinically qualified or 
validated test may also be used for enrollment. All local tumor genotyping analyses will be 
confirmed by central testing when tumor tissue is provided. A fresh biopsy will not be used to 
determine eligibility. 
The starting DL1 of SAR442720 is 140 mg Day 1 and Day 4 BIW with pembrolizumab given at 
200 mg IV Q3W. During the study, alternative BIW dose schedules, such as Day 1 and Day 2 of 
each week, or any other emergent dose schedule from the ongoing Phase 1 monotherapy 
escalation study can be explored after agreement of the Study Committee. The dose of 
SAR442720 will be escalated or de-escalated depending on the emerging safety data of the 
combination. The starting DL1 of SAR442720 (140 mg BIW) and DL2 (200 mg BIW) have been 
cleared in the ongoing Phase 1 monotherapy escalation study (https://clinicaltrials.gov; 
NCT03634982), and DL-1 (100 mg BIW) is 50% of the highest cleared dose in the ongoing 
Phase 1 monotherapy escalation study (Table 13). One of the BIW dose schedules will be tested, 
based on the safety and tolerability data from the ongoing Phase 1 monotherapy escalation study. 
The decision to initiate alternative dose levels will be made by the Study Committee after careful 
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evaluation of safety and/or PK data from the ongoing Phase 1 monotherapy escalation study and 
data generated in this combination study. Overall safety monitoring will be performed throughout 
the conduct of the study. Additional dose levels and/or additional schedules of administration 
could be tested based on emerging PK and safety data.  
The DLT observation period is 1 cycle (21 days). All the AEs occurring during treatment, unless 
due to disease progression or to a cause obviously unrelated to IMP, will be taken into 
consideration by the Sponsor and recruiting Investigators for the determination of the MTD and 
RP2D for the SAR442720 and pembrolizumab combination. The Study Committee will review 
the overall safety, PK/PD and activity data and will decide the recommended dose for the 
expansion phase. 
The Study Committee will be comprised of the Principal Investigator from each site involved in 
the dose escalation phase, clinical team members from the Sponsor (including at least the Study 
Medical Manager, Global Study Manager, and experts including the Global Safety Officer, 
pharmacokineticists, and biostatisticians). 
The Study Committee will review clinical data on a regular basis, with a review being performed 
at least at the end of each DL cohort, before the enrollment of new participants at the next DL, 
and at the end of the dose escalation phase of the study. The Study Committee in agreement with 
the Sponsor’s Study Medical Manager will decide on whether to escalate or de-escalate to the 
next DL or to add alternative dose levels during Study Committee meetings based on current 
safety profile and tolerability, available PK information, and statistical design recommendation. 
Decisions regarding participant treatment and cohort expansion will be discussed and clearly 
documented in the discussion minutes. The Study Committee in agreement with the Sponsor’s 
Study Medical Manager may permit the evaluation of additional dose levels and/or additional 
schedules of administration of SAR442720, depending upon the observed safety and DLT at each 
DL, and the safety and/or PK data observed in the ongoing Phase 1 monotherapy escalation study. 
Table 13 - Dose escalation for Part-1 
Dose Level (DL) 
SAR442720 
Pembrolizumab 
DL1  
140 mg BIW 
200 mg Q3W 
DL2 
200 mg BIW 
200 mg Q3W 
DL-1 
100 mg BIW 
200 mg Q3W 
Abbreviations: BIW = Day 1 and Day 2 of each week, Day 1 and Day 4 of each week, or any other emergent dose schedule from the ongoing 
Phase 1 monotherapy escalation study; Q3W = once every 3 weeks 
The MTD will be identified based on safety data during the DLT assessment period (Cycle 1). 
The RP2D will be based on all available safety, PK, PDy, and efficacy data for all treated 
participants. 
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Participants enrolled in the study will undergo regular safety assessments including physical 
examinations and testing as outlined in Section 8.2.1. Imaging studies (eg, computed tomography 
[CT] or magnetic resonance imaging [MRI]) will be performed at baseline and every 2 cycles 
through Cycle 6 and then every 3 cycles to assess for tumor response as per Response Evaluation 
Criteria in Solid Tumors, Version 1.1 (RECIST v1.1). Peripheral blood samples will be collected 
within Cycles 1, 2, 6 and at EOT for PK evaluation (Section 8.5). Pharmacodynamic biomarker 
assessments will be evaluated in peripheral blood and tumor samples (Section 8.6). 
The first cycle (eg, 21 days) constitutes the DLT assessment period. The first participant in the 
initial combination dose level will be observed for the first 7 days of dosing prior to dosing 
additional participants in this cohort. Following this 7-day observation period, additional 
participants may be enrolled in the cohort. In subsequent combination dose level cohorts, 
participants may be enrolled concurrently. 
Part-2 
The expansion cohort (Part-2), un-controlled, non-randomized, open-label will assess the 
anti-tumor activity and safety of SAR442720 combined with pembrolizumab in participants with 
lung cancer.  
Part-2 will assess the anti-tumor efficacy and safety of adding SAR442720 to therapeutic 
approaches with documented efficacy profile as 1L NSCLC therapy.  
• Cohort A1: participants with PD-L1 TPS ≥50% NSCLC to receive 
SAR442720 + pembrolizumab as 1L therapy. 
• Cohort A2: participants with PD-L1 TPS 1%-49% NSCLC to receive 
SAR442720 + pembrolizumab as 1L therapy. 
Part-2 of the study will start once RP2D for SAR442720 from Part-1 is confirmed. The 
SAR442720 RP2D will be 200 mg BIW, Day 1 and Day 2 of each week, administered orally 
(21 days per cycle). This dose emerged as the safe dose of SAR442720 from the escalation part 
(Part-1) of this study. Pembrolizumab will be administered as a dose of 200 mg using a 
30 minutes IV infusion on Day 1 every 3 weeks (21 days cycle) or a dose of 400 mg using a 
30 minutes IV infusion on Day 1 every 6 weeks (42 days cycle). 
The duration of the study for a participant will include: 
• Screening period: up to 28 days. 
• Treatment Period: enrolled participants will receive continuous treatment until PD, 
unacceptable AE, other full permanent discontinuation criteria as described in Section 7.1. 
• End of Treatment and Follow-up: EOT visit will occur 30 days ±5 days from last IMP 
administration or prior to initiation of further therapy. Participants will then enter the 
Observation period and will be followed differently depending on the reason leading to 
EOT: 
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- 
Participants who discontinue study treatment with radiological or clinical PD 
(per RECIST v1.1) or iCPD (per iRECIST) will be followed in the Follow-Up Visit 1 
occurring 3 months ±5 days from last IMP administration, or until start of new 
anticancer therapy or cohort cut-off, whichever comes first, before moving to the 
Survival Phone Call Follow-Up Period. 
Part-3 
Part-3 of this open-label, multi-center, un-controlled, non-randomized study, will assess the 
safety, RP2D, anti-tumor activity, and PK of SAR442720 in combination with adagrasib in 
participants with NSCLC harboring KRAS G12C mutation. 
Part-3A 
SAR442720 and adagrasib will be administered orally on a continuous basis. The starting dose 
(DL1) of SAR442720 will be 100 mg on Day 1 and Day 2 BIW with adagrasib given at 400 mg 
BID orally. The dose escalation will follow the mTPI2 design with a minimum of 3 participants 
evaluable for DLT for each dose level. Participants will be DLT-evaluable if they have taken at 
least 80% of the scheduled Cycle 1 dose of both drugs in the first 21 days of treatment. The same 
mTPI-2 design as that used in Part-1 will be used in Part-3A.  
The dose of SAR442720 will be escalated or de-escalated depending on the emerging safety data 
of the combination. The starting dose (dose level 1 [DL1]) of SAR442720 will be 100 mg BIW, 
which is 50% of the highest cleared dose in the ongoing Phase 1 monotherapy dose escalation 
study (https://clinicaltrials.gov; NCT03634982). DL2 (140 mg BIW) and DL 3 (200 mg BIW) for 
SAR442720 have been cleared in the ongoing Phase 1 monotherapy dose escalation study. The 
adagrasib starting dose (DL1) will be 400 mg BID orally, which is one dose level below the RP2D 
in monotherapy (3). Refer to Table 14 below for dose escalation. At least 6 participants need to be 
treated at the MTD and RP2D. 
Table 14 - Dose escalation for Part-3A  
Dose Level 
SAR442720 (BIW) 
Adagrasib (daily) 
Part-3 – DL(-)1 
80 mg D1, D2 
400 mg BID 
Part-3 – DL1 (starting dose) 
100 mg D1, D2 
400 mg BID 
Part-3 – DL2 
140 mg D1, D2 
400 mg BID 
Part-3 – DL3aa 
140 mg D1, D2 
600 mg BID 
Part-3 – DL3ba 
200 mg D1, D2 
400 mg BID 
Part-3 – DL4 
200 mg D1, D2 
600 mg BID 
Abbreviations: BID, twice daily; BIW, twice a week; D, day; DL, dose level. 
a DL3b is optional and may be recommended by the study committee according to the safety data before further escalating to DL4. 
Overall safety monitoring will be performed throughout the conduct of the study. Additional dose 
levels and/or additional schedules of administration can be tested based on emerging PK and 
safety data. 
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The DLT observation period is 1 cycle (21 days). All the AEs occurring during treatment, unless 
due to disease progression or to a cause obviously unrelated to IMP, will be taken into 
consideration by the Sponsor and recruiting Investigators for the determination of the MTD and 
RP2D for the SAR442720 and adagrasib combination. The Study Committee will review the 
overall safety, PK/PD, and clinical activity data and in agreement with the Sponsor’s Study 
Medical Manager, will decide the recommended dose for the expansion phase. 
The Study Committee will be comprised of the Principal Investigator from each site involved in 
the dose escalation phase, clinical team members from the Sponsor (including at least the Study 
Medical Manager, Global Study Manager, and experts when appropriate such as Global Safety 
Officer, pharmacokineticists, and biostatisticians). 
The Study Committee will review clinical data on a regular basis, with a review being performed 
at least at the end of each DL cohort, before the enrollment of new participants at the next DL, 
and at the end of the dose escalation phase of the study. The Study Committee in agreement with 
the Sponsor’s Study Medical Manager will decide on whether to escalate or de-escalate to the 
next DL or to add alternative dose levels during Study Committee meetings based on current 
safety profile and tolerability, available PK information, and statistical design recommendation. 
Decisions regarding participant treatment and cohort expansion will be discussed and clearly 
documented in the discussion minutes. The Study Committee in agreement with the Sponsor’s 
Study Medical Manager may permit the evaluation of additional DLs and/or additional schedules 
of administration of SAR442720 and adagrasib, depending upon the observed safety and DLT at 
each DL, and the safety and/or PK data observed in the ongoing study. 
In Part-3A approximately 15 to 30 DLT evaluable participants are expected to be enrolled during 
the Dose Escalation. The design of the study assumes 5 combination dose levels with 3 to 
6 participants per dose level. 
Part-3B 
The Part-3B dose expansion will assess the anti-tumor activity and safety of SAR442720 
combined with adagrasib in participants with NSCLC harboring KRAS G12C mutation.  
The Part-3B dose expansion of the study will start once RP2D for SAR442720 and adagrasib 
from the Part-3A dose escalation is confirmed.  
Approximately 40 participants will be enrolled in Part-3B dose expansion and treated at the RP2D 
identified in Part-3A (see Section 9.2).  
“Note: Enrolled participants are all participants from screened participants who have been 
allocated to an intervention regardless of whether the intervention was received or not”. 
Part-4 
The Part-4 of this Phase 1/2, open-label, multi-center, non-randomized study will assess the effect 
of food on the PK of SAR442720 tablet, when dosed in combination with pembrolizumab in 
participants with advanced malignancies. It will also evaluate the relative bioavailability of 
SAR442720 tablet formulation (test) compared to the SAR442720 capsule formulation (reference) 
when dosed in combination with pembrolizumab in participants with advanced malignancies. 
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SAR442720 and pembrolizumab will be administered on a continuous basis, with SAR442720 
administered orally at the RP2D determined from Part-1, and pembrolizumab administered 
intravenously at 200 mg Q3W or 400 mg Q6W. The SAR442720 tablet formulation (test) will be 
administered during the first cycle (21 days), and starting from C2D1, SAR442720 capsule 
formulation (reference) will be administered until the EOT. On C1D1, each participant will 
receive SAR442720 tablet in combination with pembrolizumab with a moderate-calorie 
moderate-fat breakfast after an overnight fast of 10 hours. The breakfast should be consumed 
within 0.5 hour, and there should be another 4 hour fast after the completion of breakfast. On 
C1D15, each participant will receive SAR44272 tablet in combination with pembrolizumab after 
a 10 hour overnight fast prior to dosing on C1D15, followed by a 4 hour fast postdose. On C2D1, 
each participant will receive SAR442720 capsule in combination with pembrolizumab after a 
10 hour overnight fast prior to dosing on C2D1, followed by a 4 hour fast postdose. For all other 
days (except for C1D1, C1D15, and C2D1), participants will be fasted for 1 hour prior and 1 hour 
after each SAR442720 dose. Water will be permitted for participants in either fasted or fed state, 
except for 1 hour before and 1 hour after the administration of SAR442720. Participants will be 
instructed to take SAR442720 with 240 mL of water. The menu options for the fed cohort are 
shown in Appendix 13 (Section 10.13). The timing of sample collection for PK of SA4442720 
and pembrolizumab is presented in Table 8. In Part-4, up to approximately 12 participants are 
expected to be enrolled. 
4.1.1 Dose-limiting toxicity criteria (Part-1 and Part-3A)  
Potential DLTs are defined as all AEs specified below occurring during the first cycle of 
treatment considered by the investigator to be related to study treatment, unless due to disease 
progression or to a cause obviously unrelated to IMP. 
• Grade ≥4 AEs. 
• Grade 3 neutropenia lasting >7 days or febrile neutropenia. 
• Grade 3 thrombocytopenia with clinically significant bleeding. 
• Any Grade ≥3 immune-related AEs (irAE) (Part-1, 2, and 4 only). 
An irAE can occur shortly after the first dose or several months after the last dose of 
treatment. All AEs of unknown etiology associated with drug exposure should be 
evaluated to determine possible immune etiology. If an irAE is suspected, efforts should 
be made to rule out neoplastic, infectious, metabolic, toxin or other etiologic causes prior 
to labeling an AE as an irAE. 
• Grade 3 nonhematologic AEs, including rash, nausea/vomiting, hypertension, diarrhea, 
retinopathy, or blurred vision that remain uncontrolled (does not resolve to ≤ Grade 2) for 
>72 hours despite maximal supportive care. Electrolyte abnormalities or Grade 3 
asymptomatic creatine phosphokinase (CPK) or gamma-glutamyl transferase (GGT) 
elevations that are corrected within 72 hours will not be considered DLTs. 
• Grade 3AST, ALT, and/or total bilirubin elevations that persist >5 days.  
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• Concurrent elevation of AST or ALT >3 × upper limit of normal (ULN) and total bilirubin 
>2 × ULN or international normalized ratio (INR) >1.5 in the absence of cholestasis and 
other causes (eg, viral hepatitis, other pre-existing or acute liver disease, or another drug 
capable of the observed injury), which may indicate severe drug-induced liver injury 
(possible Hy’s law case). 
• Grade 3 QTcF (defined as QT interval corrected using Fridericia’s formula [QTcF] 
>450 msec or change from baseline of QTcF >50 msec) prolongation.  
• Retinal vein occlusion (RVO) any grade 
• Toxicity related to IMP leading to 50% or less dose intensity of SAR442720 (eg, miss 
≥3 doses) and/or delay in initiation of Cycle 2 dosing of pembrolizumab by >15 days, in 
the absence of recovery to baseline or Grade ≤1 (except for alopecia, vitiligo, fatigue and 
thyroiditis) AE. Toxicity resulting in the inability to deliver at least 66.7% of the dose of 
adagrasib (Part-3A) as intended for the duration of the cycle. 
• An absolute decrease in LVEF of 20 percentage points or greater from the baseline value to 
a value that is below the institutional lower limit of normal (LLN) value, OR symptomatic 
systolic dysfunction with LVEF decrease from baseline ≥10% and/or below LLN. 
At the end of Cycle 1, each participant must be assessed by the Investigator to determine if he or 
she experienced a DLT. This information must be recorded on the appropriate electronic case 
report forms (eCRFs), and an electronic DLT notification (either DLT or not) will be sent to the 
Sponsor, before a subsequent cycle may begin. 
Potential and IMP related DLTs will be considered as AESIs. As such, Investigators are required 
to report them to the Sponsor within 24 hours of the Investigator becoming aware of each AE. The 
Investigator will attach the DLT-specific case report form (CRF) page to the transmitted 
DLT/AESI form or will complete the specific DLT form in the eCRF. 
The reported potential DLTs will be reviewed by the Sponsor and recruiting Investigators in order 
to determine their relationship to the IMP and confirm them as DLTs. 
4.1.2 Dose escalation  
In Part-1 and Part-3A, dose escalation will follow mTPI2 design with a minimum of 3 participants 
evaluable for DLT in the first cycle. A participant will be considered evaluable for DLT 
assessment if he/she receives at least 4 out of the 6 planned doses of SAR442720 in the first cycle 
and completes the DLT observation period or if he/she experiences a DLT in the DLT observation 
period. A participant who is not DLT-evaluable will be replaced to achieve a minimum of 
3 DLT-evaluable participants at the same cohort. 
The actual dose selected at each dose escalation decision, and the MTD identified at the 
conclusion of the dose escalation phase, will be determined by the Study Committee, in agreement 
with the Sponsor’s Study Medical Manager, which may select a dose at or below the model’s 
recommendation and should not select a dose that is suggested to be over toxic by the model. The 
Study Committee will review the overall safety of all dose levels. More details in the model and 
its operating characteristics can be found in Appendix 11 (Section 10.11). 
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The adaptive dose escalation design is based on the boundaries generated from the mTPI2 design. 
The dose escalation will stop if the next recommended dose has been collectively evaluated in at 
least 2 previous escalation cohorts.  
It is anticipated that in Part-1 12 to 18 DLT-evaluable participants and in Part-3A 15 to 
30 DLT-evaluable participants will be enrolled in the dose escalation. The actual total number of 
participants required will depend on the number of dose levels evaluated and on the incidence and 
timing of observed DLTs. 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN  
The first phase of the study (Part-1) constitutes a Dose Escalation, which has been designed to 
minimize the number of participants exposed to potentially subtherapeutic doses.  
In the Dose Escalation, assessment of safety and tolerability will be the primary endpoints and 
will be directly measured by the incidence of DLTs, AEs, and SAEs. The dose escalation rationale 
is provided below in Section 4.2.1.  
A mini-expansion cohort of 6 participants will be initiated to further assess the safety, PK, PD, as 
well as the preliminary anti-tumor activity of SAR442720 and pembrolizumab combination 
therapy at RP2D.  
The Part-2 of this study aims to establish the efficacy of combining the ICI pembrolizumab with 
the SHP2 inhibitor SAR442720 which may result in an increase in ORR. The goal of combination 
therapy approaches is to expand the spectrum of patients who respond to cancer immunotherapy 
and to improve the quality of clinical responses (ie, durable response OS and prolonged PFS) 
beyond what can be achieved with monotherapy alone. The established anti-tumor activity of 
PD-1/PD-L1 inhibition as monotherapy in a wide spectrum of cancers coupled with its favorable 
toxicity profile provides a strong rationale for its use as a backbone for combinatorial strategies. 
The design of the study is a non-randomized study where the experimental combination will be 
assessed in a single cohort for each indication. The ORR will be assessed using RECIST v1.1 for 
participants with NSCLC. The objective response will be assessed per Investigator in first intention. 
Central imaging reading may be done retrospectively if significant activity is observed. 
Part-3A constitutes a dose escalation study to determine the MTD and RP2D of SAR442720 in 
combination with adagrasib in participants with NSCLC and KARAS G12C mutations. The 
starting dose of SAR442720 is 50% of the highest cleared dose in monotherapy and adagrasib 
starting dose is 2/3 of RP2D for adagrasib. In the dose escalation part, assessment of safety and 
tolerability will be the primary endpoints and will be directly measured by the incidence of DLTs, 
AEs, and SAEs.  
Part-3B aims to determine the anti-tumor activity of SAR442720 in combination with adagrasib in 
participants with NSCLC and KARAS G12C mutations, which can result in an increased ORR. 
The goal of the combination therapy approach is to expand the spectrum of patients who respond 
to targeted KRAS G12C therapy and to improve the quality of clinical responses (ie, durable 
response and prolonged PFS) beyond what can be achieved with monotherapy alone. 
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The design of the study is a non-randomized study in which the experimental combination will be 
assessed in a single cohort for each indication. The ORR will be assessed using RECIST v1.1. 
The objective response will be assessed by the Investigator in first intention. Central imaging 
reading may be done retrospectively if significant activity is observed. 
Part-4 aims to assess the impact of formulation and preliminary impact of food on the PK of 
SAR442720 in combination with pembrolizumab. Part-4 is an open label, non-randomized 
fixed-sequence study, intending to assess preliminary effect of food on SAR442720 tablet and 
relative bioavailability of SAR442720 tablets versus capsules in participants with advanced 
malignancies. The PK of SAR442720 under fasted state will be served as the test treatment of 
formulation bridging; therefore, both the food effect and formulation effect can be assessed in the 
same participants, to reduce the number of participants needed.  
4.2.1 Dose escalation rationale  
The mTPI2 design is a Bayesian interval design that can be implemented in a simple fashion as 
the traditional 3+3 design, but it is more flexible and possesses superior operating characteristics. 
The mTPI2 design provides an upgrade to the modified toxicity probability interval (mTPI) 
design, with a substantially lower risk of overdosing and a better precision to identify the MTD. 
The mTPI2 design is applicable for the dose escalations in Part-1 and Part-3A. 
The target toxicity rate for the MTD is 
, with the acceptable toxicity probability interval of 
. At least 3 DLT evaluable participants will be included in each cohort. The decision 
by the Study Committee in agreement with the Sponsor’s Study Medical Manager for dose 
escalation/de-escalation or stay will be made after the completion of the first cycle of the last DLT 
evaluable participant at each cohort. The mTPI2 decision rules are based on calculating the unit 
probability mass (UPM) of intervals as follows:
 Intervals that are lower than
 indicating dose escalation, 
equivalence interval
indicating staying at the current dose level, and intervals that are 
higher than
 indicating dose de-escalation. The interval with the largest UPM will be the 
winning interval and implies the corresponding dose recommendation. The detailed mTPI2 rules 
are displayed in Table 15.  
When using Table 15, note the following: 
A) If the next dose level is considered to have unacceptable high toxicity, ie, the probability 
that the DLT rate is larger than 
 at the next dose is more than
, then the next 
enrolled cohort should be kept at current dose and the higher dose will never be used 
(Decision “DU” in Table 15).  
B) At any time, if the observed DLT rate at the current dose level is greater than
, then 
the next enrolled cohort should be de-escalated to the lower dose level, at which the DLT 
rate is less than 
.  
C) If the current dose is the lowest dose and the rule indicates dose de-escalation, treat the 
new participants at the lowest dose unless there is unacceptable high toxicity, at which 
point terminate the study for safety. If the decision based on the new cohort at the lowest 
dose still recommends dose de-escalation, new dose levels may be explored.  
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D) If the current dose is the highest dose and the rule indicates dose escalation, treat the new 
participants at the highest dose. If the decision based on the new cohort at the highest dose 
still recommends dose escalation, new dose levels may be explored.  
E) If at least 6 participants were treated at the recommended dose level, then this dose level 
will be the MTD. 
F) Skipping dose is not allowed. 
Table 15 - Dose escalation rule of the modified toxicity probability interval-2 method  
 
 
Number of participants treated at current dose 
1 
2 
3 
4 
5 
6 
7 
8 
9 
Number of dose-limiting toxicities 
0 
E 
E 
E 
E 
E 
E 
E 
E 
E 
1 
D 
D 
S 
S 
E 
E 
E 
E 
E 
2 
 
DU 
Da 
D 
D 
S 
S 
S 
E 
3 
 
 
DU 
DU 
D 
D 
D 
D 
S 
4 
 
 
 
DU 
DU 
DU 
D 
D 
D 
5 
 
 
 
 
DU 
DU 
DU 
DU 
DU 
6 
 
 
 
 
 
DU 
DU 
DU 
DU 
7 
 
 
 
 
 
 
DU 
DU 
DU 
8 
 
 
 
 
 
 
 
DU 
DU 
9 
 
 
 
 
 
 
 
 
DU 
E: Escalate to the next higher dose, S: Stay at the current dose, D: De-escalate to the next lower dose, DU: De-escalate to the next lower 
dose and the current dose will never be used again because unacceptable high toxicity 
a “D” will not be applied for first cohort of dose level 1 as the exception, however “DU” will give priority to the exception, ie, if 3 out of 
3 participants have DLT at the dose level 1, the study committee may add lower dose level to assess the safety. 
4.3 
JUSTIFICATION FOR DOSE  
Part-1 (SAR442720)  
The starting dose of SAR442720 is selected based on ongoing clinical trials. The starting dose of 
SAR442720 is 140 mg Day 1 and Day 4 BIW, 
Please refer to RMC 4630 IB for 
more details. Given the overall safety profile based on the available clinical data on 
pembrolizumab and SAR442720 monotherapy, the starting dose of SAR442720 in this 
combination study is 140 mg administered orally BIW (Day 1 and Day 4 schedule) in a 21-day 
cycle. During the study, alternative BIW dose schedules, such as Day 1 and Day 2 of each week, 
or any other emergent dose schedule from the ongoing Phase 1 monotherapy escalation study can 
be explored after agreement of the Study Committee. 
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Part-2 (SAR442720) 
Part-2 of the study will start once RP2D for SAR442720 from Part-1 is confirmed. The dose of 
SAR442720 in Part-2 will be the RP2D, which will be the highest cleared dose from Part-1 which 
will most likely be 200 mg BIW, such as D1 and D2 of each week. 
The dose of pembrolizumab for Part-1 and Part-2 is the fixed recommended dose of 200 mg IV 
Q3W or 400 mg IV Q6W.  
Part-3 (SAR442720 and adagrasib) 
The starting dose of SAR442720 is selected based on the preliminary clinical safety and 
tolerability observed in Phase 1 RMC-4630-01 monotherapy study. A dose of 200 mg BIW Day 1 
Day 2 SAR442720 has been cleared by the Dose Committee and selected as the RP2D for the 
final expansion cohort. SAR442720 is identified as a CYP3A and P-gp substrate, with CYP3A 
contributing to approximately
of total hepatocyte metabolism. Adagrasib is a strong inhibitor 
of CYP3A and a weak inhibitor of P-gp, which may increase SAR442720 exposure up to 
 
