Clinical trial NCT03637764
Conditions: Neoplasm
Keywords: Anti-CD38 monoclonal antibody
Sponsor: Sanofi
Start date: 2018-08-06; Completion date: 2022-05-11
Enrollment: 107 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Primary Objectives:

* Phase 1: To characterize the safety and tolerability of isatuximab in combination with atezolizumab in participants with unresectable hepatocellular carcinoma (HCC), platinum-refractory recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN), platinum-resistant/refractory epithelial ovarian cancer (EOC), or recurrent glioblastoma multiforme (GBM), and to determine the recommended Phase 2 dose (RP2D).
* Phase 2: To assess response rate (RR) of isatuximab in combination with atezolizumab in participants with HCC or SCCHN or EOC.
* Phase 2: To assess the progression free survival rate at 6 months (PFS-6) of isatuximab in combination with atezolizumab, or as a single agent in participants with GBM.

Secondary Objectives:

* To evaluate the safety profile of isatuximab monotherapy (GBM only), or in combination with atezolizumab in Phase 2.
* To evaluate the immunogenicity of isatuximab and atezolizumab.
* To characterize the pharmacokinetic (PK) profile of isatuximab single agent (GBM only) and atezolizumab in combination with isatuximab.
* To assess the overall efficacy of isatuximab in combination with atezolizumab, or single agent (GBM only).

Detailed description:
The total study duration per participant was up to 28 months including up to 28 days screening period, up to 24 months treatment period, and a 3 month safety follow up period.

Arms: arm 1: Participants with hepatocellular carcinoma (HCC) received atezolizumab 1200 milligrams, every 3 weeks (Q3W), intravenous (IV) infusion along with isatuximab 10 milligrams per kilogram (mg/kg), IV infusion, once weekly for 3 weeks (i.e., on Day 1, Day 8 and Day 15 of Cycle 1) and then Q3W (i.e., on Day 1 of each 21- day treatment cycle) until disease progression, unacceptable adverse events (AE), participant's decision to stop the treatment, or death or study cut-off whichever occurred first (maximum duration of exposure: 106 weeks). arm 2: Participants with squamous cell carcinoma of the head and neck (SCCHN) received atezolizumab 1200 milligrams,Q3W, IV infusion along with isatuximab 10 mg/kg, IV infusion, once weekly for 3 weeks (i.e., on Day 1, Day 8 and Day 15 of Cycle 1) and then Q3W (i.e., on Day 1 of each 21- day treatment cycle) until disease progression, unacceptable AE, participant's decision to stop the treatment, or death or study cut-off whichever occurred first (maximum duration of exposure: 108 weeks). arm 3: Participants with epithelial ovarian cancer (EOC) received atezolizumab 1200 mg, Q3W, IV infusion along with isatuximab 10 mg/kg, IV infusion, once weekly for 3 weeks (i.e., on Day 1, Day 8 and Day 15 of Cycle 1) and then Q3W (i.e., on Day 1 of each 21- day treatment cycle) until disease progression, unacceptable AE, participant's decision to stop the treatment, or death or study cut-off whichever occurred first (maximum duration of exposure: 61 weeks). arm 4: Participants with glioblastoma multiforme (GBM) received atezolizumab 1200 mg, Q3W, IV infusion along with isatuximab 10 mg/kg, IV infusion, once weekly for 3 weeks (i.e., on Day 1, Day 8 and Day 15 of Cycle 1) and then Q3W (i.e., on Day 1 of each 21- day treatment cycle) until disease progression, unacceptable AE, participant's decision to stop the treatment, or death or study cut-off whichever occurred first (maximum duration of exposure: 54 weeks).
Interventions: intervention 1: Isatuximab SAR650984 intervention 2: Atezolizumab
Intervention descriptions: intervention 1: Pharmaceutical form: solution for infusion

Route of administration: intravenous intervention 2: Pharmaceutical form: solution for infusion

Route of administration: intravenous

Protocol documents:
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 
According to template: Version Sanofi dated 12-OCT-2017 based on TransCelerate CPT version 4 
Page 1 
AMENDED CLINICAL TRIAL PROTOCOL 05 
Protocol title: 
A Phase 1/2 open-label, multi-center, safety, preliminary 
efficacy and pharmacokinetic (PK) study of isatuximab 
(SAR650984) in combination with atezolizumab or 
isatuximab alone in patients with advanced 
malignancies 
Protocol number: 
ACT15377 
Amendment number: 
05 
Compound number 
(Trademark/INN): 
SAR650984/ isatuximab 
Short title: 
Safety, preliminary efficacy and PK of isatuximab 
(SAR650984) alone or in combination with atezolizumab 
in patients with advanced malignancies 
Sponsor name: 
Legal registered 
address: 
Regulatory agency identifying number(s): 
EudraCT number: 
2018-000390-67 
IND number: 
138488 
UTN number: 
U1111-1202-0839 
Approval Date: 
23 November 2020 
Total number of pages: 151 
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Sponsor signatory: 
 
 
 
 
 
Please refer to the last page of this document for electronic signatures including date and time 
Monitoring Team’s Representative 
Name and Contact Information: 
 
 
 
 
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE  
DOCUMENT HISTORY 
 
Document 
Country/countries impacted by 
amendment 
Date, Version 
Amended Protocol 04 
All 
11-Jun-2019, Version 1 
(electronic 4.0) 
Amended Protocol 03 
All 
07-Dec-2018, Version number: 1 
(electronic 3.0) 
Amended Protocol 02 
All 
09-Aug-2018, Version number: 1 
(electronic 2.0) 
Amended Protocol 01 
All 
06-Apr-2018, Version number: 1 
(electronic 1.0) 
Original Protocol 
 
16-Feb-2018, Version number: 1 
(electronic 1.0) 
Amendment 05 (23 November 2020) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union 
OVERALL RATIONALE FOR THE AMENDMENT 
Based on the Dear Investigator Letter (DIL) that Sanofi has received from Roche, the newly 
identified potential risk of Severe Cutaneous Adverse Reactions (SCARs) with atezolizumab use 
and the associated guidelines for these dermatological events have been added.  
Protocol amendment summary of changes table 
Section # 
and Name 
Description of Change 
Brief Rationale 
2.3.2.2 Potential 
and identified 
risks for 
atezolizumab 
New identified risk of SCARs with atezolizumab 
use.  
based on the DIL that Sanofi has received from Roche 
regarding the use of atezolizumab  
10.21 
Management of 
atezolizumab-
specific adverse 
events – 
dermatologic 
events 
Recommendations with specifc details regarding 
SCARs 
based on the Dil that Sanofi has received from Roche 
regarding the use of atezolizumab 
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TABLE OF CONTENTS 
AMENDED CLINICAL TRIAL PROTOCOL 05 .............................................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE .................................................................. 3 
TABLE OF CONTENTS .................................................................................................................................. 4 
LIST OF TABLES ........................................................................................................................................... 8 
LIST OF FIGURES .......................................................................................................................................... 9 
1 
PROTOCOL SUMMARY ............................................................................................................... 10 
1.1 
SYNOPSIS ..................................................................................................................................... 10 
1.2 
SCHEMA ........................................................................................................................................ 17 
1.3 
SCHEDULE OF ACTIVITIES (SOA) .............................................................................................. 18 
2 
INTRODUCTION ............................................................................................................................ 25 
2.1 
STUDY RATIONALE...................................................................................................................... 26 
2.2 
BACKGROUND ............................................................................................................................. 29 
2.2.1 
Solid tumors ................................................................................................................................... 29 
2.2.2 
Isatuximab ...................................................................................................................................... 32 
2.2.3 
Atezolizumab .................................................................................................................................. 33 
2.3 
BENEFIT/RISK ASSESSMENT ..................................................................................................... 33 
2.3.1 
Benefits .......................................................................................................................................... 33 
2.3.2 
Potential and identified risks .......................................................................................................... 33 
2.3.3 
Potential risk related to the combination ........................................................................................ 34 
2.3.4 
Preventative measures to minimize the risk from the combination ............................................... 35 
2.3.5 
Conclusion ..................................................................................................................................... 36 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................. 37 
3.1 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 39 
4 
STUDY DESIGN ............................................................................................................................ 40 
4.1 
OVERALL DESIGN ........................................................................................................................ 40 
4.1.1 
Phase 1 (safety run-in): .................................................................................................................. 40 
4.1.2 
Phase 2 (efficacy signal search with a 2-stage design in each cohort): ........................................ 43 
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4.2 
DURATION OF STUDY PERIOD (PER PARTICIPANT) .............................................................. 44 
4.3 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ......................................................................... 44 
4.4 
JUSTIFICATION FOR DOSE ........................................................................................................ 45 
4.5 
END OF STUDY DEFINITION ....................................................................................................... 45 
5 
STUDY POPULATION .................................................................................................................. 47 
5.1 
INCLUSION CRITERIA .................................................................................................................. 47 
5.2 
EXCLUSION CRITERIA ................................................................................................................ 49 
5.3 
LIFESTYLE CONSIDERATIONS ................................................................................................... 53 
5.4 
SCREEN FAILURES...................................................................................................................... 53 
6 
STUDY INTERVENTION ............................................................................................................... 54 
6.1 
STUDY INTERVENTION(S) ADMINISTERED .............................................................................. 54 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY....................................................... 57 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ....................................... 58 
6.4 
STUDY INTERVENTION COMPLIANCE ...................................................................................... 58 
6.4.1 
Return and/or destruction of treatments ........................................................................................ 58 
6.5 
CONCOMITANT THERAPY .......................................................................................................... 59 
6.6 
DOSE MODIFICATION .................................................................................................................. 60 
6.6.1 
General rules .................................................................................................................................. 60 
6.6.2 
Dose delay and dose omission ...................................................................................................... 60 
6.6.3 
General Guidelines for Immune-Related Adverse Events (irAEs) ................................................. 61 
6.6.4 
General guidelines for the management of infusion-associated reactions .................................... 62 
6.6.5 
Retreatment of participants ............................................................................................................ 63 
6.7 
INTERVENTION AFTER THE END OF THE STUDY ................................................................... 64 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................................... 65 
7.1 
DISCONTINUATION OF STUDY INTERVENTION ...................................................................... 65 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY .................................. 66 
7.3 
LOST TO FOLLOW UP ................................................................................................................. 67 
7.4 
REPLACEMENT OF PARTICIPANTS ........................................................................................... 67 
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8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................... 68 
8.1 
EFFICACY ASSESSMENTS ......................................................................................................... 68 
8.2 
SAFETY ASSESSMENTS ............................................................................................................. 69 
8.2.1 
Physical examinations ................................................................................................................... 69 
8.2.2 
Vital signs ....................................................................................................................................... 69 
8.2.3 
Electrocardiograms ........................................................................................................................ 69 
8.2.4 
Clinical safety laboratory assessments .......................................................................................... 69 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ........................................................... 70 
8.3.1 
Time period and frequency for collecting AE and SAE information ............................................... 72 
8.3.2 
Method of detecting AEs and SAEs ............................................................................................... 72 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................................... 72 
8.3.4 
Regulatory reporting requirements for SAEs ................................................................................. 72 
8.3.5 
Pregnancy ...................................................................................................................................... 73 
8.3.6 
Disease related events and/ or disease related outcomes not qualifying as AEs or SAEs ........... 73 
8.3.7 
Guidelines for reporting product complaints incidents (including malfunctions) ............................ 74 
8.4 
TREATMENT OF OVERDOSE ...................................................................................................... 74 
8.5 
PHARMACOKINETICS .................................................................................................................. 74 
8.5.1 
Sampling time ................................................................................................................................ 74 
8.5.2 
Pharmacokinetic sample handling procedure ................................................................................ 74 
8.5.3 
Bioanalytical Methods .................................................................................................................... 75 
8.5.4 
Pharmacokinetic parameters ......................................................................................................... 75 
8.6 
PHARMACODYNAMICS ............................................................................................................... 75 
8.7 
GENETICS ..................................................................................................................................... 76 
8.8 
BIOMARKERS ............................................................................................................................... 77 
8.8.1 
Immunogenicity assessments ........................................................................................................ 77 
8.8.2 
RNA transcriptome research .......................................................................................................... 78 
8.9 
HEALTH ECONOMICS OR MEDICAL RESOURCE UTILIZATION AND HEALTH 
ECONOMICS ................................................................................................................................. 78 
9 
STATISTICAL CONSIDERATIONS .............................................................................................. 79 
9.1 
STATISTICAL HYPOTHESES ....................................................................................................... 79 
9.2 
SAMPLE SIZE DETERMINATION ................................................................................................. 79 
9.3 
POPULATIONS FOR ANALYSES ................................................................................................. 80 
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9.4 
STATISTICAL ANALYSES ............................................................................................................ 81 
9.4.1 
Efficacy analyses ........................................................................................................................... 81 
9.4.2 
Safety analyses .............................................................................................................................. 82 
9.4.3 
Other analyses ............................................................................................................................... 84 
9.5 
INTERIM ANALYSES .................................................................................................................... 84 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................ 85 
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ....... 85 
10.1.1 
Regulatory and Ethical Considerations .......................................................................................... 85 
10.1.2 
Informed Consent Process ............................................................................................................ 85 
10.1.3 
Data Protection .............................................................................................................................. 86 
10.1.4 
Committees Structure .................................................................................................................... 86 
10.1.5 
Dissemination of Clinical Study Data ............................................................................................. 87 
10.1.6 
Data Quality Assurance ................................................................................................................. 87 
10.1.7 
Source documents ......................................................................................................................... 88 
10.1.8 
Study and Site Closure .................................................................................................................. 88 
10.1.9 
Publication Policy ........................................................................................................................... 88 
10.2 
APPENDIX 2: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ................................................ 89 
10.3 
APPENDIX 3: CLINICAL LABORATORY TESTS ......................................................................... 92 
10.4 
APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION .............................................................................................................................. 94 
10.5 
APPENDIX 5: GENETICS ............................................................................................................. 97 
10.6 
APPENDIX 6: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND  FOLLOW-UP 
ASSESSMENTS ............................................................................................................................ 97 
10.7 
APPENDIX 7: MEDICAL DEVICE INCIDENTS: DEFINITION AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ................................................ 97 
10.8 
APPENDIX 8: COUNTRY-SPECIFIC REQUIREMENTS .............................................................. 98 
10.8.1 
Amendment for France .................................................................................................................. 98 
10.9 
APPENDIX 9: ABBREVIATIONS ................................................................................................... 98 
10.10 
APPENDIX 10: PROTOCOL AMENDMENT HISTORY .............................................................. 100 
10.10.1 Amendment 01 (06-April-2018) .................................................................................................... 100 
10.10.2 Amendment 02 (09-August-2018) ................................................................................................ 102 
10.10.3 Amendment 03 (07 DECEMBER 2018) ....................................................................................... 104 
10.10.4 Amendment 04 (11 June 2019) ................................................................................................... 107 
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10.11 
APPENDIX 11: RESPONSE EVALUATION CRITERIA IN SOLID TUMORS VERSION 1.1 ..... 108 
10.12 
APPENDIX 12: BARCELONA CLINIC LIVER CANCER (BCLC) STAGING 
CLASSIFICATION ........................................................................................................................ 116 
10.13 
APPENDIX 13: CHILD PUGH SCORE ........................................................................................ 116 
10.14 
APPENDIX 14: PERFORMANCE STATUS................................................................................. 117 
10.15 
APPENDIX 15: RESPONSE ASSESSMENT IN NEURO-ONCOLOGY (RANO) CRITERIA ..... 118 
10.16 
APPENDIX 16:  MODIFIED RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
FOR IMMUNE-BASED THERAPEUTICS (IRECIST) .................................................................. 118 
10.17 
APPENDIX 17: CA125 RESPONSE BY GYNAECOLOGIC CANCER INTERGROUP 
(GCIG) CRITERIA ........................................................................................................................ 120 
10.18 
APPENDIX 18: IMMUNOTHERAPY RESPONSE ASSESSMENT IN NEURO-ONCOLOGY 
(IRANO) ....................................................................................................................................... 121 
10.19 
APPENDIX 19: CLUSTER OF DIFFERENTIATION 38 BLOOD TEST INTERFERENCE 
GUIDELINE AABB2016 ............................................................................................................... 123 
10.20 
APPENDIX 20: MODIFICATION OF DIET IN RENAL DISEASE (MDRD) EQUATION .............. 127 
10.21 
APPENDIX 21: MANAGEMENT OF ATEZOLIZUMAB-SPECIFIC ADVERSE EVENTS ........... 127 
10.22 
APPENDIX 22: MANAGEMENT OF PATIENTS WITH HCV INFECTION .................................. 144 
11 
REFERENCES ............................................................................................................................. 146 
 
LIST OF TABLES  
Table 1 - Objectives and endpoints ............................................................................................................... 37 
Table 2 - Dosing schedule modification for Phase 1 ..................................................................................... 40 
Table 3 - Overview of study interventions administered ............................................................................... 54 
Table 4 - General Guidelines for Immune-Related Adverse Events ............................................................. 61 
Table 5 - Management Guidelines for Infusion-Associated Reactions ......................................................... 63 
Table 6 - List of pharmacokinetic parameters and definitions for isatuximab ............................................... 75 
Table 7 - Populations for analyses ................................................................................................................ 80 
Table 8 - Efficacy analyses ........................................................................................................................... 82 
Table 9 - Safety analyses .............................................................................................................................. 82 
Table 10 - Protocol-required safety laboratory assessments ........................................................................ 93 
Table 11 - Highly effective contraceptive methods ....................................................................................... 95 
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Table 12 - Response criteria ....................................................................................................................... 111 
Table 13 - Response in patients with target disease .................................................................................. 113 
Table 14 - Response in patients with non-target disease only.................................................................... 114 
Table 15 - Comparison of Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and modified 
Response Evaluation Criteria in Solid Tumors for immune based therapies (iRECIST) ............................ 118 
Table 16 - Assessment of timepoint response using modified Response Evaluation Criteria in Solid Tumors 
for immune based therapies (iRECIST) ...................................................................................................... 119 
Table 17 - Management Guidelines for Pulmonary Events, Including Pneumonitis ................................... 127 
Table 18 - Management Guidelines for Hepatic Events .............................................................................. 128 
Table 19 - Management Guidelines for Gastrointestinal Events (Diarrhea or Colitis) ................................ 129 
Table 20 - Management Guidelines for Endocrine Events.......................................................................... 130 
Table 21 - Management Guidelines for Ocular Events ............................................................................... 132 
Table 22 - Management Guidelines for Immune-Related Myocarditis ........................................................ 133 
Table 23 - Management Guidelines for Infusion-Associated Reactions ..................................................... 134 
Table 24 - Management Guidelines for Pancreatic Events, Including Pancreatitis .................................... 135 
Table 25 - Management Guidelines for Dermatologic Events..................................................................... 137 
Table 26 - Management Guidelines for Neurologic Disorders .................................................................... 138 
Table 27 - Management Guidelines for Immune-Related Meningoencephalitis ......................................... 139 
Table 28 - Management Guidelines for Renal Events ................................................................................ 139 
Table 29 – Management Guidelines for Immune-related Myositis .............................................................. 141 
Table 30 - Diagnostic Criteria and Recommended Management for Systemic Immune Activation ........... 143 
 
LIST OF FIGURES  
Figure 1 - Graphical Study Design ................................................................................................................ 17 
Figure 2 - Cluster of differentiation 38 H scores (3 × (% cells 3+) + 2 × (% cells 2+) + 1 × (% cells 1+) in low 
and high grade glioblastoma ......................................................................................................................... 27 
Figure 3 - Combination of anti-CD38 and anti PD-L1 in a mouse lung cancer model results in enhanced 
anti-tumor activity, decreases incidence of lung metastasis and increases the tumor infiltration of CD8+ T 
cells................................................................................................................................................................ 28 
 
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1 
PROTOCOL SUMMARY  
1.1 
SYNOPSIS  
Protocol title: A Phase 1/2 open-label, multi-center, safety, preliminary efficacy and 
pharmacokinetic (PK) study of isatuximab (SAR650984) in combination with 
atezolizumab or isatuximab alone in patients with advanced malignancies 
Short title: 
Safety, preliminary efficacy and PK of isatuximab (SAR650984) alone or in 
combination with atezolizumab in patients with advanced malignancies 
Rationale: 
Monoclonal antibodies (mAbs) that block the programmed cell death-1/programmed cell 
death-ligand 1 (PD-1/PD-L1) alone or in combination with others mAbs have changed the 
landscape of cancer immunotherapy. Isatuximab, an anti-CD38 mAb, has shown clinical response 
in relapsed/refractory multiple myeloma (MM) patients as a single agent and in combination with 
immuno-modulatory agents. Although isatuximab has not been tested in solid tumors, this study is 
designed to explore whether isatuximab may contribute to reshaping the tumor 
immune-environment and will enhance the activity of established anti-PD-L1 therapy. 
Objectives and endpoints 
 
Objectives 
Endpoints 
Primary 
• 
Phase 1: To characterize the safety and tolerability of 
isatuximab in combination with atezolizumab in 
participants with unresectable hepatocellular 
carcinoma (HCC), platinum-refractory 
recurrent/metastatic squamous cell carcinoma of the 
head and neck (SCCHN), 
platinum-resistant/refractory epithelial ovarian cancer 
(EOC), or recurrent glioblastoma multiforme (GBM), 
and to determine the recommended Phase 2 dose 
(RP2D). 
• 
Dose limiting toxicities (DLTs) (in Cycle 1), adverse 
events (AEs)/serious adverse events (SAEs), and 
laboratory abnormalities. 
• 
Maximum tolerated dose (MTD) defined as the 
highest dose level (DL) at which no more than 1 out 
of 6 participants (starting dose or DL-1) or 2 out of 
12 participants (starting dose) experience an 
investigational medicinal product (IMP)-related DLT. 
• 
Recommended Phase 2 dose (RP2D) defined as the 
dose selected for the Phase 2 portion. 
• 
Phase 2: To assess response rate (RR) of isatuximab 
in combination with atezolizumab in participants with 
HCC or SCCHN or EOC. 
• 
RR defined as the proportion of patients with 
complete response and partial response as best 
overall response (assessed by Investigators using 
Response Evaluation Criteria in Solid Tumors 
(RECIST) 1.1 see Appendix 11 Section 10.11). 
• 
Phase 2: To assess the progression free survival rate 
at 6 months (PFS-6) of isatuximab in combination 
with atezolizumab, or as a single agent in participants 
with GBM. 
• 
PFS-6 defined as the PFS rate at 6 months 
(assessed by Investigators using Response 
Assessment for Neuro-Oncology [RANO] criteria). 
 
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Objectives 
Endpoints 
Secondary 
• 
To evaluate the safety (in Phase 2) profile of 
isatuximab monotherapy (GBM only), or in 
combination with atezolizumab. 
• 
Adverse events (AE)/serious AEs and laboratory 
abnormalities (in Phase 2). 
• 
To evaluate the immunogenicity of isatuximab and 
atezolizumab. 
• 
Incidence rate of anti-drug antibodies development 
(ADA: antiisatuximab and anti-atezolizumab 
antibodies). 
• 
To characterize the pharmacokinetic (PK) profile of 
isatuximab single agent (GBM only) and 
atezolizumab in combination with isatuximab. 
• 
PK assessed from concentrations of isatuximab 
(non-compartmental analysis and population PK 
approach) and atezolizumab (population PK 
approach). 
• 
To assess overall efficacy of isatuximab in 
combination with atezolizumab, or single agent (GBM 
only). 
• 
Best percent-change from baseline in tumor burden 
change, disease control rate (DCR) defined as the 
sum of the complete response, partial response and 
stable disease rates, duration of response (DoR), 
progression free survival (PFS) (HCC, SCCHN, EOC 
per RECIST 1.1 and GBM per RANO criteria), RR 
(GBM only, per RANO criteria). 
Overall design: 
This is a Phase 1/2 open-label, non-randomized, multi-center, safety, preliminary efficacy, and 
PK study of isatuximab in combination with atezolizumab, or isatuximab alone in participants 
with advanced malignancies. The study will be conducted in 2 phases (see Section 1.2 for study 
design schema): 
Phase 1 (safety run-in): 
Patients with HCC, or SCCHN, or EOC, or GBM will be enrolled in Phase 1. 
Starting dose is 1200 mg once every 3 weeks (Q3W) for atezolizumab with isatuximab given 
10 mg/kg once weekly (QW) for 3 weeks followed by Q3W as described in the table below: 
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Dosing schedule modification for Phase 1 
Dose level (DL)  
Isatuximab 
Atezolizumab 
Starting dose 
10 mg/kg 
QW × 3 →Q3W 
1200 mg 
Q3W 
Minus -1 (DL-1) 
5 mg/kg 
QW × 3 →Q3W 
1200 mg 
Q3W 
The DLT observation period is the first cycle (21 days). The totality of the safety findings, 
including all the AEs occurring during treatment, unless due to disease progression or an 
obviously unrelated cause, will be taken into consideration by a Study Committee for the 
determination of the maximum tolerated dose and RP2D for the isatuximab and atezolizumab 
combination. 
The selection of the RP2D will be based on the observation of the DLTs rules, as illustrated in 
the table below: 
 
Isatuximab dose                          DLTs 
       Dose 
Starting dose:                               If ≤1/6 participant 
Starting dose will be RP2D 
                                       If 2/6 participants 
+6 participants at starting dose 
                                        If a total of 2/12 participants 
Starting dose will be RP2D 
                                            If a total ≥3/6 participants or a  
                                          total of ≥3/12 participants 
 
+6 participants at DL-1 
DL-1:                                               If ≤1/6 participant  
 
                                                        If 2/6 participants 
DL-1 will be the RP2D 
 
+6 participants at DL-1 
 
                                              If a total of 2/12 participants 
DL-1 will be the RP2D 
                                          If a total ≥3/6 participants or a 
                                        total of ≥3/12 participants 
Alternative dose/schedule will need to be sought 
 
 
 
The first administration of the IMP in each participant in Phase 1 is to be staggered by at least a 
3-days interval. Following the identification of the RP2D, Phase 2 will be initiated. 
The National Cancer Institute (NCI) common terminology criteria for adverse events 
(CTCAEversion 4.03 will be used to assess the severity of the AEs. Causal relationships are to be 
determined by the Investigator on the basis of the combination regimen actually administered. 
Phase 2 (efficacy signal search with a 2-stage design): 
The combination dose for Phase 2 will be determined based on safety data from Phase 1. For the 
combination cohorts, atezolizumab will be administered first, followed by isatuximab on Day 1 of 
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each cycle. Monotherapy dose for GBM (Cohort D-2) for Phase 2 will be determined based on 
results from Cohort D-1. 
Phase 2 may include up to 6 cohorts conducted with a 2-stage design as shown in below tables. 
Enrollment in Cohort A, B, C, and D-1 will be performed in parallel. Then enrollment in 
Cohort D-2and E will be performed sequentially at the end of each respective Stage 2 of previous 
cohorts depending on results observed. 
 
 Cohort A 
Cohort B 
Cohort C 
Cohort D-1 
Cohort D-2 
 HCC 
    Stage 1 then 
   Stage 2 
           SCCHN 
Stage 1 then        
Stage 2 
              EOC 
Stage 1 then        
Stage 2 
            GBM 
Stage 1 then        
Stage 2 
if positive benefit from Cohort 
D-1 Phase 2 Stage 2 
 GBM Stage 1 then Stage 2 
 
                     Isatuximab weekly for 3 weeks then Q3W + atezolizumab Q3W combination  
Isatuximab monotherapy 
weekly for 3 weeks then 
Q3W 
 
Cohort E  
If positive results in Phase 2 Stage 2 
one of the above cohorts  
Isatuximab and atezolizumab Q3W combination, without initial isatuximab weekly dosing 
 
Number of participants: 
In Phase 1, approximately 6 to 24 DLT evaluable participants are expected to be enrolled. 
In Phase 2, sufficient participants will be screened to achieve 285 treated participants with study 
intervention in cohorts A, B, C, D-1, and D-2. All treated participants will be included in the 
primary efficacy population. Section 9.2 gives details of the sample size determination.  
Additional participants may be enrolled up to a total of 350 participants. 
Intervention groups and duration: 
The duration of the study for a participant will include a screening period (up to 28 days), a 
treatment period (up to 2 years), a safety follow-up period up to 90 days and every 90 days 
follow-up visits or phone calls (until death or study cut-off). The study cut-off is planned at 
12 months after the last participant enters the study, or when all participants have had the 
opportunity to complete the end of treatment (EOT) visit 30 days after the last study treatment 
administration, whichever is the latest. 
Treatment period: The cycle duration is 21 days. Participants will continue treatment until 
disease progression confirmed by imaging performed no less than 4 weeks after initial evidence of 
progression, unacceptable AE, participant’s decision to stop the treatment, 2 years of 
uninterrupted delivery of IMP(s) without documented progressive disease (PD). 
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Safety follow-up period: After treatment discontinuation, participants will return to the study site 
30 days (±7 days) after the last dose of IMP(s), or when the participant receives another 
anti-cancer therapy, whichever is earlier, for EOT assessments. In addition, there will be an 
extended safety follow-up period for 90 days after the last dose of IMPs for ADA assessment and 
for safety assessment.  
Participants who discontinue the study treatment without PD will be followed at 90 days 
(±7 days) for disease assessment. 
Survival follow-up period: The further follow-up schedule beyond 90 days after last dose of 
IMP(s) is according to the disease progression status: 
• Participants who discontinue study treatment due to PD: phone call follow-up will be done 
every 90 days from the date of last IMP(s) administration until death or study cut-off date. 
• Participants who discontinue the study treatment without PD: will be followed every 
90 days for disease assessment until confirmation of PD or start treatment with another 
anti-cancer therapy, or until study cut-off date whichever comes first. After PD, participant 
will be followed by phone call until death or study cut-off date. 
• Participants who are still on study treatment after study cut-off date: will continue to 
receive study treatment if they benefit, and will undergo planned study procedures (except 
PK and ADA) until confirmation of PD, or start with another anti-cancer therapy, or 
treatment period ended, whichever comes first.  
All SAEs still ongoing at the end of the study treatment, and all AEs considered related to study 
treatment still ongoing or occurring after the end of study treatment, which will be followed until 
resolution/stabilization. 
Study interventions 
Investigational medicinal products: 
• Isatuximab: 
- 
Formulation: drug product concentrated solution in vials containing 20 mg/mL 
(500 mg/25 mL) isatuximab in 20 mM histidine, 10% (w/v) sucrose, 0.02% (w/v) 
polysorbate 80, pH 6.0, 
- 
Route(s) of administration: solution for intravenous (IV) infusion, 
- 
Dose regimen: the starting dose is 10 mg/kg. 
• Atezolizumab: 
- 
Formulation: drug product concentrated solution in a single-dose vial containing 
1200 mg/20 mL (60 mg/mL), 
- 
Route(s) of administration: solution for IV infusion, 
- 
Dose regimen: 1200 mg per administration. 
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Non investigational medicinal products: will be locally sourced and formulations may vary. 
All participants will receive the following premedications to prevent or reduce incidence or 
severity of infusion-associated reactions (IARs), 30 to 60 minutes prior to isatuximab infusion 
(no longer than 60 minutes). The standard premedication regimen will include: 
• Acetaminophen 650 to 1000 mg oral route (PO) (or equivalent). 
• Ranitidine 50 mg IV (or equivalent). 
• Diphenhydramine 25 to 50 mg IV (or equivalent). 
• Methylprednisolone 100 mg IV (or equivalent). 
• Montelukast 10 mg oral route (PO) (or equivalent). 
Criteria for optional premedication for IARs: 
• For a patient who has no IAR for the first 4 infusions: Premedication for the subsequent 
infusions is optional at the Investigator’s discretion. However, if during the subsequent 
infusions without premedication the patient experiences an IAR (any grade), 
premedication must be restarted for all subsequent infusions. 
• If a patient develops an IAR Grade ≤2 during their first infusion only and then experiences 
no further IARs during their next 3 infusions:  The Investigator should discuss with the 
Sponsor Medical Monitor when considering omitting premedication for the next infusion.  
If no IAR is observed for the next infusion without premedication, premedication is 
optional for the subsequent infusions at the Investigator’s discretion. However, if during 
the next infusion without premedication the patient experiences an IAR (any grade), 
premedication must be restarted for all subsequent infusions. 
When isatuximab and atezolizumab are to be administrated on the same day, the administration 
sequence is: atezolizumab, followed by premedications, followed by isatuximab. 
When only isatuximab is to be administrated on a day, the administration sequence is: 
premedications, followed by isatuximab. 
Statistical considerations: 
Data from HCC, SCCHN, EOC and GBM cohorts in Phase 2 will be analyzed and reported 
separately by cohort. 
• Analysis of primary efficacy endpoints: 
- 
For HCC, SCCHN and EOC Phase 2: RR will be summarized with descriptive 
statistics.  A 90% two-sided confidence interval will be computed using 
Clopper-Pearson method. The statistical inference will be based on the hypothesis and 
alpha level defined in the sample size calculation section, 
- 
For GBM: PFS-6 will be summarized using Kaplan-Meier method. 
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•    Analysis of secondary efficacy endpoints: 
- 
Tumor burden change: the best percent-change from baseline in tumor burden will be 
summarized and presented graphically. In addition, a summary of the area under the 
curve (AUC) and the time adjusted AUC of percent-change from baseline in tumor 
burden will also be provided as an exploratory analysis, 
- 
DOR and PFS will be summarized using Kaplan-Meier method, 
- 
RR for GBM and DCR (complete response + partial response + stable disease) will be 
summarized with descriptive statistics. 
• Analysis of safety endpoints: 
In Phase 1, the DLTs will be listed by participant using the DLT evaluable population. 
In Phase 1 and 2, the AEs will be coded according to Medical Dictionary for Regulatory 
Activities (MedDRA). AEs and laboratory abnormalities will be graded according to the 
NCI-CTCAE version 4.03. 
- 
The number (%) of participants experiencing treatment-emergent AEs (TEAEs) by 
primary system organ class (SOC) and preferred term (PT) will be summarized by 
CTCAE grade (all grades and Grade ≥3) for the all-treated population. Same table will 
be prepared for treatment-related TEAEs, AEs of special interest (AESIs), TEAEs 
leading to treatment discontinuation, serious TEAEs and TEAEs with fatal outcome. 
The post-treatment AEs will be analyzed separately, 
- 
The number (%) of participants with laboratory abnormalities (ie, all grades and 
Grade ≥3) using the worst grade during the on-treatment period will be provided for 
the all-treated population. 
• Pharmacokinetics: 
- 
Concentrations of both atezolizumab and isatuximab and PK parameters of isatuximab 
at Cycle 1 Week 1 will be descriptively summarized (mean, geometric mean, median, 
standard deviation, standard error of the mean, coefficient of variation, and minimum 
and maximum), 
- 
Immune response and pharmacodynamic endpoints: 
- 
Findings from immune markers and pharmacodynamics markers will be 
descriptively summarized and tabulated. 
Planned date for analysis cut-off: 
For each cohort, the analysis cut-off date for the primary analysis (RR for HCC, SCCHN, and 
EOC, PFS-6 for GBM) will be 6 months after the last participant’s first treatment in the cohort.  
The analysis cut-off date for the secondary efficacy endpoints including DoR and PFS will be 
12 months after the last participant’s first treatment in the cohort. The primary analysis of RR in 
the cohort for HCC, SCCHN, and EOC, and of PFS-6 in the cohort for GMB will be updated. In 
the case of inadequate efficacy for a cohort at interim analyses, the Sponsor may decide not to 
update primary nor perform secondary analyses for that cohort.  
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Data Monitoring Committee: Yes 
Study Committee: 
Composition of the Study Committee will vary based on the matter discussed, but it will generally 
include Sponsor representatives and at least two investigators responsible for the indication in 
matter. Sponsor representatives and Investigators who have enrolled at least 1 patient will review 
clinical data approximately every 2 weeks during the course of the Phase 1 part. Then 
Study Committee will convene regularly or ad hoc when required, to review data and provide 
strategic recommendations on study medical decisions such as at the end of the Stage 1 of each 
cohort and Stage 2 of Cohorts A to D-2. 
1.2 
SCHEMA  
Figure 1 - Graphical Study Design  
 