(mainly due to CYP3A inhibition). Therefore, the starting dose of SAR442720 is selected to be 
less than the RP2D at monotherapy, which is 100 mg Day 1, Day 2 (D1D2). 
SAR442720 is not anticipated to alter the PK of adagrasib.  
Part-4 (SAR442720) 
Part-4 of the study will start at the RP2D for SAR442720 from Part-1, the highest cleared dose 
from Part-1, which is 200 mg BIW, administered on D1 and D2 of each week. This dose has been 
cleared by the Dose Committee and selected as the RP2D for the combination of SAR442720 and 
pembrolizumab.  
The dose of pembrolizumab for Part-4 is the fixed recommended dose of 200 mg IV Q3W or 
400 mg IV Q6W.  
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. 
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5 
STUDY POPULATION  
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1 
INCLUSION CRITERIA  
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
I 01. All participants must be ≥18 years of age (or country’s legal age of majority if >18 years), 
at the time of signing the informed consent.  
Type of participant and disease characteristics 
I 02. Part-1 and Part-4 participants should have histologically or cytologically proven diagnosis 
of non-squamous NSCLC with metastatic disease progression after platinum-based 
chemotherapy and ICI irrespective of the sequence, ie, either concurrently or sequentially:  
- 
At least one prior line of treatment in a metastatic setting  
- 
Relapse to develop metastatic disease during or within 6 months of an 
adjuvant/neoadjuvant treatment (to be considered as first-line treatment), OR 
- 
Disease progression after or during one platinum-based chemotherapy and one ICI 
(anti-PD1/PD-L1) irrespective of the sequence, ie, concurrently or sequentially.  
OR 
Histologically proven diagnosis of advanced solid tumors including CRC that have failed, 
are intolerant to or are considered ineligible for SoC anti-cancer treatments including 
approved drugs for oncogenic drivers in their tumor type. 
I 03. Part-1 participants must have one or more of the following molecular aberrations:  
- 
KRASG12C mutations (NSCLC, CRC and any other histotype) 
- 
KRASG12A, KRASG12D, KRASG12S, KRASG12V mutations (NSCLC) 
- 
KRASG12A, KRASG12D, KRASG12S, KRASG12V and/or MSI-H or dMMR (CRC) 
- 
KRAS amplification (any histotype) 
- 
NF1 LOF (any histotype) 
- 
BRAF Class 3 mutations (any histotype) 
I 04. All participants should have at least 1 measurable disease per RECIST v1.1. An irradiated 
lesion can be considered measurable only if progression has been demonstrated on the 
irradiated lesion. 
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I 05. All participants should have Eastern Cooperative Oncology Group (ECOG) performance 
status 0-1. 
Sex 
I 06. All (male or female) participants 
Contraceptive use by men or women should be consistent with local regulations regarding 
the methods of contraception for those participating in clinical studies. 
a) Male participants 
A male participant must agree to use contraception (see Appendix 4 [Section 10.4]) during 
the intervention period and for at least 4 months (6 months for Part-3) after the last dose of 
study intervention. 
b) Female participants 
A female participant is eligible to participate if she is not pregnant (see Appendix 4 
[Section 10.4]), not breastfeeding, and at least one of the following conditions applies: 
- 
Not a woman of childbearing potential (WOCBP) as defined in Appendix 4 
[Section 10.4]). 
OR 
- 
A WOCBP who agrees to follow the contraceptive guidance in Appendix 4 
[Section 10.4]) during the intervention period and for at least 4 months (6 months for 
Part-3) after the last dose of study intervention. 
Informed Consent 
I 07. All participants should be 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.  
Part-2 (new criteria added with amendment 03) 
I 08. Cancer diagnosis at study entry: 
For participants in Cohorts A, - histologically or cytologically confirmed diagnosis of 
Stage IV (per American Joint Committee on Cancer [AJCC] 8th edition [112]) NSCLC. 
I 09. For Part-2, PD-L1 expression TPS as determined (with an absolute value provided to 
Sponsor) at local laboratory. 
- 
Cohort A1: PD-L1 expression TPS ≥50%, 
- 
Cohort A2: PD-L1 expression TPS 1%-49%.  
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I 10. Provision of tumor tissue: 
- 
Mandatory for participants enrolled with local PD-L1 testing. Baseline tumor tissue or 
slides should be provided for central lab retrospective analysis. Archival tumor tissue 
samples should be obtained from biopsies done within 6 months, and there should be 
no systemic anti-cancer therapy between collection of biopsy and enrollment. Slides 
specifications are detailed in Lab Manual. 
I 11. Prior anticancer therapy 
- 
For participants in Cohorts A1 and A2 - Have not received prior systemic therapy for 
advanced/metastatic NSCLC. Participants who received adjuvant or neoadjuvant 
therapy are eligible if the adjuvant/neoadjuvant therapy was completed at least 
6 months prior to the development of metastatic disease.  
Part-3 (new criteria added with amendment 04) 
I 12. Participants with histologically or cytologically proven metastatic NSCLC with at least 
one prior line of treatment in a metastatic setting. Prior KRAS G12C targeted therapy is 
acceptable (only in Part-3A) 
I 13. Participants must have following molecular aberration tested at the local laboratory:  
- 
KRAS G12C mutation assessed by a local Sponsor-approved test. Approved test list 
can be found in eCRF. 
5.2 
EXCLUSION CRITERIA  
Participants are excluded from the study if any of the following criteria apply: 
Medical conditions 
E 01. Predicted life expectancy ≤3 months. 
E 02. Primary central nervous system (CNS) tumors.  
E 03. Known or suspected leptomeningeal or brain metastases, symptomatic or impending spinal 
cord compression. Participants previously treated for these conditions who have had stable 
CNS disease (eg, no evidence of clinical and radiographic disease progression and 
asymptomatic in the absence of corticosteroids or anti-convulsant therapy over the 
previous 4 weeks) are eligible. 
E 04. History of cerebrovascular stroke or transient ischemic attack within previous 6 months. 
E 05. Prior solid organ or hematologic transplant. 
E 06. The following ocular abnormalities are excluded: 
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a) History or current retinal pigment epithelial detachment (RPED), central serous 
retinopathy, RVO, neovascular macular degeneration, or factors considered by the 
Investigator to present an unacceptable risk of RPED or RVO.  
b) Visible retinal pathology as assessed on ophthalmic examination that is considered a 
significant risk factor for RVO or RPED by an ophthalmologist. 
E 07. Any of the following cardiovascular abnormalities: 
a) Symptomatic congestive heart failure, New York Heart Association Class II or higher  
b) Acute coronary syndrome (eg, unstable angina, coronary artery stenting, or 
angioplasty, bypass grafting) within prior 6 months 
c) History or current uncontrolled clinically significant unstable arrhythmias 
d) Participants who have pacemakers to control atrial arrhythmias are candidates for the 
study. Participants with medically controlled atrial fibrillation >6 months prior to 
C1D1 are eligible.  
e) History of congenital long QT syndrome or prolonged QTcF interval >480 msec using 
Fridericia’s formula (unless a pacemaker is in place) or uncorrectable abnormalities in 
blood electrolytes (sodium, potassium, calcium, magnesium, phosphorus). 
f) Left ventricular ejection fraction (LVEF) < institutional LLN or <50%, whichever is 
lower. 
E 08. Treatment-related immune-mediated (or immune-related) AEs from immune-modulatory 
agents (including but not limited to anti-PD 1/PD-L1 agents and anti-CTLA 4 monoclonal 
antibodies) that caused permanent discontinuation of the agent, or that were Grade 3 or 4 
in severity, or that have not resolved to baseline at least 3 months prior to initiation of 
IMP. For other agents, treatment related immune mediated (or immune related) AEs that 
were Grade 2 or above (applies to Part-1, Part-2, and Part-4). 
E 09. Ongoing AEs (excluding alopecia and fatigue) caused by any prior anti-cancer therapy 
≥ Grade 2 (NCI-CTCAE Version 5.0). 
E 10. Active, known or suspected autoimmune disease that has required systemic treatment in 
the past 2 years (ie, with use of disease modifying agents, corticosteroids or 
immunosuppressive drugs), except for replacement therapy (eg, thyroxine, insulin, or 
physiologic corticosteroid replacement) (applies to Part-1, Part-2 and Part-4). 
E 11. History of or current interstitial lung disease, active pneumonitis, or pneumonitis that 
requires oral or IV glucocorticoids to assist with management (radiation pneumonitis in the 
radiation field is permitted; radiation pneumonitis that requires steroids is not permitted); 
history of thoracic radiation therapy of >30 Gy within 6 months of the first dose of trial 
treatment. 
E 12. Receipt of a live-virus vaccination within 28 days of planned treatment start. Receipt of 
viral vaccine that do not contain live virus within 7 days. Seasonal flu vaccines that do not 
contain live virus are permitted. 
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E 13. Known infection with human immunodeficiency virus (HIV), known uncontrolled 
hepatitis B virus (HBV) infection, known uncontrolled hepatitis-C virus (HCV) infection, 
active tuberculosis, or severe infection requiring parenteral antibiotic treatment. To control 
HBV infection, participants with positive hepatitis B surface antigen (HBsAg) should have 
started anti-HBV therapy before initiation of IMP, and the screening HBV viral load 
should be <2000 IU/mL (104 copies/mL). The anti-HBV therapy should continue 
throughout the treatment period. The HCV-treated participants must have completed their 
treatment at least 1 month prior to starting study intervention. Participants with positive 
HCV antibody and undetectable HCV RNA without anti-HCV therapy are eligible.  
E 14. Known second malignancy either progressing or requiring active treatment within the 
last 3 years (except for basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin, ductal carcinoma in situ (DCIS) of the breast, or in situ cervical cancer that has 
undergone potentially curative therapy). 
E 15. Impairment of gastrointestinal function that may alter the absorption of SAR442720 
(eg, uncontrolled nausea and vomiting, diarrhea, malabsorption syndrome, inflammatory 
bowel disease, gastrectomy, small bowel resection). 
E 16. History of severe allergic reaction to any of the study intervention components. 
Prior/concomitant therapy 
E 17. Last administration of prior anti-tumor therapy (chemotherapy, targeted agents, and 
immunotherapy) or any investigational treatment within 28 days or less than 5 times the 
half-lives of the agent (whichever is shorter) prior to the first dose of IMP.  
E 18. Participant who has received prior radiotherapy within 2 weeks of start of study 
intervention. Participants must have recovered from all radiation-related toxicities, not 
require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is 
permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease. 
E 19. Comorbidity requiring corticosteroid therapy (>10 mg prednisone/day or equivalent) 
within 14 days of IMP initiation. Physiologic replacement doses are allowed even if they 
are >10 mg of prednisone/day or equivalent, as long as they are not being administered for 
immunosuppressive intent. Inhaled or topical steroids are permitted, provided that they are 
not for treatment of an autoimmune disorder. 
E 20. Major surgery ≤28 days or non-study related minor procedures (eg, Port-a-Cath placement) 
≤7 days prior to C1D1. In all cases, the participant must be sufficiently recovered and 
stable before treatment administration. 
E 21. Any other unstable or clinically significant concurrent medical condition (eg, substance 
abuse, uncontrolled intercurrent illness including active infection, arterial thrombosis, and 
symptomatic pulmonary embolism, etc) that would, in the opinion of the investigator, 
jeopardize the safety of a participant, impact their expected survival through the end of the 
study participation, and/or impact their ability to comply with the protocol. 
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E 22. Medication and supplements that may interfere or potentiate with SAR442720 and/or 
adagrasib metabolism or toxicity PRIOR or DURING study intervention are excluded: 
- 
Strong CYP3A4 inducers or inhibitors (within 7 days prior)  
- 
Strong P-glycoprotein (P-gp) inhibitors (eg, cyclosporine, tacrolimus; within 7 days 
prior)  
- 
Strong Breast Cancer Resistance Protein (BCRP) inhibitors (eg, eltrombopag; within 
7 days prior) (applies to Part-3 only) 
- 
Proton pump inhibitors (within 3 days prior) or H2-receptor antagonists (within 1 day 
prior) during the dose escalation portion of the study 
- 
 Medications known to prolong QTc interval 
- 
Acetylsalicylic acid (low dose aspirin, anticoagulation with low-molecular weight 
heparin or direct Factor X inhibitors and LMWH are allowed. Prophylactic LMWH is 
also allowed for high risk patients with hypercoagulability). 
Diagnostic assessments 
E 23. Inadequate organ and bone marrow function at the Screening visit: 
- 
Absolute neutrophil count (ANC) <1000 µ/L (1 × 109/L). 
- 
Platelets <100 × 10³ µ/L (after at least 3 days without platelet transfusion). 
- 
Hemoglobin <9 g/dL or <5.6 mmol/L (without transfusions within 2 weeks of 
initiation of IMP). 
- 
Total bilirubin >2 × ULN. 
- 
AST and/or ALT >3 × ULN (or >5 × ULN for participants with liver metastases). 
- 
Blood creatinine >1.5 × ULN or creatinine clearance of <50 mL/min (using Cockcroft 
Gault formula or 24-hour urine collection) 
- 
Prothrombin time (PT)/international normalized ratio (INR) and activated partial 
thromboplastin time or partial thromboplastin time (aPTT/PTT) >1.3 × ULN or outside 
the therapeutic range of the local laboratory if receiving therapeutic anticoagulation 
that would affect the PT/INR. 
Other exclusions 
E 24. Individuals accommodated in an institution because of regulatory or legal order; prisoners 
or participants who are legally institutionalized. 
E 25. Participant not suitable for participation, whatever the reason, as judged by the 
Investigator, including medical or clinical conditions, or participants potentially at risk of 
noncompliance to study procedures. 
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E 26. Participants are employees of the clinical study site or other individuals directly involved 
in the conduct of the study, or immediate family members of such individuals (in 
conjunction with Section 1.61 of the International Council for Harmonisation (ICH)-Good 
Clinical Practice (GCP) Ordinance E6). 
E 27. Any specific situation during study implementation/course that may rise ethics considerations. 
E 28. 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. 
Tumor characteristics for Part-2, Part-3, and Part-4 (new criteria added with 
amendment 03): 
E 29. Following known genotypes are excluded for expansion cohorts: 
a) NRAS (except G12A/C) 
b) RASQ61 
c) KRASG13 
d) BRAF Class 1, 2, or unclassified 
e) PIK3CA 
New criteria added with amendment 04 
E 30. Subject has a known activating SHP2 mutation (eg, Noonan syndrome) 
E 31. Treatment with following agents in Part-3 only: 
- 
KRAS G12C inhibitors (Part-3B only) 
- 
SHP2 inhibitors (Part-3B only) 
- 
CYP3A substrates with a narrow therapeutic index 
5.3 
LIFESTYLE CONSIDERATIONS  
5.3.1 Meals and dietary restrictions  
1. Refrain from consumption of grapefruit or grapefruit containing products, or Seville 
oranges from 7 days before the start of study intervention until after the final dose. 
2. Fasting (except water) 1 hour prior to and 1 hour after each SAR442720 dose is required. 
On days when both medications are administered together, fasting is requisite due to the 
requirements of SAR442720. For participants in Part-3, adagrasib may be taken with or 
without food. When co-administered with SAR442720, adagrasib should be taken without 
food (as SAR442720 requirement). For participants enrolled in Part-4, meal consumptions 
will be based on the protocol instructions. Vegan and non-vegan meals are defined in the 
protocol and are comparable in terms of kilocalories as well as fat consumption and 
similar to classic meals in terms of fed conditions (non-vegan meals will be provided 
except for patients who are vegans). Please see Appendix 13 (Section 10.13). 
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5.4 
SCREEN FAILURES  
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently able to receive treatment in the study. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to respond 
to queries from regulatory authorities. Minimal information includes demography, screen failure 
reasons, eligibility criteria, and any SAE. 
Individuals who do not meet the criteria for participation in this study (ie, screen failure) may be 
rescreened without a new ICF if within 5 days of the initial screening date of screen failure. 
Rescreened participants should be assigned the same participant number as for the initial 
screening, if within 5 days of initial screening. Only hematology, chemistry, and coagulation tests 
may need to be repeated if outside the screening window. Other clinical testing will not need to be 
repeated if outside screening window (ie, within 5 days).  
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6 
STUDY INTERVENTION  
Study intervention is defined as any investigational intervention(s), marketed product(s), placebo, 
or medical device(s) intended to be administered to a study participant according to the study 
protocol. 
6.1 
STUDY INTERVENTION(S) ADMINISTERED  
Table 16 - Overview of study interventions administered in Part-1, -2, and -4  
Study 
Intervention 
name 
SAR442720 
Pembrolizumab 
Type 
Drug 
Dose formulation 
Powder-in-capsule 
Film-coated tablet 
Lyophilized powder in single-dose vial for 
reconstitution or solution in a single-dose vial 
Unit dose 
strengths 
20 mg and 100 mg  
50 mg/vial or 100 mg/4 mL (25 mg/mL) 
Dosage levels 
The starting dose depends on which combination 
is evaluated 
200 mg Q3W or 400 mg Q6W (for Part-2) 
Route of 
administration 
Oral with water after 1 hour fast; no food or drink 
(other than water) allowed for 1 hour after 
administration 
Intravenous infusion over 30 minutes in 
accordance with the product leaflet 
Use 
Experimental combination 
IMP and NIMP 
IMP 
Packaging and 
labeling 
SAR442720 capsule 
will be provided in 
8-count HDPE bottles 
 
 
Each bottle will be 
labeled as required per 
country requirement 
SAR442720 tablets 
will be provided in a 
wallet containing 
1 Aclar blister of 
8 tablets 
Each wallet will be 
labeled as required per 
country requirements 
Pembrolizumab will be provided in 50 mg 
lyophilized powder in single-dose vial for 
reconstitution or 100 mg/4 mL (25 mg/mL) 
solution in a single-dose vial 
 
Each box will be labeled as required per country 
requirement 
Current/Former 
names or aliases 
SAR442720, 
RMC-4630, 
RMC 0694630 
SAR442720 
KEYTRUDA®, pembrolizumab 
Abbreviation: BID = twice daily; BIW = Day 1 and Day 2 of each week, Day 1 and Day 4 of each week, or any other emergent dose schedule 
from the ongoing Phase 1 monotherapy escalation study; HDPE, high-density polyethylene, IMP, investigational medical product;  
NIMP, noninvestigational medical product; Q3W = once every 3 weeks; Q6W, Q3W = once every 3 weeks.  
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Table 17 - Overview of study interventions administered in Part-3  
6.1.1 Investigational medicinal product  
The number of SAR442720 20 mg and 100 mg bottles and adagrasib 200 mg bottles will be 
dispensed depending on the dose level and will cover the treatment until the next dispensation 
visit. 
When applicable, pembrolizumab will be sourced from available commercial supplies. Otherwise 
it will be relabeled by the Sponsor as per country requirements and according to Good 
Manufacturing Practice (GMP) guidelines. 
Further details on IMPs will be described in the Pharmacy Manual. 
Between the protocol-scheduled on-site visits, interim visits may be required for IMP dispensing. 
As an alternative to these visits, SAR442720 20 mg and 100 mg bottles and adagrasib 200 mg 
bottles may be supplied from the site to the participant via a Sponsor-approved courier company 
where allowed by local regulations and approved by the participant (Direct-To-Patient [DTP] 
process). 
Study 
Intervention 
name 
SAR442720 
Adagrasib 
Type 
Drugs 
Dose formulation 
Powder-in-capsule 
Film coated tablets 
Unit dose 
strengths 
20 mg and 100 mg  
200 mg 
Dosage levels 
The starting dose depends on which 
combination is evaluated 
400 mg BID or 600 mg BID; should be at 12-hour 
intervals to the extent possible 
Route of 
administration 
Oral with water after 1 hour fast; no food or drink 
(other than water) allowed for 1 hour after 
administration 
Oral with at least 240 mL (8 ounces) of water; 
may be taken with or without food 
Use 
Experimental combination 
IMP and NIMP 
IMP 
Packaging and 
labeling 
SAR442720 capsule will be provided in 8-count 
HDPE bottles 
Each bottle will be labeled as required per country 
requirements 
Adagrasib tablets will be provided in 132-count 
HDPE bottles 
Each bottle will be labeled as required per 
country requirements 
Current/Former 
names or aliases 
SAR442720, RMC-4630, RMC 0694630 
MRTX849, adagrasib 
Abbreviation: BID = twice daily; HDPE, high-density polyethylene, IMP, investigational medical product; NIMP, noninvestigational medical 
product. 
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6.1.2 Non-investigational medicinal product  
Appropriate premedication for study treatments may be administered at the Investigator’s 
discretion according to the usual clinical practice and in accordance with institutional guidelines. 
If premedication is required, all the drugs used will also be entered to the concomitant medication 
pages. 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY  
SAR442720 (powder-in-capsule drug products: 20 mg and 100 mg) is stored as following: Store 
below 30°C (86°F). Do not freeze. 
SAR442720 (aclar/aluminum blister tablets: 20 mg and 100 mg) is stored as follows: Store 
between 2°C and 30°C (36°F to 86°F). Do not freeze. 
Pembrolizumab is stored as follows:  
• Lyophilized powder: Store vials under refrigeration at 2°C to 8°C (36°F to 46°F). 
• Solution: Store vials under refrigeration at 2°C to 8°C (36°F to 46°F) in original carton to 
protect from light. Do not freeze. Do not shake. 
Adagrasib is stored as follows: 
• MRTX849 tablets are provided in single bottles (no cartons) and should be stored at room 
temperature (2°C to 25°C, 36°F to 77°F) according to the instructions on the label.  
• 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. 
• 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. 
• 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). 
Any quality issue noticed with the receipt or use of an IMP (deficiency in condition, appearance, 
pertaining documentation, labeling, expiration date, etc) must be promptly notified to the Sponsor. 
Some deficiencies may be recorded through a complaint procedure (see Section 8.3.7). 
A potential defect in the quality of IMP may be subject to initiation of a recall procedure by the 
Sponsor. In this case, the Investigator will be responsible for promptly addressing any request 
made by the Sponsor, in order to recall the IMP and eliminate potential hazards. 
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Under no circumstances will the Investigator supply IMP to a third party (except for DTP 
shipment, for which a courier company has been approved by the Sponsor), 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  
This is an open label study without randomization. No blinding or randomization will be used for 
this study. In order to minimize bias, the participants will be assigned sequentially as they are 
enrolled into the study using the inclusion and exclusion criteria as outlined in Section 5.1 and 
Section 5.2. Enrollment will be confirmed by the sponsor Medical Monitor after review of all 
supporting documentation for eligibility criteria.  
Participants will be allocated a screening number at the time of signing the ICF. If a participant is 
a screen failure, the number will not be reassigned. 
6.4 
STUDY INTERVENTION COMPLIANCE  
When participants are dosed at the site, they will receive study intervention directly from the 
Investigator or designee, under medical supervision. The date and time of each dose administered 
in the clinic will be recorded in the source documents and recorded in the case report form (CRF). 
The dose of study intervention and study participant identification will be confirmed at the time of 
dosing by a member of the study site staff other than the person administering the study 
intervention.  
When participants self-administer study intervention(s) at home, compliance with study 
intervention will be assessed at each visit. Compliance will be assessed by direct questioning, 
counting returned capsules and checking the participant diary information during the site visits 
and documented in the source documents and CRF. Deviation(s) from the prescribed dosage 
regimen should be recorded in the eCRF. 
A record of the number of SAR442720 capsules, SAR442720 tablets, and adagrasib tablets 
dispensed to and taken by each participant must be maintained and reconciled with study 
intervention and compliance records. Intervention start and stop dates, including dates for 
intervention delays and/or dose reductions will also be collected and recorded in eCRF. 
6.4.1 Missed dose  
SAR442720: If a participant misses a dose, it may be taken at the time the omission was 
discovered as long as it is within 24 hours of the original administration time. Otherwise, the dose 
should not be administered and should be recorded as an omission. The participant should not 
administer more than the recommended dose. 
Adagrasib: If a dose is inadvertently missed, the dose should be skipped if >4 hours has elapsed 
since the expected dosing time. Dosing may resume at the next schedule time. 
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6.5 
CONCOMITANT THERAPY  
Supportive care (eg, antiemetics, analgesics, blood transfusions, hematopoietic growth factor 
support) may be used at the investigator’s discretion and in accordance with institutional 
procedures. Localized radiotherapy used for palliative purposes may be considered after 
discussion with the Medical Monitor. Low dose aspirin and anticoagulation with low-molecular 
weight heparin or direct Factor X inhibitors and LMWH are allowed. Prophylactic LMWH is also 
allowed for high risk patients with hypercoagulability. Contraceptives are also allowed throughout 
the study as described in Appendix 4 (Section 10.4). 
Antacids are permitted but should not be consumed within 3 to 4 hours before or after 
SAR442720 administration. 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment or receives 
during the study must be recorded along with: 
• Reason for use 
• Dates of administration including start and end dates 
• Dosage information including dose and frequency 
• Route of administration 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
Participants must abstain from taking prescription or nonprescription drugs (including vitamins 
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. 
6.5.1 Prohibited concomitant therapy  
In addition to prohibited medications/foods listed in Exclusion Criteria (Section 5.2), a complete 
list of prohibited medications during study treatment is provided in Appendix 10 (Section 10.10). 
The following medications are prohibited while on study treatment: 
• Medications known to prolong QTc interval  
• Anti-cancer therapy (except SAR442720 and pembrolizumab or adagrasib) 
• Strong CYP3A4 inhibitors and inducers 
• Strong P-gp inhibitors  
• Strong BCRP inhibitors (Part-3 only) 
• CYP3A substrates with a narrow therapeutic index (Part-3 only) 
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• Proton pump inhibitors (only during the dose escalation portion of the study; for Part-3 
during both escalation and expansion). 
• H2-receptor antagonists (only during the dose escalation portion of the study). H2-receptor 
antagonist can be given at least 2 hours before and 10 hours after adagrasib (Part-3 only). 
• Acetylsalicylic acid (low dose aspirin and anticoagulation with low-molecular weight 
heparin or direct Factor X inhibitors and LMWH are allowed. Prophylactic LMWH is also 
allowed for high risk patients with hypercoagulability). 
6.6 
DOSE MODIFICATION  
A 21-day cycle will be maintained, and dose interruption will be noted in the 21-day cycle 
schedule. 
In the Dose Escalation cohorts, there will be no dose reductions or modifications during C1, 
21-day DLT assessment period unless a DLT has occurred. After Cycle 1 and in the final dose 
cohort, if a dose reduction is recommended, then the SAR442720 dose level should be the 
previous lower dose level considered to be tolerable in prior participants receiving that dose. 
Two dose reductions are allowed.  
In Part-2, dose reduction will be allowed for SAR442720 according to the criteria detailed below. 
SAR442720 may be reduced to the dose corresponding to one dose level below RP2D. 
Pembrolizumab dose reductions are not permitted. Pembrolizumab treatment may be interrupted 
or discontinued due to toxicity.  
In Part-3, dose reduction for SAR442720 will be as described below. SAR442720 may be reduced 
to the dose corresponding to one dose level below.  
In Part-4, dose reduction of SAR442720 is not allowed on C1D1, C1D15, and C2D1. For other 
doses, dose reduction or interruption may be allowed. Pembrolizumab dose reductions are not 
permitted. Pembrolizumab treatment may be interrupted or discontinued due to toxicity. 
Two types of dose modifications are allowed, “dose interruption” and “dose level reduction” 
according to the dose modification criteria and guidelines outlined in Section 6.6.1 below. Any 
allowed dose modification and any deviation from the intended dose (missed doses or overdoses 
due to participant error) should be documented on the dose eCRF. 
6.6.1 Dose modification criteria  
6.6.1.1 General guidelines for adagrasib (Part-3)  
The following are the general guidelines for withholding, resumption or re-challenge of treatment 
with adagrasib: 
• following adagrasib dose reduction and control of an AE, re-challenge at a higher 
adagrasib dose may be permitted after discussion with the Sponsor; 
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• if resumption of dosing for adagrasib is delayed for ≥14 days due to an AE that is at least 
suspected to be attributable to study treatment, then resumption at a reduced dose should 
be considered; 
• if treatment with adagrasib is withheld for ≥22 consecutive days, then permanent 
discontinuation from treatment with one or both agents should be considered; and 
• if a treatment-related AE recurs despite dose reduction of adagrasib to the lowest dose 
anticipated, then permanent discontinuation from study treatment should be considered, 
unless after discussion with the Sponsor it is considered to be in the best interest of the 
participant to continue. 
Treatment interruptions and modification guidelines are provided in Appendix 9 (Section 10.9). 
Additional guidelines for adagrasib: 
Hepatic Toxicities 
Hepatic toxicities that are considered to be causally related to adagrasib should initially be 
managed with treatment interruption of one or both study drugs as outlined in Table 27. 
Evaluations for confounding factors (eg, cholestasis, metastasis, or viral infection) should be 
performed as clinically indicated, and more frequent monitoring of a hepatic panel (including 
AST, ALT, alkaline phosphatase, and bilirubin) should be considered for those participants with 
transaminase increases. Following resolution of toxicity to the specified degree, dose reduction of 
adagrasib should be implemented. 
Other Laboratory Investigation-Based Toxicities 
Other laboratory investigation-based toxicities that are considered to be causally related to 
adagrasib should initially be managed with treatment interruption of adagrasib as outlined in 
Table 27. Following resolution of toxicity to the specified degree, dose reduction of adagrasib 
should be implemented. 
Cardiac Toxicities 
Cardiac toxicities that are considered to be causally related to adagrasib should initially be 
managed with treatment interruption of adagrasib as outlined in Table 27. Cardiology consultation 
should be obtained for cases of QTcF prolongation or LVEF decreases falling into the categories 
indicated in Table 27. In addition, more frequent monitoring of electrolytes that include potassium 
and magnesium should be considered for participants with vomiting, diarrhea, or past instances of 
hypokalemia or hypomagnesemia that could recur, and oral and/or intravenous supplementation 
should be considered for levels below the lower limit of normal. Additionally, arrhythmia should 
be included in the differential diagnosis of relevant AEs (eg, palpitations, syncope, pre-syncope, 
or unexplained dyspnea), and unscheduled ECGs should be performed for participants with such 
events or electrolyte abnormalities as clinically indicated. Additional assessments of LVEF should 
be performed as clinically indicated at the Investigator’s discretion if there are signs or symptoms 
of cardiotoxicity. 
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Following resolution of toxicity to the specified degree, dose reduction of adagrasib should be 
implemented. 
Pneumonitis 
Pneumonitis has been reported in the Phase 1 study of adagrasib. An evaluation should be 
performed to assess the attribution of pneumonitis to adagrasib. Pneumonitis considered to be 
causally related to adagrasib should be initially managed with treatment interruption of adagrasib 
as outlined in Table 27. Following resolution of toxicity to the specified degree, dose reduction of 
adagrasib should be implemented. 
Other Toxicities 
Other toxicities that are considered to be causally related to adagrasib should initially be managed 
with treatment interruption as outlined in Table 27. Following resolution of toxicity to the 
specified degree, dose reduction of adagrasib should be implemented. 
Hormonal Contraceptives and Thrombotic Events 
In female participants using hormonal contraceptives, the potential exists for adagrasib to inhibit 
hepatic cytochrome P450 and CYP3A4 and increase exposure to hormonal contraceptive levels, 
with the associated risk of venous thromboembolism (e.g., deep vein thrombosis or pulmonary 
embolism). Precautions should be taken in participants with recent, clinically significant 
thrombotic events, and all participants using hormonal contraceptives should be closely monitored 
for emerging signs of thrombotic events. Treatment with adagrasib should be interrupted in 
participants with signs or symptoms of thrombosis and permanently discontinued in participants 
who develop clinically significant thromboembolic complications. If in the judgment of the 
Investigator resumption of treatment with adagrasib is in the best interest of the participant, 
concomitant treatment with hormonal contraceptives should be discontinued. 
6.6.1.2 Management of diarrhea  
Evaluate for other or concomitant causes, including medications (eg, stool softeners, laxatives, 
antacids), infection including Clostridium difficile, malabsorption/lactose intolerance, fecal 
impaction, and dietary supplements high in fiber. 
For Grade 1 or 2 diarrhea, dietary modifications should be considered including cessation of 
lactose-containing products, eat small meals, and adequate hydration. Consumption of the BRAT 
(banana, rice, apples, toast) diet may be helpful. In addition, loperamide or diphenoxylate/atropine, 
or codeine may be used or alternatives in refractory cases such as octreotide and budesonide. 
For > Grade 2 diarrhea, consider hospitalization for fluid and electrolyte replacement and 
antibiotics, particularly if accompanied by fever or Grade 3 to 4 neutropenia. 
Please refer to Table 27 for dose modifications guidelines. For immune related colitis, defer to 
institutional guidelines. 
Consultation with a gastroenterologist should be considered, particularly for severe or refractory 
cases. 
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6.6.1.3 Management of ophthalmologic complications  
The causal relationship between a change in vision and the study treatment should be carefully 
explored and an ophthalmologist should be consulted. Immediate consultation should be sought 
for Grade >1 visual changes. Special attention should be given to retinal (eg, central serous 
retinopathy [CSR]) or retinal vein abnormalities (eg, RVO). If consultation cannot be obtained 
within 7 days of onset, interrupt treatment (either SAR442720 and pembrolizumab or SAR442720 
and adagrasib) until the consultation has occurred.  
If RVO is diagnosed, permanently discontinue treatment (either SAR442720 and pembrolizumab 
or SAR442720 and adagrasib) immediately and treat per institutional guidelines. If uveitis is 
diagnosed, withhold treatment (either SAR442720 and pembrolizumab or SAR442720 and 
adagrasib) and consider use of topical steroids until resolution. If CSR or neurosensory retinal 
detachment is diagnosed, withhold treatment until symptoms resolve and retinal exam shows 
resolution. Restart medication(s) at one dose level lower and close monitoring following 
re-initiation of medication(s). If > Grade 1 symptoms recur or follow-up ophthalmology 
examination worsens, withhold treatment (either SAR442720 and pembrolizumab or SAR442720 
and adagrasib) and either further decrease the dose or permanently discontinue treatment. 
6.6.1.4 Management of hypertension  
Early identification and treatment of hypertension is recommended. Evaluate for other or 
concomitant causes. Assess renal function as well as urinalysis. For recurrent or persistent 
hypertension (systolic blood pressure >140 mmHg or diastolic blood pressure >90 mmHg) treat 
according to institutional guidelines with the goal of therapy to reduce blood pressure to 
<140 mmHg systolic/90 mmHg diastolic. Hypertension associated with life-threatening 
consequences (eg, malignant hypertension, neurological deficits, hypertensive crisis), permanently 
discontinue treatment (either SAR442720 and pembrolizumab or SAR442720 and adagrasib). 
Please refer to Table 27 for dose modifications guidelines. Cardiology or nephrology consultation 
should be considered, as clinically indicated. 
6.6.1.5 Management of rhabdomyolysis or symptomatic CPK increase  
Assess for other causes of CPK elevation and rhabdomyolysis such as strenuous exercise, trauma, 
heat-related causes, ischemia, inflammatory process, etc. For CPK elevations, rule out cardiac 
causes by obtaining ECG, cardiac troponin, and CK-MB fraction. Evaluate for rhabdomyolysis 
and potential renal compromise with a clinical examination, urinalysis, and complete blood 
chemistry (eg, metabolic panel). Treat according to institutional guidelines. Early IV hydration 
with urine alkalization provided that there are no contraindications. Nephrology consultation 
should be considered, as clinically indicated. 
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6.6.1.6 Management of liver function abnormalities and hepatotoxicity  
Assess whether metastatic disease to the liver is contributing to liver function abnormalities 
and/or hepatotoxicity. Evaluate for infections or other causes of increased liver function 
abnormalities if appropriate. Consider imaging of the liver. Hold or dose reduce concomitant 
medications which may potentiate hepatotoxicity or metabolized by the liver. Evaluate extent of 
liver injury (eg, albumin level, PTT, INR) and if there is evidence of severe injury, then 
discontinue treatment (either SAR442720 and pembrolizumab or SAR442720 and adagrasib).  
Please refer to Table 27 for dose modifications guidelines for LFTs. 
6.6.1.7 Management of decrease in left ventricular ejection fraction  
Asymptomatic absolute decrease in LVEF from baseline ≥20% from baseline and below LLN, 
withhold treatment (either SAR442720 and pembrolizumab or SAR442720 and adagrasib) for up 
to 4 weeks and repeat echocardiogram (ECHO) for LVEF at 2, 4, 10, and 16 weeks after treatment 
was withheld. Restart at reduced dose if LVEF ≥LLN and absolute decrease from baseline LVEF 
<20%. Permanently discontinue if symptoms if symptoms of heart failure are present. 
Symptomatic reduction: In case of symptomatic systolic dysfunction with an LVEF decrease from 
baseline ≥10% and/or below LLN, withhold both SAR442720 and pembrolizumab for up to 
4 weeks and consider permanent discontinuation if considered causative; in Part-3 permanently 
discontinue SAR442720 and adagrasib. 
Please refer to Table 27 for dose modifications guidelines. Cardiology consultation should be 
considered. 
6.6.1.8 Management of hemorrhage  
Evaluate complete blood count and coagulation laboratories. Transfuse blood products and correct 
coagulation abnormalities as per institutional guidelines. Withhold treatment (either SAR442720 
and pembrolizumab or SAR442720 and adagrasib) if hemorrhage associated with 
thrombocytopenia, reduced platelet count from baseline, or at the discretion of investigator. 
Please refer to Table 27 for dose modifications guidelines. 
6.6.1.9 Management of pyrexia  
Evaluate for source of fever. Obtain a complete blood count (CBC). Routine infectious work-up 
and treatment with antibiotics may not be necessary for participants with uncomplicated pyrexia 
without localizing symptoms; but work-up may be completed and antibiotic may be given, based 
on the clinical assessment. Hold pembrolizumab until fever resolves and restart with same dose 
and schedule. SAR442720 or adagrasib may be held at the investigator’s discretion. Antipyretics 
may be given for treatment or as prophylaxis in participants with recurrent pyrexia associated with 
a medication. Consider short-course of low-dose corticosteroids for recurrent/recalcitrant fevers. 
Evaluation blood chemistry (ie, renal function test) for those with severe pyrexia. 
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6.6.1.10 Management of fatigue  
Other causes of fatigue should be evaluated (eg, infection, disease progression and hematological, 
electrolyte, heart failure and endocrine abnormalities). Dose-modification and/or low-dose 
corticosteroids may be considered. 
6.6.1.11 Pneumonitis  
Respiratory symptoms such as cough, shortness of breath, etc. should be investigated with a chest 
X-ray or chest CT scan. Evaluate for possible infections and other causes of respiratory 
compromise including progressive pulmonary disease, cardiac dysfunction, etc.  
6.6.1.12 Management of edema  
Evaluate for other or concomitant causes including medications. Treat according to institutional 
guidelines including the cessation of other medications known to be associated with the 
development of edema, if clinically indicated. 
6.6.1.13 Management of rash  
For macular/papular rash or perifollicular eruptions, emollients alone may be used for Grade 1 
AEs. For Grade 2 AEs, addition of antihistamines and/or topical corticosteroids are 
recommended. For Grade >2 events, oral steroids may be required. 
For dry skin, alcohol-free emollients and soap substitutes should be considered. For folliculitis or 
cysts, soap substitutes and topical or oral antibiotics are recommended. Consider surgical excision 
for symptomatic, uninfected cysts. For an erythema-nodosum type rash, emollients, topical 
steroids and analgesics are recommended. In more severe cases, dermatologic evaluation and 
systemic steroids may be required. 
Please refer to Table 27 for dose modifications guidelines. Consultation with a dermatologist 
should be considered as clinically indicated, including worsening or refractory symptoms, or 
rapidly growing lesions. 
6.7 
INTERVENTION AFTER THE END OF THE STUDY  
The end of the study is defined as the date of the last visit of the last participant in the study or last 
scheduled procedure shown in the Schedule of Activities (SOA) for the last participant in the trial 
globally. 
The participant’s treatment after the end of the study will be at discretion of treating physician. 
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7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL  
7.1 
DISCONTINUATION OF STUDY INTERVENTION  
7.1.1 Definitive discontinuation  
In rare instances, it may be necessary for a participant to permanently discontinue (definitive 
discontinuation) study intervention. If study intervention is definitively discontinued, the 
participant will remain in the study to be evaluated for 30 days. See the schedule of activities 
(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. 
If a clinically significant finding is identified (including, but not limited to changes from baseline 
in QTcF) after enrollment, the Investigator or qualified designee will determine if the participant 
can continue in the study and if any change in participant management is needed. This review of 
the ECG printed at the time of collection must be documented. Any new clinically relevant 
finding should be reported as an AE. 
Participants may stop study therapy yet continue to be monitored in the study under the following 
circumstances: 
• A participant who experiences a Grade 4 AE, including those that meet the criteria of a 
DLT (ie, during Cycle 1), but is deemed by the investigator not to meet the criteria for 
withdrawal from the study (see below). 
• Prolonged QTcF >450 msec OR change from baseline of QTcF >50 msec and that does 
not resolve after excluding other causes. 
A participant must be discontinued from protocol prescribed therapy and removed from the study 
if any of the following apply: 
• Documented disease progression based on RECIST v1.1 
- 
In certain circumstances (eg, an isolated site of progression with responses at other 
sites that may be amenable to localized radiotherapy), participants may be allowed to 
continue therapy during and after radiation with approval from sponsor Medical 
Monitor. 
• Significant AEs leading to discontinuation of study medications  
• Death 
• Participant’s request to withdraw from study treatment 
• Ineligibility 
• Unwillingness or inability to comply with study requirements 
• Initiation of alternative anticancer therapy 
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• Investigator’s decision 
- 
Clinical need for concomitant or other ancillary therapy that is not permitted in the 
study 
- 
Unrelated intercurrent illness that, in the judgment of the investigator, will affect 
assessments of clinical status to a significant degree 
- 
Investigator believes that it is in the best interest of the participant to withdraw from 
the study 
• Pregnancy 
• Lost to follow-up 
• Sponsor’s decision to terminate the study 
Participants who have stable disease as best response will be allowed to continue on treatment 
provided the investigator believes it is in the participant’s best interest and none of the above 
criteria have been met. 
During the conduct of the study, in cases where premature discontinuation of SAR442720 is 
required, the participant may continue pembrolizumab or adagrasib treatment, upon Investigator 
decision and in agreement with the Study Medical Manager. Likewise, in cases where premature 
discontinuation of pembrolizumab or adagrasib is required, the participant may continue 
SAR442720 treatment if there is presence of, or potential for, clinical benefit as assessed by the 
Investigator and Study Medical Manager. 
Participants who discontinue study treatment should complete the safety follow up or EOT visit, 
within 30 days after the last treatment dose. Participants who do not withdraw consent will also 
undergo long term follow up until death or end of study or lost to follow-up.  
Refer to SoA for data to be collected at the time of intervention discontinuation and follow-up and 
for any further evaluations that need to be completed. 
Handling of participants after definitive intervention discontinuation 
Participants will be followed-up according to the study procedures specified in this protocol up to 
the scheduled date of study completion, or up to recovery or stabilization of any AE to be 
followed-up as specified in this protocol, whichever comes last. 
If possible, and after the definitive discontinuation of intervention, the participants will be 
assessed using the procedure normally planned for the last dosing day with the IMP including a 
PK sample, if appropriate. 
All cases of definitive intervention discontinuation must be recorded by the Investigator in the 
appropriate pages of the eCRF when considered as confirmed. 
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7.1.2 Temporary discontinuation  
Temporary intervention discontinuation may be considered by the Investigator because of 
suspected AEs as described in Section 6.6 or disruption of the clinical trial due to a regional or 
national emergency declared by a governmental agency (eg, COVID-19) (Section 10.12). For all 
temporary intervention discontinuations, duration should be recorded by the Investigator in the 
appropriate pages of the CRF or 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, compliance, or 
administrative reasons. This is expected to be uncommon. 
A participant may be withdrawn from the study for any of the following reasons: 
• Participant’s withdrawal of consent for participation in the study  
• Sponsor’s decision to terminate the study 
• Participant is lost to follow up  
• Death 
If study discontinuation occurs at the same time as treatment discontinuation, every effort should 
be made to complete the safety follow up or EOT visit, within 30 days after the last treatment 
dose. See SoA for data to be collected at the time of study discontinuation and follow-up and for 
any further evaluations that need to be completed. Participants who do not withdraw consent will 
also undergo a long term follow up for survival (SoA in Section 1.3). 
The participant will be permanently discontinued both from the study intervention and from the 
study at that time. 
If the participant withdraws consent for disclosure of future information, the Sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. 
If a participant withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the Investigator must document this in the site study records. 
If participants no longer wish to take the IMP, they will be encouraged to remain in the study.  
The Investigators should discuss with them key visits to attend. The value of all their study data 
collected during their continued involvement will be emphasized as important to the public health 
value of the study.  
Participants who withdraw from the study intervention should be explicitly asked about the 
contribution of possible AEs to their decision, and any AE information elicited must be 
documented.  
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All study withdrawals should be recorded by the Investigator in the appropriate screens of the 
e-CRF and in the participant’s medical records. In the medical record, at least the date of the 
withdrawal and the reason should be documented.  
In addition, a participant may withdraw his/her consent to stop participating in the study. 
Withdrawal of consent for intervention should be distinguished from withdrawal of consent for 
follow-up visits and from withdrawal of consent for non-participant contact follow-up, 
eg, medical record checks. The site should document any case of withdrawal of consent.  
Participants who have withdrawn from the study cannot be reallocated (treated) in the study. Their 
inclusion and intervention numbers must not be reused. 
7.3 
LOST TO FOLLOW UP  
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit: 
• The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study. 
• Before a participant is deemed lost to follow up, the Investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, if 
necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study.  
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1 
(Section 10.1.9). 
 
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8 
STUDY ASSESSMENTS AND PROCEDURES  
• Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed. 
• Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The Investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.  
• Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA. 
8.1 
EFFICACY ASSESSMENTS  
Participants will be assessed for response using RECIST v1.1 (Appendix 7 [Section 10.7]) as 
assessed by the investigator. All measurable disease must be documented at screening and 
reassessed at each subsequent tumor evaluation. Response assessments will be assessed by the 
investigator based on physical examination (including measurement of cutaneous lesions) and 
CT scans or MRI. Imaging should include chest and abdomen (neck and pelvis are to be included 
depending on primary tumor type and investigator assessment). At the investigator’s discretion, 
the imaging studies may be repeated at any time if disease progression is suspected. Additional 
studies, such as positron emission tomography (PET) scans, should be performed if clinically 
indicated. Care should be taken to repeat the same modality used at screening throughout the 
study and to ensure all anatomy imaged at screening is again imaged at follow up scans for any 
given participant. As part of the tumor assessment, physical examinations should include all areas 
of tumor involvement that are amenable to examination, including biopsy sites, lymph nodes, and 
bone tenderness, if applicable. 
All imaging studies should be evaluated by a local radiologist with expertise in the imaging 
modality. The investigator is responsible for determining the overall response at each time point. 
In Part-1 and Part-4, the first response assessment will occur after completion of C2 
(C3D1 ± 7 days). Subsequent response assessments will occur every 2 cycles through the end of 
C6 (C7D1 ± 7 days) and then every 3 cycles. 
In Part-2, the assessment of anti-tumor activity documented by objective response to the IMP is 
the primary endpoint for this study and is conducted as per schedule provided in the SoA 
(Table 3). All participants treated must have at least one measurable lesion for inclusion. The 
initial tumor imaging will be performed within 28 days prior to C1D1. Scans performed as part of 
routine clinical management are acceptable for use as the screening scan if they are of diagnostic 
quality and performed within 28 days prior to the date of enrollment. On study imaging will be 
performed every 9 weeks (56 ±7 days) after the date of first IMP and if clinically indicated. 
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Imaging studies should not be adjusted for delays in cycle starts or extension. The same imaging 
technique should be used in a participant throughout the trial. CT scan/MRI of the chest, 
abdomen, pelvis and any other locations with suspicion or evidence of disease involvement is 
required for the baseline assessment. Tumor assessment is not needed for participants who start a 
new anticancer therapy. 
In Part-3A the first response assessment will occur after completion of C2 (C3D1 ± 7 days). 
Subsequent response assessments will occur every 2 cycles through the end of C6 
(C7D1 ± 7 days) and then every 3 cycles. In Part-3B, the assessment of anti-tumor activity 
documented by objective response to the IMPs is the primary endpoint for this study and will be 
conducted as per the schedule provided in the SoA (Table 4). 
A partial or complete response must be confirmed on a second examination done at least 4 weeks 
apart, in order to be documented as a confirmed response to therapy.  
8.2 
SAFETY ASSESSMENTS  
Planned time points for all safety assessments are provided in the SoA (Section 1.3). 
8.2.1 Physical examinations  
• A complete physical examination should be performed as described in SoA (Section 1.3). 
The examination should include an evaluation of the head, eyes, ears, nose, and throat 
(HEENT), dermatologic, cardiovascular, respiratory, GI (including assessments of liver 
and spleen), musculoskeletal, neurological, and lymphatic systems. As part of tumor 
assessment, physical examinations should include all areas of tumor involvement that are 
amenable to examination including sites, biopsy, lymph nodes, and bone tenderness, if 
applicable. A symptom/AE directed physical examination should be performed as 
indicated by participant presentation or reported symptoms or AEs. New or worsened 
abnormalities should be recorded as AEs, if appropriate. 
• Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
8.2.2 Vital signs  
Vital signs will be measured after 5 to 10 minutes rest and will include temperature, systolic and 
diastolic blood pressure, pulse rate, respiratory rate, and pulse oximetry. Results should be 
recorded in the CRF. 
8.2.3 Weight and height  
Weight should be measured throughout the study as indicated in the SoA (Section 1.3). Coats 
should be removed prior to measurement. Height should be measured at baseline, preferably 
without shoes. Abnormalities including >10% weight change, should be recorded as AEs, if 
appropriate. 
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8.2.4 Electrocardiograms  
Single 12-lead ECG will be obtained as outlined in the SoA (see Section 1.3) using an ECG 
machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTc 
intervals. Refer to Section 7 for QTc withdrawal criteria and any additional QTc readings that 
may be necessary. 
8.2.5 Clinical safety laboratory assessments  
• See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed and 
to the SoA (Section 1.3) for the timing and frequency.  
• The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. The 
laboratory reports must be filed with the source documents. Clinically significant 
abnormal laboratory findings are those which are not associated with the underlying 
disease, unless judged by the Investigator to be more severe than expected for the 
participant’s condition. 
• All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 30 days after the last dose of study intervention should 
be repeated until the values return to normal or baseline or are no longer considered 
clinically significant by the Investigator or medical monitor. 
- 
If such values do not return to normal/baseline within a period of time judged 
reasonable by the Investigator, the etiology should be identified and the Sponsor 
notified. 
- 
All protocol-required laboratory assessments, as defined in Appendix 2 (Section 10.2), 
must be conducted in accordance with the laboratory manual and the SoA.  
- 
If laboratory values from non-protocol specified laboratory assessments performed at 
the institution’s local laboratory require a change in participant management or are 
considered clinically significant by the Investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the CRF. 
8.2.6 ECOG performance status  
ECOG performance status (Appendix 8 [Section 10.8]) should be evaluated by the investigator by 
direct questioning of the participant at baseline and at time points throughout the study as 
delineated in the SoA (Section 1.3). 
8.2.7 Retinal examinations  
Retinal examinations performed by an ophthalmologist are required during this study as described 
in the SoA (Section 1.3). Examinations include best-corrected visual acuity including pinhole 
vision if indicated, dilated funduscopic examinations, and macular and optical coherence 
tomography (OCT). Additional tests, such as fluorescein angiography, may be utilized to monitor 
leakage and inflammation-related side effects. 
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Ophthalmic examination including full fundoscopic examination and OCT should be performed 
by an ophthalmologist. Additional examinations should be performed during study treatment as 
clinically indicated. 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS  
The definitions of AEs and SAEs, can be found in Appendix 3 (Section 10.3).  
Adverse Events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant’s legally authorized representative).  
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue SAR442720 (see Section 7).  
8.3.1 Time period and frequency for collecting AE and SAE information  
All SAEs will be collected from the signing of the ICF until the follow-up visit at the time points 
specified in the SoA (Section 1.3). 
All AE will be collected from the signing of the ICF at the time points specified in the SoA 
(Section 1.3). 
After the signing of the ICF, but prior to initiation of study intervention, only SAEs caused by a 
protocol mandated intervention will be collected (eg, SAEs related to invasive procedures, such as 
biopsies or medication washout). Any medical occurrence that begins before the start of study 
intervention but after obtaining informed consent, and which is not considered an SAE caused by 
a protocol mandated intervention will be recorded on the Medical History/Current Medical 
Conditions Section of the eCRF not the AE section. 
All SAEs and AESI will be recorded and reported to the Sponsor or designee immediately and 
under no circumstance should this exceed 24 hours, as indicated in Appendix 3 (Section 10.3). 
The Investigator will submit any updated SAE data to the Sponsor within 24 hours of it being 
available. 
Investigators are not obligated to actively seek AE or SAE after conclusion of the study 
participation. However, if the Investigator learns of any SAE, including a death, at any time after 
a participant has been discharged from the study, and he/she considers the event to be reasonably 
related to the study intervention or study participation, the Investigator must promptly notify the 
Sponsor. 
8.3.2 Method of detecting AEs and SAEs  
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3 (Section 10.3). 
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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 AESIs 
(as defined in Section 8.3.6), will be followed until resolution, stabilization, the event is otherwise 
explained, or the participant is lost to follow-up (as defined in Section 7.3). Further information 
on follow-up procedures is provided in Appendix 3 (Section 10.3). 
8.3.4 Regulatory reporting requirements for SAEs  
• Prompt notification by the Investigator to the Sponsor of an SAE within 24 hours of 
first learning of the SAE is essential so that legal obligations and ethical responsibilities 
towards the safety of participants and the safety of a study intervention under clinical 
investigation are met.  
• The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and Investigators. 
• Serious adverse events that are considered expected will be specified in the reference 
safety information (IB for SAR442720 and US Package insert or SmPC for 
pembrolizumab).  
• Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) 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 IB and will notify the IRB/IEC, if appropriate according 
to local requirements. It is the responsibility of the Sponsor to assess whether an event meets 
the criteria for a SUSAR, and therefore, is expedited to regulatory authorities. 
8.3.5 Pregnancy  
• Details of all pregnancies in female participants and, if indicated, female partners of male 
participants will be collected after the start of study intervention and until EOT. 
• If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 4 
(Section 10.4). 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
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8.3.6 Adverse event of special interest  
Adverse event of special interest 
An AESI is an AE (serious or nonserious) of scientific and medical concern specific to the 
Sponsor’s product or program, for which ongoing monitoring and immediate notification by the 
Investigator to the Sponsor within 24 hours of first learning of the AESI is required. Such events 
may require further investigation in order to characterize and understand them. Adverse events of 
special interest may be added, modified or removed during a study by protocol amendment. 
• Pregnancy of a female participant entered in a study as well as pregnancy occurring in a 
female partner of a male participant entered in a study with IMP;  
- 
Pregnancy occurring in a female participant entered in the clinical trial or in a female 
partner of a male participant entered in the clinical trial. It will be qualified as an SAE 
only if it fulfills one of the seriousness criteria (see Appendix 3 [Section 10.3]). 
- 
In the event of pregnancy in a female participant, IMP should be discontinued.  
- 
Follow-up of the pregnancy in a female participant or in a female partner of a male 
participant is mandatory until the outcome has been determined (See Appendix 4 
[Section 10.4]). 
• Symptomatic overdose (serious or nonserious) with IMP 
- 
An overdose (accidental or intentional) with SAR442720 is an event suspected by the 
Investigator or spontaneously notified by the participant (not based on systematic pills 
count) and defined as at least twice the intended dose within the intended therapeutic 
interval, adjusted according to the tested drug.  
- 
Infusion with pembrolizumab: 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. Injectable administration: at least twice the 
dose during the planned intervals 
- 
An overdose (accidental or intentional) with adagrasib is an event suspected by the 
Investigator or spontaneously notified by the participant (not based on systematic pills 
count) and is defined as any amount above the intended dose. 
• Concurrent increase in ALT and AST >3 × ULN AND total bilirubin >2 × ULN or INR 
>1.5 ULN in the absence of cholestasis and other causes (eg, viral hepatitis, other 
pre-existing or acute liver disease, or another drug capable of the observed injury), which 
may indicate severe drug-induced liver injury (possible Hy’s law). Study drug should be 
withheld until AST, ALT, return to <2 × ULN and total bilirubin returns to <1.5 × ULN. 
• Other project specific AESI(s) 
- 
QT (corrected or uncorrected) >480 msec or increased from baseline>60 msec 
(see Section 7.1.1 QT prolongation management advice)  
- 
Thrombocytopenia Grade ≥3 or any grade if associated with clinically significant 
bleeding (see Section 6.6.1.8 for hemorrhage management guidelines) 
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- 
Edema, including generalized/peripheral edema or facial/periorbital edema 
(see Section 6.6.1.12 for edema management guidelines) 
- 
All protocol defined potential or IMP related DLTs are considered as AESI, 
regardless of the cycle of occurrence (ie, after Cycle 1 in both escalation and 
expansion phases) 
8.3.7 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 
TREATMENT OF OVERDOSE  
The Sponsor does not recommend specific treatment for an overdose (defined in Section 8.3.6). 
In the event of an overdose, the Investigator should: 
1. Contact the Medical Monitor immediately. 
2. Closely monitor the participant for any AE/SAE and laboratory abnormalities until 
SAR442720 can no longer be detected systemically (at least 5 days). 
3. Obtain a plasma sample for PK analysis within 1 to 2 days from the date of the last dose of 
study intervention if requested by the Medical Monitor (determined on a case-by-case 
basis). 
4. Document appropriately in the CRF. 
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant. 
8.5 
PHARMACOKINETICS  
Plasma samples will be obtained for PK analysis of SAR442720 as outlined in the SoA 
(see Section 1.3). Concentrations at each time point will be reported. 
• 
Whole blood samples of approximately 1.5 mL will be collected and processed into plasma 
for measurement of plasma concentrations of SAR442720 as specified in the SoA 
(see Section 1.3). Instructions for the collection and handling of biological samples will be 
provided by the sponsor. The actual date and time (24-hour clock time) of each sample will 
be recorded. 
• 
Samples collected for analyses of SAR442720 plasma concentration may also be used for 
exploratory analysis, such as metabolic profiling of SAR442720. 
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Serum samples will be obtained for PK analysis of pembrolizumab as outlined in the SoA 
(see Section 1.3). Concentrations at each time point will be reported. 
• 
Whole blood samples of approximately 1.5 mL will be collected and processed into serum for 
measurement of serum concentrations of pembrolizumab as specified in the SoA 
(see Section 1.3). Instructions for the collection and handling of biological samples will be 
provided by the sponsor. The actual date and time of each sample will be recorded. 
Pharmacokinetic samples will be tested by the Sponsor or Sponsor’s designee. 
• 
Samples collected for analyses of pembrolizumab serum concentration may also be used for 
other analysis, such as immunogenicity assessment. 
• 
Plasma samples will be obtained for PK analysis of adagrasib as outlined in the SoA 
(see Section 1.3). Concentrations at each time point will be reported. 
• 
Whole blood samples of approximately 1.5 mL will be collected and processed into plasma 
for measurement of plasma concentrations of adagrasib as specified in the SoA 
(see Section 1.3). Instructions for the collection and handling of biological samples will be 
provided by the Sponsor. The actual date and time of each sample will be recorded. 
• 
For Part-3A and Part-4, the PK parameters of SAR442720 and adagrasib will be calculated 
using a non-compartmental method. The PK parameters (eg, Cmax, time to achieve maximum 
concentration [Tmax], area under the concentration–time curve from Time 0 to Time t 
[AUC0-t], area under the concentration–time curve from Time 0 to infinity [AUCinf], 
elimination half-life [t1/2], if possible, and the accumulation ratio) of SAR442720 and 
adagrasib will be assessed for each evaluable participant. 
• 
PK population analysis may be conducted to obtain the PK parameters of SAR442720, 
pembrolizumab, and/or adagrasib. If performed, the results will be summarized in a separate 
report. 
• 
Samples collected for analyses of the concentration of SAR442720, pembrolizumab, and 
adagrasib may also be used to evaluate safety or efficacy aspects related to concerns arising 
during or after the study. 
8.6 
PHARMACODYNAMICS  
Whole blood samples will be collected throughout the study as outlined in the SoA (Section 1.3). 
RNA expression signatures for RAS-MAPK pathway and other relevant genes will be used to 
explore target engagement and pharmacodynamic (PDy) modulation in Part1 and Part2.  
In Part-1, fresh tumor tissue is required for PDy biomarker analyses unless the investigator 
determines that the tumor site is not amenable to biopsy and poses a significant risk to participant 
safety. The Sponsor will evaluate this requirement on a case-by-case basis (see Section 1.3 
Table 2). An EOT biopsy will be requested and is optional. Biopsies will be collected 1) prior to 
treatment; 2) on treatment; and 3) optional at EOT or disease progression.  
In Part-2 and Part-3, baseline tumor tissue is required, on-treatment and EOT biopsy is optional 
(Table 3 and Table 4).  
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The primary purpose of the on-treatment biopsies is to assess for target inhibition by quantifying 
expression patterns of genes downstream of the RAS-MAPK, key immune pathways and 
mutational landscape. Where sufficient tumor tissue passing quality control is available, 
predictive biomarkers will be explored. Details on processes for collection and shipment can be 
found in the laboratory manual. 
8.7 
GENETICS  
Eligible mutations will be based on prior genotyping results using a clinically validated or 
qualified test. This test may have been performed on either tumor tissue or ctDNA samples. Sites 
must provide the Sponsor with the report. Where available, archival tumor tissue will be collected 
for retrospective central lab testing. Where a discrepancy lies between the local and central results 
for the eligibility defining mutation, the participant will remain on study. For data analysis 
purposes, results from the central laboratory will supersede those of the local laboratory. 
Fresh tumor biopsy is collected, where sufficient tissue passing QC is available, with the aim of 
confirming mutations identified on the genomic report provided at enrollment, assessing 
RAS-MAPK pathway and other gene expression patterns as a measurement of drug activity. In 
addition, we will use genomic data from tumor tissue to 1) define biomarkers for sensitivity, 
resistance, and toxicity to SAR442720 and other agents in combination and 2) to assess clonal 
dynamics and RNA expression changes within the tumor cell population before, during and after 
treatment. Blood sample at baseline will be used as germline control from consenting participants 
in Part-2. 
See Appendix 5 (Section 10.5) for information regarding genetic research. Details on processes 
for collection and shipment and destruction of these samples can be found in the laboratory 
manual. 
Genetic analyses will not be performed on PK samples. Participant confidentiality will be 
maintained. Any changes in the timing or addition of time points for any planned study 
assessments must be documented and approved by the relevant study team member and then 
archived in the Sponsor and site study files but will not constitute a protocol amendment. The IRB 
will be informed of any safety issues that require alteration of the safety-monitoring scheme or 
amendment of the ICF. 
8.8 
BIOMARKERS  
Blood samples will be collected as outlined in the SoA (Section 1.3) for RNA expression analysis 
for evaluation of RAS-MAPK gene signature and other gene expression patterns in Part-1 and 
Part-2 participants. The aim of this is to assess the effects of the drugs on global gene regulation. 
Blood samples will be collected as outlined in the SoA (Section 1.3) for immune-phenotyping 
analysis to evaluate modulation of key immune cells in peripheral blood in Part-1 and Part-2. 
Blood samples will be collected as outlined in the SoA (Section 1.3) for ctDNA analysis to assess 
temporal clonal dynamics in tumors. 
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Blood samples will be collected as outlines in the SoA (Section 1.3) for measurement of 
cytokine/soluble factors that are known to be modulated by RAS-MAPK pathway and/or may 
reflect changes in the immune system after exposure to SHP2 or PD-1 blockade in Part-1 and 
Part-2. 
Special procedures for collection, handling, storage and shipment of samples for biomarker 
analysis will be described in a separate laboratory manual which will be available at the 
investigational site. Samples may be stored for a maximum of 15 years (or according to local 
regulations) following the last participant’s last visit for the study at a facility selected by the 
Sponsor to enable further analysis of biomarkers related to SAR442720 and/or cancer or related 
diseases, or to develop methods, assays, prognostics and/or companion diagnostics, and 
potentially to identify new drug targets or biomarkers. 
Details of sample collection, processing and logistics are described in the laboratory manual.  
8.9 
IMMUNOGENICITY ASSESSMENTS  
Immunogenicity of pembrolizumab will not be assessed, given the fact that the incidence of 
anti-drug antibody (including neutralizing antibody) positivity is not comparable across studies 
and assays, due to several factors, including but not limited to differences in assay methodology, 
sample handling, timing of sample collection, concomitant medications, and underlying disease. 
Participants with positive treatment-emergent anti-pembrolizumab antibody is approximately 2% 
(0.5% positive neutralizing antibody) according to US Package Insert, and there was no evidence 
of an altered PK profile or increased infusion reactions in these participants. In addition, 
pembrolizumab showed flat exposure-response profile in terms of safety across a dose range of 
1 to 10 mg/kg, and it is unlikely for SAR442720 to trigger additional safety concerns of 
pembrolizumab, due to altered immunogenicity. 
As SAR442720 and adagrasib are small molecules, immunogenicity testing of SAR442720 or 
adagrasib is not required. 
8.10 
HEALTH ECONOMICS OR MEDICAL RESOURCE UTILIZATION AND HEALTH 
ECONOMICS  
Not applicable. 
8.11 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH  
Future research may help further the understanding of disease subtypes, disease biology, related 
conditions, drug response and toxicity, and can help identify new drug targets or biomarkers that 
predict participant response to treatment. Therefore, data and biological samples will be stored 
and used for future research when consented to by participants 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). 
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For participants who consent to the storage and use of their data and remaining and/or extra 
clinical samples, data and samples may be used after the study ends for future research related 
either to the drug, the mechanism of action, and the disease or its associated conditions. Such 
research may include, but is not limited to, performing assessments on DNA, RNA, proteins or 
metabolites. If future research on genetic material is performed, this will also be limited to the 
purpose of addressing research questions related to the drug, the mechanism of action, the disease 
or its associated conditions. 
In the event future research is 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 10.7). 
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  
9.1 
STATISTICAL HYPOTHESES  
The primary objective of Part-1 is to find the MTD and RP2D for the combination therapy of 
SAR442720 and pembrolizumab. In Part-2 the study is designed to assess clinical benefit of 
SAR442720 when combined with pembrolizumab. Similarly, Part-3 is designed to find the RP2D, 
explore the anti-tumor activity, and PK of SAR442720 in combination with adagrasib. Part-4 is to 
evaluate the effect of food and relative bioavailability of different formulations. Therefore, there 
is no formal statistical hypothesis and testing procedure defined in this study. 
9.2 
SAMPLE SIZE DETERMINATION  
The sample size is not calculated from statistical consideration since there will not be any formal 
statistical test performed. Overall, up to 134 participants will be enrolled.  
In Part-1, at least 6 participants need to be treated at the MTD. After MTD is identified, another 
6 participants will be treated at the MTD to confirm the decision and determine the RP2D. 
Therefore, a range of 18 to 24 DLT-evaluable (defined in Section 9.3) participants will be 
enrolled in the Part-1 of this study. The actual sample size will vary depending on DLTs observed 
and the number of dose levels explored.  
In Part-2, 40 participants, including 20 participants in Cohort A1 with PD-L1 TPS ≥50% and 
20 participants in Cohort A2 with PD-L1 TPS in 1-49%, will be enrolled at the RP2D identified 
from Part-1. Table 18 lists estimated ORR and the corresponding 90% exact CIs by number of 
responders in Part-2.  
Table 18 - Estimated objective response rate (ORR) and 90% CI in Part-2 
Number of responders 
(N=20) 
ORR 
90% CI for ORR 
(Clopper-Pearson) 
4 
20% 
(7.1%, 40.1%) 
5 
25% 
(10.4%, 45.6%) 
6 
30% 
(14.0%, 50.8%) 
7 
35% 
(17.7%, 55.8%) 
9 
45% 
(25.9%, 65.3%) 
11 
55% 
(34.7%, 74.1%) 
12 
60% 
(39.4%, 78.3%) 
With a sample size of 20 study participants in each cohort of Part-2, the probability of observing 
1 or more instances of a specific AE with a true incidence rate of 1%, 2%, or 5% is 18.2%, 33.2%, 
or 64.2%, respectively. 
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In Part-3A, a range of approximately 15 to 30 DLT-evaluable (defined in Section 9.3) participants 
will be enrolled in this study. The actual sample size will vary depending on DLTs observed and 
the number of dose levels explored.  
In Part-3B, approximately 40 participants will be enrolled at the RP2D identified from Part-3A. 
Table 19 lists the estimated ORR and the corresponding 90% exact CIs by the number of 
responders in Part-3B.  
Table 19 - Estimated objective response rate (ORR) and 90% CI in Part-3B  
Number of responders 
(N=40) 
ORR 
90% CI for ORR 
(Clopper-Pearson) 
13 
32.5% 
(20.4%, 46.6%) 
15 
37.5% 
(24.7%, 51.7%) 
17 
42.5% 
(29.2%, 56.7%) 
19 
47.5% 
(33.8%, 61.5%) 
21 
52.5% 
(38.5%, 66.2%) 
23 
57.5% 
(43.3%, 70.8%) 
24 
60.0% 
(45.8%, 73.1%) 
With a sample size of 40 study participants in Part-3B, the probability of observing 1 or more 
instances of a specific AE with a true incidence rate of 1%, 2%, or 5% is 33.1%, 55.4%, or 87.1%, 
respectively. 
In Part-4, up to approximately 12 participants are expected to be enrolled. By assuming 
intra-subject variability of the steady-state AUC is
, 12 participants will achieve a maximum 
imprecision of 
. When 9 participants are PK evaluable, the maximum imprecision will be 
approximately 
. 
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9.3 
POPULATIONS FOR ANALYSES  
The following populations are defined (Table 20). 
Table 20 - Populations for analyses  
Population 
Description 
Enrolled 
All participants who sign the ICF and have been allocated to an intervention regardless of whether 
the intervention was received or not.  
DLT-evaluable (only for 
Part-1 and Part-3A) 
Participants who take at least 4 of the 6 planned doses of SAR442720 and 28 of the 42 planned 
doses of adagrasib in the first cycle of the treatment and complete the DLT observation period. 
OR 
Participants who have any DLT observed in the DLT or DLT observation period.  
PK 
Participants who have at least one measurable SAR442720 concentration or at least one 
measurable pembrolizumab concentration or at least one measurable adagrasib concentration after 
the first dose 
PDy 
Participants who have at least one PDy marker result after the first dose 
Safety 
Participants who take at least one dose of any drug (ie, SAR442720, pembrolizumab or adagrasib) 
Abbreviations: DLT = dose-limiting toxicity, ICF = informed consent form, PDy = pharmacodynamics(s), PK = pharmacokinetic(s). 
9.4 
STATISTICAL ANALYSES  
The statistical analysis plan will be finalized prior to database lock and it 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. 
9.4.1 General considerations  
All baselines are defined as the last assessment prior to the first dose unless specified otherwise. 
The MTD recommendation will be based on the DLT-evaluable population Cycle 1 data only. All 
safety and efficacy analyses will be based on the safety population unless otherwise specified. The 
Part-1 and Part-3A analyses will be performed separately by different dose levels unless specified 
otherwise. The Part-2 and Part-3B analyses will be presented separately, with Part-2 presented by 
different cohorts and overall, and Part-3B as a single cohort. 
The analysis period will be divided into 3 segments: 
• The pre-treatment period is defined as the time from when the participants give informed 
consent to the first administration of the IMP. 
• The treatment period (ie, treatment-emergent period) is defined as the time from the 
first administration of IMP up to 30 days after the last administration of IMP. 
• The post-treatment period is defined as the time from the 31 days after the 
last administration of IMP. 
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9.4.2 Efficacy endpoint(s)  
Below table (Table 21) summarizes the efficacy endpoints involved in this study: 
Table 21 - Summary of efficacy endpoints  
Efficacy Endpoint 
Part-1/3A  
Part-2/3B 
Part-4 
ORR per RECIST v1.1 
Secondary 
Primary 
Secondary 
DoR 
Secondary 
Secondary 
Secondary 
PFS 
NA 
Secondary 
NA 
TTR 
NA 
Secondary 
NA 
CBR 
NA 
Secondary 
NA 
DCR 
NA 
Secondary 
NA 
OS 
NA 
Exploratory (only for Part-2) 
NA 
ORR per iRECIST 
NA 
Exploratory (only for Part-2) 
NA 
Abbreviations: CBR = Clinical benefit rate; DCR = disease control rate; DoR = duration of response, NA = not applicable; ORR = objective response 
rate, OS = overall survival; PFS = progression free survival, RECIST= Response Evaluation Criteria in Solid Tumors; TTR = time to response.  
The ORR is defined as the proportion of participants who achieve a confirmed complete response 
(CR) or partial response (PR) per RECIST v1.1. Objective response rate and the corresponding 
90% Clopper-Pearson 2-sided CI will be derived. Best overall response (BoR) per RECIST v1.1 
will also be summarized. ORR per iRECIST will also be presented (for Part-2 only). 
For Part-2 and Part-3B, the primary endpoint (ORR) analyses is performed when all participants 
have at least 2 post baseline tumor assessments with response durability demonstrated or 
discontinue study treatment (whichever occurs first). 
Duration of response per RECIST v1.1 is defined as the interval from the first documentation of 
CR or PR to the earlier of the first documentation of definitive disease progression or death due to 
any cause, whichever occurs first. Progression free survival per RECIST v1.1 is defined as the 
interval from the administration of the first IMP dose to the earlier of the first documentation of 
definitive disease progression or death due to any cause, whichever occurs first. Participants who 
are still alive and free from progression at the time of data cutoff date, are lost to follow-up, have 
discontinued from the study, or who have initiated subsequent anticancer therapy will be censored 
at the last adequate tumor assessment. The Kaplan-Meier estimates of the 25th, 50th, and 
75th percentiles and their associated 95% CI will be provided. The OS will also be summarized 
using Kaplan-Meier methods. 
Time to response is defined as the interval from the administration of the first IMP dose to the 
first documented CR or PR which is confirmed by a subsequent response. The TTR will be 
summarized descriptively.  
Clinical benefit rate is defined as the proportion of participants who achieved confirmed CR or PR 
at any time or SD for at least 6 months. The CBR and corresponding 90% Clopper Pearson 
2-sided CI will be derived. 
Disease control rate is defined as the proportion of participants who achieved confirmed CR or PR 
or SD. The DCR and corresponding 90% Clopper-Pearson 2-sided CI will be derived. 
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9.4.3 Safety endpoint(s)  
Safety endpoints including incidence and severity of AEs and SAEs and laboratory abnormalities 
are the primary endpoints for Part-1 and Part-3A and secondary endpoint for Part-2, Part-3B, and 
Part-4. 
9.4.3.1 Adverse events  
The TEAE period is defined as the time from the first dose of study interventions up to 30 days 
after last dose of study interventions. Only TEAEs will be summarized in tables. 
An overall summary of TEAEs will be provided. The number and percentage of participants who 
experience any of the following will be provided: 
• TEAEs 
• TEAEs of Grade ≥3 
• Grade 5 TEAE (any TEAE with a fatal outcome during the treatment period) 
• Serious TEAEs 
• Serious treatment-related TEAEs 
• TEAE leading to premature discontinuation of either SAR442720, pembrolizumab or 
adagrasib 
• TEAE leading to definitive discontinuation 
• TEAE leading to dose modifications 
• Treatment-related TEAEs. 
• Treatment-related TEAEs of Grade ≥3 
• DLTs 
The number and percentage of participants experiencing TEAEs by primary system organ class 
and PT will be summarized by NCI CTCAE version 5.0 grade (all grades and Grade ≥3). Similar 
tables will be prepared for treatment-related TEAEs, AESIs, TEAEs leading to treatment 
discontinuation, TEAEs leading to dose modification, delay, omission, serious TEAEs and 
TEAEs with fatal outcome. 
9.4.3.2 Clinical laboratory evaluations  
Clinical laboratory test results will be graded according to NCI CTCAE Version 5.0, when 
applicable. Number (%) of participants with laboratory abnormalities (ie, all grades and Grade ≥3) 
using the worst grade during the TEAE period will be provided for the all-treated population. 
When the NCI CTCAE Version 5.0 scale is not applicable, the number of participants with 
laboratory abnormality out-of-normal laboratory range value and potential clinically significant 
assessments will be displayed. 
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9.4.4 Other endpoint(s)  
Concentrations of SAR442720, pembrolizumab, and adagrasib will be summarized with 
descriptive statistics. 
For Part-3A and Part-4, PK parameter estimates, including but not limiting to the ones listed 
below, will be determined when possible for SAR442720 and adagrasib: 
• Cmax (observed) 
• Tmax (observed) 
• AUC0-t and AUCinf, if possible 
• t1/2, if possible 
• Accumulation ratio 
Unless otherwise specified, the PK parameters will be estimated based on noncompartmental 
analysis methods. These estimates will be summarized descriptively by dose cohort. All 
PK parameters will be computed using the actual elapsed time calculated relative to dose 
administration. 
For Part-4, the geometric mean ratios and 90% confidence intervals of AUC and Cmax will be 
computed for SAR442720 between fed and fasted states of tablet formulation (C1D1 to C1D15) 
and between the tablet (test) and capsule (reference) formulations (C1D15 to C2D1). In addition, 
the PK parameters in Part-4 will be analyzed using a mixed effect model, which will 
be described in detail in the statistical analysis plan. 
Population PK analysis may be conducted to obtain the PK parameters of SAR442720, 
pembrolizumab, and adagrasib. If performed, the results will be summarized in a separate report. 
Exploratory analyses may be performed to evaluate the relationship between the estimated 
PK parameters and PDs, selected safety, biomarker, or clinical effect endpoints. 
The PK and PDy analyses will be presented in a separate report. 
All other safety endpoints (ie, vital signs, ECG, ECOG, etc) will be summarized. 
9.5 
INTERIM ANALYSES  
There is no formal interim analysis 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-GCP Guidelines 
- 
Applicable laws and regulations (eg, data protection law as General Data Protection 
Regulation - GDPR) 
• The protocol, protocol amendments, ICF, IB, and other relevant documents 
(eg, advertisements) must be submitted to an IRB/IEC by the Investigator and reviewed 
and approved by the IRB/IEC before the study is initiated.  
• Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.  
• The Investigator will be responsible for the following: 
- 
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC determining whether an incidental finding 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.  
- 
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. 
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- 
In case the participant has decided to opt out, the Investigator must record in the 
site medical files that she/he does not want to know about such findings. 
- 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures. 
- 
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, 
European regulation 536/2014 for clinical studies (if applicable), 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. 
• Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study.  
• A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative.  
A participant who is rescreened is not required to sign another ICF if the rescreening occurs 
within 5 days from the previous ICF signature date. 
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The ICF will contain a separate section that addresses the use of remaining mandatory samples or 
new extra samples for optional exploratory research. The Investigator or authorized designee will 
explain to each participant the objectives of the exploratory 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. A separate consent will be required to document a participant’s 
agreement to allow any remaining specimens to be used for exploratory research. Participants who 
decline to participate in this optional research will not provide this separate consent. 
10.1.4 Data protection  
All personal data collected related to participants, Investigators, or any person involved in the 
study, which may be included in the Sponsor’s databases, shall be treated in compliance with all 
applicable laws and regulations including the GDPR (General Data Protection Regulation).  
Data collected must be adequate, relevant and not excessive, in relation to the purposes for which 
they are collected. Each category of data must be properly justified and in line with the study 
objective. 
Participant race and ethnicity will be collected in this study because these data are required by 
regulatory agencies (eg, on afro American population for the United States Food and Drug 
Administration (FDA) or on Japanese population for the Pharmaceuticals and Medical Devices 
Agency in Japan). 
• Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; 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 local data protection law. 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. 
• When archiving or processing personal data pertaining to the Investigator and/or to the 
participants, the Sponsor shall take all appropriate measures to safeguard and prevent 
access to this data by any unauthorized third party. 
• Participant data are intended to be used for the whole drug development program from 
collection to reimbursement. 
10.1.5 Committees structure  
The Study Committee will be comprised of the Principal Investigator from each site involved in 
the dose escalation phase, clinical team members from the Sponsor (including at least the Study 
Medical Manager and Global Study Manager, and experts, including the Global Safety Officer, 
pharmacokineticists, biostatisticians). 
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The Study Committee will review clinical data on a regular basis, with a review being performed 
at least at the end of each DL cohort, before the enrollment of new participants at the next DL, 
and at the end of the dose escalation phase of the study. The Study Committee in agreement with 
the Sponsor’s Study Medical Manager will decide on whether to escalate or de-escalate to the 
next DL or to add alternative dose levels during Study Committee meetings based on current 
safety profile and tolerability, available PK information, and statistical design recommendation. 
Decisions regarding participant treatment and cohort expansion will be discussed and clearly 
documented in the discussion minutes. The Study Committee in agreement with the Sponsor’s 
Study Medical Manager may permit the evaluation of additional DL and/or additional schedules 
of administration of SAR442720, depending upon the observed safety and DLT at each DL, and 
the safety and/or PK data observed in the ongoing Phase 1 monotherapy escalation study. 
10.1.6 Dissemination of clinical study data  
Sanofi shares information about clinical trials and results on publicly accessible websites, based 
on company commitments, international and local legal and regulatory requirements, and other 
clinical trial disclosure commitments established by pharmaceutical industry associations. These 
websites include clinicaltrials.gov, EU clinicaltrialregister (eu.ctr), and sanofi.com, as well as 
some national registries. 
In addition, results from clinical trials in participants 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.  
10.1.7 Data quality assurance  
• All participant data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the Sponsor or designee electronically (eg, laboratory data). The 
Investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.  
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.  
• The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
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noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in separate study documents. 
• The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
• The Sponsor assumes accountability for actions delegated to other individuals 
(eg, Contract Research Organizations). 
• Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements.  
• Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator for 25 years after the signature of the final study 
report unless local regulations or institutional policies require a longer retention period. No 
records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.  
10.1.8 Source documents  
• Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the Investigator’s site. 
• Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The Investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 
10.1.9 Study and site start and closure  
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The first act of recruitment is the first participant first visit and will be the study start date. 
The Sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
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: 
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• For study termination: 
- 
Information on the product leads to doubt as to the benefit/risk ratio 
- 
Discontinuation of further study intervention development 
• For site termination: 
- 
Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor’s procedures, or GCP guidelines 
- 
Inadequate or no recruitment (evaluated after a reasonable amount of time) of 
participants by the Investigator 
- 
Total number of participants included earlier than expected 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The Investigator shall promptly inform the subject and should assure 
appropriate subject therapy and/or follow-up. 
10.1.10 
Publication policy  
• The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor 
before submission. This allows the Sponsor to protect proprietary information and to 
provide comments.  
• The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data. In 
this case, a coordinating Investigator will be designated by mutual agreement. 
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS  
• The tests detailed in Table 22 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.  
• C2+Day 15 laboratory assessments could be done remotely if needed and after discussion 
with the Study Medical Manager. 
• Pregnancy testing. Refer to Section 5.1 for screening criteria, Appendix 4 (Section 10.4) 
for WOCBP criteria and SoA (Section 1.3) for time points.  
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• Results of each test must be entered into the eCRF. 
Table 22 - Protocol-required laboratory assessments  
Laboratory assessments 
Parameters 
Hematology 
 