. At starting dose, approximately 8 patients 
will be treated and DLTs will be assessed 
in the first 6 DLT-evaluable participants 
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1.3 
SCHEDULE OF ACTIVITIES (SOA)  
 
Evaluation 
Screening  
(up to 28 
days before 
Day 1) 
Treatment Phasea 
End of 
Treatment  
(EOT) 
Post Treatment Follow-up Phase 
Notes 
a  A cycle is 
21 days 
 
Cycle 1 
Cycle 2 and Beyond 
 
Safety follow-up Period 
Survival 
follow-up 
 
D-
28 
to 
D-
15 
D-14 
to 
D-1 
D1 
(±1) 
D8 
(± 1) 
D15 
(±1) 
D1 (± 2) 
30 (±7) days 
after last 
IMPs admin 
At 60 (±7) 
days after 
last IMPs 
admin 
At 90 (±7) 
days after 
last IMPs 
admin 
Every 90 
days  (±7)  
after last 
safety 
follow-up 
Informed consent/ 
Inclusion and exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
Informed 
Consent: 
Informed 
consent may be 
signed prior to 
D -28. 
Demography, 
Medical/Surgical and 
Disease History 
X 
 
 
 
 
 
 
 
 
 
Physical examination 
 
X 
(<7days 
prior to 
first 
dose) 
 
Xc 
Xc 
X 
X 
X 
X 
 
Section 8.2.1 
Height (at baseline 
only) /Weight/ ECOG 
(HCC,SCCHN,EOC) or 
Karnofsky PS (GBM) 
 
 
X 
X 
Xc 
Xc 
X 
X 
X 
X 
 
Section 8.2.1 
Vital Signs 
X 
X 
Xc 
Xc 
X 
X 
X 
X 
 
See 
Section 8.2.2 
Resting O2 saturation 
for SCCHN 
X 
X 
Xc 
Xc 
X 
X 
 
 
 
See 
Section 8.2.2 
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Evaluation 
Screening  
(up to 28 
days before 
Day 1) 
Treatment Phasea 
End of 
Treatment  
(EOT) 
Post Treatment Follow-up Phase 
Notes 
a  A cycle is 
21 days 
 
Cycle 1 
Cycle 2 and Beyond 
 
Safety follow-up Period 
Survival 
follow-up 
 
D-
28 
to 
D-
15 
D-14 
to 
D-1 
D1 
(±1) 
D8 
(± 1) 
D15 
(±1) 
D1 (± 2) 
30 (±7) days 
after last 
IMPs admin 
At 60 (±7) 
days after 
last IMPs 
admin 
At 90 (±7) 
days after 
last IMPs 
admin 
Every 90 
days  (±7)  
after last 
safety 
follow-up 
12-Lead ECG  
X 
 
 
 
As clinically indicated 
 
 
 
See  
Section 8.2.3 
Laboratory Assessments                                                                                                                               
Pregnancy test 
(WOCBP only)b  
 
X (within 
7 days 
prior to 
first 
dose) 
 
 
 
X 
X 
X 
X (every 30±7 
days until 5 
months after 
last dose of 
study 
treatment) 
 
b Women of 
child 
bearing 
potential 
must have 
a negative 
serum 
pregnancy 
test result 
within 
7 days 
prior to 
first IMP 
administra
tion. 
Blood Chemistry 
 
X 
X 
Xc 
Xc 
X 
X 
X 
 
X 
 
See 
Section 10.3 
Table 12 
Hematology  
 
X 
X 
Xc 
Xc 
X 
X 
X 
X 
 
Section 10.3 
Coagulation(GBM)  
 
X 
X 
Xc 
Xc 
X 
X 
 
 
 
Section 10.3 
Coagulation (for HCC, 
SCCHN, and EOC) 
 
X 
 
 
 
As clinically indicated 
 
 
 
Section 10.3 
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Evaluation 
Screening  
(up to 28 
days before 
Day 1) 
Treatment Phasea 
End of 
Treatment  
(EOT) 
Post Treatment Follow-up Phase 
Notes 
a  A cycle is 
21 days 
 
Cycle 1 
Cycle 2 and Beyond 
 
Safety follow-up Period 
Survival 
follow-up 
 
D-
28 
to 
D-
15 
D-14 
to 
D-1 
D1 
(±1) 
D8 
(± 1) 
D15 
(±1) 
D1 (± 2) 
30 (±7) days 
after last 
IMPs admin 
At 60 (±7) 
days after 
last IMPs 
admin 
At 90 (±7) 
days after 
last IMPs 
admin 
Every 90 
days  (±7)  
after last 
safety 
follow-up 
Blood Typing 
Interference Test  
 
X 
 
 
 
Cycle 2 Day 1 only 
 
 
 
 
Section 10.3 
Before each 
transfusion. 
Serology HBV and 
HCV (for HCC only) 
X 
 
 
 
 
 
 
 
 
Section 10.3 
Urinalysis (at baseline 
and if required) /urine 
dipstick 
 
X 
    X 
                                      As clinically indicated 
          X 
             X 
         X 
 
Section 10.3 
Disease Assessment 
CT/MRI (for HCC, 
SCCHN, and EOC) 
X 
 
 
 
X (Weeks 9, 18, 27, and then every 12 weeks) 
X (if necessary) 
 
X (until PD is confirmed if no PD 
documented & confirmed) 
Section 8.1 
Brain MRI (for GBM 
only) 
 
X (within 
14 days 
prior to 
first 
dose) 
 
 
 
X (Weeks 6, 12, 18, 24, and then every 9 weeks) 
X (if necessary) 
 
X (until PD is confirmed if no PD 
documented & confirmed) 
Section 8.1 
AFP (for HCC) / CA125 
(for EOC) 
 
 
X 
 
 
X (Weeks 9, 18, 27, and then every 12 weeks) 
X (if necessary) 
 
X (until PD is confirmed if no PD 
documented & confirmed) 
Section 8.1 
Isatuximab 
Administration 
 
 
X 
Xc 
Xc 
X 
 
 
 
 
c evaluation 
not 
applicable 
for Cohort 
E 
Atezolizumab 
Administration 
 
 
X 
 
 
X 
 
 
 
 
 
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Evaluation 
Screening  
(up to 28 
days before 
Day 1) 
Treatment Phasea 
End of 
Treatment  
(EOT) 
Post Treatment Follow-up Phase 
Notes 
a  A cycle is 
21 days 
 
Cycle 1 
Cycle 2 and Beyond 
 
Safety follow-up Period 
Survival 
follow-up 
 
D-
28 
to 
D-
15 
D-14 
to 
D-1 
D1 
(±1) 
D8 
(± 1) 
D15 
(±1) 
D1 (± 2) 
30 (±7) days 
after last 
IMPs admin 
At 60 (±7) 
days after 
last IMPs 
admin 
At 90 (±7) 
days after 
last IMPs 
admin 
Every 90 
days  (±7)  
after last 
safety 
follow-up 
AE/SAE Assessment 
X 
Continuously throughout period 
X (ongoing related AEs, ongoing SAEs at EOT and new related 
AE/SAEs) 
 
Prior/Concomitant 
Medication 
X (within 14 days 
prior to first dose) 
Continuously throughout period 
       X (related to AE/SAEs listed above) 
 
PK 
See Pharmacokinetics and immunogenicity Flow Chart 
ADA 
See Pharmacokinetics and immunogenicity Flow Chart 
Tumor Biopsy, Archival 
Tumor Tissue 
Collection, Biomarker 
Blood Draw 
See Biomarker Flow Chart 
Subsequent Anticancer 
Therapy Status 
 
 
 
 
 
 
X 
X 
X 
X 
 
Survival Status 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
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PHARMACOKINETICS AND IMMUNOGENICITY FLOW CHART 
Study Phase 
Treatment Phase 
Post-treatment 
Cycle  
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Subsequent Cycles 
EOT 
FUP 
(90±7 
days) 
 Day within the Cycle 
D1  
D15 
 D1 
D1 
D1 
D1 
Sample RNT (h) 
Ref: SOI 
Atezolizumab 
SOI 
EOI 
EOI  
+30 
min
- 
SOI 
- 
SOI 
- 
SOI 
- 
SOI 
- 
- 
- 
Sample time 
window 
Atezolizumab 
[-24h, 
SOI] 
±5 
min 
±10 mi
n 
- 
[-24h, 
SOI] 
- 
[-24h, 
SOI] 
- 
[-24h, 
SOI] 
- 
[-24h, 
SOI] 
- 
- 
- 
Sample RNT (h) 
Ref: SOI Isatuximab 
SOI 
- 
EOI 
EOI +4h 
72h 
168h  
(SOI of Day 8) 
SOI 
EOI 
SOI 
- 
EOI 
SOI 
- 
SOI 
- 
EOI 
EOI +1h 
SOI 
- 
- 
- 
Sample time 
window Isatuximab 
- 
- 
±10 
min 
±30 min 
±5 h 
[-24h, SOI] 
[-24h, 
SOI] 
±10 m
in 
- 
- 
±10 min 
- 
- 
- 
- 
±10 
min 
±10 min 
- 
- 
- 
- 
IMP administration (IV infusion) 
Atezolizumab 
X------------X 
X 
X 
X 
X 
Isatuximab 
X--------------X 
X 
X----------------X 
X----------------X 
X 
X------------X 
X 
Pharmacokinetics a,i
Atezolizumabj 
Sample ID 
S00 
- 
S01 
- 
S00c
- 
S00c
 - 
S00c
- 
S00 c,j
- 
SF00 
- 
Isatuximabi
Sample ID 
P00b
- 
- 
P01f
P02 
P03 
P04d,g
P05g
P06f
P00b, g
- 
P01f
P00b, g
- 
P00b, 
g 
- 
P01f
P02 
P00b, g
- 
- 
- 
Immunogenicity (ADA) a, e ,i
Atezolizumab  c, j
AS00  
- 
AS00 
- 
AS00 
- 
AS00 
- 
AS00 j
- 
ASF00 
- 
Isatuximabg,h i 
AP00
b
- 
AP00
b 
- 
AP00b 
- 
AP00b 
- 
AP00b 
- 
APF00h
a Refer to the laboratory manual for sample collection, processing and shipping.  
b Isatuximab PK or ADA predose samples should be collected before isatuximab administration and at the same time as atezolizumab predose samples when applicable. 
c Atezolizumab sample collected strictly before the start of atezolizumab infusion (during treatment phase). 
d P04 sample must be collected even if the participant withdraws the study without receiving the second administration of isatuximab. 
e After start of study treatment, if 1 drug is prematurely discontinued, ADA samples for this drug will be collected and tested on Day 1 of the 2 next cycles. The ADA sample collection for other drug should be done 
as planned. 
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f 
Sample collected just before actual end of infusion of isatuximab. 
g Isatuximab sample collected strictly before the start of isatuximab infusion (during treatment phase). 
h After FUP 90(±7) days after last isatuximab administration no further ADA will be sampled even if the status is positive or inconclusive. 
i 
Isatuximab PK and ADA samples to be collected each cycle until the last study treatment for PK and until FUP 90(±7) days after last IMP administration for ADA or at the cut-off date, whichever comes first. 
However, collection can be reduced or stopped earlier upon notification from the Sponsor based on the updated knowledge of isatuximab on PK/ADA. 
j 
For subsequent cycles, atezolizumab PK and ADA samples (pre-dose) are to be collected at Cycle 8 Day 1 and Cycle 16 Day 1 only. 
Abbreviations: SOI: Start of infusion, EOI: End of infusion, P= Plasma, S= Serum, AP= Antibody-Plasma, AS= Antibody-Serum, IMP= Investigational medicine product, D= Day, EOT= End of treatment, FUP= follow-
up period, RNT= relative nominal time, IV= Intravenous, ID= Identification,  ADA= Anti-drug antibody 
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EXPLORATORY BIOMARKER FLOW CHART 
Sample Collection 
Biomarker Analysis 
Screening 
Treatment Phase  
Post-Treatment Phase 
Notes 
  
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 5 and Beyond 
EOT 
Follow-up 
 
D-28 to D-1 
D1 (-1 
day) a 
D1 
D1 
D1 
30 (±7) days 
after last IMP 
admin 
60 (±7) days 
after last IMP 
admin 
a. Biomarker blood draw may be performed within 
1 working day prior to IMP administration. 
Peripheral Blood 
 
 
 
Immune genetic markers 
 
X 
 
 
 
 
 
 
Tumor mutational profile 
(plasma cell free DNA) 
 
X 
X 
X 
 
X 
 
 
Immunophenotyping 
 
X 
X 
X 
X (odd cycles only)  
X 
X 
Only for Phase 2 Stage 2 participants 
Plasma or serum cytokines 
X 
X 
X 
X 
X (odd cycles only)  
X 
X 
Only for Phase 2 Stage 2 participants 
Adaptive immunity 
 
X 
X (only 1 on-treatment sample, see Study 
Reference Manual for details) 
 
 
Only Phase 2 Stage 2 participants, if sufficient clinical 
response is observable in Phase 1 and Phase 2 Stage 1 
participants 
Plasma or serum Metabolites 
 
X 
X 
X 
X (odd cycles only) 
X 
 
Only Phase 2 Stage 2 participants, if sufficient clinical 
response is observable in Phase 1 and Phase 2 Stage 1 
participants 
Archival Pre-Treatment Tumor 
Tissue Collection (for HCC, 
SCCHN, EOC and GBM) 
If feasible, biomarker 
analyses listed below for 
“Baseline or on treatment 
tumor biopsy core” 
X 
 
 
 
 
 
 
Mandatory for all GBM participants.  For HCC, SCCHN, 
and EOC participants, provision of adequate archival 
tumor tissue is allowed to replace mandatory baseline 
biopsy 
Baseline or on 
treatment tumor 
biopsy core in order of 
priority (Biopsy to be 
performed for HCC, 
SCCHN, and EOC if 
adequate archival 
tissue is not available) 
Core 1 
CD38 and PD-L1 expression, 
immune contexture (IHC 
analyses)  
X 
 
X (if 
clinically 
feasible) 
 
 
 
 
 
Refer to I 02 for details. 
 
At least 1 tumor core is required, but 3 cores are 
optimal.  Refer to Laboratory Manual for details. 
Core 2 
CD38 and PD-L1 expression, 
immune contexture (IHC 
analyses)  
X 
 
X (if 
clinically 
feasible) 
 
 
 
 
Core 3 Transcriptomic analysis  
X 
 
X (if 
clinically 
feasible) 
 
 
 
 
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2 
INTRODUCTION  
Cluster of differentiation 38 
Cluster of differentiation 38 (CD38) is a type II glycosylated 45 kilodalton membrane protein that 
was identified as a lymphocyte marker (1). CD38 functions as a receptor binding to CD31 and is 
involved in cell adhesion and signal transduction. CD38 is also an ecto-enzyme catalyzing the 
synthesis and hydrolysis of cyclic adenosine-diphosphate-ribose from nicotinamide adenine 
dinucleotide to adenosine diphosphate-ribose (2). Adenosine diphosphate-ribose can be further 
converted into adenosine, a multifunctional immunosuppressive nucleoside that binds to different 
specific receptors expressed by immune effector cells (3). 
The expression of CD38 in healthy humans can be detected on natural killer (NK) cells, 
monocytes, dendritic cells, macrophages, granulocytes, activated T and B cells, and plasma cells. 
Several hematological malignancies express CD38 including those of B-lymphocyte, 
T-lymphocyte and myeloid origin. Moreover, in some solid tumors, such as prostate cancer and 
glioblastoma, CD38 expression has been shown. See Section 2.1 for additional information on 
biological functions of CD38 and its role in tumor microenvironment. 
Programmed cell death 1 protein pathway 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades (4). The PD-1 receptor-ligand interaction is a major 
pathway hijacked by tumors to suppress immune control (5). The normal function of PD-1, 
expressed on the cell surface of activated T cells under healthy conditions, is to down-modulate 
unwanted or excessive immune responses, including autoimmune reactions. PD-1 (encoded by the 
gene Pdcd1) is an immunoglobulin superfamily member related to cluster of differentiation 
28 and cytotoxic T-lymphocyte associated protein 4 (CTLA-4), which has been shown to 
negatively regulate antigen receptor signaling upon engagement of its ligands (programmed cell 
death-ligand 1 [PD-L1] and/or programmed cell death-ligand 2 [PD-L2]). The structures of 
murine PD-1 alone (6) and in complex with its ligands were first resolved (7, 8) and more recently 
the nuclear magnetic resonance-based structure of the human PD-1 extracellular region and 
analyses of the interactions with its ligands were also reported (9). 
Programmed cell death 1 protein and family members are type I transmembrane glycoproteins 
containing an immunoglobulin Variable-type domain responsible for ligand binding and a 
cytoplasmic tail which is responsible for the binding of signaling molecules. The cytoplasmic tail 
of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor tyrosine-based inhibition 
motif and an immunoreceptor tyrosine-based switch motif (ITSM). Following T cell stimulation, 
PD-1 recruits the tyrosine phosphatases SHP-1 and SHP-2 to the ITSM motif within its 
cytoplasmic tail, leading to the dephosphorylation of effector molecules, such as CD3ζ, PKCθ and 
ZAP70, which are involved in the CD3 T cell signaling cascade (10). The mechanism by which 
PD-1 down-modulates T cell responses is similar to, but distinct from that of CTLA-4 (11). 
Programmed cell death 1 protein was shown to be expressed on activated lymphocytes, including 
peripheral CD4+ and CD8+ T cells, B cells, regulatory T cells and NK cells (12). Expression has 
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also been shown during thymic development on CD4-CD8- (double negative) T cells (13) as well 
as subsets of macrophages (14) and dendritic cells (15). The ligands for PD-1 (PD-L1 and PD-L2) 
are constitutively expressed or can be induced in a variety of cell types (16). PD-L1 is expressed 
at low levels on various non-hematopoietic tissues, most notably on vascular endothelium, 
whereas PD-L2 protein is only detectably expressed on antigen-presenting cells found in 
lymphoid tissue or chronic inflammatory environments (16). Both ligands are Type I 
transmembrane receptors containing both immunoglobulin variable- and immunoglobulin 
constant-like domains in the extracellular region and short cytoplasmic regions with no known 
signaling motifs. Binding of either PD-1 ligand to PD-1 inhibits T cell activation triggered 
through the T cell receptor. Programmed cell death-ligand 2 is thought to control immune T cell 
activation in lymphoid organs, whereas PD-L1 serves to dampen unwarranted T cell function in 
peripheral tissues. Although healthy organs express little (if any) PD-L1, a variety of cancers were 
demonstrated to express abundant levels of this T cell inhibitor (17, 18) which, via its interaction 
with the PD-1 receptor on tumor-specific T cells, plays a critical role in immune evasion by 
tumors (19). As a consequence, the PD-1/PD-L1 pathway is an attractive target for therapeutic 
intervention in cancer (20). 
Five anti-PD-1 and anti-PD-L1 antibodies, nivolumab, pembrolizumab, atezolizumab, avelumab 
and durvalumab, are now approved in multiple indications including HCC and SCCHN (21, 22, 
23, 24, 25, 26, 27, 28, 29). 
2.1 
STUDY RATIONALE  
Monoclonal antibodies that block the PD-1/PD-L1 axis have changed the landscape of cancer 
therapy. Nivolumab, pembrolizumab, atezolizumab, avelumab, and durvalumab were approved by 
the US Food and Drug Administration (FDA). Despite their success, optimal outcomes for many 
patients will require combination therapies. Numerous clinical studies are currently evaluating 
anti-PD-1/PD-L1 antibodies in combination with chemotherapy, targeted therapies and other 
immunotherapies in patients with solid tumors and hematological malignancies. 
CD38 expression is well documented in hematological cancers, including MM, lymphomas and 
leukemias. In solid tumors, CD38 is found expressed on the tumor cells of treatment naïve 
prostate adenocarcinoma and glioblastoma biopsies (Sanofi report NCB22V1). Therefore, 
isatuximab monotherapy cohort will be initiated in patients with glioblastoma upon positive signal 
of isatuximab and atezolizumab combination Phase 2 Stage 2. The rationale to initiate 
monotherapy cohort is to evaluate whether the combination treatment would provide additional 
benefit compared to isatuximab monotherapy in patients with glioblastoma. Figure 2 shows the 
H-scores for CD38 in tumor tissues from glioblastoma patients with low-grade and high-grade 
diseases. H-scores in normal non-tumor brain tissues are also shown. 
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Figure 2 - Cluster of differentiation 38 H scores (3 × (% cells 3+) + 2 × (% cells 2+) + 1 × (% cells 1+) 
in low and high grade glioblastoma  
 
In other solid tumor types, CD38 is not detected on the tumor cells, although it can be detected 
within the tumor microenvironment. The role of CD38 in the solid tumor environment is not 
completely understood, but there are several findings indicating that CD38 can contribute to the 
immune-suppressive tumor microenvironment: 
A) CD38 catalyzes the conversion of nicotinamide adenine dinucleotide into immunosuppressive 
adenosine. 
B) CD38 expression is highly correlated with the expression of PD-1 and its ligands in solid 
tumor biopsies. 
C) CD38 is found upregulated in tumor models that have acquired resistance to anti-PD-L1 (30, 
31). 
D) CD38 expressing myeloid derived suppressor cells promote growth of human tumors in mice 
(32). 
E) CD38 expressing mouse tumor cells inhibit the proliferation of autologous T cells (9). 
A recent report has shown that the combination of anti-PD-L1 and CD38 antibodies induces a 
greater anti-tumor immune response than anti-PD-L1 in a mouse lung cancer model 
(K-rasLA1/+p53R172H∆g/+-derived tumor) (Figure 3) (30, 31). 
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Figure 3 - Combination of anti-CD38 and anti PD-L1 in a mouse lung cancer model results in 
enhanced anti-tumor activity, decreases incidence of lung metastasis and increases the tumor 
infiltration of CD8+ T cells  
 
Details provided in bibliographic reference (30, 31).  
Abbreviations: PD-L1=Programmed cell death-ligand 1 
 