 
Platelet count 
 
Red blood cell (RBC) count 
 
Hemoglobin 
 
Hematocrit 
 
RBC indices: 
 
Mean corpuscular volume (MCV) 
 
Mean corpuscular hemoglobin (MCH) 
 
%Reticulocytes 
 
White blood cell (WBC) count with differential: 
 
Neutrophils 
Bands (if available) 
 
Lymphocytes 
 
Monocytes 
 
Eosinophils 
 
Basophils, other cells 
Clinical chemistrya 
 
 
Blood urea nitrogen (BUN) 
 
Creatinine 
 
Glucose nonfasting 
 
Potassium 
 
Sodium 
Chloride 
Bicarbonate 
 
Calcium 
Magnesium 
Phosphorous 
Uric acid 
Albumin 
Amylase 
Lipase 
 
Aspartate aminotransferase (AST)/ Serum glutamic-oxaloacetic transaminase (SGOT) 
 
Alanine aminotransferase (ALT)/ Serum glutamic-pyruvic transaminase (SGPT) 
 
Alkaline phosphatase 
Gamma-glutamyl transferase (GGT) 
 
Total and direct bilirubin 
 
Total protein 
Routine urinalysisb 
Specific gravity 
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte esterase by 
dipstick 
Microscopic examination (if blood or protein is abnormal) 
CPK isoenzymes 
Total and heart muscle (MB) component (not required for screening purposes) 
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Laboratory assessments 
Parameters 
Other screening tests 
Coagulation test to include prothrombin time (PT)/international normalized ration (INR) and 
aPTT (or partial thromboplastin time) 
Follicle-stimulating hormone and estradiol (as needed in women of non-childbearing 
potential only)c 
Highly sensitive blood or urine human chorionic gonadotropin (hCG) pregnancy test (as 
needed for women of childbearing potential)b  
Serology: hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), and 
hepatitis C virus antibody. If hepatitis C virus antibody is positive, then obtain hepatitis-C 
RNA  
The results of each test must be entered into the case report form (CRF). 
NOTES : 
a Concurrent elevation of AST or ALT >3 x ULN AND total bilirubin >2 x ULN or INR >1.5 in the absence of cholestasis and other causes 
(eg, viral hepatitis, other pre-existing or acute liver disease, or another drug capable of the observed injury), which may indicate severe 
drug-induced liver injury (possible Hy’s law case). All events with the defined biochemical abnormalities must be reported as an SAE; and 
study medications should be permanently discontinued. 
b Local urine testing will be standard for the protocol unless blood testing is required by local regulation or IRB/IEC. For screening a blood 
test is required.  
c See Appendix 4 (Section 10.4). 
Investigators must document their review of each laboratory safety report. 
10.3 
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING  
10.3.1 Definition of AE  
AE definition 
• An AE is any untoward medical occurrence in a participant or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered related 
to the study intervention. 
• NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention. 
Events meeting the AE definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the Investigator (ie, not related to progression of underlying 
disease), eg:  
- 
Leading to IMP discontinuation or modification of dosing, and/or  
- 
Fulfilling a seriousness criterion, and/or  
- 
Defined as an AESI 
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• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study intervention administration even though 
it may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. 
• “Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy assessments. 
However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy 
will be reported as AE or SAE if they fulfil the definition of an AE or SAE.  
• The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfil the definition of an AE or SAE. Also, “lack of 
efficacy” or “failure of expected pharmacological action” also constitutes an AE or SAE. 
Events NOT meeting the AE definition 
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the participant’s condition. 
• The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
• Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.  
10.3.2 Definition of SAE  
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (eg, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
A SAE is defined as any untoward medical occurrence that, at any dose: 
a) Results in death 
b) Is life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe. 
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c) Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
d) Results in persistent disability/incapacity 
- 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
- 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
e) Is a congenital anomaly/birth defect 
f) Other situations: 
- 
Medical or scientific judgment should be exercised in deciding whether SAE reporting 
is appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the participant or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition. These events should usually be 
considered serious. 
- 
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse. 
10.3.3 Recording and follow-up of AE and/or SAE  
AE and SAE recording 
• When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
• The Investigator will then record all relevant AE/SAE information in the CRF. 
• It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE/SAE CRF page. 
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• There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be redacted on the copies of the medical records before submission to the 
Sponsor. 
• 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 
Adverse events will be graded according to the NCI CTCAE Version 5.0. NOTE: The seriousness 
and intensity of an event are assessed independently of each other. An event is defined as 
“serious” when it meets at least 1 of the predefined criteria as described in the above definition of 
an SAE, and can be assessed as any grade. A nonserious event may be assessed as either CTCAE 
Grade 1 or 2. Although CTCAE Grade 3 nonserious events are possible in some circumstances, 
the Investigator should carefully consider whether the event is best classified as serious. Any AE 
which is either a CTC Grade 4 (life threatening) or Grade 5 (has death as an outcome) is by 
definition an SAE. 
Assessment of causality 
• The Investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. 
• A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
• The Investigator will use clinical judgment to determine the relationship. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
• The Investigator will also consult the 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 Sponsor. 
• The Investigator may change his/her opinion of causality in light of follow-up information 
and send a SAE follow-up report with the updated causality assessment. 
• The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
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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 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 completed CRF. 
• The Investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information. 
10.3.4 Reporting of SAEs  
SAE reporting to the Sponsor via an electronic data collection tool 
• The primary mechanism for reporting an SAE to the Sponsor will be the electronic data 
collection tool. 
• If the electronic system is unavailable, then the site will use the paper SAE data collection 
tool (see next section) in order to report the event within 24 hours of first learning of the 
SAE. 
• The site will enter the SAE data into the electronic system as soon as it becomes available. 
• After the study is completed at a given site, the electronic data collection tool will be taken 
off-line to prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken off-
line, then the site can report this information on a paper SAE form (see next section) or to 
the Sponsor by telephone. 
SAE reporting to the Sponsor via paper CRF 
• Facsimile transmission of the SAE paper CRF is the preferred method to transmit this 
information to the Sponsor. 
• 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. 
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10.4 
APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION  
DEFINITIONS 
Contraceptive use by men or women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. 
A male participant must agree to use contraception during the intervention period and for at least 
6 months after the last dose of study intervention. 
A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least 
one of the following conditions applies: 
• Not a WOCBP OR 
• A WOCBP as defined below who agrees to follow the contraceptive guidance during the 
intervention period and for at least 6 months after the last dose of study intervention as 
described below. 
Woman of childbearing potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention, additional evaluation should be considered. 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
- 
Documented hysterectomy 
- 
Documented bilateral salpingectomy 
- 
Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than 
the above, (eg, mullerian agenesis, androgen insensitivity), Investigator discretion 
should be applied to determining study entry. 
Note: Documentation can come from the site personnel’s: review of the participant’s 
medical records, medical examination, or medical history interview. 
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3. Postmenopausal female 
- 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
- 
A high follicle-stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormone replacement therapy (HRT). However, in the absence of 
12 months of amenorrhea, confirmation with more than one FSH measurement is 
required. 
- 
Females on HRT and whose menopausal status is in doubt will be required to use 
one of the non-estrogen hormonal highly effective contraception methods if they 
wish to continue their HRT during the study. Otherwise, they must discontinue 
HRT to allow confirmation of postmenopausal status before study enrollment. 
CONTRACEPTION GUIDANCE: 
COLLECTION OF PREGNANCY INFORMATION:  
Male participants with partners who become pregnant  
• The Investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This 
applies only to male participants who receive study intervention. 
• After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. The 
female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to the Sponsor. 
Generally, the follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal status 
(presence or absence of anomalies) or indication for the procedure.  
Female participants who become pregnant  
• The Investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. The initial information will be 
recorded on the appropriate form and submitted to the Sponsor within 24 hours of learning 
of a participant’s pregnancy.  
• The participant will be followed to determine the outcome of the pregnancy. The 
Investigator will collect follow-up information on the participant and the neonate and the 
information will be forwarded to the Sponsor. Generally, follow-up will not be required 
for longer than 6 to 8 weeks beyond the estimated delivery date. Any termination of 
pregnancy will be reported, regardless of fetal status (presence or absence of anomalies) or 
indication for the procedure. 
• Any pregnancy complication or elective termination of a pregnancy for medical reasons 
will be reported as an AE or SAE.  
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• A spontaneous abortion (occurring at <22 weeks gestational age) or still birth (occurring at 
>22 weeks gestational age) is always considered to be an SAE and will be reported as such.  
• Any post-study pregnancy related SAE considered reasonably related to the study 
intervention by the Investigator will be reported to the Sponsor as described in 
Section 8.3.4. While the Investigator is not obligated to actively seek this information in 
former study participants, he or she may learn of an SAE through spontaneous reporting.  
• Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention or be withdrawn from the study.  
10.5 
APPENDIX 5: GENETICS  
Use/Analysis of Tumor 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, blood 
and tumor tissue samples will be collected for DNA analysis from consenting participants. 
• DNA samples from tumor tissue will be retrospectively analyzed to explore clinical 
activity in participants with specific molecular abnormalities. In addition, predefined 
biomarkers for the sensitivity to SHP2 and/or MEK1/2 inhibition will be evaluated.  
• DNA extracted from archival participant tumor tissue will be used to evaluate if a 
participant has specific tissue abnormalities in their DNA that may be sensitive to 
SAR442720, adagrasib, and pembrolizumab. This information will be used to confirm if a 
participant has the same mutations as their local genetic results (noncentralized testing 
laboratory) report. The local report is the basis for eligibility assessment. 
• Additional analyses may be conducted if it is hypothesized that this may help further 
understand the clinical data. 
• DNA and RNA from fresh tumor tissue will be used for research related to study 
intervention or NSCLC and/or other solid tumors. Genetic research will include whole 
exome and transcriptome studies, which will be conducted on tissue (where sufficient 
tissue is available) to explore if DNA and RNA can help identify potential biomarkers 
associated with response to SAR442720, adagrasib, and pembrolizumab. In addition, the 
biomarker of sensitivity in blood, namely ctDNA and peripheral blood mononuclear cell 
(PBMC) transcriptome will be explored.  
• The results of genetic analyses may be reported in the clinical study report or in a separate 
study summary. 
• The Sponsor will remove all participant identifiers from the participant samples to inhibit 
recognition or reidentification. The anonymized DNA samples will be stored in a secure 
storage space prior to testing for markers of drug sensitivity. All samples will be processed 
and analyzed for the purposes of this study and the output will be anonymized participant 
data, which may be applied for future research. 
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• Participant sample retention will not exceed 15 years or as per local requirements 
following the last participant’s last visit for the study. 
Use/Analysis of normal PBMC DNA 
• Where local regulations and IRB/IEC allow, blood samples will be collected for DNA 
analysis from consenting participants in Part-2. PBMC DNA will be analyzed with tumor 
DNA to study tumor specific mutations. 
10.6 
APPENDIX 6: COUNTRY-SPECIFIC REQUIREMENTS  
Not applicable.  
10.7 
APPENDIX 7: RESPONSE EVALUATION CRITIERIA IN SOLID TUMORS (RECIST 
V1.1)  
For this study, response and progression will be evaluated using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors guideline version 1.1 
(RECIST v1.1; Eisenhauer 2009). 
Measurability of Tumor at Baseline 
DEFINITIONS 
At baseline, tumor lesions/lymph nodes will be categorized as measurable or nonmeasurable as 
follows. 
Measurable Tumor Lesions 
Tumor Lesions. Must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of: 
• 10 mm by CT or MRI scan (CT/MRI scan slice thickness/interval no greater than 5 mm) 
• 10-mm caliper measurement by clinical examination (lesions that cannot be accurately 
measured with calipers should be recorded as nonmeasurable) 
• 20 mm by chest X-ray 
Malignant Lymph Nodes. To be considered pathologically enlarged and measurable, a lymph 
node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis will 
be measured and followed. 
Nonmeasurable Tumor Lesions 
All other lesions, including small lesions (longest diameter <10 mm or pathological lymph nodes 
with ≥10 to <15 mm short axis), and as well as truly nonmeasurable lesions. Lesions considered 
truly nonmeasurable include leptomeningeal disease, ascites, pleural or pericardial effusion, 
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inflammatory breast disease, lymphangitic involvement of skin or lung, and abdominal 
masses/abdominal organomegaly identified by physical examination that is not measurable by 
reproducible imaging techniques. 
Special Considerations Regarding Lesion Measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment: 
Bone Lesions: 
• Bone scan, PET 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. 
• 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 measurable lesions if the soft tissue component meets the definition of 
measurability described above. 
• Blastic bone lesions are nonmeasurable. 
Cystic Lesions: 
• Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered malignant lesions (neither measurable nor nonmeasurable) since they are, by 
definition, simple cysts. 
• Cystic lesions thought to represent cystic metastases can be considered measurable lesions 
if they meet the definition of measurability described above. However, if noncystic lesions 
are present in the same participant, these are preferred for selection as target lesions. 
Lesions with Prior Local Treatment: 
• 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. Study protocols should detail the conditions under 
which such lesions would be considered measurable. 
SPECIFICATIONS BY METHODS OF MEASUREMENTS 
MEASUREMENT OF LESIONS 
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. 
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METHODS OF ASSESSMENT 
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 done rather than clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
Clinical Lesions 
Clinical lesions will only be considered measurable when they are superficial and ≥10 mm 
diameter as assessed using calipers (eg, skin nodules). 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 also 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 and MRI 
CT is the best currently available and reproducible method to measure lesions selected for 
response assessment. Measurability of lesions on CT scan 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. MRI is also acceptable in certain 
situations (eg, for body scans). 
Ultrasound 
Ultrasound is not useful in assessment of lesion size and should not be used as a method of 
measurement. Ultrasound examinations cannot be reproduced in their entirety for independent 
review at a later date and because they are operator dependent, it cannot be guaranteed that the 
same technique and measurements will be taken from one assessment to the next. If new lesions 
are identified by ultrasound in the course of the study, confirmation by CT or MRI is advised. If 
there is concern about radiation exposure from CT, MRI may be used instead of CT in selected 
instances. 
Endoscopy and Laparoscopy 
The utilization of these techniques for objective tumor evaluation is not advised. However, they 
can be useful to confirm complete pathological response when biopsies are obtained or to 
determine relapse in trials where recurrence following complete response or surgical resection is 
an endpoint. 
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Tumor Markers 
Tumor markers alone cannot be used to assess objective tumor response. If markers are initially 
above the upper normal limit, however, they must normalize for a participant to be considered in 
complete response. 
Cytology and Histology 
These techniques can be used to differentiate between PR and CR in rare cases if required by 
protocol (eg, residual lesions in tumor types such as germ cell tumors, where known residual 
benign tumors can remain). When effusions are known to be a potential adverse effect of 
treatment (eg, with certain taxane compounds or angiogenesis inhibitors), the cytological 
confirmation of the neoplastic origin of any effusion that appears or worsens during treatment can 
be considered if the measurable tumor has met criteria for response or stable disease in order to 
differentiate between response (or stable disease) and progressive disease. 
TUMOR RESPONSE EVALUATION 
ASSESSMENT OF OVERALL TUMOR BURDEN AND MEASURABLE DISEASE 
To assess objective response or future progression, it is necessary to estimate the overall tumor 
burden at baseline and to use this as a comparator for subsequent measurements. Measurable 
disease is defined by the presence of at least one measurable lesion, as detailed above. 
BASELINE DOCUMENTATION OF “TARGET” AND “NONTARGET” LESIONS 
When more than one 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. This means 
that if a participant has only one or 2 organ sites involved, a maximum of 2 and 4 lesions, 
respectively, will be recorded. 
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, and should be those that lend themselves to reproducible 
repeated measurements. It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement, in which circumstance, the next largest lesion which can be 
measured reproducibly should be selected. 
Lymph Nodes 
Lymph nodes merit special mention since they are normal anatomical structures that may be 
visible by imaging even if not involved by tumor. As noted above, 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. The short axis of the node is the diameter normally used by radiologists to judge if a node is 
involved by solid tumor. Nodal size is normally reported as 2 dimensions in the plane in which the 
image is obtained (for CT scan this is almost always the axial plane; for MRI, the plane of 
acquisition may be axial, sagittal, or coronal). The smaller of these measures is the short axis. For 
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example, an abdominal node which is reported as being 20 mm × 30 mm has a short axis of 
20 mm and qualifies as a malignant measurable node. In this example, 20 mm should be recorded 
as the node measurement. All other pathological nodes (those with short axis ≥10 but <15 mm) 
should be considered nontarget lesions. Nodes that have a short axis <10 mm are considered 
nonpathological and should not be recorded or followed. 
Sum of Diameters 
A sum of the diameters (longest for non-nodal lesions and short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum diameters. As noted above, if 
lymph nodes are to be included in the sum, only the short axis is added into the sum. 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 
nontarget lesions and should also be recorded at baseline. Measurements are not required, and these 
lesions should be followed as “present,” “absent,” or, in rare cases, “unequivocal progression.” In 
addition, it is possible to record multiple nontarget lesions involving the same organ as a single item 
on the CRF (eg, “multiple enlarged pelvic lymph nodes” or “multiple liver metastases”). 
RESPONSE CRITERIA 
Evaluation of Target Lesions 
 
Response 
Evaluation of Target Lesions 
Complete Response (CR) 
Disappearance of all target lesions. Any pathological lymph nodes (whether target or 
nontarget) must have reduction in short axis to <10 mm). 
Partial Response (PR) 
At least a 30% decrease in the sum of diameters of target lesions, taking as reference the 
baseline sum of diameters. 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, 
taking as reference the smallest sum diameters while on study. 
Progressive Disease (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 one or more new lesions is also 
considered progression. 
Special Notes on Assessment of Target Lesions 
Lymph Nodes: 
Lymph nodes identified as target lesions should always have the short axis measurement recorded 
(measured in the same anatomical plane as the baseline examination), even if the nodes regress to 
below 10 mm. Thus, when lymph nodes are included as target lesions, the “sum” of lesions may not 
be zero even if complete response criteria are met, since a normal lymph node is defined as having a 
short axis <10 mm. Case report forms or other data collection methods may therefore be designed to 
have target nodal lesions recorded in a separate Section where, in order to qualify for CR, each node 
must achieve a short axis <10 mm. For PR, stable disease (SD), and progressive disease, the actual 
short axis measurement of the nodes is to be included in the sum of target lesions. 
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Target Lesions that Become “Too Small to Measure”: 
While on study, 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 become so faint on CT scan that the radiologist may 
not feel comfortable assigning an exact measure and may report them as “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 (derived from 5-mm slice thickness). 
Note: It is less likely that this rule will be used for lymph nodes since they usually have a 
definable size when normal and are frequently surrounded by fat such as in the retroperitoneum; 
however, if a lymph node is believed to be present and is faintly seen but too small to measure, a 
default value of 5 mm should be assigned in this circumstance as well. To reiterate, however, if 
the radiologist is able to provide an actual measurement, it should be recorded even if it is below 
5 mm. 
Lesions that Split or Coalesce on Treatment: 
When non-nodal lesion “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 Nontarget Lesions 
This section provides the definitions of the criteria used to determine the tumor response for the 
group of non-target lesions. Although 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. 
 
 
Response 
Evaluation of Nontarget Lesions 
Complete Response (CR) 
Disappearance of all nontarget lesions and normalization of tumor marker level. All lymph 
nodes must be nonpathological in size (<10 mm short axis) 
Non-CR/ Non-PD 
Persistence of one or more nontarget lesion(s) and/or maintenance of tumor marker level 
above the normal limits 
Progressive Disease (PD) 
Appearance of one or more new lesions and/or unequivocal progression of existing non-
target lesions 
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Special Notes on Assessment of Progression of Non-target Disease 
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 nontarget 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 one or more non-target lesions is 
usually not sufficient to quality for unequivocal progression status. The designation of overall 
progression solely on the basis of change in non-target disease in the face of SD or PR of target 
disease will therefore be extremely rare.  
When the Participant has Only Nonmeasurable Disease 
This circumstance arises in some Phase III trials when it is not a criterion of study entry to have 
measurable disease. The same general concepts apply here as noted above, however, in this 
instance there is no measurable disease assessment to factor into the interpretation of an increase 
in non-measurable disease burden. Because worsening in nontarget disease cannot be easily 
quantified (by definition: if all lesions are truly nonmeasurable), 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 nonmeasurable 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. While it would 
be ideal to have objective criteria to apply to nonmeasurable disease, the very nature of that 
disease makes it impossible to do so; therefore, the increase must be substantial. 
New Lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some comments 
on detection of new lesions are important. There are no specific criteria for the identification of 
new radiographic lesions; however, 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 [eg, some “new” bone lesions that may be simply healing 
or flare of pre-existing lesions]). This is particularly important when the participant’s baseline 
lesions show partial or complete response. 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 evidence of PD 
even if he/she did not have brain imaging at baseline. 
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If a new lesion is equivocal, eg, because of its small size, continued therapy and follow-up 
evaluation will clarify if it represents truly new disease. If repeat scans confirm there is definitely 
a new lesion, then progression should be declared using the date of the initial scan. 
FDG-PET 
While fluorodeoxyglucose PET (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: 
• Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion 
- 
A positive FDG-PET scan lesion is one which is FDG avid with an uptake greater than 
twice that of the surrounding tissue on the attenuation corrected image 
• 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. 
A “positive” FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image 
EVALUATION OF BEST OVERALL RESPONSE 
The BoR is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for PD the smallest measurements recorded since the 
treatment started). The participant’s BoR assignment will depend on the findings of both target 
and non-target disease and will also take into consideration the appearance of new lesions. 
Time point Response (Overall Response) 
It is assumed that at each protocol-specified time point, a response assessment occurs. Table 23 
provides a summary of the overall response status calculation at each time point for participants 
who have measurable disease at baseline. 
When participants have nonmeasurable (therefore non-target) disease only, Table 24 is to be used. 
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Table 23 - Time point response: Participants with target lesions (with or without nontarget lesions)  
Target Lesions 
Nontarget Lesions 
New Lesion 
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 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Abbreviations: CR, complete response; NE, not evaluable; PD, progressive disease; PR, partial response; SD, stable disease. 
Table 24 - Time point response: Participants with nontarget lesions only  
Nontarget Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PDa  
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or no 
PD 
Any 
Yes 
PD 
Abbreviations: CR, complete response; NE, not evaluable; PD, progressive disease. 
a Non-CR/non-PD” is preferred over “stable disease” for nontarget disease since stable disease is increasingly used as an endpoint for 
assessment of efficacy in some trials; thus, assigning “stable disease” when no lesions can be measured is not advised. 
Missing Assessments and Unevaluable 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 is 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. For 
example, if a participant had a baseline sum of 50 mm with 3 measured lesions and, during the 
study, only 2 lesions were assessed, but those gave a sum of 80 mm; the participant will have 
achieved PD status, regardless of the contribution of the missing lesion. 
Best Overall Response: All Time points 
The BoR is determined once all data for the participant is known. 
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Best response determination in trials where confirmation of complete or partial response is 
required: Complete or partial responses may be claimed only if the criteria for each are met at a 
subsequent time point as specified in the protocol (generally 4 weeks later). In this circumstance, 
the BoR can be interpreted as in Table 25. 
Table 25 - Best overall response when confirmation is required  
Overall 
Response at 
First Time point 
Overall Response at 
Subsequent Time 
point 
Best Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD, or PRa 
CR 
SD 
SD, provided minimum duration for SD was met; otherwise, PD 
CR 
PD 
SD, provided minimum duration for SD was met; otherwise, PD 
CR 
NE 
SD, provided minimum duration for SD was met; otherwise, NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD, provided minimum duration for SD was met; otherwise, PD 
PR 
NE 
SD, provided minimum duration for SD was met; otherwise, NE 
NE 
NE 
NE 
Abbreviations: CR, complete response; NE, not evaluable; PD, progressive disease; PR, partial response; SD, stable disease. 
a If a CR is truly met at the first time point, any disease seen at a subsequent time point, even disease meeting PR criteria relative to baseline, 
qualifies as PD at that point (since disease must have reappeared after CR). Best response would depend on whether the minimum duration 
for SD was met. However, sometimes CR may be claimed when subsequent scans suggest small lesions were likely still present and in fact 
the participant had PR, not CR, at the first time point. Under these circumstances, the original CR should be changed to PR and the best 
response is PR. 
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. 
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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 nontarget disease as shown in 
Table 23, Table 24, and Table 25. 
Conditions that define “early progression, early death and un-evaluability” are study-specific and 
should be clearly described in each protocol (depending on treatment duration, treatment 
periodicity). 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends upon this determination, it is recommended 
that the residual lesion be investigated (fine-needle aspirate/biopsy) before assigning a status of 
complete response. FDG-PET may be used to upgrade a response to a CR in a manner similar to a 
biopsy in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring. The use of FDG-PET in this circumstance should be prospectively described in the 
protocol and supported by disease specific medical literature for the indication. However, it must 
be acknowledged that both approaches may lead to false positive CR due to limitations of 
FDG-PET and biopsy resolution/sensitivity. 
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. 
10.8 
APPENDIX 8: EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
PERFORMANCE STATUS SCALE  
ECOG Performance Status 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (eg, light 
house work or office work) 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities; up and about more than 50% of waking 
hours 
3 
Capable of only limited self-care; confined to bed or chair more than 50% of waking hours 
4 
Completely disabled; cannot carry on any self-care; totally confined to bed or chair 
5 
Dead 
Abbreviations: ECOG, Eastern Cooperative Oncology Group. 
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10.9 
APPENDIX 9: GENERAL GUIDELINES FOR THE MANAGEMENT OF ADVERSE 
EVENTS  
Investigators must be extremely vigilant and be ready to intervene early in the management of 
AEs, particularly immune-related AEs because the onset of symptoms of irAEs (eg, pneumonitis) 
may be subtle. 
• Detailed guidance for the management of specific AEs (colitis, endocrine AE, 
pneumonitis, renal AE, dermatologic AE, hepatitis, ophthalmologic AE [uveitis], etc.) is 
provided in Table 27. 
• General guidance is provided in Table 26 below. 
• If a participant experiences several AEs which involve different recommendations, the 
most conservative recommendation should be followed. 
The recommendations provided in Table 26 and Table 27 should be seen as guidelines, and the 
treating physician should exercise clinical judgment based on the symptoms and condition of the 
individual participant. 
Table 26 - General guidelines  
Severity 
Withhold/restart 
/discontinue 
SAR442720 
treatment 
Withhold/restart/discontinue 
the combination drug 
(Pembrolizumab or 
adagrasib) treatment 
Supportive care 
Grade 1 
No action 
No action 
Provide symptomatic treatment. 
Grade 2 
No action 
May delay or omit the 
pembrolizumab dose until Grade ≤1 
Adagrasib dose modification/ dose 
interruption per Investigators 
discretion unless otherwise defined 
in Table 27. 
Consider systemic corticosteroids (Prednisone 
0.5 to 1 mg/kg/day or equivalent) in addition to 
appropriate symptomatic treatment. 
Grade 3  
 
Grade 4 
Delay the treatment until toxicity improves to Grade ≤1 or 
baseline. 
Permanently discontinue 
For any Grade 3-4 immune-related adverse 
event, if symptoms worsen or do not improve 
on adequate corticosteroids (prednisone 1 to 
2 mg/kg/day or equivalent) within 48 to 
72 hours), consider additional 
immunosuppressive agents (to be selected 
from agents such as: infliximab, 
cyclophosphamide, cyclosporine and 
mycophenolate mofetil). Referral of the 
participant to a specialized unit for assessment 
and treatment should be considered. 
 
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Table 27 - Dose modification guidelines for combination regimens (SAR442720 and pembrolizumab 
combination or SAR442720 and adagrasib combination) 
AE 
Action 
Skin reactions 
Grade 1 or 2 (tolerable): Administer supportive care and continue study drugs 
Intolerable Grade 2-Grade 3: Hold both drugs until < Grade 2. If improves to < Grade 2 within 4 weeks, 
then reduce SAR442720 by one dose level and resume combination drugs at the same dose level.  
Suspected Stevens-Johnson Syndrome (SJS) or toxic epidermal necrolysis (TEN): Withhold both drugs 
until adverse reactions recover to Grade 0-1. 
Grade 4: Hold both drugs until < Grade 1. If improves to < Grade 1 within 4 weeks, resume, reduce 
SAR442720 by two dose levels and resume combination drugs at the same dose level.  
Grade 4 or confirmed SJS or TEN: Permanently discontinue both drugs  
If  Grade 3 rash recurs despite two SAR442720 dose level reductions, permanently discontinue 
both drugs. 
If rash does not improve within 4 weeks, permanently discontinue both drugs. 
Ocular symptoms 
> Grade 2 
Hold both study drugs and obtain ophthalmology consult. 
RVO: Any grade, permanently discontinue both drugs (Part-1, 2, and 4 only). In Part-3 permanently 
discontinue SAR442720 but may continue adagrasib, please consult with the Medical Monitor. 
Neurosensory retinal detachment: Hold both drugs until resolution to ≤ Grade 1. If resolves within 
4 weeks, then reduce SAR442720 by one dose level. If visual symptoms > Grade 2 recur despite 
two dose level reductions, permanently discontinue both drugs. (Part-1, 2 and 4 only). In Part-3 
permanently discontinue SAR442720 but may continue adagrasib, please consult with the Medical 
Monitor. 
Uveitis/iritis > Grade 2: Hold both study drugs. If resolves to ≤ Grade 1 within 4 weeks, then reduce 
SAR442720 dose by one level and resume both study drugs. If recurs despite two dose level reductions 
of SAR442720, permanently discontinue both drugs. If > Grade 1 symptoms recur or follow-up 
ophthalmology examination results worsen, withhold treatment (either SAR442720 and pembrolizumab or 
SAR442720 and adagrasib) and either further decrease dose or permanently discontinue treatment. 
Other > Grade 2 AE: Hold SAR442720. If AE doesn’t improve within 2 weeks, then consider holding the 
combination drug. If no improvement within 4 weeks from onset, consider permanently discontinuing 
both drugs. In ambiguous cases, please consult with the Medical Monitor. 
Hemorrhage 
> Grade 3 
Rule out other causes. 
Grade 3: Hold both study drugs until resolution to ≤ Grade 1. If hemorrhage is associated with 
thrombocytopenia or reduced platelet count from baseline hold both drugs. In Part-1, 2, and 4, if resolves 
within 4 weeks, consider restarting SAR442720 at a lower dose and restarting pembrolizumab at same 
dose (dose reduction is not allowed for pembrolizumab). In Part-3, if resolves within 4 weeks, consider 
restarting SAR442720 and adagrasib at a lower dose. In ambiguous cases, please consult with the 
Medical Monitor. 
Grade 4 or CNS hemorrhage: permanently discontinue both drugs. 
Diarrhea and 
other GI toxicities 
Grade 1-2 Diarrhea: Maximal supportive care. Continue both drugs at current doses. 
Grade 3 Diarrhea: Hold both study drugs (if receiving maximal supportive care) until ≤Grade 1. If 
improves within 4 weeks, then dose reduce SAR442720 and adagrasib (in Part-3), and start 
pembrolizumab at same dose (in Part1, 2 and 4); if diarrhea is not resolved to ≤ Grade 1 within 4 weeks, 
permanently discontinue both drugs.  
Grade 3 Nausea >72 hours despite therapy; hold both drugs until ≤ Grade 1 or return to baseline, dose 
reduce SAR442720 and adagrasib (in Part-3), 
Grade ≥3 Pancreatitis, permanently discontinue both drugs. 
Asymptomatic Grade 3 Amylase or Lipase Elevation >8 days, hold until ≤ Grade 1 or return to baseline, 
resume both drugs at same dose. 
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AE 
Action 
Colitis 
Grade 2 or 3: Withhold both study drugs until adverse reactions recover to Grades 0 to 1. 
Grade 4 or recurrent Grade 3: Permanently discontinue both study drugs. 
Please consult Medical Monitor for ambiguous cases. 
Hepatitis, liver 
function test 
abnormalities 
(AST, ALT, and/or 
total bilirubin) 
Grade 1: Continue both study drugs at current doses. 
Grade 2: In Part-1, 2, and 4, continue SAR442720 and withhold pembrolizumab until adverse reactions 
recover to Grade 0 to 1 
In Part-3, continue SAR442720 and reduce adagrasib one dose level. 
Grade 3: Rule out other causes such as metastatic liver disease, concomitant drugs, infection, etc. 
Withhold both study drugs until improves < Grade 1, then dose reduce SAR442720 and adagrasib one 
dose level (in Part-3) and resume pembrolizumab at the same dose (Part-1, 2 and 4). If AE does not 
improve or recurs, dose reduce another dose level of SAR442720. No dose modification required for 
isolated GGT. In Part-1, 2, and 4 hold SAR442720; if no improvement in LFTs after SAR442720, withhold 
pembrolizumab as well. If Grade ≥3 with AST or ALT occurs, permanently discontinue both study drugs. 
In case of liver metastasis with baseline Grade 2 elevation of AST or ALT, hepatitis with AST or ALT 
increases ≥50% and lasts ≥1 week: Permanently discontinue pembrolizumab. Action with SAR442720 or 
adagrasib should be discussed with the Medical Monitor. 
Grade 4: see general Grade 4 non-heme AEs. In Part-1, 2, and 4 hold both SAR442720 and 
pembrolizumab. If resolves, restart both medications, SAR442720 at reduced dose (pembrolizumab dose 
reduction is not allowed). If no improvement to < Grade 1 within 4 weeks, permanently discontinue both 
drugs.  
In Part-3 permanently discontinue both study drugs. Concurrent treatment-emergent / treatment related 
elevation of AST or ALT >3 x ULN AND total bilirubin >2 x ULN or INR >1.5 in the absence of cholestasis 
and other causes (eg, viral hepatitis, other pre-existing or acute liver disease, or another drug capable of 
the observed injury), which may indicate severe drug-induced liver injury (possible Hy’s law case). Both 
medications should be permanently discontinued.  
If liver injury is due to other causes such as viral hepatitis, acute liver disease, or another drug capable of 
liver injury, evaluate the extent of liver injury (eg, albumin level, PTT, INR etc) and if considered to be 
severe, discontinue both medications.  
QTcF 
prolongation 
Rule out other factors for arrhythmia including myocardial ischemia, electrolyte abnormalities, and 
concomitant medications. Evaluate concomitant medications that prolong QTcF (eg, 5-HT3 receptor 
antagonist anti-emetics etc) and discontinue the suspected concomitant medication, as feasible. Hold 
discontinue both study drugs per below instructions. Consult cardiology. 
Grade 3: Hold both study drugs until QTcF <480 msec; correct electrolytes; consult cardiology. If 
resolves within 4 weeks, restart both drugs; SAR442720 and adagrasib at one dose level lower 
(pembrolizumab dose reduction is not allowed); otherwise permanently discontinue.  
Repeat ECG at 2 weeks and 4 weeks after restarting. Perform additional ECGs monitoring at D15 of each 
subsequent cycle for 3 cycles then as instructed by the SoA. For recurrence of QTc prolongation follow 
the guidelines above and reduce dose of SAR442720 and adagrasib by another dose level 
(pembrolizumab dose reduction is not allowed). Permanently discontinue both SAR442720 and 
pembrolizumab if after correction of associated risk factors and dose reductions, the QTcF increase 
meets values of both >500 msec and >60 msec change from pre-treatment values.  
In Part-3: If QTcF Prolongation* > 500 msec and increases by > 60 msec on at least 2 ECGs ≤ 22 days, 
hold adagrasib until ≤ Grade 1 or return to baseline (<15 msec above baseline). Resume adagrasib at 
one or two dose levels lower. If QTcF Prolongation* > 500 msec and increases by > 60 msec on at least 
2 ECGs > 22 days, discontinue adagrasib.  
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AE 
Action 
Reduction in 
LVEF and other 
cardiac toxicities 
Asymptomatic reduction: absolute decrease in LVEF ≥ 20% from baseline and below LLN, withhold 
treatment (either SAR442720 and pembrolizumab or SAR442720 and adagrasib) for up to 4 weeks and 
repeat echocardiogram (ECHO) for LVEF at 2, 4, 10, and 16 weeks after hold. Restart at reduced dose if 
LVEF ≥ LLN and absolute decrease from baseline LVEF < 20%. Permanently discontinue if symptoms of 
heart failure are present. 
Symptomatic reduction: In case of symptomatic systolic dysfunction with an LVEF decrease from baseline 
≥10% and/or below LLN, withhold both SAR442720 and pembrolizumab for up to 4 weeks and consider 
permanent discontinuation if considered causative; in Part-3 permanently discontinue SAR442720 and 
adagrasib. Consult cardiology and the Medical Monitor.  
If reinitiating treatment, ALL of the following must be present: an EF decrease not considered to be 
associated with the study drug, symptoms resolve, LVEF > LLN, and absolute decline from baseline was 
<10%; otherwise, permanently discontinue both drugs.  
If reinitiating treatment, restart both study drugs, SAR442720 and adagrasib at a lower dose (pembrolizumab 
dose reduction is not allowed). Please consult with the Medical Monitor for individual cases. 
All participants who require dose reduction of SAR442720 due to treatment related systolic dysfunction 
should have ECHO at 2 weeks, 4 weeks, 10 and 16 weeks, then per protocol or as clinically indicated. 
In Part-3: 
For all other Grade ≥3 cardiac toxicities/adverse drug reactions hold study treatment until recovery to 
≤ Grade 1 or to baseline. Adagrasib/SAR442720 treatment may resume at one dose level lower. For QTc 
prolongation please refer to the previous bullet. Please consult with the Medical Monitor for individual cases. 
Hypertension 
Grade 2: Treat according to institutional guidelines with goals blood pressure < Grade 1. Continue both drugs. 
Grade 3: Treat according to institutional guidelines with goal blood pressure < Grade 1. Consider holding 
SAR442720 and continue pembrolizumab and adagrasib. If improved restart SAR442720 at reduced dose 
level.  
Grade 4: Treat according to institutional guidelines. Discontinue both SAR442720 and pembrolizumab. In 
Part-3 hold adagrasib until ≤Grade 1 or baseline, then may resume one dose level lower. 
Hematologic lab 
abnormalities 
> Grade 3  
Assess for other causes. Hold concomitant medications associated with myelosuppression. 
Grade 3 neutropenia, thrombocytopenia: Hold both drugs if clinically indicated until < Grade 1 or baseline. 
If improves within 4 weeks, restart pembrolizumab or adagrasib at same dose and administer SAR442720 
one dose level lower. If does not improve within 4 weeks, discontinue both drugs. 
Grade 3 febrile neutropenia: Hold both drugs until fever resolves and ANC < Grade 1 or baseline. If 
improves within 2 weeks, restart pembrolizumab at same dose and SAR442720 and adagrasib 1 dose 
level lower. If does not improve within 2 weeks, discontinue both drugs. 
Grade 3 anemia: Assess transfusion history. Transfuse per institutional guidelines. Continue 
pembrolizumab, and hold SAR442720 if clinically indicated until < Grade 1. If improves within 4 weeks, 
restart SAR442720 one dose level lower. If does not improve within 4 weeks, consider discontinuation of 
both drugs. Hold adagrasib until ≤ Grade 1 or baseline and may resume at the same dose level. 
Grade 4 cytopenias: Hold both drugs until resolves to < Grade 1 or baseline. If improves within 4 weeks, 
restart both drugs; reduce both SAR442720 and adagrasib one dose level lower (pembrolizumab dose 
reduction is not allowed). If does not improve within 4 weeks, discontinue both drugs. 
Thrombocytopenia associated with clinically significant bleeding, at any level: Hold both drugs and follow 
hemorrhage recommendations. 
Uncomplicated Thrombocytopenia (without clinically significant bleeding):  
Grade 1 to 2: Continue treatment at current dose level and frequency and monitor closely 
Grade 3 to 4: Manage per institution guidelines and interrupt dosing of both study drugs until participant 
recovers to Grade 1 or better. If recovery occurs, the investigator may resume dosing both study drugs at 
the same dose level and frequency, if clinically appropriate. If Grade 3 to 4 events recur again, hold dose 
until recovery to Grade 1 or better and consider re-introducing study drug at reduced frequency, or 
withdrawing participant from study therapy. 
Please contact Medical Monitor for ambiguous cases. 
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AE 
Action 
Other non-
hematologic AEs 
Intolerable Grade 2 or Grade 3: Hold both drugs until ≤ Grade 1. If improves within 4 weeks, then resume 
pembrolizumab at same dose and dose reduce SAR442720 in Part-1, 2, 4. In Part-3 dose reduce both 
SAR442720 and adagrasib; if not resolved.to ≤Grade 1 within 4 weeks, permanently discontinue both 
drugs (SAR442720 and pembrolizumab or SAR442720 and adagrasib). If event recurs, hold both drugs 
and consider dose reduction the drug not previously dose reduced upon improvement ≤ Grade 1.  
Grade 4: Consider permanent discontinuation both drugs. Otherwise, discuss with sponsor Medical 
Monitor and hold both drugs until ≤ Grade 1, if improves within 4 weeks, then consider resuming 
pembrolizumab, and both SAR442720 and adagrasib with dose reduction (pembrolizumab dose reduction 
is not allowed). Of SAR442720. For recurrent Grade 4 AE, permanently discontinue both drugs.  
Based on the investigator’s assessment of the AE, either one, both SAR442720 and pembrolizumab or 
SAR442720 and adagrasib may be held if a clear attribution may be established. 
Grade ≥3 non hematological laboratory abnormalities if clear attribution may be established hold both 
drugs, upon improvement to ≤ Grade 1 resume SAR442720 and adagrasib lower dose level; resume 
pembrolizumab same dose level. Grade ≥3 non hematological laboratory abnormalities if clear attribution 
may be established hold both drugs, upon improvement to ≤ Grade 1 resume SAR442720 and adagrasib 
lower dose level; resume pembrolizumab at same dose level. 
Nephritis 
Grade 2 with creatinine >1.5 to ≤3 times upper limit of normal (ULN): In Part-1, 2, and 4 continue 
SAR442720 and withhold pembrolizumab until adverse reactions recover to Grade 0 to 1. In Part-3, 
continue SAR442720 and consider continuing adagrasib at the same dose level or one dose level lower. 
Grade ≥3 with creatinine >3 times ULN: Permanently discontinue pembrolizumab. In Part-3, if Grade ≥3 
creatinine increased ≤22 days hold adagrasib until ≤ Grade 1or return to baseline, then adagrasib 
treatment may resume at the same dose level or one dose level lower. For Grade ≥3 creatinine increased 
>22 days discontinue adagrasib. Action taken with SAR442720 should be discussed with Medical Monitor 
depending on the clinical case. 
Endocrinopathies 
(applies to Part-1, 
2, 4) 
Grade 2 adrenal insufficiency and hypophysitis: continue SAR442720 and withhold pembrolizumab until 
controlled by hormone replacement. 
Grade 3 or 4 adrenal insufficiency or symptomatic hypophysitis, Type 1 diabetes associated with 
Grade ≥3 hyperglycemia (glucose >250 mg/dL or >13.9 mmol/L) or associated with ketoacidosis. 
Hyperthyroidism Grade ≥3: continue SAR442720 and withhold pembrolizumab until adverse reactions 
recover to Grades 0 to 1.  
For patients with Grade 3 or Grade 4 endocrinopathies that improved to Grade 2 or lower and controlled 
with hormone replacement, if indicated, continuation of pembrolizumab may be considered after 
corticosteroid taper, if needed. Otherwise pembrolizumab treatment should be discontinued. 
Hypothyroidism may be managed with replacement therapy without treatment interruption. 
Other immune-
related adverse 
reactions (applies 
to Part-1, 2, 4) 
Based on the severity and type of reaction (Grade 2 or Grade 3): Continue SAR442720 and withhold 
pembrolizumab until adverse reactions recover to Grades 0 to 1. SAR442720 may need to be withheld 
temporarily depending on the individual case assessment. 
Grade 3 or Grade 4 myocarditis; Grades 3 or Grade 4 encephalitis; Grade 3 or Grade 4 Guillain-Barre 
syndrome and all Grade 4 or recurrent Grade 3 immune related adverse reactions: Permanently 
discontinue both study drugs. 
Consult with Medical Monitor as necessary. 
Pembrolizumab 
Infusion-related 
reactions (applies 
to Part-1, 2, 4) 
Grades 3 or Grade 4 infusion related reactions: Permanently discontinue pembrolizumab. 
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AE 
Action 
Pneumonitis 
Part-1, 2, and 4: For Grade 2 hold both drugs and re-start when toxicity resolves to ≤Grade 1  
For Grades 3 and 4 – Permanently discontinue treatment with pembrolizumab and withhold SAR442720. 
However, once recovered to ≤Grade 1, treatment with SAR442720 may be re-started at a lower dose. 
In Part-3; Grade 1 consider reducing adagrasib by one dose level. Grade 2 hold adagrasib until ≤ Grade 1 
or return to baseline. If resumed, decrease by one dose level lower. For Grade 2 recurrent or Grade 3 
pneumonitis, discontinue both study drugs.  
“Both study drugs” refer to either SAR442720 and pembrolizumab (in Part-1, 2, and 4) or SAR442720 and adagrasib (in Part-3) 
10.10 APPENDIX 10: MEDICATION CLASSES THAT POTENTIALLY PROLONG QTC, 
STRONG CYP3A INHIBITORS AND/OR INDUCERS, PROTON PUMP INHIBITORS, H-2 
RECEPTOR ANTAGONISTS, STRONG P-GP INHIBITORS AND OTHER PROHIBITED 
MEDICATION CLASSES  
A partial list of drug classes that potentially prolong QTc, drugs that are strong CYP3A inhibitors 
and/or inducers, drugs that are proton pump inhibitors and H-2 receptor antagonists, drugs that are 
strong P-gp inhibitors, and other prohibited medications classes is provided below.  
 