Isatuximab can induce different immuno-modulatory mechanisms that can contribute to reshape 
the tumor microenvironment and enhance the anti-tumor activity of anti-PD-1 antibodies: 
A) Isatuximab decreases circulating regulatory T cell counts and increases total T cell counts in 
MM patients. 
B) Isatuximab restores T cell function inhibited by regulatory T cells (9). 
C) Isatuximab induces activation of NK cells and increases their cytolytic activity. 
D) Isatuximab increases macrophage phagocytic activity and M1 polarization. 
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Isatuximab has shown clinical response in relapsed/refractory MM patients as a single agent and 
in combination with immunomodulatory agents. Although isatuximab has not been tested yet in 
solid tumors, we hypothesize, based on the immunomodulatory activities described above, that 
isatuximab may contribute to reshaping the tumor immune-environment and will enhance the 
activity of anti-PD-L1 therapy. 
2.2 
BACKGROUND  
2.2.1 Solid tumors  
2.2.1.1 Hepatocellular Carcinoma  
Hepatocellular carcinoma is a rising cause of cancer related deaths worldwide (29). The leading 
cause of HCC is associated with chronic hepatitis B (33%), alcohol (30%) or hepatitis C (21%) 
(33). The majority of HCC patients are detected at an advanced or end stage (13). Systemic 
treatment options for advanced disease are limited with sorafenib being the only approved 
effective standard of care in the first line unresectable advanced setting. The objective RR (1 to 
3%) is minimal and survival benefit (6.5 to 10.7 months versus 4.2 to 7.9 months with placebo) is 
modest in both Caucasian and Asian population (34, 35). Recently, lenvatinib, another vascular 
endothelial growth factor receptor inhibitor, has demonstrated similar survival benefit to sorafenib 
(13.6 months versus 12.3 months) in a Phase 3 study (36). The FDA has accepted a supplemental 
new drug application for lenvatinib as a frontline systemic treatment for patients with advanced 
hepatocellular carcinoma in September 2017. For patients who were able to tolerate sorafenib but 
subsequently progressed on sorafenib, regorafenib has been approved based on an overall survival 
(OS) benefit compared with placebo (10.6 months versus 7.8 months) (3). In September 2017, 
nivolumab received accelerated approval from the FDA in patients who have been previously 
treated with sorafenib, supporting the use of immunotherapy for treatment of HCC in the 
second-line setting. 
HCC is an immunogenic tumor in an immunotolerant environment.  The chronic inflammatory 
conditions in the liver (eg, cirrhosis, hepatitis B virus (HBV)/hepatitis C virus (HCV) infection) 
contribute to the immunosuppressive tumor microenvironment through T cell exhaustion, with 
presence of PD-1 expressing tumor-infiltrating lymphocytes in HCC lesions, supporting the use of 
PD-1/PD-L1 immune checkpoint blockade as a therapeutic strategy (14, 2, 37). 
Multiple anti-PD-1/PD-L1 inhibitors (including pembrolizumab, atezolizumab, and durvalumab) 
are being developed, as a monotherapy or in combination, for treatment of patients with HCC. In 
the Phase 1/2 study CheckMate040, nivolumab achieved a RR of 14% (central review using 
RECIST 1.1) in the 145 patients who received sorafenib. More importantly, responses were 
observed irrespective of HCC etiology or PD-L1 expression. The response was durable 
(9.9 months) and most disease stabilizations lasted at least 6 months. The safety profile observed 
in patients with advanced HCC was generally similar to that observed in patients with other 
cancers, with the exception of a higher incidence of elevations in transaminases (18% Grade 3/4 
aspartate aminotransferase [AST], 11% Grade 3/4 alanine aminotransferase [ALT]) and bilirubin 
(7% Grade 3/4 bilirubin) levels. Immune-mediated hepatitis requiring systemic corticosteroids 
occurred in 5% of patients. US FDA accelerated approval was granted based on this study (2). 
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Durvalumab, a human immunoglobulin G1 antibody targets PD-L1, also demonstrated some 
clinical activity in patients with HCC (could be positive for HBV or HCV) with a RR of 10% and 
similar median OS as nivolumab (13.2 months, as of Oct 2016). The most common Grade 3/4 
TEAE was elevation in transaminases (7.5% AST and 5.0% ALT). Although the preliminary 
results are encouraging, most patients with HCC do not respond to PD-1/PD-L1 inhibitors 
monotherapy. 
The current study (ACT15377) will evaluate the safety, tolerability, and RRs of isatuximab in 
combination with atezolizumab as primary objective, in patients with unresectable HCC who 
progressed on/after or are intolerant to sorafenib. 
2.2.1.2 Squamous cell carcinoma of head and neck  
Approximately 60% of patients with SCCHN are diagnosed with locoregionally advanced disease 
(12). More than 50% of these patients will have recurrence within 3 years with chemotherapy or 
chemoradiation (5, 6). There is about 10% of patients present with metastatic disease (15). 
First-line palliative treatment for patients with recurrent or metastatic SCCHN is platinum-based 
system therapy. Adding cetuximab to cisplatin/carboplatin plus 5-fluorouracil followed by 
maintenance cetuximab improves RR from 20% to 36%, and survival from 7.4 months to 
10.1 months (16). For the patients who have cancer progression within 6 months after 
platinum-based chemotherapy administered in the context of primary or recurrent disease, the 
prognosis is poor. ORRs to second-line chemotherapy or anti-EGFR agent are 6-13%. Median 
survival is approximately 6 months (8, 11, 17). 
Nivolumab and pembrolizumab are the first PD-1 immune checkpoint inhibitors granted with US 
FDA approval for treating patients with recurrent/metastatic SCCHN who progress on or after 
platinum-based chemotherapy.  Nivolumab was shown to be superior to standard of care (median 
OS 7.5 months versus 5.1 months, RR 13% versus 5.8%, respectively) in platinum-refractory 
population regardless of PD-L1 status in Phase 3 Checkmate 141 (11). Pembrolizumab, which 
was granted accelerated approval based on RR of 16% to 18% in patients with recurrent and 
metastatic SCCHN did not meet primary endpoints in a randomized study when compared to 
standard of care (18, 19, 20). Atezolizumab monotherapy also demonstrated clinical activity in the 
PD-L1 expression enriched recurrent and metastatic SCCHN population from a Phase 1 study. 
The overall RR was 22%, and median OS was 6 months (38). Multiple clinical trials are ongoing 
to evaluate the use of PD-1/PD-L1 immune checkpoint inhibitors in combination with therapies to 
improve clinical outcomes in patients with recurrent/metastatic SCCHN (9). 
The current study (ACT15377) will evaluate the safety, tolerability, and RRs of isatuximab in 
combination with atezolizumab as primary objective, in patients with recurrent/metastatic 
SCCHN who progressed on/after one and no more than two lines of platinum-based therapy. 
2.2.1.3 Epithelial ovarian cancer  
Epithelial ovarian cancer, which accounts for a majority of diagnoses of ovarian cancer, is further 
subdivided into various cell types, grades, and anatomic locations. The most common form is 
high-grade serous ovarian cancer, which accounts for approximately 70% of all EOC (39). More 
than 60% of patients with ovarian cancer are diagnosed with advanced (stage III–IV) disease, the 
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mainstay of treatment for which is upfront surgical cytoreduction followed by adjuvant 
platinum-based chemotherapy. Bevacizumab is approved (excluding the United States) as a 
first-line treatment in combination with standard chemotherapy (40). Platinum-based therapy 
(plus bevacizumab) continues to be the principal regimen used to treat platinum-sensitive tumors 
(defined as relapse at least 6 months after completion of last platinum-based therapy). However, 
platinum resistance eventually occurs in virtually all patients with recurrent EOC, as response 
usually lasts for only a few months and with each subsequent course of therapy the treatment free 
interval shortens until the disease is declared “platinum-resistant” (defined as progression within 
6 months of platinum-based therapy) or “platinum-refractory” (defined as progression during or 
within 4 weeks after the last dose) (32). 
For the patients who harbor mutations in the genes encoding breast cancer type 1 and 2 
susceptibility protein (BRCA1 and BRCA2), which occur in 10–15% of ovarian cancers, 
poly(ADP ribose) polymerase (PARP) inhibitors are transforming the treatment landscape (41). 
The first PARP inhibitor, olaparib is approved as a maintenance therapy in germline 
BRCA-mutated patients with platinum-sensitive recurrent disease based on a randomized Phase 3 
study (PFS 19.1 months versus 5.5 months) (42). 
Commonly used treatments in the setting of recurrent platinum-resistant EOC nowadays include 
pegylated liposomal doxorubicin (PLD), paclitaxel (weekly) and topotecan (40, 43). These single 
agent chemotherapies were reported to result in PFS of 3-4 months, OS of about 12 months, and 
RRs ranging from 10% to 15% (32). Management of recurrent platinum-resistant EOC remains 
challenging due to toxicities associated with cytotoxic agents and emergent of drug resistance. 
Studies have shown that EOC, particularly those of high-grade serous, is most likely associated 
with pattern of adaptive immune resistance and may be more likely to respond to immune 
checkpoint inhibitors (44, 45). Immune checkpoint inhibitors are being extensively tested in the 
clinic for treatment of recurrent EOC. To date, anti-PD-1/PD-L1 monotherapy have demonstrated 
similar RRs and PFS as single agent chemotherapy in platinum-resistance disease in small 
Phase 1/2 studies (46, 47, 48). However, durable responses were noted with avelumab, nivolumab 
and pembrolizumab which created enthusiasm as durable responses are atypical in this setting. A 
randomized Phase 3 study evaluating avelumab in combination with PLD in patients with 
platinum-resistant/refractory ovarian cancer is currently underway (49). 
The current study (ACT15377) will evaluate the safety, tolerability, and RRs of isatuximab in 
combination with atezolizumab as primary objective, in patients with platinum-resistant/refractory 
recurrent EOC, who received no more than 3 lines of systemic therapy for platinum-sensitive 
disease and no prior therapy for platinum-resistant/refractory disease 
(specific to France: see Appendix 8 in Section 10.8.1). 
2.2.1.4 Glioblastoma Multiforme  
Adult GBM is one of the most aggressive primary cancers of the brain with a 5-year survival rate 
of 5% (50). Treatment of newly diagnosed GBM consists of maximal safe surgical resection, 
followed by radiotherapy with concurrent and maintenance temozolomide. Adding temozolomide 
improves median PFS to 6.9 months and OS to 14.6 months (51). Only 10% of patients survive 
longer than 5 years. O-6-methylguanine-DNA methyltransferase gene methylation status 
identifies patients most likely to benefit from the addition of temozolomide (52).  
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At tumor progression, treatment options are scarce and of poor effectiveness. Lomustine is one of 
the commonly used treatments for recurrent GBM with an OS of <8.6 months, RRs of 4-5%, and 
PFS rate at 6 months of 8-19% (median PFS <2 months) (53, 54, 55). Bevacizumab was approved 
by the US FDA for treatment of recurrent GBM based on RRs of 20-26% in two Phase 2 studies 
(25, 26). However, the improved RRs of bevacizumab did not translate into meaningful OS 
(<10 months versus <8.6 months for lomustine). It has been hypothesized that the pseudoresponse 
of bevacizumab is attributed to its normalization effect as an anti-angiogenic agent which 
interferes with magnetic resonance imaging (MRI) interpretation during disease assessment (21). 
Glioblastoma multiforme is recognized as an immunosuppressive neoplasm due to activation of 
various immune escape mechanisms including the PD-1/PD-L1 pathway. Upregulation of PD-L1 
expression was detected in >70% of recurrent GBM tumor specimens, along with 
sparse-to-moderate density of tumor infiltrating lymphocytes (22). Contrary to conventional belief 
where immune responses were limited in the brain due to the blood brain barrier (BBB), the BBB 
has selective permeability for immune cells regulating the brain microenvironment. Glioblastoma 
cells are also known to release factors that disrupt the BBB, permitting infiltration of activated 
macrophages and lymphocytes (23, 24). Tumor-specific immune memory response has been 
demonstrated in orthotopic immunocompetent murine glioblastoma model where treatment with 
immune checkpoint inhibitors including anti-PD-1/PD-L1 led to long-term survival. In particular, 
increased activated CD8+ and natural killer cells, decreased suppressive immune cells were 
observed in the tumor microenvironment and draining cervical lymph nodes (56). Multiple 
clinical trials are ongoing to evaluate PD-1/PD-L1 inhibitors as a monotherapy or in combination 
for treatment of recurrent GBM. Although in the Phase 3 CheckMate 143 study, single agent 
nivolumab did not improve OS in patients with recurrent GBM compared to bevacizumab 
(9.8 versus 10 months), durable response was observed with nivolumab (DoR 11 versus 
5.3 months) (30). CD38 protein expression was observed in glioblastoma biopsies, suggesting that 
addition of anti-CD38 therapy to anti-PD-1/PD-L1 may potentiate tumor-specific immune 
response (see Section 2.1). 
2.2.2 Isatuximab  
Isatuximab (SAR650984) is a mAb that binds selectively to a unique epitope on the human 
surface antigen CD38. Isatuximab kills tumor cells via multiple biological mechanisms; 
antibody-dependent cellular-mediated cytotoxicity, antibody-dependent cellular-mediated 
phagocytosis, complement-dependent cytotoxicity and direct induction of apoptosis 
(pro-apoptosis) without crosslinking. Isatuximab treatment of CD38-expressing cells also results 
in inhibition of CD38 enzymatic activity. 
At the cut-off date of 05 January 2018, a total of 675 patients were treated with isatuximab. 
All patients had hematological malignancy. 
Refer to the isatuximab Investigator’s Brochure for the most updated nonclinical and clinical 
studies of isatuximab. 
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2.2.3 Atezolizumab  
Atezolizumab is a humanized immunoglobulin G1 mAb that targets PD-L1 and inhibits the 
interaction between PD-L1 and its receptors, PD-1 and B7-1 (also known as CD80), both of 
which function as inhibitory receptors expressed on T cells. Therapeutic blockade of PD-L1 
binding by atezolizumab has been shown to enhance the magnitude and quality of tumor-specific 
T cell responses, resulting in improved anti-tumor activity (57, 58). Atezolizumab has minimal 
binding to Fc receptors, thus eliminating detectable Fc-effector function and associated 
antibody-mediated clearance of activated effector T cells. 
Atezolizumab shows anti-tumor activity in both nonclinical models and cancer patients and is 
being investigated as a potential therapy in a wide variety of malignancies. Atezolizumab is being 
studied as a single agent in the advanced cancer and adjuvant settings, as well as in combination 
with chemotherapy, targeted therapy, and cancer immunotherapy. 
Atezolizumab is approved in multiple countries for the treatment of urothelial carcinoma (UC) 
and for the treatment of non-small cell lung cancer (NSCLC). 
Refer to the atezolizumab Investigator’s Brochure for details on nonclinical and clinical studies. 
The current study (ACT15377) will evaluate the safety, tolerability, and PFS rate at 6 months 
(historic benchmark for GBM) of isatuximab in combination with atezolizumab as primary 
objective, in patients with recurrent GBM. 
2.3 
BENEFIT/RISK ASSESSMENT  
Overall, scientific rationale (see Section 2.1) and the anticipated possible benefit/risk ratio of 
isatuximab in combination with atezolizumab support the conduct of study ACT15377 in 
participants with HCC, SCCHN, EOC, and GBM. 
2.3.1 Benefits  
Refer to Section 2.1. 
2.3.2 Potential and identified risks  
2.3.2.1 Isatuximab  
Isatuximab has been investigated either as monotherapy or in combination in patients with 
hematological malignancies. The safety profile of isatuximab monotherapy has been best 
characterized in study TED10893 (Phase 1 and Phase 2, including 181 patients with MM), where 
the most common TEAEs, excluding the AEs corresponding to laboratory abnormalities, include 
IARs, fatigue, nausea, upper respiratory infection, cough, back pain and diarrhea. 
Infusion-associated reactions occurred in 49.4% of the patients from TED10893 Phase 1 
(concluded). 
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The IARs associated with isatuximab in patients who are administered appropriate primary 
prophylaxis (see also Section 2.3.4) are most common with the first administration of the drug, are 
not dose-dependent, are Grade 1 to 2 severity, are manageable with standardized precautions 
detailed in each study protocol, are resolved either spontaneously or with standard medication by 
the next day following the infusion, and the patients do not appear to sustain sequelae. The IARs 
generally do not cause treatment discontinuation, and do not tend to recur at subsequent 
administrations of isatuximab. 
In addition to the occurrence of IARs, cytokine release syndrome, influenza-like illness, and fever 
have also been observed in patients treated with isatuximab; these reactions may involve 
immunogenicity mechanisms (human antihuman antigen) and hypersensitivity reactions, and are 
well-known to occur in association with other therapeutic mAb proteins. These adverse reactions, 
whether acute or delayed, may be serious and systemic (eg, anaphylactic reaction). 
Please refer to the current version of the isatuximab Investigator’s Brochure. 
2.3.2.2  Atezolizumab  
Atezolizumab has been investigated as monotherapy or in combination with other therapeutic 
regimens in multiple indications including HCC, SCCHN, EOC, and GBM. The safety profile of 
atezolizumab as a monotherapy has been best characterized in its approved indications including 
locally advanced or metastatic UC and metastatic NSCLC. The most common adverse reactions 
(≥20%) in these patients include fatigue, decreased appetite, nausea, and constipation, urinary 
tract infection (UC), diarrhea (UC), pyrexia (UC), dyspnea (NSCLC), cough (NSCLC), and 
musculoskeletal pain (NSCLC). Other important identified risks of atezolizumab consist of 
infusion-related reactions, and immune-related AEs (irAEs). Specifically, irAEs that were 
identified as risks for atezolizumab include immune-related pneumonitis, immune-related 
hepatitis, immune-related colitis, immune-related endocrinopathies, immune-related 
meningoencephalitis. Immune-related AEs are primarily manageable either by steroid treatments 
or withholding atezolizumab treatment. Recently, a new risk of SCARs has been identified, this 
risk is rare, potentially fatal, and mainly constituted by erythema multiforme, acute generalized 
exanthematous pustulosis, Stevens-Johnson syndrome (SJS), Toxic Epidermal Necrolysis (TEN), 
and drug rash with eosinophilia and systemic symptoms (DRESS). 
Refer to the latest version of atezolizumab Investigator’s Brochure for most updated details. 
2.3.3 Potential risk related to the combination  
Based on the available clinical data from each individual drug, the potentially overlapping adverse 
drug reactions (ADRs) anticipated with the isatuximab and atezolizumab combination consist 
mainly of  IAR, pyrexia, and pneumonia, which are all manageable. 
The irAEs specific to atezolizumab have not been identified as potential risks of isatuximab. The 
participants in the current study will be monitored according to the atezolizumab Investigator’s 
Brochure, with additional preventative measures as described in detail below. 
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2.3.4 Preventative measures to minimize the risk from the combination  
To minimize the risk of IARs, all the participants treated with isatuximab should routinely receive 
primary prophylactic treatment with diphenhydramine 25 to 50 mg IV (or equivalent), 
methylprednisolone 100 mg IV (or equivalent), ranitidine 50 mg IV, acetaminophen 650 to 
1000 mg orally, and montelukast 10 mg orally, 30 to 60 minutes (and never longer than 
60 minutes) prior to the isatuximab infusion to minimize the incidence and severity of IAR. To 
further mitigate the incidence and severity of IARs, it is recommended that the initial infusion rate 
of isatuximab should not exceed 175 mg of isatuximab per hour. In the absence of IARs after 
1 hour of infusion, the infusion rate can be increased by 50 mg/hour increments every 30 minutes, 
to a maximum of 400 mg/hour. In the event of an IAR during study treatment infusion, action will 
be taken as per Section 10.21, Metamizole (dipyrone) is prohibited in treating atezolizumab 
associated infusion-associated reactions, due to its potential for causing agranulocytosis. 
Guidelines for medical management of infusion-associated reactions are provided in Table 23. 
Criteria for optional premedication for IARs: 
• For a patient who has no IAR for the first 4 infusions: Premedication for the subsequent 
infusions is optional at the Investigator’s discretion. However, if during the subsequent 
infusions without premedication the patient experiences an IAR (any grade), 
premedication must be restarted for all subsequent infusions. 
• If a patient develops an IAR Grade ≤2 during their first infusion only and then experiences 
no further IARs during their next 3 infusions: The Investigator should discuss with the 
Sponsor Medical Monitor when considering omitting premedication for the next infusion. 
If no IAR is observed for the next infusion without premedication, premedication is 
optional for the subsequent infusions at the Investigator’s discretion. However, if during 
the next infusion without premedication the patient experiences an IAR (any grade), 
premedication must be restarted for all subsequent infusions. 
To minimize the risk of potential immune-related TEAEs related to atezolizumab, the exclusion 
criteria in the current study include: 
• Treatment-related immune-mediated (or immune-related) AEs from immune-modulatory 
agents (including but not limited to anti-CTLA-4 mAbs) 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. 
• Comorbidity requiring systemic corticosteroid therapy (>10 mg prednisone/day or 
equivalent for patients with HCC, SCCHN, and EOC). 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. 
• Active, known, or suspected autoimmune disease.  
• History of or current interstitial lung disease or pneumonitis (radiation pneumonitis in the 
radiation field is permitted); history of thoracic radiation received thoracic radiation 
therapy of >30 Gy within 6 months of the first dose of trial treatment. 
• History of moderate immune-mediated ADRs (eg, colitis, hepatitis, etc). 
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Additionally, careful monitoring of AEs and laboratory abnormalities, continuous direct 
communication between the Investigators and the monitoring team, and the adherence to the dose 
modification rules specified in the study protocol, are the continuous measures that will minimize 
the risks in study participants. 
General guidelines for the management of irAEs, including some specific irAEs such as 
pneumonitis, hepatitis, colitis, myocarditis, meningoencephalitis, pancreatic AEs, endocrine AEs, 
ocular AEs, dermatologic AEs, neurologic AEs, are provided in Appendix 21: Section 10.21).  
2.3.5 Conclusion  
Overall, the anticipated benefit/risk ratio of isatuximab in combination with atezolizumab 
supports the conduct of study ACT15377 in patients with advanced HCC, SCCHN, EOC, and 
GBM. 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of ACT15377 may be found in the Investigator’s Brochure  
SAR650984 – Isatuximab and Investigator’s Brochure-atezolizumab. 
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3 
OBJECTIVES AND ENDPOINTS  
Table 1 - Objectives and endpoints  
Objectives 
Endpoints 
Primary 
• 
Phase 1: To characterize the safety and tolerability of 
isatuximab in combination with atezolizumab in 
participants with unresectable hepatocellular 
carcinoma (HCC), platinum-refractory 
recurrent/metastatic squamous cell carcinoma of the 
head and neck (SCCHN), platinum-
resistant/refractory epithelial ovarian cancer (EOC), 
or recurrent glioblastoma multiforme (GBM), and to 
determine the recommended Phase 2 dose (RP2D). 
• 
DLTs (in Cycle 1), adverse events (AEs)/serious 
adverse events (SAEs), and laboratory abnormalities. 
• 
MTD defined as the highest dose level at which no 
more than 1 out of 6 participants (starting dose or 
DL-1) or 2 out of 12 participants (starting dose) 
experience an IMP related DLT. 
• 
RP2D defined as the dose selected for the Phase 2 
portion. 
• 
Phase 2: To assess response rate (RR) of isatuximab 
in combination with atezolizumab in participants with 
HCC or SCCHN or EOC. 
• 
RR defined as the proportion of patients with 
complete response and partial response as best 
overall response (assessed by Investigators using 
RECIST 1.1 see Appendix 11: Section 10.11). 
• 
Phase 2: To assess the progression free survival rate 
at 6 months (PFS-6) of isatuximab in combination 
with atezolizumab, or as a single agent in participants 
with GBM 
• 
PFS-6 defined as the PFS rate at 6 months 
(assessed by Investigators using Response 
Assessment for Neuro-Oncology [RANO] criteria). 
Secondary 
• 
To evaluate the safety (in Phase 2) profile of 
isatuximab monotherapy (GBM only), or in 
combination with atezolizumab 
• 
AEs/serious AEs and laboratory abnormalities (in 
Phase 2) 
• 
To evaluate the immunogenicity of isatuximab and 
atezolizumab 
• 
Incidence rate of anti-drug antibodies development 
(ADA: anti-isatuximab and anti-atezolizumab 
antibodies) 
• 
To characterize the pharmacokinetic (PK) profile of 
isatuximab single agent (GBM only) and 
atezolizumab in combination with isatuximab. 
• 
PK assessed from concentrations of isatuximab 
(non-compartmental analysis and population 
PK approach) and atezolizumab (population 
PK approach). 
• 
To assess overall efficacy of isatuximab in 
combination with atezolizumab, or single agent (GBM 
only) 
• 
Best percent-change from baseline in Tumor burden 
change, disease control rate (DCR) defined as the 
sum of the complete response, partial response and 
stable disease rates, duration of response (DoR), 
PFS (HCC, SCCHN, EOC per RECIST 1.1 and GBM 
per RANO), RR (GBM only, per RANO criteria) 
Tertiary/exploratory 
• 
To explore additional efficacy parameters of 
isatuximab in combination with atezolizumab, or 
single agent (GBM only). 
• 
For participants with HCC, SCCHN, and EOC: 
- 
RR, DCR, DoR, and PFS by modified Response 
Evaluation Criteria in Solid Tumors for 
immune-based therapies (iRECIST 
(see Appendix 16 Section 10.16), 
 
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Objectives 
Endpoints 
- 
Time to response (TTR), time to progression 
(TTP) based on RECIST 1.1 and iRECIST, and 
overall survival (OS). 
• 
For participants with HCC: 
- 
Alpha-fetoprotein (AFP) reduction from baseline 
and relation with clinical response. 
• 
For participants with EOC: 
- 
CA125 response by Gynaecologic Cancer 
Intergroup (GCIG) criteria  
(See Appendix 17: Section 10.17) and relation 
with clinical response. 
• 
For participants with GBM:  
- 
RR, DCR, DoR, and PFS by Immunotherapy 
Response Assessment in Neuro-Oncology 
(iRANO) (See Section 10.18), 
- 
OS-6 defined as the overall survival rate at 
6 months, 
- 
TTR, TTP (based on RANO and iRANO) and 
OS. 
• 
To evaluate the relationships between clinical 
response and tumor markers as potential predictive 
biomarkers of response.  
• 
The relationship between clinical response and CD38 
expression (in infiltrating immune cells and tumor 
cells), PD-L1 expression (in tumor cells) and immune 
contexture in tumor at baseline. 
• 
To explore immune genetic markers which are 
important for effector functions of Isatuximab as 
potential predictive markers of response. 
• 
Immune genetic determinants (such as 
polymorphisms in FCγR receptors) in blood at 
baseline. 
• 
To perform PK/pharmacodynamics analysis if 
possible with any relevant pharmacodynamics 
markers mentioned above, and correlation with 
safety/efficacy endpoints. 
• 
Pharmacodynamic biomarkers in response to IMP: 
immunophenotype in peripheral blood, immune 
contexture in tumor biopsies and cytokine levels in 
plasma or serum from peripheral blood. 
• 
Tumor mutational profile will be analyzed at baseline 
and upon treatment in plasma cell free DNA from 
peripheral blood and correlated to response to IMP. 
• 
If sufficient clinical response is observable in Phase 1 
and Phase 2 Stage 1 patients, analysis of Isatuximab 
enzymatic activity might be performed at baseline 
and upon treatment by measuring metabolites in 
plasma or serum from peripheral blood and 
correlated to response to IMP. 
• 
If sufficient clinical response is observable in Phase 1 
and Phase 2 Stage 1 patients, further 
characterization of the immune response might be 
performed by analysing humoral and T cell adaptive 
immune response at baseline and upon treatment in 
peripheral blood and correlated to response to IMP. 
• 
Determination of exposure-response relationships 
with efficacy, safety, and biomarkers, if possible. 
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3.1 
APPROPRIATENESS OF MEASUREMENTS  
Each of the efficacy and safety assessments chosen for use in this study is considered well 
established and relevant in a hemato-oncology setting. In addition, suitable steps have been built 
into each of these assessments to ensure their reliability and accuracy and to minimize any risks to 
patient safety. 
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4 
STUDY DESIGN  
4.1 
OVERALL DESIGN  
This is a Phase 1/2 open-label, non-randomized, multi-center, safety, preliminary efficacy, and 
PK study of isatuximab in combination with atezolizumab, or isatuximab alone in participants 
with advanced malignancies. The study will be conducted in 2 parts (see Section 1.2 for study 
design schema): 
4.1.1 Phase 1 (safety run-in):  
Participants with HCC, SCCHN, EOC, or GBM will be enrolled in Phase 1.  
Starting dose and de-escalation design: 
Starting dose is 1200 mg once every 3 weeks (Q3W) for atezolizumab with isatuximab given 
10 mg/kg once weekly (QW) for 3 weeks followed by Q3W (atezolizumab given first). The table 
below (Table 2) details the dosing schedule modification for Phase 1. Based on safety, alternative 
dosing schedule may be considered. Overall safety monitoring will be performed throughout the 
conduct of the study. 
Table 2 - Dosing schedule modification for Phase 1  
Dose level (DL) 
Isatuximab 
Atezolizumab 
Starting dose 
10 mg/kg 
QW × 3 ->Q3W 
1200 mg 
Q3W 
Minus -1 
(DL-1) 
5 mg/kg 
QW × 3 ->Q3W 
1200 mg 
Q3W 
Abbreviations: DL: Dose level; QW: once weekly, Q3W: once every 3 weeks. 
The DLT observation period is 1 cycle (21 days). 
At starting dose, up to approximately 8 patients will be treated and decision will be based on the 
DLTs assessed in the first 6 DLT-evaluable participants (1 cycle, 21 days): 
• If ≤1/6 participant has DLT, the starting dose will be the RP2D. 
• If 2/6 participants have DLT, 6 additional participants will be enrolled at starting dose 
level: 
- 
If a total of 2/12 participants treated at starting dose have DLT, starting dose will be 
the RP2D, 
- 
If a total of ≥3/12 participants have DLT, dose will be de-escalated to dose level minus 
1 (DL-1). 
• If ≥3/6 participants have DLT, dose will be de-escalated to DL-1. 
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An additional 6 participants may be enrolled at DL-1: 
• If ≤1/6 participant has DLT, DL-1 will be the RP2D. 
• If 2/6 participants have DLT, 6 additional participants will be enrolled at DL-1: 
- 
If a total of 2/12 participants treated at starting dose have DLT, DL-1 will be the 
RP2D, 
- 
If a total of ≥3/6 or ≥3/12 participants have DLT, an alternative dose/schedule might 
be considered from a safety viewpoint by the Sponsor. 
Investigational medical product initiation in each patient treated in Phase 1 is to be staggered by at 
least 3 days.  
Dose limiting toxicity: 
Any AEs specified below occurring during the first cycle of treatment, unless due to disease 
progression or an obviously unrelated cause will be considered a DLT, if confirmed by the Study 
Committee. The duration of the DLT observation period will be longer for participants who delay 
initiation of Cycle 2 due to treatment-related AE for which the duration must be assessed in order 
to determine if the event is a DLT. The NCI-CTCAE version 4.03 will be used to assess the 
severity of AEs. 
Hematological abnormalities are defined as any of the following: 
• Grade 4 neutropenia for 7 or more consecutive days. 
• Grade 3 to 4 neutropenia complicated by fever (temperature ≥38.5°C on more than 
1 occasion) or microbiologically or radiographically documented infection. 
• Grade 3 thrombocytopenia associated with clinically significant bleeding requiring clinical 
intervention, or Grade 4 thrombocytopenia. 
Non-hematological abnormalities 
• Findings consistent with a Hy’s law case, consisting of all the following 3 components: 
- 
Grade ≥2 AST or ALT elevation simultaneous with Grade ≥2 total bilirubin elevation 
without initial findings of cholestasis (such as elevated serum alkaline phosphatase 
[ALP]), 
- 
No other reason can be found to explain the combination of increased AST or ALT 
and bilirubin, such as viral hepatitis A, B, or C, pre-existing or acute liver disease 
(such as HCC or liver metastasis), or in absence of another drug capable of causing the 
observed injury. 
• Grade 4 non-hematologic AE, except: 
- 
Either Grade 4 AST, Grade 4 ALT, or bilirubin elevation Grade 4 that improve to 
Grade ≤2 within 3 weeks of onset for participants with SCCHN, EOC, or GBM 
without liver metastasis, 
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- 
Either Grade 4 AST, Grade 4 ALT, or bilirubin elevation Grade 4 that improve to 
Grade ≤3 within 3 weeks of onset for participants with liver metastasis or HCC with 
abnormal baseline value (ie, Grade 1 or 2), 
- 
Grade 4 laboratory abnormality that is resolve within 3 days with or without 
therapeutic intervention. 
• Grade 3 to 4 cytokine release syndrome. 
• Grade 3 non-hematological AE lasting >3 days with optimal supportive care, except: 
- 
Grade 3 fatigue, 
- 
Allergic reaction/hypersensitivity attributed to isatuximab or atezolizumab, 
- 
Grade 3 laboratory abnormality that is asymptomatic, 
- 
Either Grade 3 AST, Grade 3 ALT, or bilirubin elevation Grade 3, for participants with 
liver metastasis or HCC with abnormal baseline value (ie, Grade 1 or 2), 
- 
Grade 3 nausea, vomiting, or diarrhea if well controlled by systemic medication within 
7 days, 
- 
Grade 3 immune-related AE that improves to Grade ≤1 within 3 weeks of onset, 
- 
Grade 3 arthralgia that can be adequately managed with supportive care or that 
improves to Grade ≤2 within 7 days, 
- 
Grade 3 elevation of serum creatinine that is not accompanied by elevations in blood 
urea nitrogen (BUN) or other signs of renal injury or that can be attributed to other 
etiologies such as disease-related obstructions, 
- 
Grade 3 autoimmune thyroiditis or other endocrine abnormality that can be managed 
by endocrine therapy or hormone replacement, 
- 
Grade 3 infusion reaction, 
- 
Grade 3 skin rash that improves to Grade ≤1 within 7 days with appropriate supportive 
care. 
• Delay in initiation of Cycle 2 more than 14 days due to treatment-related laboratory 
abnormalities/AE. 
• In addition, any other AE that the Study Committee deems to be dose limiting, regardless 
of its grade, may also be considered as DLT. 
Maximum tolerated dose and Recommended Phase 2 dose:  
Any DLT observed during Cycle 1, and also overall safety including all the AEs occurring during 
treatment, unless due to disease progression or an obviously unrelated cause, will be taken into 
consideration by a Study Committee for the determination of the MTD and RP2D for the 
isatuximab and atezolizumab combination. 
The MTD is defined as the highest dose level at which no more than 1 out of 6 participants 
(starting dose or DL-1) or 2 out of 12 participants (starting dose) experience an IMP related DLT. 
The RP2D is defined as the dose selected for the Phase 2 portion.  
Following the identification of the RP2D, Phase 2 will be initiated. 
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4.1.2 Phase 2 (efficacy signal search with a 2-stage design in each cohort):  
Phase 2 may include up to 9 cohorts: Cohorts A, B, C, and D-1 will be initiated in parallel, while 
other cohorts of the same tumor type will be open depending on results observed at the end of 
Stage 2 of the corresponding initial tumor type cohort. 
• Cohort A: HCC, isatuximab and atezolizumab combination. 
• Cohort B: SCCHN, isatuximab and atezolizumab combination. 
• Cohort C: EOC, isatuximab and atezolizumab combination. 
• Cohort D-1: GBM, isatuximab and atezolizumab combination. 
• Possibly Cohort D-2: GBM, isatuximab monotherapy. 
• Possibly Cohort E: isatuximab and atezolizumab combination in participants with one 
tumor type (HCC, SCCHN, EOC, or GBM), or isatuximab monotherapy (GBM only), 
without initial isatuximab weekly dosing. 
A 2-stage design will be used in each cohort. Enrollment in Cohort D-2 may start only if clinical 
benefit is observed in Cohort D-1 at the end of Phase 2 Stage 2 as determined by the Sponsor after 
consulting with Study Committee. 
The participants treated at the RP2D of isatuximab and atezolizumab in combination during 
Phase 1 will be included in the efficacy analysis together with participants of the same tumor type 
in Phase 2 Stage 1. Based on the predefined number of objective responses  in participants with 
SCCHN, HCC, EOC, or the predefined PFS-6 in participants with GBM, as well as any other 
relevant data observed within a treatment cohort in Phase 2 Stage 1, the study will proceed with 
Phase 2 Stage 2. After enrollment completion of Phase 2 Stage 1, if efficacy results do not warrant 
initiation of Stage 2, enrollment will be paused until sufficient results or analyses warrant 
initiation of Phase 2 Stage 2. In the case of inadequate efficacy for a cohort at interim analyses, 
the Sponsor will notify study sites regarding modification or termination of study 
procedures/scheduled activities for patients in that specific cohort. 
For participants with GBM, if clinical benefit is observed in Cohort D-1 at the end of Phase 2 
Stage 2 as determined in Section 9.2, an isatuximab monotherapy cohort may be initiated 
(Cohort D-2). Participants with GBM will be enrolled into Cohort D-2, isatuximab monotherapy 
(Phase 2 Stage 1). The isatuximab single agent dose and schedule for Cohort D-2 will be 
determined based on results from Cohort D-1. 
Based on the positive efficacy signal and the totality of data observed within a treatment cohort at 
end of Phase 2 Stage 2, the Sponsor may decide to further study in the same indication either 
isatuximab Q3W in combination with atezolizumab, or isatuximab Q3W as monotherapy in 
participants with GBM. This schedule without the initial weekly dosing may be more practical for 
participants and health care providers. Objectives and study design considerations for these 
cohorts are the same as those for other cohorts in the same tumor type, respectively. 
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4.2 
DURATION OF STUDY PERIOD (PER PARTICIPANT)  
The duration of the study for a participant will include a screening period (up to 28 days), a 
treatment period (up to 2 years), a safety follow-up period (90 days), and every 90 days follow-up 
visits or phone calls until death or study cut-off. 
Treatment period: The cycle duration is 21 days. Participants will continue treatment until 
disease progression confirmed by imaging 4 weeks after initial evidence of progression, 
unacceptable AE, patient’s decision to stop treatment, 2 years of uninterrupted delivery of IMP(s) 
without documented PD. 
Safety follow-up period: After treatment discontinuation, participant will return to the study site 
30 days (±7 days) after the last dose of IMP(s), or when the participant receives another 
anti-cancer therapy, whichever is earlier, for EOT assessments. In addition, there will be an 
extended safety follow-up period for 90 days after the last dose of IMP(s) for ADA assessment 
and for safety assessment. 
Participants who discontinue the study treatment without PD will be followed at 90 days 
(±7 days) for disease assessment. 
Survival follow-up period: The further follow-up schedule beyond 90 days after last dose of 
IMP(s) is according to the disease progression status: 
• Participants who discontinue study treatment due to PD: phone call follow-up will be done 
every 90 days from the date of last IMP(s) administration until death or study cut-off date. 
• Participants who discontinue the study treatment without PD: will be followed every 
90 days for disease assessment until confirmation of PD or start treatment with another 
anti-cancer therapy, or until study cut-off date whichever comes first. After PD, participant 
will be followed by phone call until death or study cut-off date. 
• Participants who are still on study treatment after study cut-off date: will continue to 
receive study treatment if they benefit, and will undergo planned study procedures (except 
PK and ADA) until confirmation of PD, or start with another anti-cancer therapy, or 
treatment period ended, whichever comes first. All SAEs still ongoing at the end of the 
study treatment, and all AEs considered related to study treatment still ongoing or 
occurring after the end of study treatment, which will be followed until 
resolution/stabilization. 
4.3 
SCIENTIFIC RATIONALE FOR STUDY DESIGN  
This is a Phase 1/2 open-label, non-randomized, multi-center, safety, preliminary efficacy, and 
PK study of isatuximab (SAR650984) in combination with atezolizumab or isatuximab alone in 
patients with advanced malignancies. 
Treatment beyond the second or third line in those 4 indications remains challenging with a 
significant unmet need for patients with advanced malignancies.  Combination strategies with 
immunotherapy agents have a potential to increasing their individual effectiveness in these 
patients. 
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Phase 1 is designed to characterize the safety and tolerability of isatuximab in combination with 
atezolizumab in patients with unresectable HCC, platinum-refractory recurrent/metastatic 
SCCHN, platinum-refractory EOC, or recurrent GBM, and to confirm the RP2D. 
Phase 2 is designed to assess RR of isatuximab in combination with atezolizumab in patients with 
HCC, or SCCHN, or EOC and to assess the PFS rate at 6 months (PFS-6) of isatuximab in 
combination with atezolizumab, or as a single agent in patients with GBM. 
4.4 
JUSTIFICATION FOR DOSE  
Atezolizumab is administered as an IV infusion every 3 weeks at 1200 mg dose.  
A flat IV atezolizumab dose of 1200 mg Q3W was selected as this is the standard dose used in the 
approved indications (UC and NSCLC). 
In patients with MM, isatuximab exhibits non-linear PK due to the presence of target-mediated 
drug disposition. In addition, tumor burden impacts the PK of isatuximab. 
Based on safety, efficacy, PK, and PK/pharmacodynamic analyses, the dose/schedule of 
isatuximab when used in combination with other therapies for the treatment of MM is 10 mg/kg 
QW × 4 followed by once every 2 weeks (Q2W). The half-life of isatuximab associated to the 
linear elimination is 18 days and we hypothesized that the immuno-modulatory mechanisms of 
isatuximab will be mainly involved in the pharmacological activity of isatuximab; therefore, a less 
intensive schedule of administration for isatuximab is proposed compared to the schedule used in 
patients with MMs: 10 mg/kg QW × 3 followed by Q3W.  Of note, based on updated 
pharmacokinetic characterization of isatuximab in 2019, the plasma half-life has been 
re-estimated to 28 days. 
Based on safety, efficacy, PK, and PK/pharmacodynamic data analyses, the dose/schedule of 
isatuximab when used as monotherapy for the treatment of MM is 20 mg/kg QW × 4 followed by 
Q2W. However, based on the reasons mentioned above and the hypothesis that tumor burden will 
be lower in patients with HCC, or SCCHN, or EOC, or GBM cancer compared to MM (ie, less 
target-mediated drug disposition), and because isatuximab monotherapy demonstrated activity at 
doses ≥10 mg/kg with no clear dose response between 10 mg/kg and 20 mg/kg, 10 mg/kg  
QW × 3 followed by Q3W is proposed to be tested in the monotherapy arm of this study. 
Once the plan of care is established with isatuximab 10 mg/kg QW × 3/Q3W, Q3W may be tested 
as the loading period may not be necessary to ensure activity. 
4.5 
END OF STUDY DEFINITION  
A participant is considered to have completed the study if he/she has completed all phases of the 
study including the last visit or the last scheduled procedure shown in the Schedule of Activities 
(SoA). 
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The end of study will occur at the study cut-off planned at 12 months after the last participant 
enters the study or when all participants have had the opportunity to complete the EOT visit 
30 days after the last study treatment administration, whichever is the latest. 
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5 
STUDY POPULATION  
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1 
INCLUSION CRITERIA  
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
I 01. Participant must be at least 18 years of age, at the time of signing the informed consent. 
Type of participant and disease characteristics 
I 02. For HCC, SCCHN, and EOC, disease location amenable to mandatory tumor biopsy at 
baseline (unless clinically unfeasible and after discussion with Sanofi Medical Monitor in 
Phase 1 and Phase 2 Stage 1, mandatory in Phase 2 Stage 2), and at Cycle 2 Day 1 if 
clinically feasible. Fine needle aspirates are not acceptable. Needle or excisional biopsies, 
or resected tissue are required. Provision of archival tumor tissue sample obtained at the 
time of or after progression of immediate previous line of anti-cancer treatment is allowed 
to replace mandatory baseline biopsy. For GBM, it is mandatory to provide archival tumor 
tissue sample. The biopsy taken at baseline and potentially Cycle 2 Day 1 should be from a 
lesion not previously irradiated (preferred), or the new growth area of a lesion that grows 
after irradiation. 
I 03. At least one measurable lesion for HCC, SCCHN, EOC (per RECIST 1.1  
[Appendix 11: Section 10.11]). Tumor lesions previously irradiated, or received other 
locoregional therapy, are usually not considered measurable unless there has been 
documented progression in the lesion. 
I 04. Based on the Investigator’s judgement, at this time, other anti-cancer therapy is not the 
best option for this specific patient. 
For patients with HCC: 
I 05. Histologically confirmed unresectable HCC (excluding fibrolamellar and mixed 
hepatocellular/cholangiocarcinoma). Radiology diagnosed HCC as per American 
Association for the Study of Liver Diseases criteria needs to be confirmed by histology 
before initiation of IMP. 
I 06. Barcelona Clinic Liver Cancer (BCLC) Stage C disease, or BCLC Stage B disease not 
amenable to locoregional therapy or refractory to locoregional therapy, and not amenable 
to a curative treatment approach (see Appendix 12: Section 10.12). 
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I 07. Child Pugh Class A liver score within 14 days of initiation of IMP  
(see Appendix 13:  Section 10.13). 
I 08. Documentation of progressive disease (PD) during or after treatment with either sorafenib 
or lenvatinib, or intolerance to the therapy. Intolerance is defined as permanent 
discontinuation of sorafenib or lenvatinib due to occurrence of ≥CTCAE Grade 2 
treatment-related adverse event (AE) which (1) persisted in spite of comprehensive 
supportive therapy according to institutional standards AND (2) persisted or recurred after 
sorafenib or lenvatinib treatment interruption of at least 7 days and dose reduction by one 
dose level. 
For patients with SCCHN: 
I 09. Histologically confirmed recurrent or metastatic SCCHN (oral cavity, pharynx, larynx), 
not amenable to local therapy with curative intent (surgery or radiation therapy with or 
without chemotherapy). 
I 10. Documentation of tumor recurrence or PD within 6 months of last platinum-based therapy 
in primary (ie, unresectable locally advanced disease with radiation), recurrent, or 
metastatic setting. Clinical progression after platinum-based therapy is defined as 
progression of a lesion at least 10 mm in size that is amenable to caliper measurement  
(eg, superficial skin lesion as per RECIST 1.1) or a lesion that has been visualized and 
photographically recorded with measurements and shown to have progression are eligible. 
I 11. Received and failed up to 2 lines of prior systemic anti-cancer therapy. A line of systemic 
chemotherapy is defined as any chemotherapy that was administered as part of primary 
therapy for SCCHN (eg, induction or concurrent chemo-radiotherapy) or any single-agent 
or multiple-agent chemotherapy regimen that was administered after a diagnosis of 
recurrent and/or metastatic SCCHN. 
I 12. Resting baseline O2 saturation by pulse oximetry of  ≥92% at rest. 
For patients with EOC: 
I 13. Histologically confirmed advanced epithelial ovarian, fallopian tube, or peritoneal cancer, 
excluding mucinous histology but including malignant mixed Müllerian tumors with high 
grade serous component. 
I 14. Platinum-resistant/refractory disease (specific to France only: see definition to I14 in 
Section 10.8.1): 
- 
Received up to 3 lines of prior platinum-containing therapy when the disease was 
platinum-sensitive, and, 
- 
The patients should not have received any systemic therapy for 
platinum-resistant/refractory disease. Platinum-resistant/refractory disease is defined 
as PD within 6 months following the last administered dose of platinum-containing 
therapy (resistant), or lack of response or disease progression while receiving the most 
recent platinum-containing therapy (refractory), respectively, 
- 
Previous treatment with up to one line of PARP inhibitor therapy is allowed. 
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For patients with GBM: 
I 15. Have histologically confirmed glioblastoma.  Patients with the original histology as low 
grade glioma are NOT eligible. 
I 16. Documentation of PD or first recurrence during (after at least 12 weeks from completion of 
irradiation) or after temozolomide maintenance therapy for newly diagnosed GBM treated 
with 1st line radiotherapy plus concurrent temozolomide. PD occurred within 12 weeks 
from completion of irradiation can only be defined by (1) new enhancement outside of the 
radiation field, or (2) unequivocal histological confirmation. Patients who received 
additional surgery after first recurrence ARE eligible. 
Sex 
I 17. Male or Female 
Informed Consent 
I 18. Capable of giving signed informed consent as described in Appendix 1  
(Section 10.1.2) which includes compliance with the requirements and restrictions listed in 
the informed consent form (ICF) and in this protocol. 
5.2 
EXCLUSION CRITERIA  
Participants are excluded from the study if any of the following criteria apply: 
Medical conditions 
E 01. Eastern Cooperative Oncology Group (ECOG) performance status of ≥2 (for patients with 
HCC, SCCHN, and EOC), or Karnofsky performance score of ≤70 (for patients with GBM 
(see Appendix 14: Section 10.14). 
E 02. Predicted life expectancy <3 months. 
E 03. Active brain metastases or leptomeningeal metastases. Patients with asymptomatic central 
nervous system metastases which have been stable (defined as without evidence of 
progression by MRI for at least 28 days prior to initiation of IMP and any neurologic 
symptoms have returned to baseline) following treatment with surgery or radiation therapy 
are eligible. 
E 04. Symptomatic or impending cord compression at study entry, unless appropriately treated 
beforehand and remained clinically stable and asymptomatic. 
E 05. Comorbidity requiring systemic corticosteroid therapy (>10 mg prednisone/day or 
equivalent for patients with HCC, SCCHN, and EOC). 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. 
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E 06. Significant cardiac dysfunction such as New York Heart Association classification for 
chronic heart failure III-IV, symptomatic coronary artery disease, major clinically 
significant electrocardiogram (ECG) abnormality, clinically significant ventricular 
arrhythmias; myocardial infarction within 6 months; unstable, poorly controlled angina 
pectoris despite treatment. 
For patients with SCCHN: 
E 07. Histologically confirmed recurrent or metastatic carcinoma of the nasopharynx, squamous 
cell carcinoma of unknown primary, and salivary gland or non-squamous histologies 
(eg, mucosal melanoma). 
For patients with EOC: 
E 08. Non-epithelial tumor or ovarian tumors with low malignant potential (ie, borderline 
tumors, eg, low grade serous). 
For patients with GBM: 
E 09. Have more than 1 prior recurrence. 
E 10. Presence of diffuse leptomeningeal disease or extracranial metastases. 
E 11. Tumors primarily localized or originated from the brainstem or spinal cord. 
E 12. Requires treatment with dexamethasone >4 mg/day, or bioequivalent for at least 
3 consecutive days, within 2 weeks before initiation of IMP. 
E 13. Mental impairment that may compromise ability to give informed consent and comply 
with the requirements of the study. 
E 14. Uncontrolled seizure by medication. 
Prior/concomitant therapy 
E 15. Prior treatment with an agent (approved or investigational) that blocks CD38 (patients who 
had previously participated in a study with an anti-CD38 but have written confirmation 
they were on control arm are allowed). 
E 16. Prior treatment with an agent (approved or investigational) that blocks the PD-1/PD-L1 
pathway (patients who had previously participated in a study with an anti-PD-1/PD-L1 but 
have written confirmation they were on control arm are allowed). 
E 17. Prior intravenous (IV) cytotoxic chemotherapy, antineoplastic biological therapy within  
21 days from initiation of IMP, major surgery with 28 days from initiation of IMP; and 
prior oral cytotoxic chemotherapy, hormonal therapy, tyrosine kinase inhibitor therapy, or 
completed palliative radiotherapy within 14 days from initiation of IMP. 
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For patients with GBM: 
E 18. Received vascular endothelial growth factor (VEGF)/VEGF receptor directed therapy. 
E 19. Locally directed therapies (except radiotherapy) including but not limited to stereotactic 
radiosurgery, re-irradiation, Gliadel, and therapeutics administered by direct injection or 
convection-enhanced delivery within 6 months before initiation of IMP. 
Prior/concurrent clinical study experience 
E 20. Last dose of prior investigational agent within 28 days from initiation of IMP. 
Diagnostic assessments 
E 21. Inadequate organ and bone marrow function at the Screening visit: 
- 
White blood cell (WBC) <2000/mm3 (2.0 × 109/L), 
- 
Absolute neutrophil count (ANC) <1500/mm3 (1.5 × 109/L), 
- 
Platelets <100 × 109/L for patients with SCCHN, EOC and GBM; or <75 × 109 /L for 
patients with HCC. Platelet transfusion is not allowed within 7 days before the 
screening hematological test, 
- 
Hemoglobin <9 g/dL or <5.6 mmol/L (without transfusion within 1 week), 
- 
Total bilirubin >2 upper limit of normal (ULN), 
- 
Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) >3 × ULN 
(or >5 × ULN for patients with liver metastases or HCC), 
- 
For Phase 1, patients without pre-existing or acute liver disease (including viral 
hepatitis, HCC or liver metastasis), total bilirubin >1.5 × ULN, AST and/or 
ALT >2 × ULN, ALP >2.5 × ULN, 
- 
International normalized ratio (INR) >1.7 or prothrombin time >4 seconds above 
control for patients with HCC, 
- 
Albumin <2.8 g/dL for patients with HCC, 
- 
Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m2 (Modification of 
Diet in Renal Disease [MDRD] Formula). 
E 22. Prior solid organ or bone marrow transplantation. 
E 23. Treatment-related immune-mediated (or immune-related) AEs from immune-modulatory 
agents (including but not limited to anti-CTLA4-mAbs) 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. 
E 24. History of Grade 3 immune-mediated ADRs (eg, colitis, hepatitis, etc). 
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E 25. Ongoing AEs (excluding alopecia and fatigue) caused by any prior anti-cancer therapy 
>Grade 1 (NCI-CTCAE v4.03). 
E 26. Active, known, or suspected autoimmune disease. 
E 27. History of or current interstitial lung disease or pneumonitis (radiation pneumonitis in the 
radiation field is permitted); history of thoracic radiation received thoracic radiation 
therapy of >30 Gy within 6 months of the first dose of trial treatment. 
E 28. Receipt of a live-virus vaccination within 28 days of planned treatment start. Seasonal flu 
vaccines that do not contain live virus are permitted. 
E 29. Known additional 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, or in situ cervical cancer that has undergone potentially curative therapy). 
E 30. Women of childbearing potential (WOCBP) or male patients with female partners of 
childbearing potential not protected by highly effective method of birth control and/or who 
are unwilling or unable to be tested for pregnancy (see Appendix 4: Section 10.4). 
E 31. Pregnant or breastfeeding women or women who intend to become pregnant during 
participation in the study. 
E 32. Known intolerance or hypersensitivity to any component of isatuximab, atezolizumab, or 
pre-medication. 
E 33. History or current evidence of any condition, therapy, or laboratory abnormality that might 
confound the results of the trial, interfere with the patient’s participation for the full 
duration of the trial, or is not in the best interest of the patient to participate, in the opinion 
of the treating Investigator. 
E 34. Known uncontrolled HIV infection, active tuberculosis, or severe infection requiring 
parenteral antibiotic treatment. 
E 35. Known uncontrolled hepatitis B virus (HBV) infection: 
• Anti-HBV therapy started before initiation of IMP and HBV viral load <2000 IU/mL 
(104 copies/mL) are eligible. The anti-HBV therapy should continue throughout the 
treatment period. 
• Positive anti-HBc, anti-HBs, negative HBsAg, and HBV virus load without 
HBV therapy are eligible. 
E 36. Known untreated current HCV infection. 
• Anti-HCV therapy started before initiation of IMP are eligible. The anti-HCV therapy 
should continue throughout the treatment period until seroconversion. 
• Positive HCV antibody and undetectable HCV RNA without anti-HCV therapy are 
eligible. 
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For patients with HCC: 
E 37. Esophageal or gastric variceal bleeding within the past 12 weeks. 
E 38. Clinically apparent ascites on physical examination. Ascites detectable on imaging studies 
only ARE eligible. 
E 39. Complete portal vein or inferior vena cava occlusion, or cardiac involvement of HCC 
based on imaging. 
E 40. Clinically diagnosed hepatic encephalopathy within 3 months before initiation of IMP. 
E 41. Prior systemic therapy for HCC in the advanced (incurable) setting other than sorafenib or 
lenvatinib. 
E 42. Locoregional therapy to liver (transcatheter chemoembolization, transcatheter 
embolization, hepatic arterial infusion, radiation, radioembolization, or ablation) within 
4 weeks before initiation of IMP. 
5.3 
LIFESTYLE CONSIDERATIONS  
Not applicable. 
5.4 
SCREEN FAILURES  
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently treated. 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 details, eligibility criteria, 
and any SAE. 
Patient who does not meet protocol entry criteria may be rescreened once during the open 
screening period, providing he/she meets at that time all inclusion and exclusion criteria. A 
different patient identification will be issued, while the other identification for this patient should 
be recorded as Screen Failure. There is no requirement for a waiting period between a screen 
failure date and the rescreening date. Patients that are rescreened must sign a new consent form 
and all screening procedures must be repeated. 
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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  
INVESTIGATIONAL MEDICINAL PRODUCTS: 
Table 3 - Overview of study interventions administered  
Study intervention name 
Isatuximab 
Atezolizumab 
Dosage formulation 
Concentrated solution for infusion 
Concentrated solution for infusion 
Unit dose strength(s)/Dosage 
level(s) 
20 mg/mL (500 mg/25 mL) isatuximab in 20 mM 
histidine, 10% (w/v) sucrose, 0.02% (w/v) 
polysorbate 80, pH 6.0 
1200 mg/20 mL (60 mg/mL) 
Route of administration and 
duration 
Intravenous infusion as described in the 
pharmacy manual 
Intravenous infusion over 
60 (±15) minutes per administration. If 
the first infusion is tolerated, all 
subsequent infusions may be delivered 
over 30 (±10) minutes. 
Dosing instructions 
Phase 1 
Starting dose: 
Isatuximab: 10 mg/kg weekly for 3 weeks (QW × 3; ie. on D1, D8, and D15 of Cycle 1), 
then every 3 weeks (Q3W) (ie, on Day 1 of each 21-day cycle) 
Atezolizumab (administrated before isatuximab): 1200 mg Q3W, (ie, on Day 1 of each 
21-day cycle)  
Dose Level -1 (may be implemented if ≥3/12 with DLT or if ≥3/6 participants with DLT at 
starting dose): 
Isatuximab: 5 mg/kg QW × 3, then Q3W 
Atezolizumab (administrated before isatuximab): 1200 mg Q3W 
Phase 2:  
For the combination Cohorts A, B, C, and D-1, atezolizumab will be administered first 
followed by isatuximab on Day 1 of each cycle.  Isatuximab will be administered at the 
RP2D determined based on safety data from Phase 1. 
Monotherapy dose for GBM in Cohort D-2 will be determined based on results from 
Cohort D-1 and schedule of administration will be weekly for first cycle, followed by one 
dose every 3 weeks.  
For the possible Cohort E, implemented if positive results are observed in the Phase 2 
Stage 2 one tumor type (same as A, B, C, or D-1/D-2), atezolizumab will be administered 
first followed by isatuximab on Day 1 of each cycle (for combination regimen), and 
isatuximab will be administered at the RP2D determined based on safety data from 
Phase 1RP2D without initial isatuximab weekly dosing.  
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Study intervention name 
Isatuximab 
Atezolizumab 
Packaging and labeling 
In single dose vials 
30 mL (C1P2F2) glass vials fitted with 
elastomeric closure. 
The label contents will be in accordance with 
the local regulatory specifications and 
requirements. 
 