Medications known to prolong QTc 
Amiodarone 
Anagrelide 
Arsenic Trioxide  
Azithromycin 
Chloroquine 
Chlorpromazine 
Cilostazol 
Ciprofloxacin 
Citalopram 
Disopyramide 
Dofetilide 
Donepezil 
Dronedarone 
Droperidol 
Erythromycin 
Escitalopram 
Flecainide  
Fluconazole 
Haloperidol 
Ibutilide 
Levofloxacin 
Methadone 
Moxifloxacin 
Ondansetron 
Oxaliplatin 
Pentamidine  
Pimozide 
Procainamide 
Propofol 
Quinidine 
Sevoflurane 
Sotalol 
Terfenadine  
Thioridazine  
Vandetanib 
Gatifloxacin 
Clarithromycin 
Cocaine 
Domperidone 
Donepezil 
Hydroxychloroquine 
 
Strong CYP3A Inhibitors 
Boceprevir 
Idelalisib 
Posaconazole 
Clarithromycin 
Indinavir and ritonavir 
Ritonavir 
Cobicistat 
Itraconazole 
Saquinavir and ritonavir 
Conivaptan 
Ketoconazole 
Telaprevir 
Danoprevir and ritonavir 
Lopinavir and ritonavir 
Tipranavir and ritonavir 
Diltiazem 
Nefazodone 
Troleandomycin 
Elvitegravir and ritonavir 
Nelfinavir 
Voriconazole 
Grapefruit juice 
Paritaprevir and ritonavir and (ombitasvir and/or dasabuvir) 
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Atazanavir 
Telithromycin 
Strong CYP3A Inducers 
Carbamazepine 
Mitotane 
Rifampin 
Enzalutamide 
Phenytoin 
St. John’s wort 
Apalutamide 
Phenobarbital 
 
Proton Pump Inhibitors (PPIs)  
Omeprazole  
Lansoprazole  
Dexlansoprazole 
Rabeprazole 
Pantoprazole  
Esomeprazole 
Ilaprazole 
 
 
H-2 Receptor Antagonists  
Ranitidine  
Famotidine  
Cimetidine  
Nizatidine  
 
 
Strong P-gp Inhibitors  
Amiodarone  
Carvedilol  
Clarithromycin  
Dronedarone  
Itraconazole  
Lapatinib 
Lopinavir and Ritonavir  
Propafenone  
Quinidine  
Ranolazine  
Ritonavir  
Saquinavir and Ritonavir  
Telaprevir  
Tipranavir and Ritonavir  
Verapamil 
CYP3A Substrates with Narrow Therapeutic Index 
Alfuzosin 
Alprazolam 
Budesonide 
Conivaptan 
Cyclosporine 
Dihydroergotamine 
Eletriptan 
Eplerenone 
Ergotamine 
Everolimus 
Fentanyl 
Lomitapide 
Lovastatin 
Lurasidone 
Midazolam 
Naloxegol 
Nisoldipine 
Ranolazine 
Rivaroxaban 
Sildenafil 
Simvastatin 
Sirolimus 
Ticagrelor 
Tolvaptan 
Triazolam 
 
 
Strong Inhibitor of BCRP 
Eltrombopag 
Curcumin 
Cyclosporine 
CYP2B6 Substrates with Narrow Therapeutic Index 
Bupropion 
Cyclophosphamide 
Efavirenz 
CYP2C9 Substrates with Narrow Therapeutic Index 
Warfarin 
 
 
CYP2C9 Moderate/Sensitive Substrates 
Celecoxib 
Glimperide 
Tolbutamide 
CYP2D6 Substrates with Narrow Therapeutic Index 
Thioridazine 
Pimozide 
 
CYP3A Moderate/Sensitive Substrates 
Alfentanil 
Aprepitant 
Atorvastatin 
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Avanafil 
Buspirone 
Colchicine 
Darifenacin 
Ebastine 
Eliglustat 
Felodipine 
Ibrutinib 
Maraviroc 
Quetiapine 
Rilpivirine 
Sildenafil 
Tacrolimus 
Tadalafil 
Vardenafil 
P-gp Substrates with Narrow Therapeutic Index 
Dabigatran 
Digoxin 
 
Antacids and H2-antagonists 
Cimetidine 
Famotidine 
Nizatidine 
Ranitidine 
 
 
Please note that this list is not comprehensive.  
The list and updates of medications that are known to prolong QTc may be obtained from 
www.crediblemeds.org.  
For additional information and updates concerning strong CYP3A inhibitors and inducers and 
strong P-gp inhibitors, refer to the following link: 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractio
nsLabeling/ucm093664.htm 
In addition, consult the prescribing information when determining whether a concomitant 
medication can be safety administered with study treatment. Contact the Medical Monitor if 
questions arise regarding medications not listed. 
10.11 APPENDIX 11: SIMULATION REPORT – ASSESSMENT OF PERFORMANCE  
In Part-1 and Part-3A, there are not many dose levels included in the dose escalation. Therefore, 
interval design, specifically mTPI2, will be used in the dose escalation process.  
The goal of assessing the mTPI2 design’s performance is to evaluate its overall operating 
characteristics by comparing with 3+3 design under a range of scenarios for hypothetical DLT 
dose-response relationship that may occur during the conduct of the study. Here, the performance 
comparison of mTPI2 and 3+3 is presented for Part-1. Since the mTPI2 and 3+3 designs both 
consider doses in a discrete space, the performance comparison will be considered similar for 
Part-1 and Par-3A. 
SPECIFICATION OF SIMULATION SCENARIOS 
The planned starting dose levels are 100 mg (Dose level 1), 140 mg (Dose level 2) and 200 mg 
(Dose level 3). The first cohort will start with 140 mg. 
Four scenarios were defined for DLT rate at all dose levels as shown in Figure 6. The scenarios 
were selected to represent a wide range of possible cases: the true MTD is dose level 2 
(Scenario 2 and 3), dose level 3 (Scenario 1) and even higher than dose level 3 (Scenario 4). 
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Please note that it is strongly believed that the chance of dose level 1 being the MTD is extremely 
low based on the monotherapy results. Therefore, the scenario of dose level 1 being the MTD is 
not in the consideration. Also, the Scenario 2 and 3 have the same DLT trend. They cover the 
lower and upper bounds of the target toxicity interval at dose level 2. In order to make the plot 
self-explained, indicators will be used along with each scenario. For each dose level, “L” indicates 
low rate of DLT, and “T” indicates target rate of DLT which refers to MTD. “H” indicates high 
rate of DLT. For example, Scenario 1 would be indicated as LLT while Scenario 4 would be 
indicated as LLL. 
PERFORMANCE 
To evaluate the design performance for the 4 scenarios described above, the following measures 
will be discussed. 
• Probability of a dose level selected as MTD 
• Mean number of participants treated at each dose level 
Results based on n=1000 simulated trials. The target DLT rate is set to be 
. 
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Abbreviations: DLT = dose-limiting toxicity, H = high rate of DLT, L = low rate of DLT, T = target rate of DLT which refers to MTD 
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Using the hypothetical scenarios specified above, the results for mTPI2 are plotted in Figure 7 and 
Figure 9. The results from 3+3 design are presented in Figure 8 and Figure 10 for a comparison 
purpose.  
In general, mTPI2 design can find the true MTD more accurately than the 3+3 design. The 
3+3 design is more conservative than the mTPI2. The chance of finding the correct MTD (in red) 
is higher than any other dose level for all scenarios in mTPI2 design. While in Scenario 2 and 3, 
3+3 design is much conservative to recommend the 100 mg as MTD in more than 
 of 
simulated trials. Specifically, when the true DLT rate changes from 
 in Scenario 2 to 
 in 
Scenario 3, the 3+3 design will recommend 100 mg from 
. The mTPI2 recommends 
the 140 mg as MTD consistently (
) in both scenarios. In Scenario 1, the 3+3 design is 
not able to differentiate 140 mg and 200 mg when the true MTD is 200 mg (
). Even 
in Scenario 4 where the true MTD is >200 mg, the 3+3 design still identify the MTD as <100 in 
 of the simulations. Also, when 2 DLTs were observed out of 3 participants, the 3+3 design 
will claim the MTD has to be lower than the current dose level while the mTPI2 design will just 
recommend a lower dose level for the next cohort but keep the decision of recommending the 
current dose level open. Overall, the accuracy of mTPI2 is satisfactory and 3+3 is too 
conservative. 
The sample size needed for both designs are roughly 3 cohorts (9 participants) for all scenarios. 
But more participants are treated at a dose level below the MTD in 3+3 compared to mTPI2 
(
) because 3+3 is too conservative.  
To conclude, mTPI2 design can provide a more accurate MTD recommendation compared to 
3+3 design with similar sample size. 
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Figure 7 - Probability of a dose level selected as MTD for mTPI2  
Abbreviations: H = high rate of DLT, L = low rate of DLT, MTD = maximum tolerated dose, mTPI2 = modified toxicity probability interval 2, 
T = target rate of DLT which refers to MTD 
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Figure 8 - Probability of a dose level selected as MTD for 3+3  
Abbreviations: H = high rate of DLT, L = low rate of DLT, MTD = maximum tolerated dose, T = target rate of DLT which refers to MTD 
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Figure 9 - Mean number of participants per dose level for mTPI2  
Abbreviations: H = high rate of DLT, L = low rate of DLT, MTD = maximum tolerated dose, mTPI2 = modified toxicity probability interval 2, 
T = target rate of DLT which refers to MTD 
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Figure 10 - Mean number of participants per dose level for 3+3  
Abbreviations: H = high rate of DLT, L = low rate of DLT, T = target rate of DLT which refers to MTD 
Guo W, Wang SJ, Yang S, Lynn H, Ji Y. Bayesian interval dose-finding design addressing Ockham's razor: mTPI-2. Contemp Clin Trials. 
2017;58:23-33. 
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10.12 APPENDIX 12: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY  
A regional or national emergency declared by a governmental agency (eg, public health 
emergency, natural disaster, pandemic, 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 Good 
Clinical Practice 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 
screening, enrollment, and administration of study intervention may be delayed. 
• 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.  
• Procedures to be considered in the event of a regional or national emergency declared by a 
governmental agency: 
• If onsite visits are not possible, remote visits (eg, with home nurses, home health vendor, 
etc) may be planned for the collection of possible safety and/or efficacy data. 
• If onsite visits are not possible, visit windows may be extended for assessment of safety 
and/or efficacy data that cannot be obtained remotely. 
• Use of local clinic or laboratory locations may be allowed. 
• Contingencies implemented due to emergency will be documented. 
• The participant may be verbally informed prior to initiating any changes that are to be 
implemented for the duration of the emergency (eg, study visit delays/treatment extension, 
use of local labs). 
 
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10.13 APPENDIX 13: MENUS AND COMPOSITION FOR FOOD EFFECT STUDY  
Table 28 - Option 1: Moderate-Calorie, Moderate-Fat Breakfast, Non-Vegan  
Item 
Qty 
U/M 
Cals (kcal) 
Fat (g) 
Prot (g) 
Carb (g) 
Wheat breada 
2 
Slice 
120 
1.0 
8.0 
22.0 
Skippy peanut butter 
pouchb 
1 
Packet 
200 
16.0 
7.0 
6.0 
Grape or strawberry 
jellyc 
3 
Packet 
105 
0.0 
0.0 
27.0 
Banana, fresh, 
medium, 7” – 7-7/8” 
1 
Each 
105 
0.39 
1.29 
26.95 
2% milk 
8 
Ounce 
130 
5.0 
8.0 
12.0 
Total (g) 
 
 
660 
22.39 
24.29 
93.95 
Calories (kcal) 
 
 
- 
201.51 
97.16 
375.80 
Percent by calories 
 
 
- 
29.9% 
14.4% 
55.7% 
Abbreviations: Carb, carbohydrate; Cals, calories; Prot. Protein; Qty, quantity. 
a Nature’s Own 100% whole wheat bread OR Wonder 100% whole wheat bread. 
b A Skippy creamy peanut butter individual packet, 32 g (or measure 1.12 oz out of a jar) OR Jif creamy peanut butter, red cap (measure 
1.12 Oz out of a jar). 
c A Smucker’s individual packet of grape or strawberry jelly, 0.5 oz packet, OR Heinz concord grape or strawberry jelly, 0.5 Oz packet. 
Table 29 - Moderate-Calorie, Moderate-Fat Breakfast, Vegan  
Item 
Qty 
U/M 
Cals (kcal) 
Fat (g) 
Prot (g) 
Carb (g) 
Wheat Breada 
2 
Slice 
120 
1.0 
8.0 
22.0 
Skippy Peanut Butter 
Pouchb 
1 
Packet 
200 
16.0 
7.0 
6.0 
Grape or Strawberry 
Jellyc 
2 
Packet 
70 
0.0 
0.0 
18.0 
Banana, fresh, 
medium, 7 – 7-7/8” 
1 
Each 
105 
0.39 
1.29 
26.95 
Vanilla soy milk, silkd 
/ vanilla soy milk, 
great valuee 
8 /  
12 
Ounce /  
Ounce 
130 /  
133 
3.5 /  
4.4 
6.0 /  
8.9 
18.0 /  
16.3 
Total (g)  
 
 
625 
20.89 
22.29 
90.95 
Calories (kcal) 
 
 
- 
188.01 
89.16 
363.80 
Percent by calories 
 
 
- 
29.3% 
13.9% 
56.8% 
Abbreviations: Carb, carbohydrate; Cals, calories; Prot. Protein; Qty, quantity. 
a Nature’s Own 100% whole wheat bread OR Wonder 100% whole wheat bread. 
b Skippy Creamy peanut butter individual packet, 32 g (or measure 1.12 oz out of a jar) OR Jif creamy peanut butter, red cap (measure out 
of jar 1.12 Oz). 
c A Smucker’s individual packet of grape or strawberry jelly, 0.5 oz packet OR Heinz concord grape or strawberry jelly, 0.5 oz packet. 
d  A Silk brand (very vanilla), 8 oz OR Great Value brand (organic vanilla), 12 oz. 
e For the vegan option, the total, calories, percent by calories, are based on silk vanilla soy milk. 
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10.14 APPENDIX 14: ABBREVIATIONS  
 
AE: 
adverse event 
AESI: 
adverse event of special interest 
ALT: 
alanine aminotransferase 
ANC: 
absolute neutrophil count 
ATE: 
arterial thromboembolic event 
BCRP: 
breast cancer resistance protein 
BID: 
twice daily 
BIW: 
twice a week 
BoR: 
best overall response 
CBR: 
clinical benefit rate 
CFR: 
Code of Federal Regulations 
CI: 
confidence interval 
CNS: 
central nervous system 
CPK: 
creatinine phosphokinase 
CR: 
complete response 
CRC: 
colorectal cancer 
CRF: 
case report form 
CSR: 
central serous retinopathy 
CT: 
computed tomography 
ctDNA: 
circulating tumor DNA 
CYP: 
cytochrome P450 
DCR: 
disease control rate 
DL: 
dose level 
DL1: 
dose level 1 
DL2: 
dose level 2 
DL3: 
dose level 3 
DLT: 
dose-limiting toxicity 
DoR: 
duration of response 
DTP: 
direct-to-patient 
ECG: 
electrocardiogram 
ECHO: 
echocardiogram 
ECOG: 
Eastern Cooperative Oncology Group 
eCRF: 
electronic case report form 
EOT: 
end of treatment 
EU: 
European Union 
FDA: 
United States Food and Drug Administration 
FDG-PET: 
fluorodeoxyglucose positron emission tomography 
FSH: 
follicle-stimulating hormone 
GCP: 
Good Clinical Practice 
GDPR: 
General Data Protection Regulation 
GGT: 
gamma-glutamyl transferase 
GLP: 
Good Laboratory Practice 
HBsAg: 
hepatitis B surface antigen 
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HBV: 
hepatitis B virus 
HCV: 
hepatitis‑C virus 
HRT: 
hormone replacement therapy 
IB: 
Investigator’s Brochure 
ICF: 
informed consent form 
ICH: 
International Council for Harmonisation 
ICI: 
immune checkpoint inhibitor 
IEC: 
Independent Ethics Committee 
IMP: 
investigational medicinal product 
INR: 
international normalized ratio 
irAE: 
immune-related adverse event 
IRB: 
Institutional Review Board 
IV: 
intravenous 
LLN: 
lower limit of normal 
LVEF: 
left ventricular ejection fraction 
MAPK: 
mitogen-activated protein kinase 
MRI: 
magnetic resonance imaging 
MTD: 
maximum tolerated dose 
mTPI: 
modified toxicity probability interval 
mTPI2: 
modified toxicity probability interval 2 
NCI CTCAE: 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NE: 
not evaluable 
NF1: 
neurofibromin 1 
NSCLC: 
non-small cell lung cancer 
OCT: 
optical coherence tomography 
ORR: 
objective response rate 
OS: 
overall survival 
PD: 
progressive disease 
PD-1: 
programmed cell death protein 1 
PD-L1: 
programmed death-ligand 1 
PDy: 
pharmacodynamic 
PET: 
positron emission tomography 
PFS: 
progression free survival 
P-gp: 
P-glycoprotein 
PK: 
pharmacokinetic(s) 
PR: 
partial response 
PT: 
preferred term, prothrombin time 
PTT: 
partial thromboplastin time 
Q3W: 
once every 3 weeks 
QTcF: 
QT interval corrected using Fridericia’s formula 
RECIST: 
Response Evaluation Criteria in Solid Tumours 
RP2D: 
recommended Phase 2 dose 
RPED: 
retinal pigment epithelial detachment 
RTK: 
receptor tyrosine kinase 
RVO: 
retinal vein occlusion 
SAE: 
serious adverse event 
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SD: 
stable disease 
SHP2: 
Src Homology region 2 domain-containing protein tyrosine phosphatase 2 
SoA: 
schedule of activities 
SoC: 
standard of care 
SUSAR: 
suspected unexpected serious adverse reaction 
TEAE: 
treatment-emergent adverse event 
TPS: 
tumor proportion score 
TTR: 
time to response 
ULN: 
upper limit of normal 
UPM: 
unit probability mass 
VTE: 
venous thromboembolic event 
WOCBP: 
woman of childbearing potential 
 
10.15 APPENDIX 15: PROTOCOL AMENDMENT HISTORY  
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
Amended protocol 03 (29-Mar-2021) 
This amended protocol (amendment 03) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union (EU). 
OVERALL RATIONALE FOR THE AMENDMENT 
The following changes need to be implemented into the protocol of TCD16210 study 
(SHP2/Pembrolizumab combo): 
A new POC generating cohort of approximately 40 patients (NSCLC, PD1 naïve) is to be added. 
This change will result in the changes in the overall study design, schedule of assessments, 
eligibility criteria, treatment duration, sample size, statistical considerations, laboratory 
assessments. Safety sections are to be updated in line with most recent information available. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Title page and Section 1.1 
(Synopsis) 
Protocol title and short title were updated 
A new POC generating cohort 
(Part-2) of 40 patients (NSCLC, 
PD1 naïve) has been added 
Section 1 (PROTOCOL 
SUMMARY) and Synopsis 
Disclosure Statement: has been updated from ''This is a 
single arm treatment'' to ''This is a two-parts treatment 
study''. 
Section 1 (PROTOCOL 
SUMMARY) and Synopsis 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 2 
(INTRODUCTION) 
Section 2.1 (STUDY RATIONALE) has been updated with 
new information and rationale of adding new cohort. 
New Section 2.2.1 (Rationale for NSCLC) was added with 
information on NSCLC population. 
New Section 2.2.2 (Current standard of care in NSCLC) was 
added with current standard of care for NSCLC. 
New Section 2.2.3 (Rationale for combining SAR442720 
with pembrolizumab) was added with rationale for 
combining SAR442720 with pembrolizumab. 
Section 2.3 (BENEFIT/RISK ASSESSMENT) was updated 
with new information on benefits assessment, COVID-19 
risk assessment section and with a new table on potential 
risks of SAR442720.  
Overall study design, schedule 
of assessments, eligibility 
criteria, treatment duration, 
sample size, statistical 
considerations, laboratory 
assessments, and. safety 
sections were adjusted to 
accommodate Part-2 of the 
study. 
 
Risk assessment strategies for 
COVID-19 related disruptions 
were added. 
Section 3 (OBJECTIVES 
AND ENDPOINTS) 
Objectives and endpoints table was updated with new  
Part-2 of the study. 
Overall study design, objectives 
and endpoints were adjusted to 
accommodate Part-2 of the 
study. 
Section 4 (STUDY 
DESIGN) 
Section 4.1 (OVERALL DESIGN) was updated with new 
Part-2 of the study. 
Section 4.2 (SCIENTIFIC RATIONALE FOR STUDY 
DESIGN) was updated with scientific rationale for Part-2 of 
the study. 
Section 4.3 (JUSTIFICATION FOR DOSE) was updated 
with SAR442720 and pembrolizumab doses for Part-2 of the 
study. 
Section 4.4 (End of study definition) was updated with new 
definition. 
Overall study design, schedule 
of assessments, eligibility 
criteria, treatment duration, 
sample size, statistical 
considerations, laboratory 
assessments, and. safety 
sections were adjusted to 
accommodate Part-2 of the 
study. 
Section 5 (STUDY 
POPULATION) 
Section 5.1 (INCLUSION CRITERIA): the inclusion criteria, 
I8, I9, I10, and I11 for Part-2 were added. 
Section 5.2 (EXCLUSION CRITERIA) was rearranged, 
exclusion criteria E1 was corrected for typo, E3 was 
updated, E4 was deleted for conciseness and clarity, 
present E12 & E17 were updated for clarity, present E22 
was refined due to emerging safety data, previous E19 was 
deleted, present E19 was added, and the exclusion criterion 
for Part-2 of the study was added. 
 
Section 6 (STUDY 
INTERVENTION) 
Section 6.1 (Table-10) was updated with the dose of 
pembrolizumab for Part-2. 
Section 6.5 (CONCOMITANT THERAPY) was updated with 
the treatment of direct Factor X inhibitors and LMWH. 
Section 6.5.1 (Prohibited concomitant therapy) was updated 
with newly allowed therapies. 
Section 6.6 (DOSE MODIFICATION) was updated with 
dose modification criteria for Part-2. 
Section 6.6.1.1 (management of diarrhea) was additionally 
updated with alternative medicines in order to treat diarrhea.  
Section 6.7 (INTERVENTION AFTER THE END OF THE 
STUDY) was updated with deletion of definition of end of 
study. 
 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 7 
(DISCONTINUATION OF 
STUDY INTERVENTION 
AND PARTICIPANT 
DISCONTINUATION/WITH
DRAWAL) 
Section 7.1.2 (Temporary discontinuation) was updated with 
information on COVID-19 related disruptions. 
 
Section 8 (STUDY 
ASSESSMENTS AND 
PROCEDURES) 
Section 8.1 (EFFICACY ASSESSMENTS) was updated with 
modification of Part-1 assessments and addition of Part-2 
assessments. 
Section 8.3.4 (Regulatory reporting requirements for SAEs) 
was updated with suggested texts included in the recent 
template. 
Section 8.6 (PHARMACODYNAMICS) was updated with 
Part-2 sample collections.  
Section 8.7 (GENETICS) was updated with baseline blood 
sample collections from consenting participants. 
Section 8.8 (BIOMARKERS) was updated with new sample 
collection procedures. 
New Section 8.11 (USE OF BIOLOGICAL SAMPLES AND 
DATA FOR FUTURE RESEARCH) was added. 
 
Section 9 (STATISTICAL 
CONSIDERATIONS) 
 
Section 9.1 (STATISTICAL HYPOTHESES) was updated 
with statistical hypotheses related to Part-2 of the study.  
Section 9.2 (SAMPLE SIZE DETERMINATION) was 
updated with sample sizes of Part-1 and Part-2 and a new 
table of estimated objective response rate (ORR) was 
added. A "Note" for enrolled participants is deleted. 
Section 9.3 (Population for analyses) was updated with the 
description for “Enrolled”. 
Section 9.4.1 (General considerations) was expanded with 
new information on analysis period. 
Section 9.4.2 (Efficacy endpoints) was updated with an 
expanded table on efficacy end points and end point 
definitions. Primary endpoint(s)' was changed to ''efficacy 
endpoints'. 
Section 9.4.3 (Secondary endpoints) was changed to 
“Safety endpoints” and further subsections related to safety 
were added. 
New Section 9.4.3.1 (Adverse events) was added and 
updated with list of adverse events. 
Section 9.4.4 (other endpoints) was updated with 
information on the presentation of data. 
Section 9.5 (INTERIM ANALYSES) was updated stating 
that no interim analyses were planned. 
 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 10 (SUPPORTING 
DOCUMENTATION AND 
OPERATIONAL 
CONSIDERATIONS) 
Section 10.5 Appendix 5 (GENETICS) was updated with 
new information on DNA analysis. 
Section 10.9 Appendix 9 (GENERAL GUIDELINES FOR 
THE MANAGEMENT OF IMMUNE RELATED ADVERSE 
EVENTS) Dose modification outlines in Table-19 were 
extensively updated for clarity. 
New Section 10.12 Appendix 12 (CONTINGENCY 
MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A 
GOVERNMENTAL AGENCY) was added with information 
on COVID-19 disruptions. 
Section 10.14 Appendix 14 (PROTOCOL AMENDMENT 
HISTORY) was updated with changes in last protocol 
amendment. 
Contingency measures were 
included for unintended 
disruptions. 
Section 11 (Reference) 
Section 11 was updated with new references. 
 