ISATUXIMAB will be presented as a 
concentrate for solution for infusion in vials 
containing 20 mg/mL (500 mg/25 mL) 
isatuximab in 20 mM histidine, 10% (w/v) 
sucrose, and 0.02% (w/v) polysorbate 80 at pH 
6.0 buffer. This product will be supplied for 
parenteral administration as a sterile, 
nonpyrogenic, injectable, 20 mg/mL concentrate 
for solution for infusion, essentially free of 
visible particulates. Each vial will contain a 
nominal content of 500 mg isatuximab C1P2F2. 
The fill volume will be established to ensure 
removal of 25 mL. 
For participant administration, the appropriate 
volume of isatuximab will be diluted in an 
infusion bag of 0.9% sodium chloride solution. 
The final infusion volume corresponding to the 
dose of isatuximab will be administered for a 
period of time that will depend on the dose 
administered and will be based on protein 
amount given per hour. 
Preferred diluents are: 
0.9% Sodium chloride for injection 100 mL, 
250 mL or 500 mL bags in polyolefins 
(so covers also polyethylene (PE) or 
polypropylene (PP)) or polyvinyl chloride (PVC) 
(with DEHP) Or Dextrose 5% for injection 100 
mL, 250 mL or 500 mL bags in polyolefins (so 
covers also PE or PP) or PVC (with DEHP). 
Detailed instructions for dilution of the 
isatuximab concentrate are provided in the 
Pharmacy Manual. 
In single dose vials 
Glass vial fitted with elastomeric 
closure. 
The label contents will be in 
accordance with the local regulatory 
specifications and requirements 
 
ATEZOLIZUMAB will be presented as 
a concentrate for solution for infusion in 
vials containing 60 mg/mL. Each 20 mL 
vial of concentrate contains 1200 mg 
atezolizumab. After dilution, 1 mL of 
solution contains approximately 4.4 mg 
of atezolizumab. 
Preferred diluents are: 
sodium chloride 9 mg/mL (0.9%) 
solution 
 
No incompatibilities have been 
observed between Tecentriq and 
intravenous bags with product-
contacting surfaces of PVC, PE or 
polyolefin. In addition, no 
incompatibilities have been observed 
with in-line filter membranes composed 
of polyethersulfone or polysulfone, and 
infusion sets and other infusion aids 
composed of PVC, PE, polybutadiene, 
or polyetherurethane. The use of in-line 
filter membranes is optional. 
 
Detailed instructions for dilution of the 
atezolizumab concentrate are provided 
in the Pharmacy Manual. 
Manufacturer 
Bulk Drug Product 
SANOFI AVENTIS DEUTSCHLAND GmbH 
FRANKFURT GERMANY Industriepark 
Höchst 65926 FRANKFURT GERMANY 
Manufacturer of the biological active 
substance  
F. Hoffmann-La Roche AG 
Grenzacherstrasse 124 4070 Basel 
SWITZERLAND  
Manufacturer responsible for batch 
release  
Roche Pharma AG Emil-Barell-Strasse 
1 79639 Grenzach-Whylen GERMANY 
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Rate and duration of infusion: 
The duration of infusion for atezolizumab is 1200 mg over 60 minutes per administration. If the 
first infusion is tolerated, all subsequent infusions may be delivered over 30 minutes. 
For isatuximab, the rate of infusion should be initiated at 175 mg/hour: 
• First infusion: initiate infusion at 175 mg/hour. In the absence of IARs after 1 hour of 
infusion, increase infusion rate by 50 mg/hour increments every 30 minutes, to a 
maximum of 400 mg/hour. 
• Subsequent infusions: initiate infusion at 175 mg/hour. In the absence of IAR after 1 hour 
of infusion, increase rate by 100 mg/hour increments every 30 minutes, to a maximum of 
400 mg/hour. 
NON INVESTIGATIONAL MEDICINAL PRODUCTS: 
Non investigational medicinal products will be locally sourced and formulation may vary. 
All participants will receive the following premedications to prevent or reduce incidence or 
severity of IARs, 30 to 60 minutes prior to the isatuximab infusion (no longer than 60 minutes). 
The premedication agents will consist of: 
• Acetaminophen 650 to 1000 mg oral route (PO) (or equivalent). 
• Ranitidine 50 mg IV (or equivalent). 
• Diphenhydramine 25 to 50 mg IV (or equivalent). 
• Methylprednisolone 100 mg IV (or equivalent). 
• Montelukast 10 mg oral route (PO) (or equivalent). 
Criteria for optional premedication for IARs: 
• For a patient who has no IAR for the first 4 infusions: Premedication for the subsequent 
infusions is optional at the Investigator’s discretion. However, if during the subsequent 
infusions without premedication the patient experiences an IAR (any grade), 
premedication must be restarted for all subsequent infusions. 
• If a patient develops an IAR Grade ≤2 during their first infusion only and then experiences 
no further IARs during their next 3 infusions:  The Investigator should discuss with the 
Sponsor Medical Monitor when considering omitting premedication for the next infusion. 
If no IAR is observed for the next infusion without premedication, premedication is 
optional for the subsequent infusions at the Investigator’s discretion. However, if during 
the next infusion without premedication the patient experiences an IAR (any grade), 
premedication must be restarted for all subsequent infusions. 
When isatuximab and atezolizumab are to be administrated on the same day, the administration 
sequence is: atezolizumab, followed by premedications, followed by isatuximab. 
When only isatuximab is to be administrated on a day, the administration sequence is: 
premedications, followed by isatuximab. 
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METHOD OF ASSIGNING PATIENTS TO THE STUDY: 
All patients who signed the study ICF will be assigned a patient number. Each patient will receive 
an incremental identification number per site corresponding to their order of enrollment in the 
study. Those patients, who meet all the inclusion criteria and none of the exclusion criteria, will 
be eligible for registration in the study.  
All eligible patients will be enrolled into the Phase 1 (safety run-in) of the study. Any proportion 
of patients with each tumor type can be enrolled. 
Once RP2D has been determined, eligible patients will then enter in parallel the Phase 2 part of 
Cohorts A, B, C, and D-1 depending on the type of tumor. If positive benefits observed from 
GBM Cohort D-1 Phase 2 Stage 2, an isatuximab monotherapy cohort (Cohort D-2) will be 
initiated for patient with GBM. 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY  
1. The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention and only authorized 
site staff may supply or administer study intervention. All study intervention must be 
stored in a secure, environmentally controlled, and monitored (manual or automated) area 
in accordance with the labeled storage conditions with access limited to the Investigator 
and authorized site staff. 
3. The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records). 
4. Further guidance and information for the final disposition of unused study interventions 
are provided in the pharmacy manual and/or monitoring plan. 
Any quality issue noticed with the receipt or use of an IMP (deficiency in condition, appearance, 
pertaining documentation, labeling, expiration date, etc) must be promptly notified to the Sponsor. 
Some deficiencies may be recorded through a complaint procedure. 
A potential defect in the quality of IMP may be subject to initiation of a recall procedure by the 
Sponsor. In this case, the Investigator will be responsible for promptly addressing any request 
made by the Sponsor, in order to recall the IMP and eliminate potential hazards. 
Under no circumstances will the Investigator supply IMPs to a third party (except for DTP 
shipment, for which a courier company has been approved by the Sponsor), allow the IMPs to be 
used other than as directed by this clinical trial protocol, or dispose of IMPs in any other manner. 
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Storage conditions: 
Isatuximab: Control of isatuximab storage conditions, especially control of temperature 
(eg, refrigerated storage), and information on in-use stability and instructions for handling the 
Sanofi compound should be managed according to the rules provided by the Sponsor. 
Isatuximab is to be stored at +2°C to +8°C (36°F to 46°F), protected from light. All vials must be 
kept in their box until use. No protection from light is required for storage in the infusion bags. 
Details of the storage conditions for the diluted solution are provided in the Pharmacy Manual. 
Atezolizumab: Control of atezolizumab storage conditions, especially control of temperature 
(eg, refrigerated storage), and information on in-use stability and instructions for handling the 
compound should be managed according to the rules provided by the Sponsor. 
Atezolizumab is to be stored at +2°C to +8°C (36°F to 46°F), protected from light. All vials must 
be kept in their box until use. No protection from light is required for storage in the infusion bags. 
Details of the storage conditions for the diluted solution are provided in the Pharmacy Manual. 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING  
This is an open-label, non-randomized study; therefore, blinding is not applicable. 
6.4 
STUDY INTERVENTION COMPLIANCE  
Administration of the IMP will be supervised by the Investigator or Sub-investigator. 
The person responsible for drug dispensing is required to maintain adequate records of the IMPs. 
These records (eg, drug movement form) include the date the IMPs are received from the 
Sponsor, dispensed to the participant and destroyed or returned to the Sponsor. The packaging 
batch number (IP number) and the treatment number on the vial must be recorded on the drug 
accountability form. The person responsible for drug administration to the participant will record 
precisely the date and the time of the drug administration to the participant. 
6.4.1 Return and/or destruction of treatments  
Partially-used and used study treatments will be destroyed at the study site according to the 
standard practices of the site after an accurate accountability has been performed and signed by 
the Investigator (or the pharmacist). A detailed treatment log form of the destroyed study 
treatment will be established with the Investigator (or the pharmacist) and countersigned by the 
Investigator and the Monitoring Team. 
The Investigator must not destroy the unused IMP unless Sanofi provides written authorization. 
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6.5 
CONCOMITANT 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.  
• Concomitant medications forbidden for use are described below: 
- 
Concurrent treatment with any other anti-neoplasm therapy not specified in the 
protocol, including chemotherapy, immunotherapy, hormonal therapy, targeted 
therapy, biological therapy, or other investigational drug or curative radiotherapy. 
However, palliative radiotherapy or procedures may be given to control symptoms. 
The irradiated area should be as small as possible. In all such cases, the possibility of 
tumor progression should be ruled out by physical, biochemical, and radiological 
assessments of the tumor. The irradiated area cannot be used as a parameter for 
response assessment, 
- 
Investigational therapy (other than protocol-mandated study treatment) is prohibited 
within 28 days prior to initiation of study treatment and during study treatment, 
- 
Concomitant systemic corticosteroids are prohibited, except for: 
- 
The participants with GBM or central nervous system lesions as an urgent 
treatment, 
- 
Use in the premedication defined in the study protocol, 
- 
Treatment of an irAE, 
- 
Treatment of any life-threatening emergency, 
- 
Physiologic replacement, as long as they are not being administered for 
immunosuppressive intent, and 
- 
A brief course (≤7 days) of systemic corticosteroid for prophylaxis (eg, contrast 
dye allergy) or for the treatment of non-autoimmune conditions (eg, delayed-type 
hypersensitivity reactions caused by contact allergen). 
- 
Live attenuated vaccines (eg, FluMist®) are prohibited within 4 weeks prior to 
initiation of study treatment, and for 5 months after the last dose of atezolizumab. 
Prophylactic vaccination that does not contain live virus is recommended for influenza 
A and B virus, pneumococci, and haemophilus influenza, 
- 
Prophylactic use of hematopoietic growth factors (eg, granulocyte colony-stimulating 
factor, granulocyte macrophage colony-stimulating factor, erythropoietin) during the 
DLT observation period. Curative treatment is allowed, 
- 
Systemic immunostimulatory agents (including, but not limited to, interferons and 
interleukin-2) are prohibited within 4 weeks or 5 half-lives of the drug, whichever is 
longer, prior to initiation of study treatment and during study treatment because these 
agents could potentially increase the risk for autoimmune conditions when given in 
combination with atezolizumab, 
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- 
Systemic immunosuppressive medications (including, but not limited to, 
cyclophosphamide, azathioprine, methotrexate, and thalidomide) are prohibited during 
study treatment because these agents could potentially alter the efficacy and safety of 
atezolizumab. 
Other concomitant medication may be considered on a case-by-case basis by the Investigator in 
consultation with the Medical Monitor if required. 
6.6 
DOSE MODIFICATION  
6.6.1 General rules  
Cycle delay (ie, delay of both IMPs for Cycle ≥2), dose delay of isatuximab within Cycle 1 or 
dose omission (ie, omission of either isatuximab or atezolizumab within a cycle for combination 
cohorts) are permitted in case of toxicity.  
Administration of the study treatment will be discontinued in the event of a TEAE that persists 
despite appropriate dose modifications or any other AE that, in the opinion of the Investigator, 
warrants discontinuation. 
There will be no dose adjustment for atezolizumab or isatuximab. 
If 1 of the 2 drugs (atezolizumab or isatuximab) is prematurely permanently discontinued, the 
other drug can be continued until disease progression confirmed by imaging no less than 4 weeks 
after initial evidence of progression, unacceptable AE, participant’s decision to stop the treatment, 
2 years of uninterrupted delivery of IMP without documented PD. The end of treatment (EOT) 
assessment in this case will be 30 days after the date of the last IMP administration. 
6.6.2 Dose delay and dose omission  
Within a cycle, the treatment window is ±1 day for each of the weekly isatuximab administrations 
and ±2 days for each of the Q3W administrations. Within a cycle, a dose is deemed to have been 
delayed if the treatment is ≥2 days beyond the theoretical day of treatment for weekly isatuximab 
dose, and ≥3 days beyond the theoretical day of treatment for Q3W cycle. The participant will 
receive the next infusion/cycle after recovery from the AE. 
Participants may have dose delay, cycle delay, or dose omission if an AE occurs and he/she does 
not recover according to the following rules: 
• In Cycle 1 (for weekly administration of isatuximab) if an AE occurs and the participant 
does not recover on the day of planned infusion or within the following 3 days, infusion of 
isatuximab (in D8 or D15) may be omitted. 
• In Cycle 2 and beyond, if an AE occurs and the participant does not recover on the day of 
planned infusion, the cycle will be delayed up to a maximum of 2 weeks. 
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• If the AE is not recovered within 14 days:  
- 
Study treatment may resume with one IMP and omission of the other. (Either 
isatuximab or atezolizumab) providing the participant’s benefit from the study 
treatment as per Investigator’s judgment, 
- 
Study treatment may be delayed up to 84 days, 
- 
After a cycle delay of >14 days and ≤84 days, or 2 to 4 consecutive dose omissions of 
one IMP, it is per Investigator’s decision to restart the study treatment or the IMP that 
is omitted, if a clear benefit from therapy is observed and after consultation with the 
Sponsor, 
- 
The study treatment must be definitely permanently discontinued if the cycle delay is 
longer than 84 days, or if more than 4 consecutive dose omissions of one IMP, the IMP 
will be prematurely discontinued. 
6.6.3 General Guidelines for Immune-Related Adverse Events (irAEs)  
Investigators must be extremely vigilant and be ready to intervene early in the management of 
immune-mediated AEs (irAEs) because the onset of symptoms of irAEs (eg, pneumonitis) may be 
subtle. 
Detailed guidance for the management of specific irAEs (colitis, endocrine AE, pneumonitis, 
dermatologic AE, hepatitis, ophthalmologic AE [uveitis], myocarditis, IARs, pancreatitis, 
neurologic, and meningoencephalitis), is provided in Appendix 21 (Section 10.21). 
• General guidance is provided in Table 4. 
• If a participant experiences several irAEs which involve different recommendations, the 
most conservative recommendation should be followed. 
The recommendations provided in Appendix 21 (Section 10.21) and Table 4 should be seen as 
guidelines, and the treating physician should exercise clinical judgment based on the symptoms 
and condition of the individual participant. 
Table 4 - General Guidelines for Immune-Related Adverse Events  
Severity 
Next administration Isatuximab 
and/or Atezolizumab 
Supportive care 
Grade 1 
No action 
Provide symptomatic treatment 
Grade 2 
May delay cycle 
Consider systematic corticosteroids (prednisone 0.5 to 
1 mg/Kg/day or equivalent) in addition to appropriate 
symptomatic treatment. 
Grade 3 
 
Grade 4 
Delay the cycle until the toxicity improves 
to Grade≤1 or baseline. 
Discontinue prematurely Atezolizumab if 
unable to reduce corticosteroid dose to 
<10 mg per day prednisone equivalent 
within 12 weeks of toxicity. 
For any (Grade 3-4) irAE, 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 adding 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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6.6.4 General guidelines for the management of infusion-associated reactions  
Participants should routinely receive premedications prior to isatuximab infusion as detailed in 
Section 6.1 to reduce the risk and severity of IARs commonly observed with mAbs. 
Infusion-associated reactions typically occur within 24 hours from the start of the infusion. 
If an IAR is observed, participants must also be informed of the potential risk of recurrent similar 
reactions at subsequent infusions. The guidelines for management of IARs, cytokine release 
syndrome, and anaphylactic reactions are summarized in Table 5. 
Participants who experience Grade 2 IARs may resume isatuximab/atezolizumab infusion after 
temporary interruption, under close monitoring and with therapy as needed.  
Participants may receive additional medication per the judgment of the Investigator. Additional 
recommended medications are: diphenhydramine 25 mg IV (or equivalent) and 
methylprednisolone 100 mg IV (or equivalent).   
Once a Grade 2 IAR has improved or resolved according to Table 5 and Metamizole (dipyrone) 
is prohibited in treating atezolizumab associated infusion-associated reactions, due to its 
potential for causing agranulocytosis. 
Guidelines for medical management of infusion-associated reactions are provided in Table 23. 
Table 23, the infusion may be restarted: 
• For atezolizumab, the infusion should be restarted at half the rate being given at the time 
of event onset. 
• For isatuximab, the infusion should be restarted at half (87.5 mg/h) the initial infusion rate. 
If symptoms do not recur after 30 minutes, the infusion rate may be increased in 
50 mg/hour increments every 30 minutes, to a maximum of 400 mg/hour. 
Participants with Grade 3 or 4 IAR must have atezolizumab and/or isatuximab prematurely 
permanently discontinued and appropriate therapy should be administered: 
• If a Grade 3 or higher IAR occurs during atezolizumab infusion, it should be prematurely 
permanently discontinued. The participant can continue treatment with isatuximab. 
• If a Grade 3 or higher IAR occurs after the start of isatuximab infusion, the participant 
should prematurely permanently discontinue treatment with both atezolizumab and 
isatuximab. 
Grade 2 or higher IARs for isatuximab and any grade IARs for atezolizumab must be reported as 
AESIs (see Section 8.3). Study personnel should consult the Medical Monitor for further guidance 
regarding re-treatment of participants with infusion reactions and regarding issues of 
premedication management (eg, alternative medications for participants allergic or intolerant to 
premedication agents), or to determine if locally used equivalent medications are acceptable. 
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Table 5 - Management Guidelines for Infusion-Associated Reactions  
Event 
Management Atezolizumab 
Management Isatuximab 
IAR, Grade 1  
Reduce infusion rate to half the rate being given 
at the time of event onset. 
After the event has resolved, the investigator 
should wait for 30 minutes while delivering the 
infusion at the reduced rate. 
If the infusion is tolerated at the reduced rate for 
30 minutes after symptoms have resolved, the 
infusion rate may be increased to the original 
rate. 
Continue isatuximab infusion per the judgment of 
the Investigator following close direct monitoring of 
the participant’s clinical status. 
Isatuximab infusion may be stopped at any time if 
deemed necessary. If stopped, IAR will be 
classified as Grade 2 as per NCI-CTCAE           
IAR, Grade 2 
Interrupt atezolizumab/isatuximab infusion. 
Administer aggressive symptomatic treatment (eg, oral or IV antihistamine, anti-pyretic medication, 
glucocorticoids, epinephrine, bronchodilators, oxygen). 
After symptoms have resolved to Grade ≤1 (for isatuximab) or baseline (for atezolizumab), resume 
infusion at half the initial infusion rate for isatuximab and at half the rate being given at the time of event 
onset for atezolizumab. 
For subsequent infusions, consider administration of oral premedication with antihistamines, 
anti-pyretics, and/or analgesics and monitor closely for IARs. 
-Blood samples for additional safety labs will be collected for isatuximab 
IAR*, Grade 3 or 4 
Stop infusion. 
Administer aggressive symptomatic treatment (eg, oral or IV antihistamine, anti-pyretic, glucocorticoids, 
epinephrine, bronchodilators, oxygen). 
Prematurely permanently discontinue atezolizumab or Isatuximab or permanently discontinue both 
atezolizumab and isatuximab and contact Medical Monitor.  
IAR = infusion-associated reaction; NCI-CTCAE = National Cancer Institute-common terminology criteria for adverse events 
* Applicable to Grade 3 or 4 cytokine release syndrome and anaphylactic reactions 
6.6.5 Retreatment of participants  
The participants must have recovered to NCI-CTC AE Grade ≤1 or to his/her baseline status 
before initiation of the next cycle at the same dose level. In those cases of clear clinical benefit, a 
participant will continue treatment until disease progression confirmed by imaging 4 weeks after 
initial evidence of progression as detailed in Section 4.2, unacceptable AE, participant’s decision 
to stop the treatment, 2 years of uninterrupted delivery of IMP without documented PD. 
A cycle is 21 days, and deemed to have been delayed if the treatment is >3 days beyond the 
theoretical day of treatment. The reason for dose delay will be provided. In the event of an AE 
causing a delay, including a DLT, in order for participants to be retreated, see Section 6.6 and 
Appendix 21 (Section 10.21) for retreatment recommendations. 
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6.7 
INTERVENTION AFTER THE END OF THE STUDY  
The IMPs will not be provided after the end of the treatment period. 
The participant’s treatment after discontinuation of last IMP will be at the discretion of the 
treating physician. 
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7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL  
7.1 
 DISCONTINUATION OF STUDY INTERVENTION   
The IMPs should be continued whenever possible.  
In case the IMP is stopped, it should be determined whether the stop can be made temporarily; 
permanent IMP discontinuation before disease progression should be a last resort. Any IMP 
discontinuation must be fully documented in the electronic case report form (eCRF). In any case, 
the patient should remain in the study until the documentation of progressive disease. 
Pregnancy will lead to definitive treatment discontinuation in all cases. 
Treatment with the IMPs or the last IMP should be discontinued in any of the following cases: 
• At the participant’s request, at any time and irrespective of the reason (participant’s 
decision), or at the request of their legally authorized representative without any effect on 
their care. 
“Legally authorized representative” is considered to be an individual or judicial or other body 
authorized under applicable law to consent on behalf of a prospective patient to the patient’s 
participation in the procedure(s) involved in the research.  
Participant’s decision for treatment should be distinguished from participant’s decision for 
follow-up visits and from participant’s decision for non-participant contact follow-up, eg, medical 
records check. 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 should be explicitly asked about the contribution of possible AEs to 
their decision to withdraw consent, and any AE information elicited should be documented. 
Preferably the participant should withdraw consent in writing and, if the participant or the 
participant’s representative refuses or is physically unavailable, the site should document any case 
of participant’s decision. 
• If, in the Investigator’s opinion, continuation of the study treatment would be detrimental 
to the participant’s well-being, such as: 
- 
Confirmation of disease progression, 
- 
Unacceptable AE, 
- 
Poor compliance to the study protocol, 
- 
Any other reason such as intercurrent illness that prevents further administration of 
study treatment (will be specified). 
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• Participant is lost to follow-up. 
• Completion of the 2 year treatment period. 
See the 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 permanent intervention discontinuation 
All permanent treatment discontinuation must be recorded by the Investigator in the appropriate 
screen of eCRF when considered as confirmed. After study treatment is discontinued, participants 
should complete a visit 30 days after the last administration of the IMP or before administration of 
further anti-cancer therapy, whichever is earlier as described in the Study reference manual. 
Participants who have been withdrawn from the study treatment cannot be re-entered into the 
study. 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. 
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. 
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. 
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. 
If participants no longer wish to take the IMP(s), they will be encouraged to remain in the study. 
The Investigators should discuss with them key visits to attend. The value of all their study data 
collected during their continued involvement will be emphasized as important to the public health 
value of the study. 
Participants who withdraw from the study intervention should be explicitly asked about the 
contribution of possible AEs to their decision, and any AE information elicited must be 
documented. 
All study withdrawals should be recorded by the Investigator in the appropriate screens of the 
eCRF and in the participant’s medical records. In the medical record, at least the date of the 
withdrawal and the reason should be documented. 
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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 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.  
7.4 
REPLACEMENT OF PARTICIPANTS  
During the Phase 1 part of the study, a participant may be considered not evaluable for DLT and 
may be replaced at the same dose level as described in Section 4.1.1. 
Participants treated in the Phase 2 part of the study who are withdrawn from study treatment will 
not be replaced. 
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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. 
• Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention. 
• 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  
The primary and secondary efficacy endpoint will be assessed by RECIST 1.1  
(Appendix 11: Section 10.11) criteria for participants with HCC, SCCHN and EOC. All 
participants treated must have at least one measurable intact lesion for inclusion (see Section 5.1, 
inclusion criterion I 04).  
For participants with GBM, efficacy will be assessed by RANO criteria  
(Appendix 15: Section 10.15). 
Tumor assessment will be performed at fixed intervals as described in SoA, and the assessment 
window is not impacted by dose delay or dose omission. 
All tumor assessment data should be recorded to related eCRF pages based on RECIST 1.1 
criteria (Appendix 11;Section 10.11). As a requirement of RECIST 1.1 criteria, 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. Based on RECIST for 
immunotherapies (iRECIST [Appendix 16: Appendix 16: Section 10.16]), progressive disease 
should also be confirmed on a second examination done at least 4 weeks apart to exclude pseudo 
progression.  
Exploratory efficacy endpoints will be assessed by iRECIST (Appendix 16: Section 10.16), for 
participants with HCC, SCCHN or EOC or iRANO (Appendix 18: Section 10.18), for participants 
with GBM and some biomarkers.  
Imaging should be available for a central review upon Sponsor’s request. 
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8.2 
SAFETY ASSESSMENTS  
Planned time points for all safety assessments are provided in the SoA. 
8.2.1 Physical examinations  
• A complete physical examination will include, at a minimum, assessments of the major 
body systems. Height only at baseline and weight will also be measured and recorded. 
• Performance status as measured by the ECOG (for HCC, SCCHN, and EOC) or 
Karnofsky scale (for GBM). 
• Investigators should pay special attention to clinical signs related to previous illnesses. 
• Any new finding or worsening of previous finding during treatment period should be 
reported as a new AE. 
8.2.2 Vital signs  
During treatment phase, vital signs are to be monitored just before starting infusion of the IMPs, 
every hour during the infusion, and at the end of infusion. Also to be performed as clinically 
indicated. 
• Temperature, pulse rate, respiratory rate, and blood pressure will be assessed. 
• Blood pressure and pulse measurements will be assessed with a completely automated 
device. Manual techniques will be used only if an automated device is not available. 
• Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest 
for the participant in a quiet setting without distractions (eg, television, cell phones). 
• Oxygen saturation (SCCHN only). 
8.2.3 Electrocardiograms  
• 12-lead ECG will be obtained as outlined in the SoA (see Section 1.3). 
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. Clinically significant abnormalities should be reported as AE, except for at the 
screening assessment if the detected finding is linked to a preexisting condition. In that case, the 
diagnosis should be recorded in the patient’s medical history.  
8.2.4 Clinical safety laboratory assessments  
See Appendix 2 (Section 10.3) for the list of clinical laboratory tests to be performed and to the 
SoA for the timing and frequency.  
• The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents. Clinically significant 
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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 and that either lead to IMP(s) discontinuation or dose modification 
or fulfill a serious or AESI definition (note: remaining laboratory tests are reported in 
eCRF pages for Hematology, Biochemistry). 
• All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or 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 eCRF.  
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS  
The safety of the participants in this clinical trial is primarily dependent on the clinical 
Investigator’s monitoring and assessment of their participants. 
After the occurrence of two patients with Grade ≥3 or one patient with Grade ≥4 reports of 
cytokine release syndrome or anaphylactic reactions, unless they result from an obviously 
unrelated cause, further enrollment will be halted until a thorough safety review is conducted and 
submitted to FDA for review. 
Adverse event of special interest 
An AESI is an AE (serious or non-serious) of scientific and medical concern specific to the 
isatuximab or atezolizumab programs, for which ongoing monitoring and immediate notification 
by the Investigator to the Sponsor is required. Such AEs 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. 
Dose limiting toxicities (as defined in Section 4.1) are considered as AESIs in the Phase 1 of this 
study, and as such, the Investigators will be required to report them to the Sponsor within 
24 hours of the Investigator becoming aware of the AE. The Investigator will attach the 
DLT-specific eCRF page to the DLT/AESI form. 
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The following conditions are also considered AESIs and as such, the Investigators will be 
required to report them to the Sponsor within 24 hours of the Investigator becoming aware of the 
AE: 
• Grade ≥2 acute IARs with isatuximab. 
• Any grade IARs with atezolizumab. 
• Grade ≥3 immune-related TEAEs. 
• Any grade of the following TEAEs with atezolizumab: pneumonitis, colitis, 
endocrinopathies (diabetes mellitus, pancreatitis, adrenal insufficiency, hyperthyroidism, 
and hypophysitis), systemic lupus erythematosus, neurologic disorders (Guillain-Barré 
syndrome, myasthenic syndrome, myasthenia gravis, and meningoencephalitis), nephritis, 
ocular toxicities, myositis, myopathies, vasculitis, and autoimmune hemolytic anemia. 
• Grade ≥2 cardiac disorders with atezolizumab. 
• Pregnancy of a female subject entered in a study as well as pregnancy occurring in a 
female partner of a male subject entered in a study with IMP/noninvestigational medicinal 
product (NIMP).  
Pregnancy occurring in a female participant entered in the clinical trial or in a female partner 
of a male participant entered in the clinical trial. It will be qualified as an SAE only if it fulfills 
one of the seriousness criteria (see Appendix 3 [Section 10.3]). 
- 
In the event of pregnancy in a female participant, IMP should be discontinued.  
- 
Follow-up of the pregnancy in a female participant or in a female partner of a male 
participant is mandatory until the outcome has been determined  
(See Appendix 4 [Section 10.4]) 
• Symptomatic overdose (serious or non-serious) with isatuximab/NIMP: 
- 
An overdose (accidental or intentional) with isatuximab is defined as an increase of at 
least 30% of the intended administered dose at each infusion (expressed in unit per 
body weight) to be administered in the specified duration or if the dose is administered 
in less than half the recommended duration of administration. 
- 
An overdose (accidental or intentional) with the NIMP is defined as increase of at least 
30% of the intended administered dose at each administration expressed in unit per 
body weight. 
- 
In case of accidental or intentional overdose with the IMP/NIMP, even not fulfilling a 
seriousness criterion, is to be reported to the Sponsor immediately (within 24 hours) 
using the AE form together with the SAE complementary form to be entered in the 
eCRF. 
• Of note, asymptomatic overdose has to be reported as a standard AE. 
The definitions of an AE or SAE can be found in Appendix 3 (Section 10.3). 
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An AE will be reported by the patient (or, when appropriate, by a caregiver, surrogate, or the 
patient's legally authorized representative).  
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study treatments (see Section 7).  
8.3.1 Time period and frequency for collecting AE and SAE information  
All the SAEs and AEs will be collected from the signing of the ICF until the last follow-up visit at 
the time points specified in the SoA (Section 1.3). 
All the SAEs and AESIs will be recorded and reported to the Sponsor or designee within 
24 hours, as indicated in Appendix 3 (Section 10.2). The Investigator will submit any updated 
SAE data to the Sponsor within 24 hours of them 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, or of a death, that occurs after the 
last dose of the IMP administration, and he/she considers the AE or outcome to be reasonably 
related to the study intervention or study participation, the Investigator must promptly notify the 
Sponsor. 
The method of recording, evaluating, and assessing the causal relationship of AEs and SAEs and 
the procedures for completing and transmitting SAE reports are provided in Appendix 3 
(Section 10.2). 
8.3.2 Method of detecting AEs and SAEs  
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/SAE report, the Investigator is required to proactively follow each participant 
at subsequent visits.  All SAEs and AESIs and related as defined in Section 8.3, will be followed 
until resolution, stabilization, or up to when the participant is lost to follow-up (as defined in 
Section 7.3). Further information on follow-up procedures is given in Appendix 3 (Section 10.2). 
8.3.4 Regulatory reporting requirements for SAEs  
• Prompt notification by the Investigator to the Sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met.  
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• 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 
(IRBs)/Independent Ethics Committees (IECs), and Investigators. 
• 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. The respective IBs of isatuximab and 
atezolizumab contain the Reference Safety Information (RSI) to be used in the 
determination of whether an ADR is to be considered expected.  
• An Investigator who receives an Investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will review 
and then file it along with the Investigator’s Brochure and will notify the IRB/IEC, if 
appropriate according to local requirements. 
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 5 months after 
the last dose of isatuximab (male and female participants) or atezolizumab (female 
participants only), whichever comes last. 
• 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, and ectopic pregnancy) are considered SAEs. 
8.3.6 Disease related events and/ or disease related outcomes not qualifying as AEs or 
SAEs  
The following disease related events (DREs) are common in patients with cancer and can be 
serious/life threatening: 
• Progression of underlying disease, as it is the study endpoint. 
• Death due to progression of underlying disease, if it occurs after 30 days of the last 
IMP administration. All other deaths that occur within the 30 days of last study 
intervention should be reported as a SAE. 
Because these events are typically associated with the disease under study, they will not be 
reported according to the standard process for expedited reporting of SAEs even though the event 
may meet the definition of a SAE. These events will be recorded on the corresponding page in the 
patient’s eCRF within the appropriate time frame. 
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8.3.7 Guidelines for reporting product complaints incidents (including malfunctions)  
Any defect in the IMP(s) 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  
There is no information on specific recommendations regarding overdose with isatuximab or 
atezolizumab. In case of overdose, patients should be closely monitored for signs or symptoms of 
adverse reactions, and appropriate symptomatic treatment should be instituted. 
In the event of an overdose, the Investigator should: 
1. Contact the Medical Monitor immediately. 
2. Closely monitor the participant for any AE/SAE and laboratory abnormalities. 
3. Document the quantity of the excess dose as well as the duration of the overdose in the 
eCRF. 
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant. 
8.5 
PHARMACOKINETICS  
8.5.1 Sampling time  
The sampling times for blood collection can be found in the PK and immunogenicity flow chart 
(Section 1.3). 
It is of utmost importance to collect all blood samples at the specified times and according to the 
specifications for collection, storage, and shipment as defined in a separate laboratory manual. 
Samples missed or lost, for any reason, should be recorded. Actual dates and times of blood 
collection should be recorded in the eCRF.  The dates and times of drug administration should 
also be precisely recorded. 
8.5.2 Pharmacokinetic sample handling procedure  
Detailed instructions for sample preparation and shipping for atezolizumab and isatuximab 
PK will be provided to the study sites in a separate Laboratory Manual. 
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8.5.3 Bioanalytical Methods  
Isatuximab in plasma and atezolizumab in serum will be analyzed by immunoassay.  Details will 
be provided in a separate Laboratory Manual.  
8.5.4 Pharmacokinetic parameters  
8.5.4.1 Non-compartmental analysis - isatuximab  
Pharmacokinetic parameters will be calculated with PKDMS software (Pharsight), using 
non-compartmental methods, from isatuximab plasma concentrations. The parameters will 
include, but may not be limited to, the following: 
Table 6 - List of pharmacokinetic parameters and definitions for isatuximab  
Parameters 
                Definition 
Ceoi 
Concentration observed at the end of intravenous infusion 
Cmax 
Maximum concentration observed after the first infusion 
tmax 
Time to reach Cmax 
Clast 
Last concentration observed above the lower limit of quantification after the first infusion 
tlast 
Time of Clast 
Ctrough 
Concentration observed just before treatment administration during repeated dosing 
AUC0-T 
Area under the plasma concentration versus time curve calculated using the trapezoidal method over the 
dosing interval (T; ie, 7 days for isatuximab) after the first infusion 
8.5.4.2 Population approach – isatuximab and atezolizumab  
In addition to atezolizumab, population PK approaches may be used for isatuximab. If done, the 
data generated will be reported in a separate stand-alone report(s). 
8.6 
PHARMACODYNAMICS  
Tumor biopsies* will be collected at baseline** and during treatment**, for the following 
pharmacodynamic biomarker analyses: 
• CD38 positive cells, PD-L1 positive cells and immune-contexture (such as T cells, B cells, 
activating or inhibitory receptors) by immunohistochemistry (IHC) or Fluorescent 
Multiplex IHC in formalin-fixed paraffin-embedded (FFPE) tumors. 
• Transcriptomic immune profiling by techniques such as NGS (RNAseq) on RNAlater 
preserved tumor if enough tumor material is available or by Nanostring on available 
FFPE tumor sample. 
*Fine needle aspirates are not acceptable. Needle or excisional biopsies, or resected tissue are 
required. Provision of adequate archival tumor tissue sample obtained at the time of or after 
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progression of immediate previous line of anti-cancer treatment is allowed to replace mandatory 
baseline biopsy. For GBM, it is mandatory to provide archival tumor tissue sample. The biopsy 
taken at baseline and potentially Cycle 2 Day 1 should be from a lesion not previously irradiated 
(preferred), or the new growth area of a lesion that grows after irradiation. 
** Tumor biopsy at baseline is mandatory (unless clinically unfeasible and after discussion with 
Sanofi Medical Monitor in Phase 1 and Phase 2 Stage 1, mandatory in Phase 2 Stage 2). During 
treatment, tumor biopsies will be taken at Cycle 2 Day 1, unless clinically unfeasible and after 
discussion with Sanofi Medical Monitor. Peripheral blood samples will be collected at baseline 
and during treatment, for the following pharmacodynamics biomarker analyses: 
Immunophenotyping to assess the immunomodulatory effects of isatuximab and atezolizumab. 
More particularly, immune cell subsets (such as B cells, T cells, NK cells, neutrophils, and 
regulatory cells), as well as immune regulatory markers (such as activating and inhibitory 
receptors) will be characterized by techniques such as flow cytometry at baseline, during, and 
after treatment only on Phase 2 Stage 2 patients. 
Peripheral blood cytokine concentration (such as interferon-γ, tumor necrosis factor‑α, interleukin 
(IL)-2, IL-6, IL-12, IL‑4, IL-10, transforming growth factor-ß) will be evaluated at baseline, 
during, and after treatment by enzyme‑linked immunosorbent assay-based techniques. 
Tumor mutational profile (ie, somatic mutations in genes) will be analyzed at baseline, during and 
after treatment in plasma cell free DNA and followed as a potential marker of response to IMP or 
of acquired resistance to treatment. Subtractive mutation analysis will be performed with germline 
DNA data to identify tumoral specific variations. 
If sufficient clinical response is observable in Phase 1 and Phase 2 Stage 1 patients, further 
characterization of the immune response might be performed on Phase 2 Stage 2 patients by 
analyzing humoral and T cell adaptive immune response at baseline, during and after treatment in 
peripheral blood. 
If sufficient clinical response is observable in Phase 1 and Phase 2 Stage 1 patients, analysis of 
Isatuximab enzymatic activity might be performed at baseline, during, and after treatment by 
measuring metabolites in plasma or serum from peripheral blood. 
8.7 
GENETICS  
Blood sample for DNA isolation will be collected from participants during the clinical study. 
Plasma cell free DNA will be isolated from peripheral blood at baseline, during and after 
treatment to analyze tumor mutational profile (ie, somatic mutations), as described in Section 8.6. 
Peripheral blood samples will be collected for DNA isolation at baseline for the following 
biomarker analyses: 
• Immune genetic determinants (including FcγRIII polymorphisms) will be analyzed.  
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• Peripheral blood samples will also be used as a control for tumor mutational profile 
analysis as described in Section 8.6. Subtractive mutation analysis will be performed with 
germline DNA from this peripheral blood sample data to identify tumoral specific 
variations. 
Blood DNA for immune genetic determinants and for control of tumor mutational profile analysis 
will not be used to determine the likelihood of the participant or his/her family members 
developing a disease. 
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 laboratory manual. 
8.8 
BIOMARKERS  
During the study additional analyses, not specified in the protocol but related to the drug action 
and/or effect of isatuximab/atezolizumab, may be conducted on samples pending evolving 
literature. 
After study completion, for patients who have consented to it, remaining samples will be kept for 
other possible exploratory analyses. Results of these analyses will not be included in the clinical 
study report (CSR) but in a stand-alone report, if applicable. 
These other research analyses will help to understand either disease subtypes or drug response, or 
to develop and/or validate a bioassay method, or to identify new drug targets or biomarkers. 
These samples will remain labelled with the same identifiers used during the study (ie, participant 
ID).  
They will be transferred to a Sanofi site (or a subcontractor site) which can be located outside of 
the country where the study is conducted. The Sponsor has included safeguards for protecting 
patient confidentiality and personal data (see Section 10.1.3).These samples maybe stored for a 
period of up to 5 years after completion of the final study report. After that period, any samples 
remaining will be destroyed. 
8.8.1 Immunogenicity assessments  
The atezolizumab and isatuximab ADA sampling times for blood collection can be found in the 
PK/PD Flow Chart (Section 1.3). 
It is of the utmost importance to collect all the blood samples at the specified times and according 
to specifications for collection, storage, and shipment as defined in a separate laboratory manual. 
Samples missed or lost, for any reason should be recorded. Actual dates and times of blood 
collection should be recorded in the eCRF.  The dates and times of drug administration should 
also be precisely recorded. 
ADA against isatuximab in plasma and ADA against atezolizumab in serum will be analyzed by 
immunoassay.  Details will be provided in a separate Laboratory Manual.  
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8.8.2 RNA transcriptome research  
Transcriptome studies will be conducted using NGS (RNAseq) on RNAlater preserved tumor if 
enough tumor material is available or by Nanostring on available FFPE tumor sample and/or 
alternative equivalent technologies, which facilitates the simultaneous measurement of the relative 
abundances of thousands of ribonucleic acid (RNA) species resulting in a transcriptome profile 
for each and tumor biopsy sample. This will enable the evaluation of changes in transcriptome 
profiles that may correlate with biological response relating to disease or the action of study 
intervention. 
The same samples may also be used to confirm findings by application of alternative 
technologies. 
8.9 
HEALTH ECONOMICS OR MEDICAL RESOURCE UTILIZATION AND HEALTH 
ECONOMICS  
Not applicable. 
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9 
STATISTICAL CONSIDERATIONS  
9.1 
STATISTICAL HYPOTHESES  
Phase 1 
There is no formal statistical hypothesis in Phase 1 safety run-in. 
Phase 2 
For HCC and SCCHN, the null hypothesis is that the true RR is ≤15%, and the alternative 
hypothesis is that the true RR is ≥30%.  For EOC, the null hypothesis is that the true RR is ≤20% 
and the alternative hypothesis is that the true RR is ≥40%.   
For GBM, the null hypothesis is that the true PFS-6 is ≤20% and the alternative hypothesis is that 
the true PFS-6 is ≥35%. 
9.2 
SAMPLE SIZE DETERMINATION  
Phase 1 
Approximately 6 (assuming 6 participants for the starting dose) to 24 (assuming 12 participants 
for the starting dose, and 12 participants for DL-1) DLT evaluable participants are expected to be 
enrolled. The actual sample size will vary depending on DLTs observed and the number of dose 
levels explored. Participants who are not evaluable for DLT assessment in Phase 1 may be 
replaced. 
Phase 2 
Phase 2 of the study is to evaluate initial anti-tumor activity based on tumor response using 
RECIST 1.1 criteria for HCC, SCCHN and EOC, and RANO criteria for GBM. The efficacy 
evaluation is based on 2-stage design with 85% power at 5% one-sided alpha level for each of the 
participant cohorts, respectively.  
The assumption of RR, the required sample sizes, and the number of responders at each stage are 
provided below for HCC, SCCHN and EOC: 
Indication 
H0 
H1 
Sample size 
Number (%) of responses 
to reject H0 
Stage 1 
Final 
Stage 1 
Final 
HCC & 
SCCHN 
15% 
30% 
26 
59 
≥5 (19.2%) 
≥14 (23.7%) 
EOC 
20% 
40% 
17 
37 
≥4 (23.5%) 
≥12 (32.4%) 
Abbreviations: H0=null hypothesis; H1=alternative hypothesis; HCC=hepatocellular carcinoma; SCCHN=squamous cell carcinoma of the head 
and neck; EOC=epithelial ovarian cancer. 
Note: Based on the number of objective responses and the totality of data observed within a treatment cohort in Phase 2 Stage 1, the Sponsor 
may decide to advance such a treatment cohort to Phase 2 Stage 2 after consulting with Study Committee. 
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The assumption of PFS-6, the required sample sizes, and PFS-6 at each stage are provided below 
for GBM: 
Indication 
H0 
H1 
Sample size 
Number (%) of responses 
to reject H0 
Stage 1 
Final 
Stage 1 
Final 
GBM 
20% 
35% 
31 
65 
>19.4% 
>27.7% 
Abbreviations: H0=null hypothesis; H1=alternative hypothesis; GBM=glioblastoma multiforme. 
Note: Based on the PFS-6 and the totality of data observed within a treatment cohort in Phase 2 Stage 1, the Sponsor may decide to advance 
such a treatment cohort to Phase 2 Stage 2 after consulting with Study Committee. 
Participants who received the recommended dose regimen in Phase 1 will be also included in 
Phase 2 Stage 1 (eg, if 6 HCC participants were enrolled in Phase 1, only 20 HCC participants 
will be needed to complete the Phase 2 Stage 1 HCC cohort). 
In Phase 2, approximately 285 participants are expected to be enrolled (assuming Cohort A, B, C, 
D-1, and D-2 complete 2 stages), including approximately 131 in Phase 2 Stage 1 and 
approximately 154 participants in Phase 2 Stage 2. The participants who are treated with RP2D in 
Phase 1 will be counted as Phase 2 participants. 
If isatuximab Q3W in combination with atezolizumab or as monotherapy (GBM only) without the 
isatuximab QW for 3 weeks is to be tested in HCC, SCCHN, EOC, or GBM 65 additional 
participants are expected to be enrolled. As a consequence, a total to up to 350 participants may 
be enrolled. 
9.3 
POPULATIONS FOR ANALYSES  
For purposes of analysis, the following populations are defined (Table 7): 
Table 7 - Populations for analyses  
Population 
Description 
All treated  
For both Phase 1 and Phase 2 of the study, the all-treated population will include all 
participants who have given their informed consent and received at least 1 dose (even 
incomplete) of either isatuximab or atezolizumab. 
This population is the primary population for the analyses of efficacy and safety 
parameters, unless otherwise noted. All analyses using this population will be based on 
the dose level actually received in the first cycle. 
DLT evaluable (Phase 1) 
The DLT evaluable population is defined as participants in Phase 1 who received the 
planned doses of isatuximab and atezolizumab during Cycle 1, and complete the DLT 
observation period after the first IMP administration, unless they discontinue the study 
treatment(s) due to DLT. The dose recommended for Phase 2 will be determined on the 
DLT evaluable population. 
Response evaluable population 
The response evaluable population will include all patients who fulfill eligibility criteria in 
the all-treated population with an evaluable baseline assessment and at least one 
evaluable post-baseline response assessment during the treatment period. 
This population is the secondary analysis population for efficacy. 
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Population 
Description 
PK 
The PK population will include all participants from the all-treated population with at 
least 1 drug concentration after drug administration (whatever the cycle and even if the 
dose is uncomplete). 
ADA evaluable 
The ADA evaluable population includes all participants from the all-treated population 
with at least 1 non-missing ADA result after the drug administration. 
PDy 
The pharmacodynamic population will include all participants from the all-treated 
population with at least 1 pharmacodynamic marker result after the first dose of study 
treatment. 
Abbreviations: ADA=Anti-drug antibody; DLT=Dose limiting toxicities; PDy=Pharmacodynamics; PK=Pharmacokinetics. 
9.4 
STATISTICAL ANALYSES  
The statistical analysis plan will be developed and finalized before database lock and will describe 
the participant populations to be included in the analyses, and procedures for accounting for 
missing, unused, and spurious data. This section is a summary of the planned statistical analyses 
of the primary and secondary endpoints. 
General statistical approach: 
Data from HCC, SCCHN, EOC, and GBM cohorts (Cohorts A, B, C, D-1, and D-2) in Phase 2 
will be analyzed and reported separately by cohort. 
Planned date for analysis cut-off: 
For each cohort, the analysis cut-off date for the primary analysis (RR for HCC, SCCHN and 
EOC, PFS-6 for GBM) is planned at 6 months after the last participant’s first treatment in the 
cohort.  
The analysis cut-off date for secondary efficacy endpoints including DoR and PFS will be 
12 months after the last participant’s first treatment in the cohort. The primary analysis of RR in 
the cohort for HCC, SCCHN, and EOC, and of PFS-6 in the cohort for GMB will be updated. 
9.4.1 Efficacy analyses  
All-treated population will be the primary analysis population for efficacy endpoints. In addition, 
similar analysis will be performed using the response evaluable population as a secondary 
analysis.  
9.4.1.1 Analysis of primary efficacy endpoints  
For HCC, SCCHN and EOC, RR will be summarized with descriptive statistics. A 90% 2-sided 
confidence interval will be computed using Clopper-Pearson method. The statistical inference will 
be based on the hypothesis and alpha level defined in the sample size calculation section. 
For GBM, PFS-6 will be summarized using Kaplan-Meier method. 
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9.4.1.2 Analysis of secondary efficacy endpoints:  
The following secondary endpoints will be analyzed: 
• Tumor burden change: the best percent-change from baseline in tumor burden will be 
summarized and presented graphically. In addition, a summary of the area under the curve 
(AUC) and the time adjusted AUC of percent-change from baseline in tumor burden will 
also be provided as an exploratory analysis. 
• DOR and PFS will be summarized using Kaplan-Meier method. 
• RR for GBM and DCR (complete response + partial response + stable disease) will be 
summarized with descriptive statistics. 
Table 8 - Efficacy analyses  
Endpoint 
Statistical Analysis Methods 
Primary 
 
RR for HCC, SCCHN and EOC 
Descriptive statistics and Clopper-Pearson method 
PFS-6 for GBM 
Kaplan-Meier method 
Secondary 
 
Tumor burden change 
Descriptive statistics 
DOR and PFS 
Kaplan-Meier method 
RR for GBM and DCR 
Descriptive statistics 
Exploratory 
Will be described in the statistical analysis plan finalized before database lock 
Abbreviations: DCR=Disease control rate; DOR=Duration of response; EOC=Epithelial ovarian cancer; GBM=Glioblastoma multiforme; 
HCC=Hepatocellular carcinoma; PFS=Progression free survival rate; PFS-6=Progression free survival rate at 6 months; RR=Response rate; 
SCCHN=Sqamous cell carcinoma of the head and neck. 
9.4.2 Safety analyses  
All safety analyses will be performed on the all-treated population.  
Table 9 - Safety analyses  
Endpoint 
Statistical Analysis Methods 
Primary 
DLTs, AEs/Serious AEs, and laboratory abnormalities in 
Phase 1 
Descriptive statistics 
Secondary 
AEs/SAEs and laboratory abnormalities in Phase 2 
Descriptive statistics 
ADA against isatuximab and against atezolizumab 
Descriptive analysis 
Exploratory 
 