Amended protocol 02 (02-Jul-2020) 
This amended protocol (amendment 02) is considered to be nonsubstantial based on the criteria 
set forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of 
the European Union (EU) because it does not significantly impact the safety or physical/mental 
integrity of participants, nor the scientific value of the study. 
OVERALL RATIONALE FOR THE AMENDMENT 
The protocol was amended to allow an alternative twice a week (BIW) dose schedule. Additional 
changes and clarifications are summarized below. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1 Synopsis 
(Secondary endpoints and 
Statistical consideration) 
Section 3 Objectives and 
Endpoints 
Best overall response (BoR) was replaced with duration of 
response (DoR) in a secondary endpoint. DoR was removed 
from the list of the tertiary/exploratory endpoints.  
Duration of response is a 
clinically important endpoint that 
is related to quality of life. BoR 
will be summarized in this study. 
Section 1.1 Synopsis 
(Overall study design, 
Intervention groups and 
duration) 
Section 4.1 Overall Design 
Section 4.3 Justification for 
Dose 
“Day 1, Day 4” was replaced with “BIW” where needed 
throughout the text and tables. The text regarding the 
starting dose of SAR442720 was edited. 
The following text were added for clarity: 
“During the study, alternative BIW dose schedules, such as 
Day 1 and Day 2 of each week, or any other emergent dose 
schedule from the ongoing Phase 1 monotherapy escalation 
study can be explored after agreement of the Study 
Committee.” 
“The decision to initiate alternative dose levels will be made 
by the Study Committee after careful evaluation of safety 
and/or PK data from the ongoing Phase 1 monotherapy 
escalation study and data generated in this combination 
study.” 
Emergence of an alternative, 
tolerable dose schedule. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1 Synopsis 
(Overall study design) 
Section 4.1 Overall Design 
Section 10.1.5 Committee 
structure 
The following text was added: “the safety and/or PK data 
observed in the ongoing Phase 1 monotherapy escalation 
study” 
Emergence of an alternative, 
tolerable dose schedule. 
Section 1.2 Schema 
Figure 1 title updated from: “Graphical study design“  
to 
“Graphical study design of SAR442720 administered on 
Day 1 and Day 4 Pembrolizumab every 3 weeks”. 
Clarification 
 
Figure 1 “SAR442720 (Oral Day 1, Day 4 weekly per cycle)” 
replaced with “SAR442720 (Oral BIW per cycle)” 
To be consistent with the 
addition of Day 1, Day 2 or any 
other potential schedules that 
may emerge. 
Section 1.3 Schedule of 
Activities 
Section 10.2 Appendix 2 
The following text was added for laboratory assessments 
(including liver chemistries): “C2+Day 15 laboratory 
assessments could be done remotely if needed and after 
discussion with the Study Medical Manager.” 
Clarification 
Section 1.3 Schedule of 
Activities, Table 2 
Additional pharmacokinetic (PK) sample collection time 
points were added for participant receiving SAR442720 on 
the Day 1, Day 2 of each week dosing schedule. 
To monitor the concentrations of 
SAR442720 in Day1, Day 2 of 
each week dosing schedule. 
Section 1.3 Schedule of 
Activities, Table 3 
Separate row for Cycle 2 assessments has been deleted 
and combined with Cycle 3 and 4 rows. 
Clarification. 
Section 2.3.1 Risk 
assessment 
The following statement was removed: “Phototoxicity studies 
with SAR442720 have not been completed. Therefore, 
participants taking SAR442720 should use appropriate 
protection when exposed to UV radiation” 
In vitro and in vivo studies have 
been conducted and no 
indication of phototoxicity was 
observed. This information is 
included in the SAR442720 
Investigator’s Brochure (IB) v3. 
The following text, “approximately 6.4x of unbound Cmax”, 
was adjusted to “approximately 17x of unbound Cmax”. 
Clarification. 
The following paragraph was added: “Emerging data from 
ongoing studies identifies anemia as a new potential risk 
based on clinical data and preclinical evidence. In the 
monotherapy study (n=82), anemia AEs (Standardized 
MedDRA Query [SMQ]), of any grade, were reported in 
26 (31.7%) participants, including 11 (13.4%) participants 
who required blood transfusions. Grade 3 anemia events 
were reported in 13 (15.9%) participants; 3 SAE including 
1 event related to study drug. No Grade 4 anemia events 
have been reported to date. Median time to onset of anemia 
was 22 days from the start of study treatment, and median 
time to recovery was 21 days. In addition, 54 (65.9%) 
participants had a hemoglobin grade shift from baseline, of 
which 27 participants were anemic at baseline, among 
which 3 (3.7%) participants had a hemoglobin shift from 
Grade 1 to Grade 3 and 5 (6.1%) participants had a 
hemoglobin shift from Grade 2 to Grade 3. The other 
27 participants were normal at baseline, among which 
6 (7.3%) participants had a Grade 2 worsening and 2 (2.4%) 
participants had a Grade 3 worsening.” 
Anemia is the third risk which 
has been identified as potential 
risk. It was added to the protocol 
as to alert the investigators. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 4.1.1 Dose-limiting 
toxicity criteria 
Deleted “or hemorrhage” from following bullet point “Grade 3 
neutropenia lasting >7 days or febrile neutropenia or 
hemorrhage” 
Correction 
 
The following dose-limiting toxicity (DLT) criterion was 
updated from: 
• 
“Grade 3 non hematologic AEs, including rash, 
nausea/vomiting, hypertension, diarrhea, that 
remain uncontrolled for >72 hours despite 
maximal supportive care. Electrolyte abnormalities 
or Grade 3 asymptomatic CPK or GGT elevations 
that is corrected within 72 hours will not be 
considered DLTs.” 
To:  
• 
“Grade 3 nonhematologic AEs, including rash, 
nausea/vomiting, hypertension, diarrhea, 
retinopathy, or blurred vision that remain 
uncontrolled (does not resolve to ≤ Grade 2) for 
>72 hours despite maximal supportive care. 
Electrolyte abnormalities or Grade 3 asymptomatic 
CPK or GGT elevations that are corrected within 
72 hours will not be considered DLTs.” 
The changes were made to 
reflect the CTCAE definition of 
these events. Retinopathy was 
added as a DLT criteria and will 
comprise retinal detachment. 
 
The following DLT criterion was deleted:  
• 
Grade 3 retinal detachment, tear or vascular 
disorder 
Not an observed AE for this 
molecule according to the 
ongoing monotherapy study 
codes. 
Section 4.3 Justification for 
dose 
The human Ether-à go-go (hERG) safety margin-related 
details have been updated. The sentence changed from: 
“The unbound steady state maximum plasma concentration 
(Cmax,u) at 140 mg and 200 mg via D1-D4 schedule provides 
adequate hERG safety margin (9.4x for 140 mg and 6.4x for 
200 mg dose).” 
To: 
“The unbound steady state maximum plasma concentration 
(Cmax,u) at 140 mg Day 1, Day 4 and 200 mg BIW (Day 1, 
Day 4 and Day 1, Day 2) schedule provides an adequate 
hERG safety margin (≥17x).” 
Clarification based on IB v3. 
Section 5.2 Exclusion 
criteria 
Deleted “…and PI3K δ inhibitors” from exclusion criterion 
E 09. 
The following text was added to the 3rd bullet point of 
exclusion criterion 23: “…during the dose escalation portion 
of the study”. 
Exclusion criterion E 24 sub-bullet was corrected from 
“…creatinine clearance of >50 mL/min” to “…creatinine 
clearance of <50 mL/min” 
The following text was added to the 7th bullet point of 
exclusion criterion 24: “or outside the therapeutic range of 
the local laboratory if receiving therapeutic anticoagulation 
that would affect the PT/INR”. 
Corrections 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 6.5.1 Prohibited 
concomitant therapy 
The following text was added to the 5th and 6th bullet 
points:”…(only during the dose escalation portion of the 
study)” 
Clarification 
Section 6.6.1.1 
Management of diarrhea 
“Lomotil” was added for treatment of Grade 1 or 2 diarrhea. 
Clarification 
Section 6.7 Intervention 
after end of the study 
Additional details were added and text updated from: 
“Participants who continue to receive study intervention at 
the end of the study and are deriving clinical benefit from 
SAR442720 and pembrolizumab will be considered for 
enrollment in a separate extended use or roll over study.” 
To: 
“Participants who continue to receive study intervention at 
the end of the study and are deriving clinical benefit from 
SAR442720 and pembrolizumab may receive study 
intervention until disease progression, an unacceptable AE, 
or the participant’s or Investigator’s decision to stop the 
treatment.  
The end of the study is defined as the date of the last visit of 
the last participant in the study or 12 months after last 
participant is enrolled, whichever occurs first. 
The participant’s treatment after the end of the study will be 
at discretion of treating physician.” 
Clarification of study intervention 
at the end of the study.  
Section 7.1.1 Definitive 
discontinuation 
Following additional text was added: 
“During the conduct of the study, in cases where premature 
discontinuation of SAR442720 is required, the participant 
may continue pembrolizumab treatment, upon Investigator 
decision and in agreement with the Study Medical Manager. 
Likewise, in cases where premature discontinuation of 
pembrolizumab is required, the participant may continue 
SAR442720 treatment if there is presence of, or potential 
for, clinical benefit as assessed by the Investigator and 
Study Medical Manager.” 
Clarification of administration of 
investigational medicinal 
products in case of 
discontinuation of one drug.  
Section 8.2.2 Vital signs 
The duration of rest before vital signs are measured was 
adjusted (“5 to 10 minutes”).  
Clarification.  
Following text was deleted: 
“Vital signs include: temperature, blood pressure preferably 
in seated position after at least 10 minutes of rest, pulse 
rate, pulse oximetry, and respiratory rate” 
Duplicated of information and 
hence deleted.  
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Section # and Name 
Description of Change 
Brief Rationale 
Section 8.2.7 Retinal 
examinations 
Retinal examination details were updated from: 
“Retinal examinations performed by an ophthalmologist are 
required during this study as described in the SoA 
(Section 1.3). Examinations should include visual acuity, 
dilated retinal examinations, and optical coherence 
tomography (OCT) to evaluate the retinal pigment 
epithelium. Additional tests, such as fluorescein 
angiography, may be utilized to monitor leakage and 
inflammation related side effects.” 
To: 
“Retinal examinations performed by an ophthalmologist are 
required during this study as described in the SoA 
(Section 1.3). Examinations include best-corrected visual 
acuity including pinhole vision if indicated, dilated 
funduscopic examinations, and macular and optical 
coherence tomography (OCT). Additional tests, such as 
fluorescein angiography, may be utilized to monitor leakage 
and inflammation-related side effects.” 
Clarification on the proposed 
retinal examination.  
Section 9.4.3.2 Objective 
response rate (ORR) and 
duration of response (DoR) 
In alignment with the changes made in Section 3 to 
objectives and endpoints, the following description of ORR 
and DoR has been added and text regarding BoR has been 
reduced: 
“Objective response rate is defined as the proportion of 
participants who achieve a CR or PR per RECIST v1.1. 
Objective response rate and the corresponding 90%  
2-sided CI will be derived. CR or PR may be claimed only if 
the criteria for each are met at a subsequent time point as 
specified in the protocol (refer to Section 8.1 for imaging 
assessment instructions). Best overall response per 
RECIST v1.1 will also be summarized.  
Duration of response (DoR) per RECIST v1.1 is defined as 
the interval from the first documentation of complete 
response (CR) or partial response (PR) to the earlier of 
first documentation of definitive disease progression or 
death due to any cause, whichever occurs first. Participants 
who are still alive and free from progression at the time of 
data cutoff date, are lost to follow-up, have discontinued 
from the study, or who have initiated subsequent anticancer 
therapy will be censored at the last adequate tumor 
assessment. For participants who achieve CR or PR, the 
Kaplan-Meier curve will be generated. The Kaplan-Meier 
estimates of the 25th, 50th, and 75th percentiles and their 
associated 95% CI will be provided.” 
To be consistent with BoR 
replacement with DoR as a 
secondary endpoint. 
Section 9.4.4 Other 
endpoint(s) 
“DoR per RECIST v1.1” has been deleted  
DoR is now covered as a 
secondary endpoint in 
Section 9.4.3.2. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 10.9 Appendix 9, 
Table 14. Dose modification 
guidelines 
Following new AEs and pertaining action has been added: 
Colitis, Nephritis, Endocrinopathies, Other immune-related 
adverse reactions, and Pembrolizumab Infusion-related 
reactions. 
Adverse event term of "Rash" changed to "Skin Reactions" 
and corresponding action has been updated. 
Added AE of "Hepatitis" along with other liver function test 
abnormalities and corresponding action has been updated. 
Dose modification guidelines 
were amended based on health 
authority feedback. 
Throughout 
Typos have been corrected where necessary. 
Clarifications 
Throughout 
Minor editorial and document formatting revisions 
Minor, therefore have not been 
summarized 
Amended protocol 01 (06-Mar-2020) 
This amended protocol (amendment 01) is considered to be nonsubstantial based on the criteria 
set forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of 
the European Union because it does not significantly impact the safety or physical/mental 
integrity of participants, nor the scientific value of the study. 
Overall rationale for the amendment 
The protocol received comments from the US FDA regarding the DLT criteria and inclusion 
criteria. The revisions made are owing to the FDA suggestions as summarized below. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Section 4.1.1 Dose limiting 
toxicity criteria 
Added neutropenia lasting longer than 7 days 
as a potential DLT 
As requested by health authorities 
Section 4.1.2 Dose 
escalation  
Added experiencing a DLT in the DLT 
observation period to be evaluable for DLT 
assessment 
As requested by health authorities 
Section 4.2.1 Dose 
escalation rationale 
Modified the design such that at no point will 
the upper limit of the probability of toxicity be 
>33% 
As requested by health authorities 
Section 5.1 Inclusion 
criteria 
Modified I02 
As requested by health authorities 
 
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11 
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cell receptor signaling by recruiting phosphatase SHP2. J Exp Med. 2012;209(6):1201-17. 
45. Brown AP. Development of serum calcium and phosphorus as clinical biomarkers for drug 
induced systemic mineralization: case study with a MEK inhibitor. In: Bleavins MR, Carini C, 
Jurima Romet M, and Rahbari R, editors. Biomarkers in drug development: A handbook of 
practice, application, and strategy. Hoboken, NJ. John Wiley & Sons; 2010. p. 301-22. 
 
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According to template: QSD-002643 VERSION 8.0 (17-JUN-2020) 
Page 1 
STATISTICAL ANALYSIS PLAN 
Protocol title: 
A Phase 1/2, open-label, multicenter, dose escalation 
and dose expansion study of SAR442720 in 
combination with other agents in patients with 
advanced malignancies 
Protocol number: 
TCD16210 
Compound number 
(INN/Trademark): 
SAR442720 
Study phase: 
Phase 1/2 
Short title: 
Safety and efficacy study of SAR442720 in 
combination with other agents in advanced 
malignancies 
Statistician: 
Zhang, Yiding 
Statistical project leader: 
Mi, Gu 
Date of issue: 
14-Jul-2022 
Regulatory agency identifier number(s): 
Registry: 
ID 
IND: 
EudraCT 
147102 
2020-000436-22 
Total number of pages: 31 
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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 
OBJECTIVE AND ENDPOINTS ...................................................................................................... 7 
2 
SAMPLE SIZE DETERMINATION ................................................................................................ 10 
3 
ANALYSIS POPULATIONS .......................................................................................................... 12 
4 
STATISTICAL ANALYSES ........................................................................................................... 13 
4.1 
GENERAL CONSIDERATIONS .................................................................................................... 13 
4.2 
PARTICIPANT DISPOSITIONS ..................................................................................................... 13 
4.3 
SAFETY ENDPOINT(S) ................................................................................................................. 14 
4.4 
EFFICACY ENDPOINT(S) ............................................................................................................. 16 
4.5 
TERTIARY/EXPLORATORY ENDPOINT(S) ANALYSIS .............................................................. 19 
4.6 
MULTIPLICITY ISSUES ................................................................................................................ 20 
4.7 
OTHER SAFETY ANALYSES ....................................................................................................... 20 
4.7.1 
Extent of exposure ......................................................................................................................... 20 
4.7.1.1 
Overall exposure ............................................................................................................................ 20 
4.7.1.2 
SAR442720 exposure .................................................................................................................... 21 
4.7.1.3 
Pembrolizumab exposure .............................................................................................................. 22 
4.7.2 
Laboratory variables....................................................................................................................... 23 
4.7.3 
Additional safety analyses (Vital signs and electrocardiograms [ECGs]) ...................................... 23 
4.8 
OTHER ANALYSES....................................................................................................................... 24 
4.8.1 
PK analyses ................................................................................................................................... 24 
4.8.2 
Biomarker analyses........................................................................................................................ 25 
4.9 
INTERIM ANALYSES .................................................................................................................... 25 
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5 
SUPPORTING DOCUMENTATION .............................................................................................. 26 
5.1 
APPENDIX 1 LIST OF ABBREVIATIONS ..................................................................................... 26 
5.2 
APPENDIX 2 CHANGES TO PROTOCOL-PLANNED ANALYSES ............................................. 27 
5.3 
APPENDIX 3 DEMOGRAPHICS AND BASELINE CHARACTERISTICS, PRIOR OR 
CONCOMITANT MEDICATIONS .................................................................................................. 27 
5.4 
APPENDIX 4 DATA HANDLING CONVENTIONS ........................................................................ 29 
5.5 
INTERNATIONALLY AGREED SOC ORDER ............................................................................... 29 
5.6 
POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES CRITERIA ................................. 31 
 
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LIST OF TABLES  
Table 1 - Major changes in statistical analysis plan ........................................................................................ 5 
Table 2 - Objectives and endpoints ................................................................................................................. 7 
Table 3 - Populations for analyses ................................................................................................................ 12 
Table 4 - Sorting of AE tables ....................................................................................................................... 15 
Table 5 - Analyses of adverse events ........................................................................................................... 16 
Table 6 - Summary of efficacy endpoints ...................................................................................................... 17 
Table 7 - DoR analysis - Event and censoring rules ..................................................................................... 18 
Table 8 - PFS analysis - Event and censoring rules ..................................................................................... 19 
 
 
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VERSION HISTORY  
This Statistical Analysis Plan (SAP) for study SAR442720 TCD16210 is based on the protocol 
dated 26-Oct-2021. This section summarizes major changes to the statistical analysis features in 
the SAP. This SAP is approved before database lock of the expansion cohort. 
Table 1 - Major changes in statistical analysis plan  
SAP 
Version 
Approval 
Date 
Changes 
Rationale 
1.0 
 
This is the original version of SAR442720 TCD16210 SAP. 
 
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1 
INTRODUCTION  
1.1 
STUDY DESIGN  
Part-1 
This is a Phase 1 open-label, multi-center, safety, preliminary efficacy, and PK study of 
SAR442720 in combination with pembrolizumab in participants with advanced malignancies. 
The Phase 1 safety study is to characterize the safety and tolerability of SAR442720 in 
combination with pembrolizumab and to confirm the recommended Phase 2 dose (RP2D). 
Participants with either NSCLC or advanced CRC will be enrolled in the study. There is no 
minimum patient number requirement for either tumor type. 
There are 3 scheduled dose levels in the consideration: the starting dose (DL 1) of SAR442720 
(140 mg BIW), dose level 2 (DL2) (200 mg BIW) and DL-1 (100 mg BIW). The DLT 
observation period is 1 cycle (21 days). The Study Committee will review the overall safety, 
PK/PD and preliminary antitumor activity data and will decide the recommended dose for the 
expansion phase. 
Part-2 
The expansion cohort (Part-2), un-controlled, non-randomized, open-label study will assess the 
antitumor activity and safety of SAR442720 combined with pembrolizumab in participants with 
lung cancer. 
Part-2 will assess the antitumor efficacy and safety of adding SAR442720 to therapeutic 
approaches with documented efficacy profile as 1L NSCLC therapy. 
• Cohort A1: participants with PD-L1 TPS ≥50% NSCLC to receive SAR442720 + 
pembrolizumab as 1L therapy. 
• Cohort A2: participants with PD-L1 TPS 1%-49% NSCLC to receive SAR442720 + 
pembrolizumab as 1L therapy. 
Part-2 of the study will start at the RP2D for SAR442720 defined in Part-1. The SAR442720 
RP2D will be 200 mg BIW, such Day 1 and Day 2 of each week, administered orally (21 days per 
cycle). Pembrolizumab will be administrated as a dose of 200 mg using 30 minutes IV infusion on 
Day 1 every 3 weeks (21 days cycle) or a dose of 400 mg using 30 minutes IV infusion on Day 1 
ever 6 weeks (42 days cycle). 
Part-3 
Part-3 of this open-label, multi-center, un-controlled, non-randomized study, will assess the 
safety, RP2D, anti-tumor activity, and PK of SAR442720 in combination with adagrasib in 
participants with NSCLC harboring KRAS G12C mutation. 
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Part-3A of the study will investigate the safety and tolerability of SAR442720 in combination 
with adagrasib and confirm RP2D. There are 6 dose levels in consideration: the starting dose 
(dose level 1 [DL1]) of IMP combination will be 100 mg BIW and 400 mg BID for SAR442720 
and adagrasib respectively, dose level 2 (DL2) will be 140 mg BIW and 400 mg BID, dose 
level 3a (DL3a) will be 140 mg BIW and 600 mg BID, dose level 3b (DL3b) will be 200 mg BIW 
and 400 mg BID, dose level 4 (DL4) will be 200 mg BIW and 600 mg BID, and dose level (-)1 
([DL-1]) will be 80 mg BIW and 400 BID. A minimum of 3 DLT evaluable participants for each 
dose level is required. The DLT observation period is 1 cycle (21 days). The Study Committee 
will review the overall safety, PK/PD, and clinical activity data and in agreement with the 
Sponsor’s Study Medical Manager, will decide the recommended dose for the expansion phase. 
Part-3B dose expansion will assess the anti-tumor activity and safety of SAR442720 combined 
with adagrasib in participant with NSCLC harboring KRAS G12C mutation. This study will start 
once RP2D for SAR442720 and adagrasib from Part-3A dose escalation is confirmed. 
Approximately 40 participants will be enrolled. 
Part-4 of this study will assess the effect of food on PK of SAR442720 tablet, when dosed in 
combination with pembrolizumab in participants with advanced malignancies. It will also evaluate 
the relative bioavailability of SAR442720 tablet formulation (test) compared to the capsule 
formulation (reference) when dosed in combination with pembrolizumab. Approximately 
12 participants are expected to be enrolled. 
1.2 
OBJECTIVE AND ENDPOINTS  
Table 2 - Objectives and endpoints  
Part-1 
Objectives 
Endpoints 
Primary 
• 
To characterize the safety and tolerability for the 
combination of SAR442720 and pembrolizumab in 
participants with advanced solid tumors including 
NSCLC who progressed on anti-PD1/PD-L1 
containing therapy and advanced CRC after 
progression to all standard of care (SoC) therapy 
• 
Incidence, nature, and severity of treatment-emergent 
adverse events (AEs) and serious adverse events 
(SAEs), graded according to the National Cancer 
Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE) Version 5.0 for the combination 
of SAR442720 and pembrolizumab 
• 
To define the MTD and RP2D for the combination of 
SAR442720 and pembrolizumab in participants with 
solid tumors 
• 
Incidence of study drug-related dose limiting 
toxicities (DLTs) in Cycle 1 
Secondary 
 
• 
To document the pharmacokinetic (PK) for the 
combination of SAR442720 and pembrolizumab, 
and to document the PK of pembrolizumab in 
combination with SAR442720 
• 
Plasma concentrations of SAR442720 
• 
Serum concentrations of pembrolizumab 
• 
To estimate the anti-tumor effects for the 
combination of SAR442720 and pembrolizumab in 
all participants 
• 
Objective response rate (ORR) and duration of 
response (DoR) for the combination therapy of 
SAR442720 and pembrolizumab in all participants. 
ORR of combination therapy with SAR442720 and 
pembrolizumab will be based on Response 
Evaluation Criteria in Solid Tumors (RECIST) v1.1 
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Part-2 
Objectives 
Endpoints 
Primary 
• 
To determine the antitumor activity of SAR442720 
in combination with pembrolizumab 
• 
Objective response rate defined as the proportion of 
participants who have a confirmed complete 
response (CR) or partial response (PR) determined 
by investigator per RECIST v1.1 
Secondary 
• 
To assess the safety profile of SAR442720 in 
combination with pembrolizumab 
• 
Incidence of TEAEs, SAEs, laboratory abnormalities 
according to National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI 
CTCAE) V5.0 
• 
To assess other indicators of antitumor activity 
• 
Time to response (TTR) defined as the time from the 
first administration of investigational medicinal 
product (IMP) to the first documented evidence of 
PR or CR determined by investigator per RECIST 
v1.1 (for NSCLC) 
• 
DoR, defined as the time from first documented 
evidence of CR or PR until progressive disease 
(PDdetermined by investigator per RECIST v1.1 or 
death from any cause, whichever occurs first 
• 
Clinical benefit rate (CBRincluding confirmed CR or PR 
at any time or stable disease (SD) of at least 6 months 
determined by Investigator per RECIST v1.1 
• 
Progression free survival (PFS), defined as the time 
from the date of first IMP administration to the date 
of the first documented disease progression 
determined by investigator as per RECIST v1.1 or 
death due to any cause, whichever occurs first 
• 
To assess the PK of SAR442720 in combination 
with pembrolizumab, and to assess the PK of 
pembrolizumab in combination with SAR442720 
• 
Plasma concentrations of SAR442720 
• 
Serum concentration of pembrolizumab 
Part-3A 
Objectives 
Endpoints 
Primary 
• 
To define the MTD and RP2D for the combination 
of SAR442720 and adagrasib in participants with 
NSCLC and KRASG12C mutations 
• 
Incidence of study drug-related DLTs in Cycle 1 
Secondary 
• 
To characterize the safety and tolerability of 
SAR442720 in combination with adagrasib in 
participants with NSCLC and KRASG12C 
mutations 
• 
To characterize the PK of SAR442720 in 
combination with adagrasib, and to characterize 
the PK of adagrasib in combination with 
SAR442720 
• 
Incidence, nature, and severity of treatment 
emergent AEs and SAEs, graded according to the 
NCI CTCAE Version 5.0 for the combination of 
SAR442720 and adagrasib 
• 
PK parameters of SAR442720 
• 
PK parameters of adagrasib 
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Objectives 
Endpoints 
• 
To estimate the anti-tumor effects of SAR442720 in 
combination with adagrasib in all participants 
• 
ORR and DoR of SAR442720 and adagrasib in 
all participants. ORR of combination therapy with 
SAR442720 and adagrasib will be based on 
RECIST v1.1 
Part-3B  
Objectives 
Endpoints 
Primary 
• 
To determine the antitumor activity of SAR442720 
in combination with adagrasib in participants with 
NSCLC and KRASG12C mutations 
• 
Objective response rate defined as the proportion of 
participants who have a confirmed CR or PR 
determined by investigator per RECIST v1.1 
Secondary 
• 
To assess the safety profile of SAR442720 when 
combined with adagrasib in participants with 
NSCLC and KRASG12C mutations 
• 
Incidence of TEAEs, SAEs, laboratory abnormalities 
according to NCI CTCAE V5.0 
• 
To assess other indicators of antitumor activity 
• 
TTR defined as the time from the first administration 
of investigational medicinal product (IMP) to the 
first documented evidence of PR or CR determined 
by investigator per RECIST 1.1 (for NSCLC) 
• 
DoR, defined as the time from first documented 
evidence of CR or PR until progressive disease (PD) 
determined by investigator per RECIST 1.1 or death 
from any cause, whichever occurs first 
• 
CBR including confirmed CR or PR at any time or SD 
of at least 6 months (determined by investigator per 
RECIST v1.1 
• 
PFS, defined as the time from the date of first IMP 
administration to the date of the first documented 
disease progression determined by investigator as 
per RECIST v1.1 or death due to any cause, 
whichever occurs first 
• 
To assess the PK of SAR442720 in combination 
with adagrasib, and to assess the PK of adagrasib 
in combination with SAR442720 
• 
Plasma concentrations of SAR442720 and adagrasib 
Part-3 (Part-3A and Part-3B) 
Objectives 
Endpoints 
Tertiary/exploratory 
 
 
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Part-4 
Objectives 
Endpoints 
Primary 
• 
To evaluate the impact of food on the PK of 
SAR442720 when dosed in combination with 
pembrolizumab 
 
• 
To evaluate the impact of formulation (tablets vs. 
capsules) on the PK of SAR442720 when dosed in 
combination with pembrolizumab 
• 
Plasma PK parameters of SAR442720 following 
oral administration of SA442720 tablets in 
combination with pembrolizumab under fed and 
fasted states (eg. Cmax, Tmax, AUC0-last) 
• 
Plasma PK parameters of SAR442720 following 
oral administration of SAR442720 tablets (test 
formulation) and capsules (reference formulation) in 
combination with pembrolizumab under fasted state 
(eg, Cmax, Tmax, AUC0-last) 
Secondary 
• 
To assess the safety and tolerability of SAR442720 
under fasted and fed conditions in combination with 
pembrolizumab, when dosing with capsule and 
tablet formulations in combination with 
pembrolizumab 
• 
To estimate the anti-tumor effects of SAR442720 in 
combination with pembrolizumab in all participants 
• 
Incidence, nature, and severity of treatment 
emergent AEs and SAEs, graded according to the 
NCI CTCAE Version 5.0 for SAR442720 in 
combination with pembrolizumab 
 
• 
ORR and DoR of SAR442720 and pembrolizumab 
in all participants. ORR of combination therapy with 
SAR442720 and pembrolizumab will be based on 
RECIST v1.1 
2 
SAMPLE SIZE DETERMINATION  
The sample size is not calculated from statistical consideration since there will not be any formal 
statistical test performed. Overall, up to 134 participants will be enrolled. 
In Part-1, at least 6 patients need to be treated at the MTD. After MTD is identified, another 
6 patients will be treated at the MTD to confirm the decision and determine the RP2D. Therefore, 
a range of 18-24 DLT-evaluable (defined in Section 3) patients will be enrolled in the Part-1 of 
this study. The actual sample size will vary depending on DLTs observed and the number of dose 
levels explored.  
In Part-2, 40 participants, including 20 patients in Cohort A1 with PD-L1 TPS>=50% and 
20 patients in Cohort A2 with PD-L1 TPS in 1-49%, will be enrolled at the RP2D identified from 
the Part-1. With a sample size of 20 study participants in each cohort of Part-2, the probability of 
observing 1 or more instances of a specific AE with a true incidence rate of 1%, 2%, or 5% is 
18.2%, 33.2%, or 64.2%, respectively. 
Part-3A, a range of 15 to 30 DLT-evaluable participants will be enrolled in this study. The actual 
sample size will vary depending on DLTs observed and the number of dose levels explored. 
Part-3B, 40 participants will be enrolled at the RP2D identified from the Part-3A. With a sample 
size of 40 study participants in each cohort of Part-3B, the probability of observing 1 or more 
instances of a specific AE with a true incidence rate of 1%, 2%, or 5% is 33.1%, 55.4%, or 87.1%, 
respectively. 
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Part 4, 12 participants are expected to be enrolled in each group. By assuming AUC single dose 
Coefficient of Variation is 
, 12 participants in each group will achieve a maximum 
imprecision of 
. When the AUC ratio is
, the 90% CI would be 
 respectively. When 9 participants are PK evaluable in each group, the 
maximum imprecision would be
. When the AUC ratio is
, the 90% CI would be 
 respectively. 
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3 
ANALYSIS POPULATIONS  
The following populations for analyses are defined:  
Table 3 - Populations for analyses  
Population 
Description 
Enrolled 
All participants who sign the ICF and have dose allocated to an intervention 
regardless of whether the intervention was received or not. 
DLT-evaluable (only for Part-1 and  
Part-3A) 
Patients who take at least 4 of the 6 planned doses of SAR442720 (Part-1 and 
Part-3A) and 28 of the 42 planned doses of adagrasib (Part-3A) in the first cycle of 
the treatment and complete the DLT observation period. 
OR 
Patients who have any DLT observed in the DLT observation period.  
PK 
Patients who have at least one measurable SAR442720 concentration or at least 
one measurable pembrolizumab concentration after the first dose or at least 
one measurable adagrasib concentration after the first dose. 
PD 
Patients who have at least one PD marker result after the first dose 
Safety 
 