Will be described in the statistical analysis plan finalized before 
database lock 
Abbreviations: AE=Adverse event; ADA=Anti-drug antibody; DLT=Dose limiting toxicity; SAE=Serious adverse event. 
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9.4.2.1 Dose limiting toxicities  
In Phase 1, the DLTs will be listed by participant using the DLT evaluable population. 
9.4.2.2 Analyses of adverse events  
The observation period will be divided into 3 segments: screening, TEAE and post-treatment: 
• The screening period is defined as the time informed consent is signed until the first dose 
of study treatment administration. 
• The TEAE period is defined as the time from the first dose of study treatments up to 
30 days after last dose of study treatments.   
• The post-treatment period is defined as the time starting 31 days after the last dose of 
study treatments to study closure or death, whichever occurs first. 
Pre-treatment AEs are defined as any AE during the screening period. Treatment-emergent AEs 
are defined as AEs that develop, worsen (according to the Investigator’s opinion) or become 
serious during the TEAE period. Post-treatment AEs are defined as AEs that are reported during 
the post-treatment period. The primary focus of AE reporting will be on TEAEs. Pre-treatment 
and post-treatment AEs will be described separately. 
The TEAEs will be coded according to MedDRA. AEs will be graded according to the 
NCI-CTCAE version 4.03. The grade will be taken into account in the summary. For participants 
with multiple occurrences of the same PT, the maximum grade will be used. 
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. 
• TEAEs Grade 3 or 4. 
• Grade 5 TEAE (any TEAE with a fatal outcome during the treatment period). 
• Serious TEAEs. 
• Serious treatment-related TEAEs. 
• TEAE leading to permanent (full study treatment) discontinuation/premature (partial study 
treatment) discontinuation. 
• AESIs, and IARs in particular. 
• Treatment-related TEAEs. 
Treatment-related TEAEs of ≥Grade 3. 
The number and percentage of participants experiencing TEAEs by primary system organ class 
(SOC) and PT will be summarized by NCI-CTCAE grade (all grades and ≥Grade 3). Similar 
tables will be prepared for treatment-related TEAEs, AESIs, TEAEs leading to permanent or 
premature discontinuation, TEAEs leading to dose modification, serious TEAEs, TEAEs with 
fatal outcome and AEs/SAEs occurring during the post-treatment dosing period. 
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Sorting within tables should ensure the same presentation for the set of all AEs within the 
observation period (screening, on-treatment, and post-treatment). For that purpose, the table of all 
TEAEs will be presented by SOC and PT sorted by internationally agreed order unless otherwise 
specified. 
9.4.2.3 Clinical laboratory evaluations  
All the laboratory abnormalities will be graded according to NCI-CTCAE version 4.03, 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 4.03 scale is not applicable, the number of participants with 
laboratory abnormality out-of-normal laboratory range value will be displayed. 
9.4.2.4 Immunogenicity  
The findings from the analyses of immunogenicity for isatuximab and atezolizumab will be 
summarized. 
9.4.3 Other analyses  
Pharmacokinetics, pharmacodynamic, and biomarker exploratory analyses will be described in the 
statistical analysis plan finalized before database lock. The population PK analysis and 
pharmacodynamic analyses will be presented separately from the CSR.  
9.4.3.1 Analysis of PK endpoints  
Individual concentrations and non-compartmental PK parameters of isatuximab will be 
summarized by descriptive statistics (such as mean, geometric mean, median, standard deviation, 
standard error of the mean, coefficient of variation, and minimum and maximum) under the 
responsibility of Sanofi, Pharmacokinetic, Dynamic, and Metabolism department.). Individual and 
mean profiles will be presented graphically. 
9.4.3.2 Analysis of pharmacodynamic endpoints  
Findings from pharmacodynamics markers will be descriptively summarized and tabulated. 
9.5 
INTERIM ANALYSES  
The Statistical Analysis Plan will describe the planned interim analyses in greater detail. 
An interim analysis for each cohort will be performed for HCC, SCCHN, EOC, and GBM cohorts 
after the last participants remaining in the treatment period among the first 26, 26, 17 and 
31 participants, respectively, in Phase 2 have completed approximately 6 months of study 
treatment or permanently discontinued both atezolizumab and isatuximab, whichever comes first. 
The interim analysis may be conducted earlier if the required number of responses for proceeding 
to Phase 2 Stage 2 is achieved for HCC, SCCHN, and EOC cohorts. 
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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 Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines, 
- 
Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines, 
- 
Applicable laws and regulations. 
• The protocol, protocol amendments, ICF, Investigator’s Brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the Investigator and 
reviewed and approved by the IRB/IEC before the study is initiated.  
• Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.  
• The Investigator will be responsible for the following: 
- 
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC, 
- 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures, 
- 
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 
for clinical studies (if applicable), and all other applicable local regulations. 
10.1.2 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.  
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• 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.  
• Participants who are rescreened are required to sign a new ICF. 
• The ICF will contain a separate section that addresses the participation in the post-dose 
PK assessment sub-study. 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 signature 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 signature 
10.1.3 Data Protection  
• Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred.  
• The participant must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with local data protection law. The level of disclosure must also 
be explained to the participant.  
• The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
10.1.4 Committees Structure  
Data Monitoring Committee: An independent Data Monitoring Committee (DMC) will 
periodically evaluate ongoing safety data at intervals planned to be no longer than 3 months 
(starting from the confirmation of recommended Phase 2 dose) and make appropriate 
recommendations regarding the conduct of Phase 2 of this study. 
Study committee: Composition of the Study Committee will vary based on the matter discussed, 
but it will generally include Sponsor representatives and at least 2 Investigators responsible for the 
indication in matter. Sponsor representatives and Investigators who have enrolled at least 1 patient 
will review clinical data approximately every 2 weeks during the course of the Phase 1 part. Then 
Study Committee will convene regularly or ad hoc when required, to review data and provide 
strategic recommendations on study medical decisions such as at the end of the Stage 1 of each 
cohorts and Stage 2 of Cohort A to D-2. 
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10.1.5 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 clinical trial register (eu.ctr), and sanofi.com, as well as 
some national registries. 
In addition, results from clinical trials in patients are required to be submitted to peer-reviewed 
journals following internal company review for accuracy, fair balance and intellectual property. 
For those journals that request sharing of the analyzable data sets that are reported in the 
publication, interested researchers are directed to submit their request to 
clinicalstudydatarequest.com. 
Individual participant data and supporting clinical documents are available for request at 
clinicalstudydatarequest.com. While making information available we continue to protect the 
privacy of participants in our clinical trials. Details on data sharing criteria and process for 
requesting access can be found at this web address: clinicalstudydatarequest.com. 
10.1.6 Data Quality Assurance  
• All participant data relating to the study will be recorded on eCRF 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 eCRF.  
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
• The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.  
• The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.  
• Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements.  
• Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator for 25 years after study completion 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. 
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10.1.7 Source documents  
• Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the Investigator’s site. 
• Data 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. 
• The informed consent form will include a statement by which the patient allowing the 
Sponsor’s duly authorized personnel, the ethics committee (IRB/IEC), and the regulatory 
authorities to have direct access to original medical records which support the data in the 
eCRF (eg, patient's medical file, appointment books, and original laboratory records). 
These personnel, bound by professional secrecy, must maintain the confidentiality of all 
personal identity or personal medical information (according to confidentiality rules). 
10.1.8 Study and Site Closure  
The Sponsor 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 the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to: 
• 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 recruitment of participants by the Investigator. 
• Discontinuation of further study intervention development. 
10.1.9 Publication Policy  
• The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor 
before submission. This allows the Sponsor to protect proprietary information and to 
provide comments.  
• The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data. In 
this case, a coordinating Investigator will be designated by mutual agreement. 
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
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10.2 
APPENDIX 2: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING  
DEFINITION OF AE 
AE definition 
• An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered related 
to the study intervention. 
• NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention. 
Events meeting the AE definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
impacting study intervention (leading to discontinuation or dose modification.  
• Other safety assessments (eg, ECG, radiological scans, and 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). 
• 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 an AE or SAE if they fulfill the definition of an AE or SAE.  
Events NOT meeting the AE definition 
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the participant’s condition. 
• The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
• Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 
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• 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. 
DEFINITION OF SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (eg, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
A SAE is defined as any untoward medical occurrence that, at any dose: 
a) Results in death. 
b) Is life-threatening: 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe. 
c) Requires inpatient hospitalization or prolongation of existing hospitalization: 
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
d) Results in persistent disability/incapacity: 
• The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions. 
• 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. 
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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. 
RECORDING AND FOLLOW-UP OF AE AND/OR SAE 
AE and SAE recording 
• When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
• The Investigator will then record all relevant AE/SAE information in the eCRF. 
• 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 causal relationship 
• The Investigator is obligated to assess the causal relationship between study intervention 
and each occurrence of each AE/SAE; the causal relationship must be reported as YES or 
NO. 
• A "reasonable possibility" of a causal relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a causal relationship cannot 
be ruled out. 
• The Investigator will use clinical judgment to determine the causal relationship. 
• Alternative etiologies, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the AE to study intervention administration 
will be investigated and considered. 
• The Investigator will also consult the Investigator’s Brochure (IB), and/or Labeling 
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 causal relationship. 
• There may be situations in which an SAE has occurred and the Investigator has minimal 
information to include in the initial report to Monitoring team. However, it is necessary 
that the Investigator always make an assessment of causal relationship for every AE before 
the initial transmission of the SAE data to Monitoring team. 
• The Investigator may change his/her opinion regarding causal relationship in light of 
follow-up information, and send an SAE follow-up report with the updated causal 
relationship assessment. 
• The causal relationship 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 monitoring 
team to elucidate the nature and/or causal relationship of AEs as fully as possible. This 
may include additional laboratory tests or investigations, histopathological examinations, 
or consultation with other health care professionals. 
• New or updated information will be recorded in the originally completed eCRF. 
• The Investigator will submit any updated SAE or AESI data to the monitoring team within 
24 hours of receipt of the information. 
REPORTING OF SAEs 
SAE reporting to Monitoring team via an electronic data collection tool 
• The primary mechanism for reporting an SAE or AESI to Monitoring team will be the 
electronic data collection tool. 
• If the electronic system is unavailable for more than 24 hours, then the site will use the 
paper SAE/AESI data collection tool (see next section). 
• The site will subsequently enter the SAE/AESI data into the electronic system as soon as it 
becomes available again. 
• 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/AESI from a study participant or receives updated 
data on a previously reported SAE / AESI after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE / AESI form or to 
the monitoring team by fax or email. 
• Contact information for SAE/AESI reporting can be found in study reference manual. 
10.3 
APPENDIX 3: CLINICAL LABORATORY TESTS  
The tests detailed in Table 10 will be performed by the local laboratory. 
• The results must be entered into the eCRF. 
• Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol. 
• Additional tests may be performed at any time during the study as determined necessary 
by the Investigator or required by local regulations. 
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Table 10 - Protocol-required safety laboratory assessments  
Laboratory 
assessments 
Parameters 
Hematology 
Platelet count  
Red blood cell (RBC) count 
Hemoglobin 
Hematocrit 
 
White blood cell (WBC) count with 
differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Clinical chemistry 
Urea or  
Blood urea nitrogen 
(BUN) 
Uric acid 
Potassium 
Chloride 
Bicarbonate/carbon  
dioxide 
Aspartate 
aminotransferase (AST)/ 
Serum glutamic-
oxaloacetic transaminase 
(SGOT) 
Total and direct 
bilirubin 
LDH 
 
Creatinine 
eGFR (MDRD) 
Sodium 
Magnesium 
Phosphate  
Alanine 
aminotransferase 
 (ALT)/ Serum glutamic-
pyruvic transaminase 
(SGPT) 
Total protein 
Albumin 
Thyroid-stimulating 
hormone (TSH), free 
T4, free T3/total T3 
(screening, C1D1, 
every 4th cycle 
thereafter)   
 
Glucose fasting 
Calcium 
Alkaline phosphatase 
 
Routine urinalysis 
PH, glucose, protein, blood, leukocyte esterase, and microscopic examination (if blood or protein is 
abnormal) at baseline and if required. 
Quantitative or semi-quantitative (according to site practice and if such method can provide absolute 
numeric value of the parameters) analysis is only required at baseline.  Subsequent urinalysis may 
be performed; in case of positive dipstick results, quantitative or semi-quantitative analysis would be 
required. 
Other screening tests 
Serum (at baseline) or urine human chorionic gonadotropin (hCG) pregnancy test (as needed for 
women of childbearing potential).(urine pregnancy test on Day 1 of each cycle, EOT visit, and every 
30±7 days until 5 months after last dose of study treatment) 
• 
Coagulation: prothrombin time or INR and activated PTT. 
• 
Blood typing interference test. 
Serology hepatitis B surface antigen [HBsAg], and hepatitis C virus antibody for HCC only. 
NOTES : 
Blood chemistry, hematology: assessments are not required to be repeated prior to Cycle 1 Day 1 if the screening laboratory 
assessments were performed within 7 days prior to first IMP administration and met entry criteria. 
The window for blood chemistry, hematology, and urinalysis is within 1 working day prior to IMP administration. 
Investigators must document their review of each laboratory safety report. 
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10.4 
APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION  
DEFINITIONS: 
Non reproductive potential 
1. Premenopausal female with 1 of the following: 
• Documented hysterectomy. 
• Documented bilateral salpingectomy. 
• Documented bilateral oophorectomy. 
2. Postmenopausal female 
• A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle-stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence of 
12 months of amenorrhea, a single FSH measurement is insufficient.  
- 
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. 
Reproductive potential 
A woman is considered of reproductive potential (WOCBP), ie, fertile, following menarche and 
until becoming postmenopausal unless permanently sterile. Permanent sterilization methods 
include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. 
CONTRACEPTION GUIDANCE 
Females of childbearing potential or male subjects with female partners of childbearing potential 
are required to use effective contraceptive methods starting 2 weeks before study treatment 
administration, during treatment period, until 5 months after the last dose of isatuximab (male and 
female participants) or atezolizumab (female participants only), whichever comes last. 
Male participants 
• Male subjects with heterosexual partners of reproductive potential (WOCBP) are eligible 
to participate if they agree to use the following during the protocol defined timeline: 
- 
Refrain from donating sperm. 
and 
- 
At least 1 of the following conditions applies: 
- 
Are and agree to remain abstinent from penile-vaginal intercourse on a long-term and 
persistent basis, when this is their preferred and usual lifestyle. 
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or 
- 
Agree to use a male condom plus an additional contraceptive method with a failure 
rate of <1% per year (see table for female subjects). 
• Men with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile-vaginal intercourse or use a male condom for the time defined in the protocol.  
Female participants 
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception consistently and correctly as described in Table 11. 
Table 11 - Highly effective contraceptive methods  
Highly effective contraceptive methods that are user dependenta 
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulationb  
• 
Oral. 
• 
Intravaginal. 
• 
Transdermal. 
Progestogen only hormonal contraception associated with inhibition of ovulation 
• 
Oral. 
• 
Injectable. 
Highly effective methods that are user independenta 
Implantable progestogen only hormonal contraception associated with inhibition of ovulationb 
• 
Intrauterine device (IUD). 
• 
Intrauterine hormone-releasing system (IUS). 
• 
Bilateral tubal occlusion. 
Vasectomized partner  
A vasectomized partner is a highly effective contraception method provided that the partner is the sole male sexual partner of the 
WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of contraception should be 
used. 
Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study intervention. The reliability of sexual abstinence needs to be evaluated in relation to 
the duration of the study and the preferred and usual lifestyle of the participant. 
NOTES:  
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with local regulations 
regarding the use of contraceptive methods for participants participating in clinical studies.  
b Hormonal contraception may be susceptible to interaction with the study intervention, which may reduce the efficacy of the contraceptive 
method. In this case, two highly effective methods of contraception should be utilized during the intervention period and for at least 5 months  
after the last dose of study intervention 
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PREGNANCY TESTING: 
• WOCBP should only be included after a confirmed menstrual period and a negative highly 
sensitive serum pregnancy test. 
• Additional pregnancy testing is required during the intervention period and up to 5 months 
after the last dose of study intervention. 
• Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected.  
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 1 year 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 2 weeks before the first dose of isatuximab treatment, during the study, 
and within 5 months after the last dose of study treatment. 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 
be required for 1 year 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 will be reported as an 
AE or SAE. A spontaneous abortion is always considered to be an SAE and will be 
reported as such. Any post-study pregnancy related SAE considered reasonably related to 
the study intervention by the Investigator will be reported to the Sponsor as described in 
Section 8.3.4. While the Investigator is not obligated to actively seek this information in 
former study participants, he or she may learn of an SAE through spontaneous reporting.  
• Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention. 
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10.5 
APPENDIX 5: GENETICS  
Use/Analysis of DNA 
• Genetic variation may impact a participant’s response to study intervention, susceptibility 
to, and severity and progression of disease. Variable response to study intervention may be 
due to genetic determinants that impact drug absorption, distribution, metabolism, and 
excretion; mechanism of action of the drug; disease etiology; and/or molecular subtype of 
the disease being treated. 
• DNA samples will be used for research related to IMP and related diseases. They may also 
be used to develop tests/assays including diagnostic tests related to IMP administration. 
Genetic research may consist of the analysis of one or more candidate genes or analysis of 
the entire genome (as appropriate). 
• DNA samples will be analyzed for immune genetic markers (such as FcgRIII 
polymorphism) and a panel of tumor somatic mutations. Additional analyses may be 
conducted if it is hypothesized that this may help further understand the clinical data. 
• The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to IMP or study interventions of this class to understand study 
disease or related conditions. 
• The results of genetic analyses may be reported in the CSR or in a separate study 
summary. 
• The Sponsor will store the DNA samples in a secure storage space with adequate measures 
to protect confidentiality.  
• The samples will be retained while research on IMP continues but no longer than 5 years 
(or other period as per local requirements) after completion of the final study report. 
10.6 
APPENDIX 6: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND  
FOLLOW-UP ASSESSMENTS  
Not applicable. 
10.7 
APPENDIX 7: MEDICAL DEVICE INCIDENTS: DEFINITION AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING  
Not applicable. 
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10.8 
APPENDIX 8: COUNTRY-SPECIFIC REQUIREMENTS  
10.8.1 Amendment for France  
Section 5.1 Inclusion Criteria (I 14) 
I14.   Platinum-resistant/refractory disease: 
• Received up to 3 lines of prior platinum-containing therapy when the disease was 
platinum-sensitive, and, 
• Documentation of PD on or after 1 line of anti-cancer therapy for 
platinum-resistant/refractory disease (unless patients are ineligible or intolerant to standard 
of care for platinum-resistant/refractory disease). Platinum-resistant/refractory disease is 
defined as PD within 6 months following the last administered dose of platinum-
containing therapy (resistant), or lack of response or disease progression while receiving 
the most recent platinum-containing therapy (refractory), respectively. 
• Previous treatment with up to one line of PARP inhibitor therapy is allowed. 
10.9 
APPENDIX 9: ABBREVIATIONS  
 
ADA: 
anti-drug antibody 
ADR: 
adverse drug reaction 
AE: 
adverse event 
AESI: 
adverse event of special interest 
AFP: 
alpha-fetoprotein 
ALP: 
alkaline phosphatase 
ALT: 
alanine aminotransferase 
AP: 
antibody-plasma 
AS: 
antibody-serum 
AST: 
aspartate aminotransferase 
AUC: 
area under the curve 
BBB: 
blood brain barrier 
BCLC: 
Barcelona Clinic Liver Cancer 
BRCA1: 
breast cancer type 1 susceptibility protein 
BRCA2: 
breast cancer type 2 susceptibility protein 
BUN: 
Blood urea nitrogen 
CD38: 
cluster of differentiation 38 
CSR: 
clinical study report 
CTCAE: 
common terminology criteria for adverse events 
CTLA-4: 
cytotoxic T-lymphocyte-associated protein 4 
DCR: 
disease control rate 
DIL: 
Dear Investigator Letter 
DL: 
dose level 
DL-1: 
dose level minus -1 
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DLT: 
dose limiting toxicity 
DoR: 
duration of response 
DRE: 
disease related event 
DRESS: 
drug rash with eosinophilia and systemic symptoms 
ECG: 
electrocardiogram 
ECOG: 
Eastern Cooperative Oncology Group 
eCRF: 
electronic case report form 
eGFR: 
estimated glomerular filtration rate 
EOC: 
epithelial ovarian cancer 
EOI: 
end of infusion 
EOT: 
end of treatment 
FDA: 
Food and Drug Administration 
FFPE: 
formalin-fixed paraffin-embedded 
FUp: 
follow-up period 
GBM: 
glioblastoma multiforme 
GCIG: 
Gynaecologic Cancer Intergroup 
HBV: 
hepatitis B virus 
HCC: 
hepatocellular carcinoma 
HCV: 
hepatitis C virus 
IAR: 
infusion associated reaction, infusion associated reaction 
ICH: 
International Council for Harmonisation 
IHC: 
immunohistochemistry 
IMP: 
investigational medicinal product 
INR: 
international normalized ratio 
irAE: 
immune-related adverse event 
iRANO: 
Immunotherapy Response Assessment in Neuro-Oncology 
iRECIST: 
Response Evaluation Criteria in Solid Tumors for immune-based therapies , 
RECIST for immunotherapies 
ITSM: 
immunoreceptor tyrosine-based switch motif 
IV: 
intravenous 
mAb: 
monoclonal antibody, monoclonal antibody 
MDRD: 
modification of diet in renal disease 
MedDRA: 
Medical Dictionary for Regulatory Activities 
MM: 
multiple myeloma 
MRI: 
magnetic resonance imaging 
MTD: 
maximum tolerated dose 
NCI: 
national cancer institute, National Cancer Institute 
NIMP: 
noninvestigational medicinal product 
NK: 
natural killer 
NSCLC: 
non-small cell lung cancer 
OS: 
overall survival 
P: 
plasma 
PARP: 
poly (ADP ribose) polymerase 
PD: 
progressive disease 
PD-1: 
programmed cell death-1 
PD-L1: 
programmed cell death-ligand 1 
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PD-L1: 
programmed cell death-ligand 1 
PD-L2: 
programmed cell death-ligand 2 
PFS: 
progression free survival 
PFS-6: 
progression free survival rate at 6 months 
PK: 
pharmacokinetic 
PLD: 
pegylated liposomal doxorubicin 
PO: 
oral route 
PP: 
Polypropylene 
PT: 
preferred term 
Q2W: 
once every 2 weeks 
Q3W: 
once every 3 weeks 
QW: 
once weekly 
RANO: 
response assessment for neuro-oncology 
RECIST: 
Response Evaluation Criteria in Solid Tumors 
RNT: 
relative nominal time 
RP2D: 
recommended phase 2 dose 
RR: 
response rate 
S: 
serum 
SAE: 
serious adverse event 
SAE: 
serious adverse event 
SCARs: 
severe cutaneous adverse reactions 
SCCHN: 
squamous cell carcinoma of the head and neck 
SJS: 
Stevens-Johnson Syndrome 
SoA: 
Schedule of Activities 
SOC: 
system organ class 
SOI: 
start of infusion 
TEAE: 
treatment-emergent adverse event 
TEN: 
Toxic Epidermal Necrolysis 
TTP: 
Time to progression 
TTR: 
Time to response 
UC: 
urothelial carcinoma 
ULN: 
upper limit of the normal range 
VEGF: 
vascular endothelial growth factor 
WOCBP: 
woman of child-bearing potential 
 
10.10 APPENDIX 10: PROTOCOL AMENDMENT HISTORY  
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
10.10.1 
Amendment 01 (06-April-2018)  
This amendment 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 
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OVERALL RATIONALE FOR THE AMENDMENT 
Revised DLT definition and incorporated stopping rules into the protocol to mitigate patient risk 
for cytokine release syndrome and anaphylactic reactions.  In addition, possible cohorts F-H were 
removed and Q3W isatuximab regimen wil be studied in one separate cohort only. General 
provision of testing an isatuximab dose of 20 mg/kg in combination with atezolizumab was also 
removed from the protocol.  
Section # 
and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis, 
4.1.2 Phase 2 
(efficacy 
signal search 
with a 2-stage 
design in 
each cohort), 
9.1 Statistical 
hypotheses 
Updating Phase 2 may include up to 6 cohorts, with 
cohort E remaining to evaluate Q3W isatuximab 
regimen (without initial weekly loading dose for 
3 weeks) in one disease subgroup. Consequently, 
total number of participants for the study is now 
reduced to 350. 
Q3W isatuximab regimen will be studied in one separate 
cohort only, if initiated.  
4.1.1 Phase 1 
(safety run-in) 
DLT definition is revised. 
DLT definition is revised to address Grade 4 
thrombocytopenia (regardless of evidence of bleeding) 
and Grade 3 cytokine release syndrome are to be 
considered as DLT, as well as clarify time to resolution to 
baseline for a Grade 4 AST, ALT or bilirubin elevation in 
patients with liver metastases or HCC to be excluded from 
DLT definition. 
4.1.2 Phase 2 
(efficacy 
signal search 
with a 2-stage 
design in 
each cohort) 
Remove general provision of testing an isatuximab 
dose of 20 mg/kg in combination with atezolizumab. 
A protocol amendment along with supporting rationale will 
be submitted if a 20 mg/kg dose is to be evaluated. 
6.6.4 General 
guidelines for 
management 
of infusion-
associated 
reactions, 
10.21 
Appendix 21 
Indicate using the same stopping rules for infusion 
associated reactions are applied also for cytokine 
release syndrome and for anaphylactic reactions. 
 
Corrected inconsistencies between Table 5 and 
Table 25, as well as clarify that for G2 IAR, 
symptoms have to resolve to ≤G1 for isatuximab or 
baseline for atezolizumab before resuming infusion. 
Incorporate stopping rules to mitigate patient risk for 
cytokine release syndrome and anaphylaxis. 
 
Correction of inconsistencies among these tables and in 
accordance with IB. 
8.3 Adverse 
events and 
serious 
adverse 
events 
Added trial stopping rule where enrollment will be 
halted for safety review after two patients with 
Grade ≥3 or one patient with Grade ≥4 cytokine 
release syndrome or anaphylaxis events, unless 
resulting from an obviously unrelated cause. 
Incorporate trial stopping rules for cytokine release 
syndrome and anaphylaxis. 
Table 5 
Correction of typographical error in title. 
Typographical error 
10.11 
Appendix 11 
Correction of typographical error in description of 
non-target lesion consideration for pathological 
lymph nodes. 
Typographical error 
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10.10.2 
Amendment 02 (09-August-2018)  
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
OVERALL RATIONALE FOR THE AMENDMENT 
An independent Data Monitoring Committee (DMC) is implemented to review ongoing safety 
data.  Inclusion and exclusion criteria are updated to reflect mandatory tumor biopsy requirement 
and clarify exclusion of participants with active infections.  Other modifications or editorial 
changes were included to correct inconsistencies and improve operational feasibility.  
Protocol amendment summary of changes table 
Section # and 
Name 
Description of Change 
Brief Rationale 
1.1 Synopsis and 
10.1.4 Committees 
Structure 
An independent Data Monitoring Committee 
(DMC) is implemented to review ongoing safety 
data (starting from confirmation of recommended 
Phase 2 dose). 
DMC is implemented to monitor safety of the 
isatuximab + atezolizumab combination for Phase 2 in 
addition to biweekly Study Committee which will 
monitor safety data of Phase 1. 
1.3 Schedule of 
Activities (SOA) 
Treatment time window of C1D1 is updated from 
±2 days to ±1 day. 
Merged columns “Cycle 2-8”, “Cycle 9”, “ 
Cycle 10 and Beyond” into one column “Cycle 2 
and Beyond” for clarify; study procedures have 
not been changed.  
Corrected typographical error and in accordance with 
Section 6.6.2. 
Disease assessment schedule was ambiguous with the 
previous table format that it was unclear that frequency 
change should follow calendar days and not cycles. 
1.3 
Pharmacokinetics 
and 
Immunogenicity 
Flow Chart, 8.5.1 
Sampling Time, 
8.8.1 
Immunogenicity 
assessments 
Clarified sample collection details and updated 
sample collection time windows within flow chart 
to be consistent with footnote descriptions.  No 
further isatuximab ADA sample will be collected 
after FUP even if status is positive or 
inconclusive.  Defined abbreviation ID and ADA, 
removed AFP.  Updated Table 8. 
Clarification and minor corrections are implemented in 
PK/ADA flow chart to improve clarify and operation.  
Table 8 was updated to reflect details regarding 
bioanalytical methods for anti-atezolizumab antibody. 
1.3 Exploratory 
Biomarker Flow 
Chart 5.1 Inclusion 
Criteria 
Updated Biomarker Flow Chart and I02 to 
mandate tumor biopsy (for HCC, SCCHN, and 
EOC) in Phase 1 and Phase 2 Stage 1 unless 
clinically unfeasible, or provision of archival 
tissue (for GBM). 
To enable translational research in understanding the 
mechanism of isatuximab + atezolizumab in the 4 
disease types, and identify potentially predictive 
biomarker. 
2.2.2 Isatuximab 
Under background of Isatuximab, updated 
number of patients treated with isatuximab. 
Updated per IB Edition 9. 
5.2 Exclusion 
Criteria 
Updated E34 to exclude participants with active 
tuberculosis, or severe infection requiring 
parenteral antibiotic treatment. 
This is added to avoid any potential complications that 
may be brought upon by the immune modulating 
activity of atezolizumab (anti-PD-L1). 
6.1 Study 
Intervention(s) 
Administered 
Added time windows for atezolizumab infusion 
as over 60 ± 15 mins for first infusion, and 
30 ± 10 mins for subsequent infusions. 
Time windows were omitted by mistake in the original 
protocol. 
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6.6.4 General 
guidelines for the 
management of 
infusion-associated 
reactions and 
10.21 Appendix 21 
In Table 5 and Table 25, for G2 IAR, infusion 
may be resumed at half the original infusion rate 
for isatuximab and at half the rate at time of 
event onset for atezolizumab (instead of at the 
time of event onset for both IMPs). 
This is corrected to be in accordance with IBs. 
8.3 Adverse 
Events and 
Serious Adverse 
Events 
Remove atezolizumab from symptomatic 
overdose definition. 
Current definition of symptomatic overdose only applies 
to isatuximab and not atezolizumab; overdose with 
atezolizumab is also not an AESI per IB. 
8.5.3 Bioanalytical 
Methods 
Lower limit of quantification is updated from 
0.500 ng/mL to 0.500 µg/mL.  Analytical 
technique is updated to Immunoassay.  Site of 
bioanalysis for atezolizumab was updated to 
ICON (NY, USA). 
Table 6 was updated as new bioanalytical method will 
be used for isatuximab and the bioanalysis site for 
atezolizumab assay will be ICON. 
8.5.4.1 Non-
compartmental 
analysis – 
isatuximab 
Specified PK parameters will be calculated from 
isatuximab plasma concentrations.  AUClast is 
removed from the parameters and added “after 
the first infusion” at the end of definition for 
AUC0-T. 
Previously “plasma” was omitted by mistake.  Clarified 
definition of AUC0-T. 
AUClast was deleted from Table 7 as this is not 
relevant for isatuximab. 
8.5.4.2 Population 
approach – 
isatuximab and 
atezolizumab 
Removed “and more precisely to analyze the 
isatuximab plasma concentration-time profiles”. 
Plasma concentration-time profile is not relevant in this 
context as population PK approach will be used. 
8.8.1 
Immunogenicity 
assessments 
Table 8 was updated 
Table 8 was updated by adding the bioanalytical 
method and location for anti-atezolizumab antibody. 
9.4.3.1 Analysis of 
PK endpoints 
“Standard error of means” was added as part of 
descriptive statistics.  Additional details were 
also provided on endpoints. 
These changes were omitted by mistake in the previous 
version of the protocol. 
10.2 Appendix 2: 
Clinical laboratory 
tests 
Added time window for blood chemistry, 
hematology, and urinalysis is within 1 working 
day prior to IMP administration. 
This is added in accordance with time window stated in 
Study Reference Manual. 
10.2 Appendix 2: 
Clinical laboratory 
tests 
To allow semi-quantitative urinalysis (according 
to site practice and if such method can provide 
absolute numeric value of the parameters). 
Standard practice of some study sites utilize semi-
quantitative urinalysis. 
Throughout 
Grammatical corrections and formatting edits. 
To correct grammatical errors and improve readability. 
 
 
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10.10.3 
Amendment 03 (07 DECEMBER 2018)  
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union 
OVERALL RATIONALE FOR THE AMENDMENT 
The main reason for this amendment was to include management guidelines for renal events 
relating to a new identified risk of atezolizumab (previously communicated to study sites in a 
study memo).  Management guideline for systemic immune activation recently provided by F. 
Hoffmann-La Roche Ltd. was also included in this amendment.  Premedication requirements were 
modified to allow patients with no or mild infusion associated reactions to omit premedications at 
Investigators’ discretion.  Other modifications or editorial changes were included to correct 
inconsistencies and improve operational feasibility.  
Protocol amendment summary of changes table 
Section # 
and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
2.3.4 Preventive 
measures to 
minimize the risk 
from the 
combination 
6.1 Study 
intervention(s) 
administered 
Premedication requirements were 
modified. 
 
In Section 2.3.4, premedication 
administration timing was corrected from 
“15 to 30 minutes” to “30 to 60 minutes” 
prior to isatuximab infusion for 
consistency with the rest of the protocol. 
Change based on data from completed and ongoing studies to 
allow patients with no or Grade ≤2 infusion associated reactions 
(IARs) to omit premedications at Investigators’ discretion. 
Montelukast 10 mg orally or equivalent was added as a 
premedication based on recent references (i, ii, iii) that this 
addition may decrease incidence and respiratory symptoms of 
IAR. 
Correction was made in Section 2.3.4 for consistency. 
References: 
(i) Chari A, Mark TM, Krishnan A, Stockerl-Goldstein K, Usmani 
SZ, Londhe A, et al. Use of Montelukast to Reduce Infusion 
Reactions in an Early Access Program (EAP) of Daratumumab 
in United States Patients with Relapsed or Refractory Multiple 
Myeloma [abstract]. Blood. 2016;128:2142. 
(ii) Nooka AK, Gleason C, Sargeant MO, Walker M, Watson M, 
Panjic EH, Lonial S. Managing Infusion Reactions to New 
Monoclonal Antibodies in Multiple Myeloma: Daratumumab and 
Elotuzumab. J Oncol Pract. 2018;14(7):414-22. 
(iii) Reece DE and Phillips MJ.  Infusion Reactions With 
Monoclonal Antibody Therapy in Myeloma: Learning From 
Experience.  J Oncol Pract. 2018; 14(7): 425-6. 
1.3 
Pharmacokinetics 
and 
Immunogenicity 
Flow Chart 
Specified that PK/ADA sample collection 
may be reduced upon notification from 
the Sponsor based on updated 
knowledge of isatuximab on PK/ADA. 
To allow flexibility and quick implementation in reducing PK/ADA 
sampling if updated knowledge becomes available, 
2.2.1.3 Epithelial 
ovarian cancer 
Corrected EOC patients should receive 
no more than 3 lines (instead of 2 lines) of 
systemic therapy for platinum-sensitive 
disease for consistency with I14. 
Correction of typographical error. 
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Section # 
and Name 
Description of Change 
Brief Rationale 
2.3.4 Preventive 
measures to 
minimize the risk 
from the 
combination 
5.2 Exclusion 
Criteria 
“Inhaled or topical steroids are permitted, 
provided that they are not for treatment of 
an autoimmune disorder” was removed 
from Section 2.3.4 and E05. 
Specified that the exclusion of patients 
with comorbidity requiring corticosteroid 
therapy refers to systemic corticosteroid 
therapy only. 
Clarification - as participants with active, known or suspected 
autoimmune disorder are ineligible per E26. 
4.1.2 Phase 2 
(efficacy signal 
search with a 2-
stage design in 
each cohort) 
Removed duplicated text regarding timing 
of observed responses before proceeding 
to Stage 2. 
Original wording created confusion. The deletion also removes 
unnecessary duplication, as this is covered in Section 9.5. 
5.1 Inclusion 
Criteria 
Corrected “radiatherapy" to “radiotherapy” 
in I11.  Also, corrected “after a diagnosis 
of recurrent SCCHN” to “after a diagnosis 
of recurrent and/or metastatic SCCHN” 
for consistency with other eligibility 
criteria. 
Correction of typographical error, and the incorrect omission of 
“and/or metastatic” SCCHN. 
5.1 Inclusion 
Criteria 
The phrase in I16 “unless the recurrence 
is outside the radiation field or there is 
unequivocal histologic confirmation of 
tumor progression” is replaced with “PD 
occurred within 12 weeks from completion 
of irradiation can only be defined by (1) 
new enhancement outside of the radiation 
field, or (2) unequivocal histological 
confirmation.”. 
Original wording in I16 created confusion. This eligibility criterion 
is clarified to improve study sites’ understanding without 
changing the patient population. 
5.1 Inclusion 
Criteria 
 
 
Section 10.8 
I14 was clarified that only patients with 
resistant-refractory disease are eligible for 
EOC cohort, for consistency with the rest 
of the protocol. 
France only Amendment: I14 was 
modified to enroll EOC patients who have 
received or failed 1 line of anti-cancer 
therapy for platinum-resistant/refractory 
disease (unless patients are ineligible or 
intolerant to standard of care for platinum 
resistant/refractory disease). 
Clarification. 
 
 
 
While the EOC Treatment Guidelines recommend clinical trials, 
chemotherapy, or targeted therapy for patients with platinum-
resistant/refractory disease, patients in France will receive 
(unless ineligible or intolerant to) one other available therapy 
before joining this study. 
5.2 Exclusion 
Criteria 
Section 10.22 
Added a new criterion (E36) to exclude 
patients with known untreated current 
hepatitis C (HCV) virus (subsequent 
criteria renumbered accordingly). 
Added guidelines of patients with HCV 
infection. 
Specific guidelines are put in place on how to manage patients 
with positive HCV results at screening. 
6.5 Concomitant 
Therapy 
Clarified that any palliative procedures 
(including radiotherapy) may be given to 
control symptom. 
Clarification and alignment within program. 
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Section # 
and Name 
Description of Change 
Brief Rationale 
6.5 Concomitant 
Therapy 
Clarified exceptions for use of systemic 
corticosteroids (including management of 
irAEs). 
Previous guidance on prohibited use of corticosteroids was 
inconsistent with management guidelines. 
6.6.2 Dose delay 
and dose 
omission 
Treatment window of "±1 day" and "±2 
days" corresponds to delay of beyond "≥2 
days" and "≥3 days" (corrected from ">2 
days" and ">3 days"). 
In Cycle 1, if an AE occurs and the 
participant does not recover within 3 
days, infusion of isatuximab (D8 or D15) 
may be omitted only; therefore the words 
“or delayed” have been removed. 
To correct inconsistency in treatment windows. 
 
 
Within Cycle 1, dose delay was not intended to be allowed as 
Cycle 1 consists of weekly dosing of isatuximab (delay of 
infusion for more than 3 days should result in dose omission 
instead). 
6.6.4 General 
guidelines for 
management of 
infusion-
associated 
reactions 
Following Grade 2 IAR, infusion may be 
restarted for atezolizumab at half the rate 
being given at the time of event onset, 
and not “half the original infusion rate”. 
This correction was missed in the previous amendment where 
the same change was applied in Tables 5 and 25. 
8.5.3 
Bioanalytical 
Methods 
Removed Table 6 (Bioanalytical methods 
for isatuximab and atezolizumab 
pharmacokinetic analysis). 
Details on bioanalytical methods will be provided in Laboratory 
Manual instead. 
8.8.1 
Immunogenicity 
assessments 
Removed Table 8 (Bioanalytical methods 
for immunogenicity assessment) and 
removed duplicated information 
presented in Section 1.3. 
Clarification; details on bioanalytical methods for 
immunogenicity assessment will be provided in Laboratory 
Manual instead. 
9.3 Populations 
for Analyses 
Response evaluable population: Added 
that patients must fulfill all eligibility 
criteria. 
Clarification. 
9.5 Interim 
Analyses 
To clarify the timing of interim analysis 
and that interim analysis is performed on 
a per-cohort basis. 
Interim analyses for HCC, SCCHN, and 
EOC cohorts are changed to be 
performed when the last participants 
remaining in the treatment period of 
Phase 2 Stage 1 have completed 
approximately “6 months” of study 
treatment instead of “6 cycles”. 
Original wording on interim analyses created confusion.  Interim 
analyses for HCC, SCCHN, and EOC cohorts are changed to 
coincide with previously defined primary analysis cut-off date to 
alleviate operational burden. 
10.21 
Management of 
Atezolizumab-
Specific Adverse 
Events 
Included management guidelines for renal 
events and systemic immune activation. 
F. Hoffmann-La Roche Ltd. reported a new identified risk of 
immune-related nephritis associated with the use of 
atezolizumab.  The company has also provided additional 
management guideline on systemic immune activation to be 
included in study protocol. 
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Section # 
and Name 
Description of Change 
Brief Rationale 
Section 10.21 
Other changes include: 
Inconsistencies correction. 
 
 
 
 
 
Introductory paragraphs were included for 
each type of atezolizumab-specific AE. 
 
Inconsistencies include, for example: correction of “delay cycle” 
to “delay or omit dose” for consistency with Section 6.6.2 where 
dose omission is allowed; ensuring descriptions for isatuximab 
management are in the correct column of the tables. 
 
To provide additional relevant information for management of 
atezolizumab-specific AEs in alignment with the atezolizumab 
program (adapted from atezolizumab IB). 
Throughout 
Grammatical corrections and formatting 
edits. 
To correct grammatical errors and improve readability. 
10.10.4 
Amendment 04 (11 June 2019)  
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union 
OVERALL RATIONALE FOR THE AMENDMENT 
Based on updated pharmacokinetic characterization of isatuximab, the plasma half-life has been 
re-estimated to 28 days. As duration of contraceptive measures is required to last for 5 half-lives, 
a revised duration of contraceptive measures of 5 months after the last isatuximab dose is 
required. In addition, management guidelines for immune-related myositis are also included in the 
Appendix (information that has previously been communicated in February 2019 to study 
Investigators).  
Protocol amendment summary of changes table 
Section # 
and Name 
Description of Change 
Brief Rationale 
1.3 Schedule of 
activities; 
8.3.5 Pregnancy; 
10.3 Clinical 
laboratory tests; 
10.4 
Contraceptive 
guidance and 
collection of 
pregnancy 
information 
Pregnancy test is extended to monthly until 5 
months after last dose of study treatment. 
Monthly pregnancy test is implemented until end of the 
extended contraception period. 
4.4 Justification 
for Dose 
Re-estimation of isatuximab half-life of 28 days is 
included. 
Based on updated pharmacokinetic characterization of 
isatuximab. 
10.4  
Contraceptive 
guidance and 
collection of 
Updated effective contraceptive methods are 
required until 5 months after last dose of study 
treatment. 
5 months of contraception period after last dose of 
isatuximab is required based on updated 
pharmacokinetic analysis. 
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Section # 
and Name 
Description of Change 
Brief Rationale 
pregnancy 
information 
10.21 
Management of 
Atezolizumab-
Specific Adverse 
Events 
Management guideline for immune-related 
myositis is included. 
Immune-related myositis was identified as a risk for 
atezolizumab.  Management guideline for immune-
related myositis was previously communicated and was 
not included in the protocol amendment. 
 
10.11 APPENDIX 11: RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
VERSION 1.1  
Details provided in bibliographic reference (59). 
Measurability of tumor at baseline 
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as 
follows. 
Measurable lesions must be accurately measured in at least 1 dimension (longest diameter in the 
plane of the measurement to be recorded) with a minimum size of: 
• 10 mm by CT scan (CT scan slice thickness no greater than 5 mm). 
• 10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable). 
• 20 mm by chest X-ray. 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node 
must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended 
to be no greater than 5 mm). At baseline and in follow-up, only the short axis will be measured 
and followed. 
Non-measurable lesions are all other lesions, including small lesions (longest diameter <10 mm or 
pathological lymph nodes with ≥10 to <15 mm short axis), as well as non-measurable lesions. 
Lesions considered non-measurable include: leptomeningeal disease, ascites, pleural or pericardial 
effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, and abdominal 
masses/abdominal organomegaly identified by physical exam that is not measurable by 
reproducible imaging techniques. 
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Special considerations regarding lesion measurability: 
• Bone lesions: 
- 
Bone scan, positron emission tomography scan or plain films are not considered 
adequate imaging techniques to measure bone lesions. However, these techniques can 
be used to confirm the presence or disappearance of bone lesions, 
- 
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as CT or 
MRI can be considered as measurable lesions if the soft tissue component meets the 
definition of measurability described above, 
- 
Blastic bone lesions are non-measurable. 
• Cystic lesions: 
- 
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts, 
- 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if 
non-cystic lesions are present in the same patient, these are preferred for selection as 
target lesions. 
• Lesions with prior local treatment: 
- 
Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
locoregional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion. 
Method of assessment 
All measurements should be recorded in metric notation, using calipers if clinically assessed. All 
baseline evaluations should be performed as close as possible to the treatment start and never 
more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging based evaluation should 
always be performed rather than clinical examination unless the lesion(s) being followed cannot 
be imaged but are assessable by clinical examination. 
• Clinical lesions: Clinical lesions will only be considered measurable when they are 
superficial and ≥10 mm diameter as assessed using calipers. For the case of skin lesions, 
documentation by color photography including a ruler to estimate the size of the lesion is 
suggested. As noted above, when lesions can be evaluated by both clinical exam and 
imaging, imaging evaluation should be undertaken since it is more objective and may be 
reviewed at the end of the study. 
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• Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new 
lesions. However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung. 
• CT, MRI: CT is the best currently available and reproducible method to measure lesions 
selected for response assessment. Measurability of lesions on CT scan is based on the 
assumption that CT slice thickness is 5 mm or less. When CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion should be twice the slice 
thickness. 
• Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement. If new lesions are identified by ultrasound in the course of 
the study, confirmation by CT or MRI is advised. 
• Endoscopy, laparoscopy: The utilization of these techniques for objective tumor 
evaluation is not advised. 
• Tumor markers: Tumor markers alone cannot be used to assess objective tumor 
response. 
• Cytology, histology: These techniques can be used to differentiate between PR and CR in 
rare cases if required by protocol. 
Baseline documentation of ‘target’ and ‘non target’ lesions 
When more than 1 measurable lesion is present at baseline all lesions up to a maximum of 
5 lesions total (and a maximum of 2 lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline. 
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, and should lend themselves to reproducible repeated 
measurements. 
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
≥15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. All 
other pathological nodes (those with short axis ≥10 mm but <15 mm) should be considered 
non-target lesions. Nodes that have a short axis <10 mm are considered non-pathological and 
should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. The baseline sum diameters 
will be used as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required and 
these lesions should be followed as ‘present’, ‘absent’, or ‘unequivocal progression’. In addition, 
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it is possible to record multiple non-target lesions involving the same organ as a single item on the 
case (eg, ‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver metastases’). 
Response criteria 
Response criteria are described in Table 12.  
Table 12 - Response criteria  
Response criteria 
Evaluation of target lesions 
CR 
Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) 
must have reduction in short axis to <10 mm. 
PR 
At least a 30% decrease in the sum of diameters of target lesions, taking as reference the 
baseline sum diameters. 
PD 
At least a 20% increase in the sum of diameters of target lesions, taking as reference the 
smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition 
to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 
5 mm. (Note: the appearance of 1 or more new lesions is also considered progression). 
SD 
Neither sufficient shrinkage from the baseline study to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
Abbreviations: CR=complete response; PD=progressive disease; PR=partial response; SD=stable disease. 
Special notes on the assessment of target lesions 
Lymph nodes identified as target lesions should always have the actual short axis measurement 
recorded and should be measured in the same anatomical plane as the baseline examination, even 
if the nodes regress to below 10 mm on study. This means that when lymph nodes are included as 
target lesions, the ‘sum’ of lesions may not be zero even if CR criteria are met, since a normal 
lymph node is defined as having a short axis of <10 mm. For PR, SD and PD, the actual short axis 
measurement of the nodes is to be included in the sum of target lesions. 
Target lesions that become ‘too small to measure’: All lesions (nodal and non-nodal) recorded at 
baseline should have their actual measurements recorded at each subsequent evaluation, even 
when very small (eg, 2 mm). However, sometimes lesions or lymph nodes which are recorded as 
target lesions at baseline become so faint on CT scan that the radiologist may not feel comfortable 
assigning an exact measure and may report them as being ‘too small to measure’. When this 
occurs it is important that a value be recorded on the eCRF. If it is the opinion of the radiologist 
that the lesion has likely disappeared, the measurement should be recorded as 0 mm. If the lesion 
is believed to be present and is faintly seen but too small to measure, a default value of 5 mm 
should be assigned. 
When non-nodal lesions ‘fragment’, the longest diameters of the fragmented portions should be 
added together to calculate the target lesion sum. Similarly, as lesions coalesce, a plane between 
them may be maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion. If the lesions have truly coalesced such that they are no longer separable, the 
vector of the longest diameter in this instance should be the maximal longest diameter for the 
‘coalesced lesion’. 
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Evaluation of non-target lesions 
While some non-target lesions may actually be measurable, they need not be measured and 
instead should be assessed only qualitatively at the time points specified in the protocol. 
• CR: Disappearance of all non-target lesions and normalization of tumor marker level. 
All lymph nodes must be non-pathological in size (<10 mm short axis). 
• Non-CR/Non-PD: Persistence of 1 or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits. 
• Progressive Disease: Unequivocal progression of existing non-target lesions. (Note: the 
appearance of 1 or more new lesions is also considered progression). 
The concept of progression of non-target disease requires additional explanation as follows: 
When the patient also has measurable disease; in this setting, to achieve ‘unequivocal progression’ 
on the basis of the non-target disease, there must be an overall level of substantial worsening in 
non-target disease such that, even in presence of SD or PR in target disease, the overall tumor 
burden has increased sufficiently to merit discontinuation of therapy. A modest ‘increase’ in the 
size of 1 or more non-target lesions is usually not sufficient to qualify for unequivocal progression 
status. 
When the patient has only non-measurable disease; to achieve ‘unequivocal progression’ on the 
basis of the non-target disease, there must be an overall level of substantial worsening such that 
the overall tumor burden has increased sufficiently to merit discontinuation of therapy. A modest 
‘increase’ in the size of 1 or more non-target lesions is usually not sufficient to qualify for 
unequivocal progression status. Because worsening in non-target disease cannot be easily 
quantified (by definition: if all lesions are truly non-measurable) a useful test that can be applied 
when assessing patients for unequivocal progression is to consider if the increase in overall 
disease burden based on the change in non-measurable disease is comparable in magnitude to the 
increase that would be required to declare PD for measurable disease: ie, an increase in tumor 
burden representing an additional 73% increase in ‘volume’ (which is equivalent to a 
20% increase diameter in a measurable lesion). Examples include an increase in a pleural effusion 
from ‘trace’ to ‘large’, an increase in lymphangitic disease from localized to widespread, or may 
be described in protocols as ‘sufficient to require a change in therapy’. If ‘unequivocal 
progression’ is seen, the patient should be considered to have had overall PD at that point. 
New lesions 
The appearance of new malignant lesions denotes disease progression. The finding of a new 
lesion should be unequivocal: ie, not attributable to differences in scanning technique, change in 
imaging modality or findings thought to represent something other than tumor (for example, some 
‘new’ bone lesions may be simply healing or flare of preexisting lesions). This is particularly 
important when the patient’s baseline lesions show PR or CR. For example, necrosis of a liver 
lesion may be reported on a CT scan report as a ‘new’ cystic lesion, which it is not. 
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A lesion identified on a follow-up study in an anatomical location that was not scanned at baseline 
is considered a new lesion and will indicate disease progression. An example of this is the patient 
who has visceral disease at baseline and while on study has a CT or MRI brain ordered which 
reveals metastases. The patient’s brain metastases are considered to constitute PD even if he/she 
did not have brain imaging at baseline.  
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents new disease. If repeat scans confirm that there is a 
new lesion, then progression should be declared using the date of the initial scan. 
While fluorodeoxyglucose-positron emission tomography (FDG-PET) response assessments need 
additional study, it is sometimes reasonable to incorporate the use of FDG-PET scanning to 
complement CT scanning in assessment of progression (particularly possible ‘new’ disease). New 
lesions on the basis of FDG-PET imaging can be identified according to the following algorithm: 
A) Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based 
on a new lesion. 
B) No FDG-PET at baseline and a positive FDG-PET at follow-up: 
- 
If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed 
by CT, this is PD, 
- 
If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG 
PET scan). If the positive FDG PET at follow-up corresponds to a preexisting site of 
disease on CT that is not progressing on the basis of anatomic images, this is not PD. 
Evaluation of best overall response 
Time point response: At each protocol-specified time point, a response assessment should occur. 
Table 13 provides a summary of the overall response status calculation at each time point for 
patients who have measurable disease at baseline. 
Table 13 - Response in patients with target disease  
Target lesions 
Non-target lesions 
New lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
Inevaluable 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Abbreviations: CR=complete response; PD=progressive disease; PR=partial response; SD=stable disease.  
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When patients have non-measurable (therefore non-target) disease only, Table 14 is to be used. 
Table 14 - Response in patients with non-target disease only  
Non-target lesions 
New lesions 
Overall response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD 
Not all evaluated 
No 
Inevaluable  
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
Abbreviations: CR=complete response; PD=progressive disease; PR=partial response; SD=stable disease. 
Missing assessments and inevaluable designation: When no imaging/measurement is done at all at 
a particular time point, the patient is not evaluable (NE) at that time point. 
If only a subset of lesion measurements are made at an assessment, usually the case is also 
considered NE at that time point, unless a convincing argument can be made that the contribution 
of the individual missing lesion(s) would not change the assigned time point response. This would 
be most likely to happen in the case of PD. When no imaging/measurement is done at all at a 
particular time point, the patient is NE at that time point. 
If only a subset of lesion measurements are made at an assessment, usually the case is also 
considered NE at that time point, unless a convincing argument can be made that the contribution 
of the individual missing lesion(s) would not change the assigned time point response. This would 
be most likely to happen in the case of PD. 
Special notes on response assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to ‘normal’ 
size (<10 mm), they may still have a measurement reported on scans. This measurement should be 
recorded even though the nodes are normal in order not to overstate progression should it be based 
on increase in size of the nodes. As noted earlier, this means that patients with CR may not have a 
total sum of ‘zero’ on the eCRF. 
In trials where confirmation of response is required, repeated ‘NE’ time point assessments may 
complicate best response determination. The analysis plan for the trial must address how missing 
data/assessments will be addressed in determination of response and progression. For example, in 
most trials it is reasonable to consider a patient with time point responses of PR, -NE, and -PR as 
a confirmed response. 
Patients with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be reported as ‘symptomatic 
deterioration’. Every effort should be made to document objective progression even after 
discontinuation of treatment. Symptomatic deterioration is not a descriptor of an objective 
response: it is a reason for stopping study therapy. 
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The objective response status of such patients is to be determined by evaluation of target and non 
target disease. For equivocal findings of progression (eg, very small and uncertain new lesions; 
cystic changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment. If at the next scheduled assessment, progression is confirmed, the date of progression 
should be the earlier date when progression was suspected. 
Duration of response 
The duration of overall response is measured from the time measurement criteria are first met for 
CR/PR (whichever is first recorded) until the first date that recurrent or PD is objectively 
documented (taking as reference for PD the smallest measurements recorded on study). 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that recurrent disease is objectively documented. 
Stable disease is measured from the start of the treatment until the criteria for progression are met, 
taking as reference the smallest sum on study (if the baseline sum is the smallest, this is the 
reference for calculation of PD). 
Reproduced from: Eisenhauer EA, Therasse P, Bogaerts J et al. New response evaluation criteria 
in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228 47. 
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10.12 APPENDIX 12: BARCELONA CLINIC LIVER CANCER (BCLC) STAGING 
CLASSIFICATION  
Stage (60) 
PST 
Tumor status 
Liver function studies 
Tumor Stage 
Okuda Stage 
Stage A: early HCC 
A1 
0 
Single 
I 
No portal hypertension and normal 
bilirubin 
A2 
0 
Single 
I 
Portal hypertension and normal 
bilirubin 
A3 
0 
Single 
I 
Portal hypertension and abnormal 
bilirubin 
A4 
0 
3 tumors <3 cm 
I-II 
Child-Pugh A-B 
Stage B:  intermediate HCC 
0 
Large multinodular 
I-II 
Child-Pugh A-B 
Stage C:  advanced HCC 
1-2* 
Vascular invasion or 
extrahepatic spread 
I-II 
Child-Pugh A-B 
Stage D:  end-stage HCC 
3-4† 
Any 
III 
Child-Pugh C 
PST, Performance Status Test 
Stage A and B, All criteria should be fulfilled 
* Stage C, at least one criteria:  PST 1-2 or vascular invasion/extrahepatic spread 
†Stage D, at least one criteria:  PST 3-4 or Okuda Stage III/Child-Pugh C 
10.13 APPENDIX 13: CHILD PUGH SCORE  
Score 
Points 
Child-Pugh A 
5-6 
Child-Pugh B 
7-9 
Child-Pugh C 
>9 
 
Scoring 
 
Score 
Measure 
1 Point 
2 Points 
3 Points 
Ascites 
Absent 
Slight 
Moderate 
Serum bilirubin (mg/dL) 
<2.0 
2.0 – 3.0 
>3.0 
Serum albumin (g/dL) 
>3.5 
2.8 – 3.5 
<2.8 
PT prolongation 
or INR 
<4 sec 
<1.7 
4 – 6 sec 
1.7 – 2.3 
>6 sec 
>2.3 
Encephalopathy grade 
None 
1 – 2 
3 – 4 
 
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Encephalopathy Grading 
Encephalopathy Grade 
Clinical Definition 
Grade 0 
Normal consciousness, personality, and neurological examination 
Grade 1 
Restless, sleep disturbed, irritable/agitated, tremor, and impaired handwriting 
Grade 2 
Lethargic, time-disoriented, inappropriate, asterixis, and ataxia 
Grade 3 
Somnolent, stuporous, place-disoriented, hyperactive reflexes, and rigidity 
Grade 4 
Unrousable coma, no personality/behavior, decerebrate 
 
10.14 APPENDIX 14: PERFORMANCE STATUS  
Eastern Cooperative Oncology Group 
Performance Status Scale (61) 
Karnofsky Performance Scale (62) 
Grade 
Descriptions 
Percentage 
Description 
0 
Fully active, able to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence of 
disease. 
90 
Able to carry on normal activity; minor signs 
or symptoms of disease. 
1 
Restricted in physically strenuous activity, but 
ambulatory and able to carry out work of a light or 
sedentary nature (eg, light housework, office work). 
80 
Normal activity with effort; some signs or 
symptoms of disease. 
70 
Cares for self, unable to carry on normal 
activity or to do active 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. 
60 
Requires occasional assistance, but is able 
to care for most of his/her needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
Capable of only limited self-care, confined to bed or 
chair more than 50% of waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization indicated.  
Death no imminent. 
4 
Completely disabled. Cannot carry on any self-care.  
Totally confined to bed or chair. 
20 
Very sick, hospitalization indicated.  Death 
not imminent. 
10 
Moribund, fatal processes progressing 
rapidly. 
5 
Dead. 
0 
Dead. 
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10.15 APPENDIX 15: RESPONSE ASSESSMENT IN NEURO-ONCOLOGY (RANO) 
CRITERIA  
Details provided in bibliographic reference (63). 
Criterion 
CR 
PR 
SD 
PD 
T1 gadolinium enhancing disease 
None 
≥50% ↓ 
<50% ↓ but <25% ↑ 
≥25% ↑ * 
T2/FLAIR 
Stable or ↓ 
Stable or ↓ 
Stable or ↓ 
↑ * 
New lesion 
None 
None 
None 
Present * 
Corticosteroids 
None 
Stable or ↓ 
Stable or ↓ 
NA † 
Clinical status 
Stable or ↓ 
Stable or ↑ 
Stable or ↑ 
↓ * 
Requirement for response 
All 
All 
All 
Any * 
Abbreviations:  CR = complete response; PR = partial response; SD = stable disease, PD = progressive disease; FLAIR = fluid-attenuated 
inversion recovery; NA = not applicable. 
* Progression occurs when this criterion is present. 
† Increase in corticosteroids alone will not be taken into account in determining progression in the absence of persistent clinical deterioration. 
10.16 APPENDIX 16:  MODIFIED RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
FOR IMMUNE-BASED THERAPEUTICS (IRECIST)  
Details provided in bibliographic reference (56). 
Table 15 - Comparison of Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and modified 
Response Evaluation Criteria in Solid Tumors for immune based therapies (iRECIST)  
 
RECIST 1.1 
iRECIST 
Definitions of measurable and 
non-measurable disease; numbers, and 
site of target disease 
Measurable lesions are ≥10 mm in 
diameter (≥15 mm for nodal lesions); 
maximum of 5 lesions (2 per organ); all 
other disease is considered non-target 
(must be ≥10 mm in short axis for nodal 
disease) 
No change from RECIST 1.1; however, 
new lesions are assessed as per 
RECIST 1.1 but are recorded separately 
on the case report form (but not included 
in the sum of lesions for target lesions 
identified at baseline) 
Complete response, partial response, or 
stable disease 
Cannot have met criteria for progression 
before complete response, partial 
response, or stable disease 
Can have had iUPD (one or more 
instances), but not iCPD, before iCR, 
iPR, or iSD 
Confirmation of complete response or 
partial response 
Only required for non-randomized trials 
As per RECIST 1.1 
Confirmation of stable disease 
Not required 
As per RECIST 1.1 
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RECIST 1.1 
iRECIST 
New lesions 
Result in progression; recorded but not 
measured 
Results in iUPD but iCPD is only 
assigned on the basis of this category if 
at next assessment additional new 
lesions appear or an increase in size of 
new lesions is seen (≥5 mm for sum of 
new lesion target or any increase in new 
lesion non-target); the appearance of 
new lesions when none have previously 
been recorded, can also confirm iCPD 
Independent blinded review and central 
collection of scans 
Recommended in some circumstances -
eg, in some trials with progression-based 
endpoints planned for marketing approval 
Collection of scans (but not independent 
review) recommended for all trials 
Confirmation of progression 
Not required (unless equivocal) 
Required 
Consideration of clinical status 
Not included in assessment 
Clinical stability is considered when 
deciding whether treatment is continued 
after iUPD 
“i” indicated immune responses assigned using iRECIST. 
Abbreviations: iCPD=confirmed progression; iCR=complete response; iPR=partial response; iSD=stable disease; iUPD=unconfirmed 
progression; RECIST=Response Evaluation Criteria in Solid Tumors 
Table 16 - Assessment of timepoint response using modified Response Evaluation Criteria in Solid 
Tumors for immune based therapies (iRECIST)  
Target 
lesions 
Non-target 
lesions 
New 
lesions 
Timepoint 
response 
with no 
previous 
iUPD in any 
category 
Timepoint response with previous iUPD in 
any categorya 
iCR 
iCR 
No 
iCR 
iCR 
iCR 
Non-iCR/non-iUPD 
No 
iPR 
iPR 
iPR 
Non-iCR/non-iUPD 
No 
iPR 
iPR 
iSD 
Non-iCR/non-iUPD 
No 
iSD 
iSD 
iUPD with 
no change, 
or with a 
decrease 
from last 
timepoint 
iUPD with no 
change, or 
decrease from last 
timepoint 
Yes 
Not applicable 
New lesions confirm iCPD if new lesions were previously 
identified and they have increased in size (≥5 mm in sum 
of measures for new lesion target or any increase for new 
lesion non-target) or number; if no change is seen in new 
lesions (size or number) from last timepoint, assignment 
remains iUPD 
iSD, iPR, 
iCR 
iUPD 
No 
iUPD 
Remains iUPD unless iCPD is confirmed on the basis of a 
further increase in the size of non-target disease (does not 
need to meet RECIST 1.1 criteria for unequivocal 
progression) 
iUPD 
Non-iCR/non-iUPD, 
or iCR 
No 
iUPD 
Remains iUPD unless iCPD is confirmed on the basis of a 
further increase in sum of measures ≥5 mm; otherwise, 
assignment remains iUPD 
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Target 
lesions 
Non-target 
lesions 
New 
lesions 
Timepoint 
response 
with no 
previous 
iUPD in any 
category 
Timepoint response with previous iUPD in 
any categorya 
iUPD 
iUPD 
No 
iUPD 
Remains iUPD unless iCPD is confirmed based on a 
further increase in previously identified target lesion iUPD 
in sum of measures ≥5 mm or non-target lesion iUPD 
(previous assessment need not have shown unequivocal 
progression) 
iUPD 
iUPD 
Yes 
iUPD 
Remains iUPD unless iCPD is confirmed on the basis of a 
further increase in previously identified target lesion iUPD 
sum of measures ≥5 mm, previously identified non-target 
lesion iUPD (does not need to be unequivocal), or an 
increase in the size or number of new lesions previously 
identified 
Non-iUPD 
or 
progression 
Non-iUPD or 
progression 
Yes 
iUPD 
Remains iUPD unless iCPD is confirmed on the basis of 
an increase in the size or number of new lesions 
previously identified 
a Previously identified in assessment immediately before this timepoint. 
“i” indicates immune responses assigned using iRECIST Target lesions, non-target lesions, and new lesions defined according to RECIST 1.1 
principles; if no pseudoprogression occurs, RECIST 1.1 and iRECIST categories for complete response, partial response, and stable disease 
would be the same. 
Abbreviations: iCPD=confirmed progression; iCR=complete response; iPR=partial response; iSD=stable disease; iUPD=unconfirmed 
progression; non-iCR/non-iUPD=criteria for neither CR nor PD have been met; RECIST=Response Evaluation Criteria in Solid Tumors. 
10.17 APPENDIX 17: CA125 RESPONSE BY GYNAECOLOGIC CANCER INTERGROUP 
(GCIG) CRITERIA  
Guidelines for using CA-125 response have been developed. Please refer to 
http://www.gcig.igcs.org/CA-125.html. Patients should have a pre-treatment CA-125 of at least 
twice the ULN in order to be considered for CA-125 response. Patients are not evaluable by 
CA-125 if they have received mouse antibodies or if there has been medical and/or surgical 
interference with their peritoneum or pleura during the previous 28 days. In those patients, a 
CA-125 response would be obtained the moment the CA-125 is reduced by 50% and this should 
be confirmed with a consecutive CA-125 assessment not earlier than 28 days after the previous 
one, with however the date of the first 50% reduction to be the reference date for the CA-125 
response. 
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10.18 APPENDIX 18: IMMUNOTHERAPY RESPONSE ASSESSMENT IN 
NEURO-ONCOLOGY (IRANO)  
Details provided in bibliographic reference (64). 
 