PK evaluable (Part-4 only) 
Patients who take at least one dose of any IMP (i.e., SAR442720, pembrolizumab, 
or adagrasib) 
Patients who complete all of cycle 1 and C2D1 with meal information, full PK, and 
no dose reduction/missed doses on C1D1, C1D15 and C2D1. Missing some PK 
samples may still be considered as evaluable and will be assessed case-by-cased. 
Abbreviations: DLT = dose-limiting toxicity, ICF = informed consent form, PD = pharmacodynamic(s), PK = pharmacokinetic(s) 
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4 
STATISTICAL ANALYSES  
4.1 
GENERAL CONSIDERATIONS  
In general, continuous data will be summarized using the number of observations available, mean, 
standard deviation (SDs), 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 MTD recommendation and DLT summary will be based on the 
DLT-evaluable population Cycle 1 data only excluding the 6 patients in the mini-expansion. All 
safety and efficacy analyses will be based on the safety population unless otherwise specified. The 
Part-1 and Part-2 analyses will be performed separately unless specified otherwise. Part-1 
analyses will be presented by different dose levels, and Part-2 analyses will be presented by 
cohorts defined by different PD-L1 TPS. Part-3A analyses will be presented by dose levels, and 
Part-3B analyses, unless otherwise specified, will be presented overall. Part-4 analyses will be 
presented overall. 
Observation period  
The observation period will be divided into 3 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. [After last IMP administration + 31 days] 
4.2 
PARTICIPANT DISPOSITIONS  
The number (and percentage) of participants included in each of the analysis populations listed in 
Table 3 will be summarized. 
Screen failures are defined as participants who consent to participate in the study but are not 
subsequently dosed. The number (and percentage) of screen failures and reasons for screen 
failures will be provided. 
Regarding intervention discontinuation, the following definitions will be used: 
• Permanent full intervention discontinuation is defined as the discontinuation of all the 
study drugs 
The number (and percentage) of participants in the following categories will be provided:  
• Enrolled population 
• Safety population 
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• DLT evaluable population (only for Part-1 and Part-3A) 
• Pharmacokinetics population 
• Pharmacodynamic population 
• Participants who did not complete the study treatment as per protocol and main reason for 
full treatment discontinuation and treatment withdrawal by subject 
•  Participants who did not complete study/follow-up period as per protocol and main reason 
for study discontinuation 
• Subject survival status 
Protocol deviations 
Critical and major protocol deviations (automatic or manual) will be summarized in the safety 
population. 
4.3 
SAFETY ENDPOINT(S)  
Safety endpoints including incidence and severity of AEs and SAEs and laboratory abnormalities 
are the primary endpoints for Part-1 and Part-3A and secondary endpoints for Part-2, Part-3B, and 
Part-4. 
All AEs will be graded according to National Cancer Institute Common Terminology for Adverse 
Events (NCI-CTCAE) version 5.0 and coded to a lower-level term (LLT), preferred term (PT), 
high-level term (HLT), high-level group term (HLGT), and associated primary system organ class 
(SOC) using the Medical Dictionary for Regulatory Activities (MedDRA) version 24.1.  
The AEs will be analyzed in the following 3 categories: 
• Pre-treatment AEs: AEs that developed, worsened or became serious during the 
pre-treatment period 
• Treatment-emergent adverse events (TEAE)s: AEs that developed, worsened or became 
serious during the on-treatment period 
• Post-treatment AEs: AEs that developed, worsened or became serious during the 
post-treatment period  
Similarly, the deaths will be analyzed in the on-treatment and post-treatment periods. The primary 
focus of AE reporting 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.  
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If the assessment of the relationship to IMP is missing for an AE, this AE will be assumed as 
related to IMP. If the severity/grade is missing for one of the treatment-emergent occurrences of 
an AE, the severity/grade will be imputed with the maximal severity of the other occurrences. If 
the severity is missing for all the occurrences, the severity/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 4.  
Table 4 - Sorting of AE tables  
AE presentation 
Sorting rules 
SOC and PT 
By the internationally agreed SOC order and decreasing frequency of PTsa 
PT 
By decreasing frequency of PTsa 
a Sorting will be based on the overall incidence 
Analysis of all adverse events 
An overall summary of TEAEs will be provided. The number and percentage of participants who 
experience any of the following will be provided: 
• TEAEs  
• Any grade >= 3 TEAE  
• Any treatment emergent SAE 
• Grade 5 TEAE (any TEAE with a fatal outcome during the treatment-emergent period or 
all-cause mortality) 
• Serious TEAEs 
• Serious treatment-related TEAEs. 
• TEAE leading to premature discontinuation of either SAR442720 or pembrolizumab or 
adagrasib 
• TEAE leading to permanent full intervention discontinuation (definitive discontinuation) 
• TEAE leading to dose modifications 
• Treatment-related TEAEs 
• Treatment-related TEAEs of grade >= 3 
• AESI 
• DLTs 
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The AE summaries of participants experiencing TEAEs by primary SOC and preferred term will 
be generated with number (%) of participants experiencing at least one event in Table 5. The 
analyses will be performed for all grades combined and for grades ≥3 according to NCI CTCAE 
v5.0. Similar tables will be prepared for treatment-related TEAEs, AESIs, TEAEs leading to 
treatment discontinuation, TEAEs leading to dose modification, delay, omission, serious TEAEs 
and TEAEs with fatal outcome. 
Table 5 - Analyses of adverse events  
Type of AE 
MedDRA levels 
All TEAE 
Primary SOC, and PT 
TEAE related to SAR442720 as per Investigator’s judgment 
Primary SOC and PT 
Treatment emergent SAE 
Primary SOC and PT 
Treatment emergent SAE related to SAR442720 as per 
Investigator’s judgment 
Primary SOC and PT 
Treatment emergent SAE related to pembrolizumab as per 
Investigator’s judgment 
Primary SOC and PT 
Treatment emergent SAE related to adagrasib as per Investigator’s 
judgment 
Primary SOC and PT 
TEAE leading to permanent full intervention discontinuation 
Primary SOC and PT 
TEAE leading to permanent discontinuation of SAR442720 
Primary SOC and PT 
TEAE leading to permanent discontinuation of pembrolizumab 
Primary SOC and PT 
TEAE leading to permanent discontinuation of adagrasib 
Primary SOC and PT 
TEAE leading to death 
Primary SOC and PT 
TEAE leading to dose modification (including dose delay, dose 
reduction and dose omission) of SAR442720 
Primary SOC and PT  
 
Analysis of deaths 
The deaths will be summarized by observation period ie, number (%) of deaths during the 
on-treatment period and number (%) of deaths during post-treatment period.  
Analysis of adverse events of special interest (AESIs)  
Adverse events of special interest (AESIs) in Section 8.3.7 of protocol amendment 4 will be 
selected for analyses as indicated from CRF. Number (and percentage) of participants 
experiencing at least one event will be provided for each event of interest. Tables will be sorted as 
indicated in Table 4.  
4.4 
EFFICACY ENDPOINT(S)  
Efficacy endpoints involved in this study are summarized in the following table (Table 6). 
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Table 6 - Summary of efficacy endpoints  
Efficacy Endpoint 
Part-1/3A  
Part-2/3B  
Part-4 
ORR per RECIST 1.1 
Secondary 
Primary 
Secondary 
DoR 
Secondary 
Secondary 
Secondary 
PFS 
NA 
Secondary 
NA 
TTR 
NA 
Secondary 
NA 
CBR 
NA 
Secondary 
NA 
OS 
NA 
Exploratory 
NA 
ORR per iRECIST 
NA 
Exploratory 
NA 
The Best Overall Response (BOR) by RECIST 1.1 will be summarized. The Objective Response 
Rate (ORR) by RECIST 1.1 is calculated as the proportion of participants with BOR as Complete 
Response (CR) or Partial Response (PR). The 90% two-sided confidence interval for ORR will be 
computed using the Clopper-Pearson method.  
The primary analysis using the Objective Response Rate (ORR) is performed when all 
participants have at least 2 post baseline tumor assessments with response durability demonstrated 
or discontinued study treatment (whichever occurs first). ORR is defined as proportion of 
participants who have confirmed complete response (CR) or partial response (PR) determined by 
investigator per RECIST v1.1. The 90% CI is estimated using Clopper Pearson method. 
The BOR of CR or PR needs to be confirmed by a subsequent assessment. BOR per RECIST 1.1 
will be summarized. Waterfall plot will be generated for the best change from baseline for target 
lesions for each participant. 
Duration of response (DoR) according to RECIST v1.1 will be summarized. The DoR will be 
defined as the time interval from the date of the first occurrence of CR or PR that is subsequently 
confirmed (eg, in case of a patient who has four assessments as PR SD PR PR, the second PR date 
will be used for the calculation) to the date of the first documentation of disease progression or 
death due to disease progression, whichever occurs first. Participants who are still alive and free 
from progression at the time of data cutoff date, are lost to follow-up, have discontinued from the 
study, or who have initiated subsequent anticancer therapy will be censored at the last adequate 
tumor assessment. For participants who achieve CR or PR, the Kaplan-Meier curve will be 
generated. The detailed censoring rules are listed in Table 7 below. DoR will be analyzed for 
responders using Kaplan-Meier methods and following estimates will be provided: 
• Kaplan-Meier estimates of the 25th, 50th and 75th percentiles and their associated 
90% CIs will be provided. The 90% CIs will be constructed using a log-log transformation 
of the survival function and the methods of Brookmeyer and Crowley. 
• Number of patients at risk as well as the probabilities of being event-free at least 2, 4, 6, 8, 
10 and 12 months with 90% CIs will be estimated using the Kaplan-Meier method and 
a log-log approach based on a normal approximation following the Greenwood’s formula. 
• Kaplan-Meier curves will be plotted. These plots will include the number of patients at 
risk at key time points. 
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In addition, number (and percentage) of events and patients censored will be presented with type 
of events and reason of censoring.  
Table 7 - DoR analysis - Event and censoring rules  
Situation 
Date of outcome 
Outcome 
Category 
Ongoing and no documented 
progression 
Date of the last evaluable tumor 
assessment documenting no 
progression 
Censored 
Ongoing without progression 
Documented progression (or Death) 
at or between scheduled visits 
Date of progression (or Date of 
death) 
Event 
Documented progression 
(or Death without documented 
progression) 
Documented progression (or Death) 
occurring after two or more non-
evaluable tumor assessmenta 
Date of the last evaluable tumor 
assessment documenting no 
progression 
Censored  
Event occurred after two or more 
missed tumor assessment 
Initiation of further anti-cancer 
therapy 
 Date of the last evaluable tumor 
assessment before start date of 
further anti-cancer therapy 
Censored 
Initiation of further anti-cancer 
therapy 
a An event occurring at least 19 weeks (excluded) after the last evaluable tumor assessment 
Progression Free Survival (PFS) per RECIST v1.1 is defined as the time from the date of the 
first IMP administration of to the first documentation of definitive disease progression or death 
due to any cause, whichever occurs first. Participants who are still alive and free from progression 
at the time of data cutoff date, are lost to follow-up, have discontinued from the study, or who 
have initiated subsequent anticancer therapy will be censored at the last adequate tumor 
assessment. The detailed censoring rules are listed in the Table 8 below. PFS will be analyzed 
using Kaplan-Meier methods and following estimates will be provided: 
• Kaplan-Meier estimates of the 25th, 50th and 75th percentiles and their associated 
90% CIs will be provided. The 90% CIs will be constructed using a log-log transformation 
of the survival function and the methods of Brookmeyer and Crowley. 
• Number of patients at risk as well as the probabilities of being event-free at least 2, 4, 6, 8, 
10 and 12 months with 90% CIs will be estimated using the Kaplan-Meier method and 
a log-log approach based on a normal approximation following the Greenwood’s formula. 
• Kaplan-Meier curves will be plotted. These plots will include the number of patients at 
risk at key time points. 
In addition, number (%) of events and patients censored will be presented with type of events and 
reason of censoring.  
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Table 8 - PFS analysis - Event and censoring rules  
Situation 
Date of outcome 
Outcome 
Category 
No baseline tumor assessments 
Date of first dose 
Censored 
No baseline tumor assessments 
No evaluable post-baseline tumor 
assessments 
Date of first dose 
Censored 
No evaluable post-baseline tumor 
assessments 
Ongoing and no documented 
progression 
Date of the last evaluable tumor 
assessment documenting no 
progression 
Censored 
Ongoing without progression 
Documented progression (or Death) 
at or between scheduled visits 
Date of progression (or Date of 
death) 
Event 
Documented progression (or 
Death without documented 
progression) 
Documented progression (or Death) 
occurring after two or more non-
evaluable tumor assessmenta 
Date of the last evaluable tumor 
assessment documenting no 
progression 
Censored  
Event occurred after two or more 
missed tumor assessment 
Initiation of further anti-cancer 
therapy 
 Date of the last evaluable tumor 
assessment before start date of 
further anti-cancer therapy 
Censored 
Initiation of further anti-cancer 
therapy 
a An event occurring at least 19 weeks (excluded) after the last evaluable tumor assessment 
Time to response (TTR) is defined as the time interval from the administration of the first IMP 
dose to the first documented CR or PR which is confirmed by a subsequent response. The TTR 
will be summarized descriptively.  
Clinical Benefit Rate (CBR) is defined as the proportion of participants who achieved confirmed 
CR or PR at any time or SD for at least 6 months. The CBR and corresponding 90% Clopper 
Pearson 2-sided CI will be derived. 
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4.6 
MULTIPLICITY ISSUES  
There is no formal statistical test performed. Therefore, no multiplicity issue applies. 
4.7 
OTHER SAFETY ANALYSES  
All safety analyses will be performed on the safety population as defined in Section 3, unless 
otherwise specified, using the following common rules: 
• The analysis of the safety variables will be essentially descriptive, and no testing is 
planned.  
4.7.1 Extent of exposure  
4.7.1.1 Overall exposure  
The dose information will be assessed by the following variables: 
• Overall number of cycles started, defined by the number of cycles in which at least 
one dose of any study interventions is administered. 
• Duration of IMP 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. 
The last day of exposure is the day before the theoretical date of the next administration 
(after the last administration), defined as the maximum between: 
- 
The last administration date + 3 for SAR442720 
The last administration date + 20 for Pembrolizumab given at 200 mg IV Q3W or + 41 
for Pembrolizumab given at 400 mg IV Q6W 
The total number of cycles started will be summarized as a quantitative variable and by category 
(1-3 cycles, 4-6 cycle, ......, ≥16 cycles). The duration of overall exposure will be summarized 
quantitatively. 
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4.7.1.2  SAR442720 exposure   
The dose information will be assessed by the following: 
• Number of doses 
• Number of cycles started per participant  
• Duration of SAR442720 exposure (in weeks) is defined by (date of last administration of 
SAR442720 + 3 – date of first administration of SAR442720 + 1)/7 
• Actual dose (mg)  
• Cumulative dose (mg): the cumulative dose is the sum of all actual doses of SAR442720, 
given from first to last administration  
• Actual dose intensity (ADI in mg/week): defined as the cumulative dose divided by the 
duration of SAR442720 exposure (in weeks) 
• Planned dose intensity (PDI in mg/week): corresponds to the planned dose multiplied by 
the theoretical total number of doses started and divided by the theoretical cycle duration 
expressed in weeks (ie, 3weeks per cycle started) 
• Relative dose intensity (RDI, in %):100 ×
ADI (mg/week) 
PDI (mg/week) 
The total number of doses, number of cycles started by participant will be summarized as 
a quantitative variable and by category (1-3 cycles, 4-6 cycle, ......, ≥16 cycles). Duration of 
SAR442720 exposure, cumulative dose, ADI and RDI will be summarized quantitatively. 
The following variables will be derived to describe dose modifications:  
• Dose reduction: The first administration will not be counted as a dose reduction. For the 
second and subsequent SAR442720 administrations, dose reduction will be determined 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. 
• Dose omission is defined as a dose not administered at the scheduled visit but 
administered afterwards. “Not taken” information from eCRF dosing page to be taken into 
account to identify dose omissions. 
• Dose delay: a dose is deemed to have been delayed if the dose is administrated up to 
3 days after the theoretical date 
Dose modifications will be analyzed by participant, cycle and dose as follows:  
• Participant (number of participants treated will be used as denominator) 
- 
Number (%) of participants with at least 1 dose reduction  
- 
Number (%) of participants with at least 1 dose omission 
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• Cycle (number of cycles started will be used as denominator) 
- 
Number (%) of cycles with at least 1 dose reduction  
- 
Number (%) of cycles with at least 1 dose omission 
4.7.1.3 Pembrolizumab exposure  
The dose information will be assessed by the following: 
• Number of doses 
• Number of cycles started per participant  
• Duration of pembrolizumab exposure (in weeks) is defined by (date of last administration 
of pembrolizumab + 20 (200mg IV Q3W) or 41 (400mg IV Q6W) – date of 
first administration of pembrolizumab + 1)/7 
• Actual dose (mg)  
• Cumulative dose ([mg]): the cumulative dose is the sum of all actual doses of 
pembrolizumab, given from first to last administration  
• Actual dose intensity (ADI in mg/week): defined as the cumulative dose divided by the 
duration of pembrolizumab exposure (in weeks) 
• Planned dose intensity (PDI in mg/week): corresponds to the planned dose multiplied by 
the theoretical total number of doses started and divided by the theoretical cycle duration 
expressed in weeks (ie, 3weeks per cycle started) 
• Relative dose intensity (RDI, in %):100 ×
ADI (mg/week) 
PDI (mg/week) 
The total number of doses, number of cycles started by participant will be summarized as 
a quantitative variable and by category (1-3 cycles, 4-6 cycle, ......, ≥16 cycles). Duration of 
pembrolizumab exposure, cumulative dose, ADI and RDI will be summarized quantitatively. 
The following variables will be derived to describe dose modifications:  
• Dose reduction: The first administration will not be counted as a dose reduction. For the 
second and subsequent pembrolizumab administrations, dose reduction will be determined 
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. 
• Dose omission is defined as a dose not administered at the scheduled visit but 
administered afterwards. “Not taken” information from eCRF dosing page to be taken into 
account to identify dose omissions. 
• Dose delay: a dose is deemed to have been delayed if the dose is administrated up to 
3 days after the theoretical date. 
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• Dose interruption and the reason of interruption (as collected in the eCRF). Dose will be 
considered interrupted if the administration is stopped during the infusion before it is 
completed regardless of whether it is restarted. 
Dose modifications will be analyzed by participant, cycle and dose as follows:  
• Participant (number of participants treated will be used as denominator) 
- 
Number (%) of participants with at least 1 dose reduction  
- 
Number (%) of participants with at least 1 dose omission 
- 
Number (%) of participants with at least 1 dose interruption 
• Cycle (number of cycles started will be used as denominator) 
- 
Number (%) of cycles with at least 1 dose reduction  
- 
Number (%) of cycles with at least 1 dose omission 
- 
Number (%) of cycles with at least 1 dose interruption 
4.7.2 Laboratory variables  
Hematological and clinical biochemistry toxicities will be assessed from laboratory test 
parameters. 
A summary table will present the frequency of patients with any grade of abnormal laboratory 
tests and with Grade≥ 3 abnormal laboratory tests occurring during on-treatment period. For 
patients with multiple occurrences of the same laboratory variable during the treatment, the 
maximum grade (worst) per patient will be used. The denominator used for percentage calculation 
is the number of patients with at least 1 evaluation of the laboratory test during the considered 
observation period. For laboratory tests for which NCI-CTCAE V5.0 scale is not applicable, the 
frequency of evaluable patients outside normal ranges will be provided. 
If relevant, selected laboratory tests will be plotted describing mean changes from baseline and 
associated +/- STD throughout the on-treatment period. 
4.7.3 Additional safety analyses (Vital signs and electrocardiograms [ECGs])  
The following vital signs and electrocardiogram (ECG) variables will be analyzed. They will be 
converted into standard international units. 
• Vital signs: heart rate, systolic and diastolic blood pressure, weight, pulse rate, respiratory 
rate, pulse oximetry, and ECOG performance status  
• ECG variables: heart rate, PR, QRS, QT, and corrected QTc (according to 
Bazett/Fridericia)/ECG assessments will be described as normal or abnormal 
For vital sign variables, potentially clinically significant abnormalities (PCSA) values are defined 
as abnormal values considered medically important by the Sponsor according to predefined 
criteria/thresholds based on literature review. PCSA criteria will determine which participants had 
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at least 1 PCSA during the on-treatment period, taking into account all evaluations performed 
during the on-treatment period, including nonscheduled or repeated evaluations. The incidence of 
PCSA any time during the on-treatment period will be summarized. 
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  
4.8 
OTHER ANALYSES  
4.8.1  PK analyses   
Concentrations of SAR442720, pembrolizumab and adagrasib will be summarized by scheduled 
visit and nominal timepoint.  
All concentration values below the lower limit of quantitation (LLOQ) will be treated as zero in 
all summary statistics excepted for the geometric mean and associated coefficient of variation for 
which they will be considered as missing.  
For Part-3A and Part-4, PK parameter estimates, including but not limiting to the ones listed 
below, will be determined when possible, for SAR442720 and adagrasib: 
• Maximal concentration: Cmax (observed) 
• Time to reach maximal concentration: Tmax (observed) 
• Area-under-the-curve from time 0 to t: AUC0-t  
• Area-under-the-curve from time 0 to infinity, if possible: AUC0-inf, if possible 
• t1/2, if possible 
• Accumulation ratio 
Unless otherwise specified, the PK parameters will be estimated based on noncompartmental 
analysis methods. These estimates will be summarized descriptively by dose cohort. All PK 
parameters will be computed using the actual elapsed time calculated relative to dose 
administration. 
For Part-4, the geometric mean ratios and 90% confidence intervals of AUC0-inf and Cmax will be 
computed for SAR442720 between fed and fasted states of tablet formulation (C1D1 to C1D15) 
and between the tablet (test) and capsule (reference) formulations (C1D15 to C2D1). In addition, 
the PK parameters in Part-4 will be analyzed using a mixed effect model, which will be described 
in detail in the statistical analysis plan. 
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Population PK analysis may be conducted to obtain the PK parameters of SAR442720, 
pembrolizumab, and adagrasib. If performed, the results will be summarized in a separate report. 
Exploratory analyses may be performed to evaluate the relationship between the estimated PK 
parameters and PDs, selected safety, biomarker, or clinical effect endpoints. 
The PK and PDy analyses will be presented in a separate report. 
4.8.2 Biomarker analyses  
The biomarker analysis population is defined separately for blood-based and tumor tissue-based 
biomarkers. The biomarker analysis population includes all enrolled patients who receive at 
least one dose of any study drug and have at least one biomarker parameter from the 
corresponding assay sample with at least one baseline biomarker measurement. 
For analysis of pharmacodynamic biomarkers, no values will be imputed for missing data. 
Duplicate biomarker (ie, more than one set of data for a particular visit) is not expected. For 
continuous data, if duplicate data is received, the results will be averaged, and the average value 
will be used. The average value will be added to the analysis dataset. For non-continuous data, the 
results will be reviewed by the study team and a representative sample will be selected. The 
representative sample will be flagged in the analysis dataset. 
Continuous endpoints will be summarized by descriptive statistics, including the mean, standard 
deviation, median, minimum, and maximum values. 
Correlations of biomarker results with measures of anti-tumor efficacy will be examined. 
Graphical display will be provided for level of biomarkers at baseline and/or ratio of values to 
baseline at each timepoint and by cohort. Box and Whisker plots will be produced for level of 
biomarkers at baseline each timepoint and by cohort. Line plot will be produced for level of 
biomarker expression across time. 
4.9 
INTERIM ANALYSES  
No formal interim analysis is planned. 
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5 
SUPPORTING DOCUMENTATION  
5.1 
APPENDIX 1 LIST OF ABBREVIATIONS  
 
ADI: 
actual dose intensity 
AE: 
adverse event 
AESIs: 
adverse events of special interest 
BID: 
twice a day 
BIW: 
twice a week 
CBR: 
clinical benefit rate 
CI: 
confidence interval 
CR: 
complete response 
CRC: 
colorectal cancer 
ctDNA: 
circulating tumor DNA 
DLT: 
dose limiting toxicities 
ECG: 
electrocardiogram 
ECOG: 
Eastern Cooperative Oncology Group 
eCRF: 
electronic case report form 
IMP: 
investigational medicinal product 
IV: 
intravenous 
LLOQ: 
lower limit of quantitation 
MTD: 
maximum tolerated dose 
NCI-CTCAE: 
National Cancer Institute Common Terminology for Adverse Events 
NSCLC: 
non-small cell lung cancer 
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 
RDI: 
relative dose intensity 
RECIST: 
response evaluation criteria in solid tumors 
RP2D: 
recommended Phase 2 dose 
SAE: 
serious adverse event 
SAP: 
statistical analysis plan 
SD: 
standard deviation 
SoC: 
standard of care 
TEAE: 
treatment-emergent adverse event 
TTR: 
time to response 
WHO-DD: 
World Health Organization-drug dictionary 
 
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5.2 
APPENDIX 2 CHANGES TO PROTOCOL-PLANNED ANALYSES  
Not applicable. 
5.3 
APPENDIX 3 DEMOGRAPHICS AND BASELINE CHARACTERISTICS, PRIOR OR 
CONCOMITANT MEDICATIONS  
Demographics, baseline characteristics, medical surgical history 
The following demographics, baseline characteristics, medical, surgical history and disease 
characteristics at baseline will be summarized using descriptive statistics in the safety population. 
Demographic and baseline characteristics  
• Age in years as quantitative variable and in categories (<65, 65 to <75, ≥75)  
• Gender (Male, Female) 
• Race (Asian, White, Not Reported, Unknown)  
• Ethnicity (Hispanic or Latino, not Hispanic or Latino, not reported, unknown) 
• Baseline height (cm) 
• Baseline weight (kg) 
Medical history and specific history of Pericardial Effusion will be summarized using the 
MedDRA version 24.1.  
Disease diagnosis history will be summarized including time from initial diagnosis to first study 
treatment administration, cancer type, location, cancer stage, CNS involvement, extent of disease 
at study entry. 
• If only the day-component is missing, the 15th will be used.  
• If only a year is present, and it is the same as the year of the first dose of study drug, the 
15th of January will be used unless it is later than the first dose, in which case the date of 
the first of January will be used, unless other data indicates that the date is earlier.  
• If only a year is present, and it is not the same as the year of the first dose of study drug, 
the 15th of June will be used, unless other data indicate that the date is earlier.  
Prior or concomitant medications 
All medications will be coded using the March 1, 2022 version of World Health Organization-
Drug Dictionary (WHO-DD). 
• Prior medications are those the participant used prior to first IMP intake. Prior medications 
can be discontinued before first administration or can be ongoing during treatment period. 
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• Concomitant medications are any interventions received by the participant concomitantly 
to any IMP during the on-treatment period/from the first administration of IMP to the 
last IMP intake.  
• Post-treatment medications are those the participant took 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. 
The prior and concomitant and post-treatment medications will be summarized for the safety 
population. The summaries will be sorted by decreasing frequency of anatomic category (ATC) 
based on incidence in the total group. In case of equal frequency, alphabetical order will be used. 
Participants will be counted once in each ATC category (anatomic or therapeutic) linked to the 
medication.  
Anticancer therapies  
Prior anticancer therapies will be summarized including number of patients with at least one prior 
anticancer therapy, best response, number of regimens and category of regimens (0, 1, 2, >=3). In 
addition, patients with the prior radiation therapy and prior surgery will also be summarized.  
For initial diagnosis with partial date, following rules can be applied to implement date 
imputation:  
• If only the day-component is missing, the 15th will be used. 
• If only a year is present, and it is the same as the year of the first dose of study drug, 
the 15th of January will be used unless it is later than the first dose, in which case the 
date of the first of January will be used, unless other data indicates that the date is 
earlier. 
• If only a year is present, and it is not the same as the year of the first dose of study 
drug, the 15th June will be used, unless other data indicate that the date is earlier. 
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5.4 
APPENDIX 4 DATA HANDLING CONVENTIONS  
Unscheduled visits 
Unscheduled visit measurements of laboratory data, vital signs, ECG and other safety 
measurements will be used for computation of baseline, the last/worst on-treatment value, and the 
shift summaries for safety. They will also be included in the by-visit summaries if they are 
re-allocated to scheduled visits. 
5.5 
INTERNATIONALLY AGREED SOC ORDER  
The internationally agreed order (Guideline on summary of product characteristics, 
December 1999, European commission) for SOC: 
1. Infections and infestations 
2. Neoplasms benign and malignant (including cysts and polyps) 
3. Blood and the lymphatic system disorders 
4. Immune system disorders 
5. Endocrine disorders 
6. Metabolism and nutrition disorders 
7. Psychiatric disorders 
8. Nervous system disorders 
9. Eye disorders 
10. Ear and labyrinth disorders 
11. Cardiac disorders 
12. Vascular disorders 
13. Respiratory, thoracic and mediastinal disorders 
14. Gastrointestinal disorders 
15. Hepato-biliary disorders 
16. Skin and subcutaneous tissue disorders 
17. Musculoskeletal, connective tissue and bone disorders 
18. Renal and urinary disorders 
19. Pregnancy, puerperium and perinatal conditions 
20. Reproductive system and breast disorders 
21. Congenital and familial/genetic disorders 
22. General disorders and administration site conditions 
23. Investigations 
24. Injury and poisoning 
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25. Surgical and medical procedures 
26. Social circumstances 
27. Product Issues 
The other terms are sorted by dictionary code order. 
VV-CLIN-0632235 1.0


Statistical Analysis Plan  
14-Jul-2022 
SAR442720-TCD16210 
Version number: 1 
Property of the Sanofi group - strictly confidential 
Page 31 
5.6 
 POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES CRITERIA  
 
Parameter 
PCSA 
Comments 
Vital signs 
HR 
≤50 bpm and decrease from baseline 
≥20 bpm 
≥120 bpm and increase from 
baseline≥20 bpm 
To be applied for all positions (including missing) except STANDING. 
SBP 
≤95 mmHg and decrease from baseline 
≥20 mmHg 
≥160 mmHg and increase from baseline 
≥20 mmHg 
To be applied for all positions (including missing) except STANDING. 
DBP 
≤45 mmHg and decrease from baseline 
≥10 mmHg 
≥110 mmHg and increase from baseline 
≥10 mmHg 
To be applied for all positions (including missing) except STANDING. 
Weight 
≥5% increase from baseline  
≥5% decrease from baseline 
FDA Feb 2007. 
Laboratory 
Hematocrit 
≤0.37 v/v (Male) ; ≤0.32 v/v (Female) 
≥0.55 v/v (Male) ; ≥0.5 v/v (Female) 
 
RBC 
≥6 Tera/L 
Unless specifically required for particular drug development, the 
analysis is redundant with that of Hb. 
Otherwise, consider FDA criteria. 
Monocytes 
>0.7 Giga/L 
 
Basophils 
>0.1 Giga/L 
 
Chloride 
<80 mmol/L 
>115 mmol/L 
 
CRP 
>2 ULN or >10 mg/L (if ULN not 
provided) 
FDA Sept 2005. 
Blood Urea 
Nitrogen 
≥17 mmol/L 
 
pH 
 
≤4.6 
≥8 
 
eGFR (MDRD) 
≥60 - <90 mL/min/1.73 m2 (mild 
impairment) 
 
 
≥30 - <60 mL/min/1.73 m2 (moderate 
impairment) 
 
 
≥15 - <30 mL/min/1.73 m2 (severe 
impairment) 
 
 
<15 mL/min/1.73 m2 (end stage renal 
disease) 
 
VV-CLIN-0632235 1.0


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VV-CLIN-0632235 1.0