 
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Key considerations for RANO, immune-related response criteria (irRC), and iRANO: 
 
RANO 
irRC 
iRANO 
(if ≤6 months 
after start of 
immunotherapy) 
iRANO 
(if >6 months 
after start of 
immunotherapy) 
Is a repeat scan required to confirm radiographic 
PD for patients without significant clinical decline? 
No 
Yes 
Yes 
No 
Minimal time interval for confirmation of progression 
for patients without significant clinical decline? 
Not applicable 
≥4 weeks 
≥3 months 
Not applicable 
Is further immunotherapy treatment allowed after 
initial radiographic PD (if clinically stable) pending 
progression confirmation? 
Not applicable 
Yes 
Yes 
Not applicable 
Does a new lesion define PD? 
Yes 
No 
No 
Yes 
 
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10.19 APPENDIX 19: CLUSTER OF DIFFERENTIATION 38 BLOOD TEST INTERFERENCE 
GUIDELINE AABB2016  
 
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10.20 APPENDIX 20: MODIFICATION OF DIET IN RENAL DISEASE (MDRD) EQUATION  
Glomerular filtration rate (mL/min/1.73 m2) = 175 × (Serum Creatinine)-1.154 × (Age)-0.203 × 
(0.742 if Female) × (1.212 if African American). 
10.21 APPENDIX 21: MANAGEMENT OF ATEZOLIZUMAB-SPECIFIC ADVERSE EVENTS  
Pulmonary Events 
All pulmonary events should be thoroughly evaluated for other commonly reported etiologies 
such as pneumonia or other infection, lymphangitic carcinomatosis, pulmonary embolism, heart 
failure, chronic obstructive pulmonary disease, or pulmonary hypertension. Management 
guidelines for pulmonary events are provided in Table 17. 
Table 17 - Management Guidelines for Pulmonary Events, Including Pneumonitis  
Event 
Isatuximab 
management  
Atezolizumab 
management 
Action and guidance 
Pulmonary 
event, 
Grade 1  
No change in dose 
No change in dose 
Monitor closely 
Re-evaluate on serial imaging. 
Consider patient referral to pulmonary 
specialist. 
Pulmonary 
event, 
Grade 2 
Delay or omit dose until 
resolves to Grade ≤1 for a 
maximum of 2 weeks 
(see Section 6.6.2) 
Delay cycle until Grade ≤1a 
If event resolves to Grade 1 or 
better, resume atezolizumaba 
And isatuximab  
If event does not resolve to 
Grade 1 or better, permanently 
discontinue atezolizumab and 
resume isatuximabb 
Refer patient to pulmonary and infectious 
disease specialists and consider 
bronchoscopy or BAL. 
Initiate treatment with 1−2 mg/kg/day oral 
prednisone or equivalent. 
Contact Medical Monitorb 
For recurrent events, treat as a Grade 3 or 4 
event. 
Pulmonary 
event, 
Grade 3 or 4 
Grade 3: Delay or omit 
isatuximab until resolves to 
Grade ≤1 for a maximum of 
2 weeks (see Section 6.6.2) 
 
Grade 4: discontinue 
isatuximab 
 Discontinue atezolizumab 
Contact Medical Monitorc 
Bronchoscopy or BAL is recommended. 
Initiate treatment with 1−2 mg/kg/day oral 
prednisone or equivalent 
If event does not improve within 48 hours 
after initiating corticosteroids, consider adding 
an immunosuppressive agent 
If event resolves to Grade 1 or better, taper 
corticosteroids over 1 month 
a Atezolizumab may be withheld for a longer period of time (ie,  12 weeks after event onset) to allow for corticosteroids (if initiated) to be 
reduced to  10 mg/day oral prednisone or equivalent.  The acceptable length of the extended period of time must be agreed upon by the 
investigator and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day oral prednisone or equivalent before 
atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the immune-related 
event.  Patients can be re-challenged with atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 
Abbreviation: BAL = bronchoscopic alveolar lavage 
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Hepatic Events 
Eligible patients must have adequate liver function, as manifested by measurements of total 
bilirubin and hepatic transaminases, and liver function will be monitored throughout study 
treatment. Management guidelines for hepatic events are provided in Table 18. 
For patients with elevated LFTs, concurrent medication, viral hepatitis, and toxic or neoplastic 
etiologies should be considered and addressed, as appropriate. 
Table 18 - Management Guidelines for Hepatic Events  
Event 
Isatuximab 
management 
Atezolizumab 
management 
Action and guidance 
Hepatic 
event, 
Grade 1 
No change in dose 
No change in dose 
Monitor LFTs until values resolve to within normal 
limits 
Hepatic 
event, 
Grade 2 
No change in dose 
Withhold or omit dose until 
Grade ≤1a 
If event resolves to Grade 1 or 
better, resume atezolizumabb 
If event does not resolve to 
Grade 1 or better while 
withholding atezolizumab, 
permanently discontinue 
atezolizumabc 
All events: 
Monitor LFTs more frequently until return to baseline 
values 
Events of >5 days’ duration: 
Initiate treatment with 1−2 mg/kg/day oral prednisone 
or equivalent 
Contact Medical Monitorc 
Hepatic 
event, 
Grade 3 or 4 
 Delay or omit 
isatuximab until 
Grade ≤2 for a 
maximum of 2 weeks 
(see Section 6.6.2) 
Discontinue atezolizumab 
Contact Medical Monitorc 
Consider patient referral to gastrointestinal specialist 
for evaluation and liver biopsy to establish etiology of 
hepatic injury 
Initiate treatment with 1−2 mg/kg/day oral prednisone 
or equivalent 
If event does not improve within 48 hours after 
initiating corticosteroids, consider adding an 
immunosuppressive agent 
If event resolves to Grade 1 or better, taper 
corticosteroids over 1 month 
a Atezolizumab may be withheld for a longer period of time (ie,  12 weeks after event onset) to allow for corticosteroids (if initiated) to be 
reduced to  10 mg/day oral prednisone or equivalent.  The acceptable length of the extended period of time must be agreed upon by the 
investigator and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day oral prednisone or equivalent before 
atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the immune-related 
event.  Patients can be re-challenged with atezolizumab only after approval has been documented by both the Investigator (or an 
appropriate delegate) and the Medical Monitor.  
Abbreviation: LFT = liver function tests. 
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Gastrointestinal Events 
Management guidelines for diarrhea or colitis are provided in Table 19. 
All events of diarrhea or colitis should be thoroughly evaluated for other more common 
etiologies.  
Table 19 - Management Guidelines for Gastrointestinal Events (Diarrhea or Colitis)  
Event 
Isatuximab 
management 
Atezolizumab management 
Action and guidance 
Diarrhea or 
colitis, Grade 1 
No change in dose 
No change in dose 
Initiate symptomatic treatment 
Endoscopy is recommended if symptoms 
persist for 7 days 
Monitor closely 
Diarrhea or 
colitis, Grade 2 
Delay or omit dose 
until ≤Grade1 for a 
maximum of 2 weeks 
(see Section 6.6.2) 
Delay cycle until Grade ≤1a 
If event resolves to Grade 1 or 
better, resume atezolizumab and 
isatuximabb 
If event does not resolve to Grade 1 
or better, permanently discontinue 
atezolizumab and resume 
isatuximabc 
Initiate symptomatic treatment. 
Patient referral to GI specialist is 
recommended 
For recurrent events or events that 
persist 5 days, initiate treatment with 
1−2 mg/kg/day oral prednisone or equivalent 
Contact Medical Monitorc 
Diarrhea or 
colitis, Grade 3 
Delay or omit dose 
until ≤Grade 1 for a 
maximum of 2 weeks 
(see Section 6.6.2) 
 Delay dose until Grade ≤1a 
If event resolves to Grade 1 or 
better, resume atezolizumab and 
isatuximabb 
If event does not resolve to Grade 1 
or better, permanently discontinue 
atezolizumab and resume 
isatuximabc 
Refer patient to GI specialist for evaluation and 
confirmatory biopsy. 
Initiate treatment with 1−2 mg/kg/day IV 
methylprednisolone or equivalent and convert 
to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
Contact Medical Monitorc 
Diarrhea or 
colitis, Grade 4 
Discontinue 
treatment  
Discontinue treatment 
Contact Medical Monitorc 
Refer patient to GI specialist for evaluation and 
confirmation biopsy 
Initiate treatment with 1−2 mg/kg/day IV 
methylprednisolone or equivalent and convert 
to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement 
If event does not improve within 48 hours after 
initiating corticosteroids, consider adding an 
immunosuppressive agent. 
If event resolves to Grade 1 or better, taper 
corticosteroids over 1 month. 
a Atezolizumab may be withheld for a longer period of time (ie,  12 weeks after event onset) to allow for corticosteroids (if initiated) to be 
reduced to  10 mg/day oral prednisone or equivalent.  The acceptable length of the extended period of time must be agreed upon by the 
Investigator and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day oral prednisone or equivalent before atezolizumab 
can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the immune-related event.  
Patients can be re-challenged with atezolizumab only after approval has been documented by both the investigator (or an appropriate 
delegate) and the Medical Monitor.  
Abbreviation: GI = gastrointestinal. 
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Endocrine Events 
Management guidelines for endocrine events are provided in Table 20. 
The patient should be referred to an endocrinologist if an endocrinopathy is suspected. 
Table 20 - Management Guidelines for Endocrine Events  
Event 
Isatuximab 
management 
Atezolizumab 
management 
Action and guidance 
Asymptomatic 
hypothyroidism 
No change in dose 
No change in dose 
Initiate treatment with thyroid 
replacement hormone. 
Monitor TSH weekly. 
Symptomatic 
hypothyroidism 
Delay or omit dose until 
resolve to ≤Grade 2 for 
a maximum of 2 weeks 
(see Section 6.6.2) 
Delay cycle. 
Resume atezolizumab and 
isatuximab when symptoms are 
controlled and thyroid function is 
improving. 
Initiate treatment with thyroid 
replacement hormone. 
Monitor TSH weekly. 
Consider patient referral to 
endocrinologist. 
 
Asymptomatic 
hyperthyroidism 
No change in dose 
No change in dose 
TSH 0.1 mU/L and 0.5 mU/L: 
Monitor TSH every 4 weeks. 
TSH <0.1 mU/L: 
Follow guidelines for symptomatic 
hyperthyroidism. 
Symptomatic 
hyperthyroidism 
Delay or omit dose until 
resolve to ≤Grade 2 for 
a maximum of 2 weeks 
(see Section 6.6.2) 
Delay cycle. 
Discontinue treatment and 
contact Medical Monitor for 
life-threatening immune-related 
hyperthyroidismc 
Resume atezolizumab and 
isatuximab when symptoms are 
controlled and thyroid function is 
improving. 
Initiate treatment with anti-thyroid drug 
such as methimazole or carbimazole 
as needed. 
Consider patient referral to 
endocrinologist. 
Symptomatic adrenal 
insufficiency, 
Grade 2−4  
Grade 2: no change in 
dose. 
Grade 3, 4: delay or omit 
dose until resolves to 
≤Grade 2 for a 
maximum of 2 weeks 
(see Section 6.6.2) 
Omit/withhold atezolizumab until 
≤Grade 1a 
If event resolves to Grade 1 or 
better and patient is stable on 
replacement therapy, resume 
atezolizumabb 
If event does not resolve to 
Grade 1 or better or patient is not 
stable on replacement therapy 
while withholding atezolizumab, 
permanently discontinue 
atezolizumab and 
continue/resume isatuximabc 
Refer patient to endocrinologist. 
Perform appropriate imaging. 
Initiate treatment with 1−2 mg/kg/day 
IV methylprednisolone or equivalent 
and convert to 1−2 mg/kg/day oral 
prednisone or equivalent upon 
improvement. 
Contact Medical Monitorc 
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Event 
Isatuximab 
management 
Atezolizumab 
management 
Action and guidance 
Hyperglycemia, 
Grade 1 or 2  
No change in dose. 
 
No change in dose 
Initiate treatment with insulin if 
needed. 
Monitor for glucose control. 
Hyperglycemia, 
Grade 3 or 4 
Delay or omit dose for a 
maximum of 2 weeks 
(see Section 6.6.2)  
Resume isatuximab 
when symptoms resolve 
and glucose levels are 
stable. 
Delay cycle. 
Resume atezolizumab when 
symptoms resolve and glucose 
levels are stable. 
Initiate treatment with insulin. 
Monitor for glucose control. 
 
Hypophysitis 
(pan-hypopituitarism), 
Grade 2 or 3  
Grade 2: No change in 
dose 
Grade 3: delay or omit 
dose until resolves to 
≤Grade 2 for a 
maximum of 2 weeks 
(see Section 6.6.2) 
      Omit/withhold atezolizumaba 
If event resolves to Grade 1 or 
better, resume atezolizumabb 
If event does not resolve to  
Grade 1 or better while 
withholding atezolizumab, 
permanently discontinue 
atezolizumabc 
Refer patient to endocrinologist. 
Perform brain MRI (pituitary protocol). 
Initiate treatment with 1−2 mg/kg/day 
IV methylprednisolone or equivalent 
and convert to 1−2 mg/kg/day oral 
prednisone or equivalent upon 
improvement. 
Initiate hormone replacement as 
clinically needed. 
Contact Medical Monitorc 
For recurrent hypophysitis, treat as a 
Grade 4 event. 
Hypophysitis 
(pan-hypopituitarism), 
Grade 4  
Delay or omit isatuximab 
until resolves to 
≤Grade 2 for a 
maximum of 2 weeks 
(see Section 6.6.2) 
Discontinue atezolizumab 
Contact Medical Monitorc 
Refer patient to endocrinologist. 
Perform brain MRI (pituitary protocol). 
Initiate treatment with 1−2 mg/kg/day 
IV methylprednisolone or equivalent 
and convert to 1−2 mg/kg/day oral 
prednisone or equivalent upon 
improvement. 
Initiate hormone replacement as 
clinically needed. 
a Atezolizumab may be withheld for a longer period of time (ie, 12 weeks after event onset) to allow for corticosteroids (if initiated) to be 
reduced to  10 mg/day oral prednisone or equivalent.  The acceptable length of the extended period of time must be agreed upon by the 
investigator and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day oral prednisone or equivalent before 
atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the immune-related 
event.  Patients can be re-challenged with atezolizumab only after approval has been documented by both the Investigator (or an 
appropriate delegate) and the Medical Monitor. 
Abbreviation: MRI: magnetic resonance imaging; TSH: thyroid-stimulating hormone. 
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Ocular Events 
An ophthalmologist should evaluate visual complaints (eg, uveitis, retinal events). 
Management guidelines for ocular events are provided in Table 21. 
Table 21 - Management Guidelines for Ocular Events  
Event 
Isatuximab 
management 
Atezolizumab management 
Action and guidance 
Ocular event, 
Grade 1  
No change in dose 
No change in dose 
Patient referral to ophthalmologist is 
strongly recommended. 
Initiate treatment with topical 
corticosteroid eye drops and topical 
immunosuppressive therapy. 
If symptoms persist, treat as a 
Grade 2 event. 
Ocular event, 
Grade 2 
No change in dose 
Omit/withhold dose until Grade ≤1a 
If event resolves to Grade 1 or better, 
resume atezolizumabb 
If event does not resolve to Grade 1 
or better while withholding 
atezolizumab, permanently 
discontinue atezolizumab and 
continue/ resume isatuximabc 
Patient referral to ophthalmologist is 
strongly recommended. 
Initiate treatment with topical 
corticosteroid eye drops and topical 
immunosuppressive therapy. 
Contact Medical Monitorc 
Ocular event, 
Grade 3 or 4 
Delay or omit isatuximab 
until resolves to 
≤Grade 2 for a maximum 
of 2 weeks  
(see Section 6.6.2) 
Discontinue atezolizumab 
Contact Medical Monitorc 
Refer patient to ophthalmologist. 
Initiate treatment with 1−2 mg/kg/day 
oral prednisone or equivalent.   
If event resolves to Grade 1 or better, 
taper corticosteroids over 1 month. 
a Atezolizumab may be withheld for a longer period of time (ie,  12 weeks after event onset) to allow for corticosteroids (if initiated) to be 
reduced to ≤10 mg/day oral prednisone or equivalent.  The acceptable length of the extended period of time must be agreed upon by the 
investigator and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over ≥1 month to ≤10 mg/day oral prednisone or equivalent before atezolizumab 
can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the immune-related event.  
Patients can be re-challenged with atezolizumab only after approval has been documented by both the investigator (or an appropriate 
delegate) and the Medical Monitor. 
Immune-Related Myocarditis 
Immune-related myocarditis needs to be distinguished from myocarditis resulting from infection 
(commonly viral, eg, in a patient who reports a recent history of gastrointestinal illness), ischemic 
events, underlying arrhythmias, exacerbation of pre-existing cardiac conditions, or progression of 
malignancy. A cardiologist should be consulted. 
Patients with signs and symptoms of myocarditis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in Table 22. 
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Table 22 - Management Guidelines for Immune-Related Myocarditis  
Event 
isatuximab 
management 
Atezolizumab 
management 
Action and guidance 
Immune-related 
myocarditis, 
Grade 1 
No change in dose 
No change in dose 
Refer patient to cardiologist. 
Initiate treatment as per institutional 
guidelines. 
Immune-related 
myocarditis, 
Grade 2 
No change in dose 
Omit/withhold dose until 
Grade ≤1a 
If event resolves to Grade 1 or 
better, resume atezolizumabb 
If event does not resolve to 
Grade 1 or better while 
withholding atezolizumab, 
permanently discontinue 
atezolizumab and 
resume/continue isatuximabc 
Contact Medical Monitor. 
Refer patient to cardiologist. 
Initiate treatment as per institutional 
guidelines and consider antiarrhythmic drugs, 
temporary pacemaker, ECMO, or VAD as 
appropriate. 
Consider treatment with 1−2 mg/kg/day IV 
methylprednisolone or equivalent and convert 
to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvementa 
Contact Medical Monitorc 
Immune-related 
myocarditis, 
Grade 3−4 
Delay or omit isatuximab 
until resolves to ≤Grade 2 
for a maximum of 2 weeks 
(see Section 6.6.2) 
Discontinue atezolizumab 
Contact Medical Monitorc 
Refer patient to cardiologist. 
Initiate treatment as per institutional 
guidelines and consider antiarrhythmic drugs, 
temporary pacemaker, ECMO, or VAD as 
appropriate. 
Initiate treatment with 1−2 mg/kg/day IV 
methylprednisolone or equivalent and convert 
to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement a, b 
If event does not improve within 48 hours 
after initiating corticosteroids, consider adding 
an immunosuppressive agent. 
If event resolves to Grade 1 or better, taper 
corticosteroids over 1 month. 
a Atezolizumab may be withheld for a longer period of time (ie, 12 weeks after event onset) to allow for corticosteroids (if initiated) to be 
reduced to  10 mg/day oral prednisone or equivalent.  The acceptable length of the extended period of time must be agreed upon by the 
investigator and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day oral prednisone or equivalent before atezolizumab 
can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the immune-related event.  
Patients can be re-challenged with atezolizumab only after approval has been documented by both the investigator (or an appropriate 
delegate) and the Medical Monitor. 
Abbreviation: ECMO = extracorporeal membrane oxygenation; VAD = ventricular assist device. 
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Infusion-Associated Reactions 
Metamizole (dipyrone) is prohibited in treating atezolizumab associated infusion-associated 
reactions, due to its potential for causing agranulocytosis. 
Guidelines for medical management of infusion-associated reactions are provided in Table 23. 
Table 23 - Management Guidelines for Infusion-Associated Reactions  
Event 
Management 
isatuximab 
Management 
atezolizumab 
Action and guidance 
IAR, Grade 1  
Continue isatuximab infusion 
per the judgment of the 
Investigator following close 
direct monitoring of the 
patient’s clinical status. 
 
Isatuximab infusion may be 
stopped at any time if deemed 
necessary. If stopped, IAR will 
be classified as Grade 2 
Reduce infusion rate to half 
the rate being given at the 
time of event onset. 
 
For atezolizumab, after the event has resolved, 
the investigator should wait for 30 minutes 
while delivering the infusion at the reduced 
rate. If the infusion is tolerated at the reduced 
rate for 30 minutes after symptoms have 
resolved, the infusion rate may be increased to 
the original rate. 
IAR, Grade 2 
Interrupt isatuximab infusion 
Interrupt atezolizumab 
infusion. 
 
Administer aggressive symptomatic treatment 
(eg, oral or IV antihistamine, anti-pyretic 
medication, glucocorticoids, epinephrine, 
bronchodilators, oxygen). 
After symptoms have resolved to Grade ≤1 
(for isatuximab) or baseline (for atezolizumab), 
resume infusion at half the initial rate for 
isatuximab and at half the rate being given at 
the time of event onset for atezolizumab. 
For subsequent infusions, consider 
administration of oral premedication with 
antihistamines, anti-pyretics, and/or analgesics 
and monitor closely for IARs. 
IAR*, Grade 3 
or 4 
Stop infusion. 
If occurred during atezolizumab 
infusion, permanently 
discontinue atezolizumab and 
continue with isatuximab. 
If occurred during isatuximab 
infusion, permanently 
discontinue both. 
Stop infusion. 
Permanently discontinue 
atezolizumab 
Administer aggressive symptomatic treatment 
(eg, oral or IV antihistamine, anti-pyretic, 
glucocorticoids, epinephrine, bronchodilators, 
oxygen). 
Contact Medical Monitora 
a Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the immune-related event.  
Patients can be re-challenged with atezolizumab only after approval has been documented by both the investigator (or an appropriate 
delegate) and the Medical Monitor. 
Abbreviation: IAR = infusion-associated reaction. 
* Applicable to Grade 3 or 4 cytokine release syndrome and anaphylactic reactions. 
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Pancreatic Events 
The differential diagnosis of acute abdominal pain should include pancreatitis. Management 
guidelines for pancreatic events, including pancreatitis, are provided in Table 24. 
Table 24 - Management Guidelines for Pancreatic Events, Including Pancreatitis  
Event 
Isatuximab 
management 
Atezolizumab 
management 
Action and guidance 
Amylase and/or 
lipase elevation, 
Grade 1 
No change in dose 
No change in dose 
Monitor amylase and lipase prior to dosing. 
Amylase and/or 
lipase elevation, 
Grade 2 
No change in dose 
No change in dose 
 
Monitor amylase and lipase weekly. 
For prolonged elevation (eg 3 weeks), 
consider treatment with 10 mg/day oral 
prednisone or equivalent. 
Amylase and/or 
lipase elevation, 
Grade 3 or 4 
Delay or omit dose until 
≤Grade 2 for a maximum of 
2 weeks (see Section 6.6.2) 
and resume isatuximab 
Delay cycle and then 
Withhold/omit 
atezolizumab for up to 
12 weeks after event 
onseta 
If event resolves to 
Grade 1 or better, 
resume atezolizumabb 
If event does not resolve 
to Grade 1 or better while 
withholding atezolizumab, 
permanently discontinue 
atezolizumab 
 
 
Refer patient to GI specialist. 
Monitor amylase and lipase every other 
day. 
If no improvement, consider treatment with 
1−2 mg/kg/day oral prednisone or 
equivalent. 
Contact Medical Monitorc 
For recurrent events, permanently 
discontinue atezolizumab and contact 
Medical Monitorc 
Immune-related 
pancreatitis, 
Grade 2 or 3 
 
Grade 2: no change in dose 
Grade 3: delay or omit dose 
until ≤Grade 2 for a maximum 
of 2 weeks (see Section 6.6.2) 
Grade 2: omit/withhold 
atezolizumab 
Grade 3: Delay cycle and 
then Withhold/omit 
atezolizumaba 
If event resolves to 
Grade 1 or better, 
resume atezolizumabb 
If event does not resolve 
to Grade 1 or better while 
withholding atezolizumab, 
permanently discontinue 
atezolizumabc 
Refer patient to GI specialist. 
Initiate treatment with 1−2 mg/kg/day IV 
methylprednisolone or equivalent and 
convert to 1−2 mg/kg/day oral prednisone 
or equivalent upon improvement. 
Contact Medical Monitorc 
For recurrent events, permanently 
discontinue atezolizumab and contact 
Medical Monitorc 
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Event 
Isatuximab 
management 
Atezolizumab 
management 
Action and guidance 
Immune-related 
pancreatitis, 
Grade 4 
Discontinue isatuximab 
Discontinue atezolizumab 
Contact Medical Monitorc 
Refer patient to GI specialist. 
Initiate treatment with 1−2 mg/kg/day IV 
methylprednisolone or equivalent and 
convert to 1−2 mg/kg/day oral prednisone 
or equivalent upon improvement. 
If event does not improve within 48 hours 
after initiating corticosteroids, consider 
adding an immunosuppressive agent. 
If event resolves to Grade 1 or better, taper 
corticosteroids over 1 month. 
a Atezolizumab may be withheld for a longer period of time (ie,  12 weeks after event onset) to allow for corticosteroids (if initiated) to be 
reduced to  10 mg/day oral prednisone or equivalent. The acceptable length of the extended period of time must be agreed upon by the 
investigator and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day oral prednisone or equivalent before 
atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the immune-related 
event. Patients can be re-challenged with atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.  
Abbreviation: GI = gastrointestinal. 
Dermatologic Events 
Severe Cutaneous Adverse Reactions (SCARs) are a heterogeneous group of immunologically 
mediated drug eruptions. 
Although rare, these events are potentially fatal, and mainly constituted by erythema multiforme, 
acute generalized exanthematous pustulosis, SJS, TEN, and DRESS. 
The recommendations for SCARs are: 
• For suspected SCARs the patients should be referred to a dermatologist for further 
diagnosis and management 
• Atezolizumab should be withheld for patients with suspected SJS or TEN 
• Atezolizumab should be permanently withdrawn for any grade confirmed SJS or TEN 
• Caution should be used when considering the use of atezolizumab in a patient who has 
previously experienced a severe or life-threatening skin adverse reaction on prior 
treatment with other immune-stimulatory anticancer agents. 
Regarding other dermatological events, a  dermatologist should evaluate persistent and/or severe 
rash or pruritus. Management guidelines for other dermatologic events are provided in Table 25. 
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Table 25 - Management Guidelines for Dermatologic Events  
Event 
Isatuximab 
management 
Atezolizumab 
management 
Action and guidance 
Dermatologic 
event, Grade 1  
No change in dose 
No change in dose 
Consider treatment with topical 
corticosteroids and/or other symptomatic 
therapy (eg, antihistamines). 
Dermatologic 
event, Grade 2  
No change in dose 
No change in dose 
Consider patient referral to dermatologist. 
Initiate treatment with topical 
corticosteroids. 
Consider treatment with higher-potency 
topical corticosteroids if event does not 
improve. 
Dermatologic 
event, Grade 3  
No change in dose 
Omit/withold atezolizumaba 
If event resolves to Grade 1 or 
better, resume atezolizumabb 
If event does not resolve to 
Grade 1 or better while 
withholding atezolizumab, 
permanently discontinue 
atezolizumab 
Refer patient to dermatologist. 
Initiate treatment with 10 mg/day oral 
prednisone or equivalent, increasing dose 
to 1−2 mg/kg/day if event does not 
improve within 48−72 hours. 
Contact Medical Monitorc 
Dermatologic 
event, Grade 4 
Delay or omit isatuximab 
until ≤Grade 3 for a 
maximum of 2 weeks 
(see Section 6.6.2) 
Discontinue atezolizumab 
Contact Medical Monitorc 
a Atezolizumab may be withheld for a longer period of time (ie,  12 weeks after event onset) to allow for corticosteroids (if initiated) to be 
reduced to  10 mg/day oral prednisone or equivalent.  The acceptable length of the extended period of time must be agreed upon by the 
investigator and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day oral prednisone or equivalent before atezolizumab 
can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the immune-related event.  
Patients can be re-challenged with atezolizumab only after approval has been documented by both the investigator (or an appropriate 
delegate) and the Medical Monitor.  
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Neurologic Disorders 
Patients may present with signs and symptoms of sensory and/or motor neuropathy. Diagnostic 
work-up is essential for an accurate characterization to differentiate between alternative etiologies. 
Management guidelines for neurologic disorders are provided in Table 26. 
Table 26 - Management Guidelines for Neurologic Disorders  
Event 
Isatuximab 
management 
Atezolizumab management 
Action and guidance 
Immune-related 
neuropathy, 
Grade 1 
No change in dose 
No change in dose 
Investigate etiology 
Immune-related 
neuropathy, 
Grade 2  
No change in dose 
Omit/withhold dose until Grade ≤1a 
If event resolves to Grade 1 or 
better, resume atezolizumabb 
If event does not resolve to Grade 1 
or better while withholding 
atezolizumab, permanently 
discontinue atezolizumab 
Investigate etiology. 
Initiate treatment as per institutional 
guidelines. 
Contact Medical Monitorc 
Immune-related 
neuropathy, 
Grade 3 or 4 
Delay or omit isatuximab until 
≤Grade 2 for a maximum of 
2 weeks (see Section 6.6.2) 
Discontinue atezolizumab 
Contact Medical Monitorc 
Initiate treatment as per institutional 
guidelines. 
Myasthenia gravis 
and Guillain-Barré 
syndrome (any 
grade) 
Discontinue isatuximab 
Discontinue atezolizumab 
Contact Medical Monitorc 
Refer patient to neurologist. 
Initiate treatment as per institutional 
guidelines. 
Consider initiation of 
1−2 mg/kg/day oral or IV 
prednisone or equivalent. 
a Atezolizumab may be withheld for a longer period of time (ie,  12 weeks after event onset) to allow for corticosteroids (if initiated) to be 
reduced to  10 mg/day oral prednisone or equivalent.  The acceptable length of the extended period of time must be agreed upon by the 
investigator and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day oral prednisone or equivalent before atezolizumab 
can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the immune-related event.  
Patients can be re-challenged with atezolizumab only after approval has been documented by both the investigator (or an appropriate 
delegate) and the Medical Monitor.  
Immune-Related Meningoencephalitis 
Immune-related meningoencephalitis should be suspected in any patient presenting with signs or 
symptoms suggestive of meningitis or encephalitis, including, but not limited to, headache, neck 
pain, confusion, seizure, motor or sensory dysfunction, and altered or depressed level of 
consciousness. Encephalopathy from metabolic or electrolyte imbalances needs to be 
distinguished from potential meningoencephalitis resulting from infection (bacterial, viral, or 
fungal) or progression of malignancy, or secondary to a paraneoplastic process. 
Patients with signs and symptoms of meningoencephalitis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in Table 27. 
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Table 27 - Management Guidelines for Immune-Related Meningoencephalitis  
Event 
Management 
Immune-related 
meningoencephalitis, all 
grades 
Permanently discontinue isatuximab and atezolizumab and contact Medical Monitora 
Refer patient to neurologist. 
Initiate treatment with 1−2 mg/kg/day IV methylprednisolone or equivalent and convert to 
1−2 mg/kg/day oral prednisone or equivalent upon improvement. 
If event does not improve within 48 hours after initiating corticosteroids, consider adding an 
immunosuppressive agent. 
If event resolves to Grade 1 or better, taper corticosteroids over 1 month. 
a Resumption of isatuximab and atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the 
immune-related event.  Patients can be re-challenged with atezolizumab only after approval has been documented by both the investigator 
(or an appropriate delegate) and the Medical Monitor. 
Renal Events 
Eligible patients must have adequate renal function, and renal function, including serum 
creatinine, should be monitored throughout study treatment.  Patients with abnormal renal 
function should be evaluated and treated for other more common etiologies (including prerenal 
and postrenal causes, and concomitant medications such as non-steroidal anti-inflammatory 
drugs).  Refer the patient to a renal specialist if clinically indicated.  A renal biopsy may be 
required to enable a definitive diagnosis and appropriate treatment. 
Patients with signs and symptoms of nephritis, in the absence of an identified alternate etiology, 
should be treated according to the guidelines in Table 28. 
Table 28 - Management Guidelines for Renal Events  
Event 
Isatuximab 
management 
Atezolizumab management 
Action and guidance 
Renal event, 
Grade 1 
No change in dose 
No change in dose 
Monitor kidney function, including creatinine, 
closely until values resolve to within normal 
limits or to baseline values. 
Renal event, 
Grade 2 
Delay or omit dose 
until resolves to 
≤Grade 1 for a 
maximum of 2 weeks 
(see Section 6.6.2) 
Withhold dose for up to 12 weeks 
after event onseta 
If event resolves to Grade 1 or 
better, resume atezolizumabb 
If event does not resolve to Grade 1 
or better while withholding 
atezolizumab, permanently 
discontinue atezolizumab and 
contact Medical Monitorc 
Refer patient to renal specialist. 
Initiate treatment with corticosteroids 
equivalent to 1-2 mg/kg/day oral prednisone. 
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Event 
Isatuximab 
management 
Atezolizumab management 
Action and guidance 
Renal event, 
Grade 3 or 4 
Grade 3:  delay or omit 
dose until resolves to 
≤Grade 1 for a 
maximum of 2 weeks 
(see Section 6.6.2) 
Grade 4:  discontinue 
treatment. 
Discontinue. 
Contact Medical Monitorc 
Refer patient to renal specialist and consider 
renal biopsy. 
Initiate treatment with corticosteroids 
equivalent to 1-2 mg/kg/day oral prednisone. 
If event does not improve within 48 hours after 
initiating corticosteroids, consider adding an 
immunosuppressive agent. 
If event resolves to Grade 1 or better, taper 
corticosteroids over ≥1 month. 
a Atezolizumab may be withheld for a longer period of time (ie, >12 weeks after event onset) to allow for corticosteroids (if initiated) to be 
reduced to the equivalent of ≤10 mg/day oral prednisone.  The acceptable length of the extended period of time must be agreed upon by the 
Investigator and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over ≥1 month to the equivalent of ≤10 mg/day oral prednisone before 
atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the immune related event.  
Patients can be re challenged with atezolizumab only after approval has been documented by both the Investigator (or an appropriate 
delegate) and the Medical Monitor. 
Immune-related Myositis 
Immune-related myositis has been associated with the administration of atezolizumab.  Myositis 
or inflammatory myopathies are a group of disorders sharing the common feature of inflammatory 
muscle injury; dermatomyositis and polymyositis are among the most common disorders.  Initial 
diagnosis is based on clinical (muscle weakness, muscle pain, skin rash in dermatomyositis), 
biochemical (serum creatine kinase increase), and imaging (electromyography/MRI) features, and 
is confirmed with a muscle biopsy. 
Patients with signs and symptoms of myositis, in the absence of an identified alternate etiology, 
should be treated according to the guidelines in Table 29.  
 
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Table 29 – Management Guidelines for Immune-related Myositis  
Event 
Isatuximab 
management 
Atezolizumab management 
Action and guidance 
Immune-
related 
myositis, 
Grade 1 
No change in dose 
No change in dose 
Refer patient to rheumatologist or neurologist. 
Initiate treatment as per institutional guidelines. 
Immune-
related 
myositis, 
Grade 2 
Delay or omit dose 
until resolves to 
≤Grade 1 for a 
maximum of 2 weeks 
(see Section 6.6.2) 
Withhold dose for up to 12 weeks 
after event onset and contact 
Medical Monitora 
If event resolves to Grade 1 or 
better, resume atezolizumabb 
If event does not resolve to Grade 1 
or better while withholding 
atezolizumab, permanently 
discontinue atezolizumab and 
contact Medical Monitorc 
Refer patient to rheumatologist or neurologist. 
Initiate treatment as per institutional guidelines. 
Consider treatment with corticosteroids 
equivalent to 1-2 mg/kg/day IV 
methylprednisolone and convert to 1-2 
mg/kg/day oral prednisone or equivalent upon 
improvement.  If corticosteroids are initiated 
and event does not improve within 48 hours 
after initiating corticosteroids, consider adding 
an immunosuppressive agent. 
Immune-
related 
myositis, 
Grade 3 
Delay or omit dose 
until resolves to 
≤Grade 1 for a 
maximum of 2 weeks 
(see Section 6.6.2) 
Withhold dose for up to 12 weeks 
after event onset and contact 
Medical Monitora 
If event resolves to Grade 1 or 
better, resume atezolizumabb 
If event does not resolve to Grade 1 
or better while withholding 
atezolizumab, permanently 
discontinue atezolizumab and 
contact Medical Monitorc 
Refer patient to rheumatologist or neurologist. 
Initiate treatment as per institutional guidelines.  
Respiratory support may be required in more 
severe cases. 
Initiate treatment with corticosteroids 
equivalent to 1-2 mg/kg/day IV 
methylprednisolone, or higher-dose bolus if 
patient is severely compromised (eg., cardiac 
or respiratory symptoms, dysphagia, or 
weakness that severely limits mobility); convert 
to 1-2 mg/kg/day oral prednisone or equivalent 
upon improvement.  If event does not improve 
within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent. 
For recurrent events, treat as a Grade 4 event. 
Immune-
related 
myositis, 
Grade 4 
Discontinue. 
Discontinue. 
Contact Medical Monitorc 
Refer patient to rheumatologist or neurologist. 
Initiate treatment as per institutional guidelines.  
Respiratory support may be required in more 
severe cases. 
Initiate treatment with corticosteroids 
equivalent to 1-2 mg/kg/day IV 
methylprednisolone, or higher-dose bolus if 
patient is severely compromised (eg., cardiac 
or respiratory symptoms, dysphagia, or 
weakness that severely limits mobility); convert 
to 1-2 mg/kg/day oral prednisone or equivalent 
upon improvement.  If event does not improve 
within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent. 
If event resolves to Grade 1 or better, taper 
corticosteroids over  ≥1 month. 
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Event 
Isatuximab 
management 
Atezolizumab management 
Action and guidance 
a Atezolizumab may be withheld for a longer period of time (ie, >12 weeks after event onset) to allow for corticosteroids (if initiated) to be 
reduced to the equivalent of ≤10 mg/day oral prednisone.  The acceptable length of the extended period of time must be agreed upon by the 
Investigator and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over ≥1 month to the equivalent of ≤10 mg/day oral prednisone before 
atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the immune related event.  
Patients can be re-challenged with atezolizumab only after approval has been documented by both the Investigator (or an appropriate 
delegate) and the Medical Monitor. 
 
Systemic Immune Activation 
Systemic immune activation is a rare condition characterized by an excessive immune response.  
Given the mechanism of action of atezolizumab, systemic immune activation is considered a 
potential risk when atezolizumab is given in combination with other immunomodulating agents. 
Recommendations regarding early identification and management of systemic immune activation 
are provided below.  In the event of suspected systemic immune activation, atezolizumab should 
be withheld and clinical specialists (eg, rheumatology, clinical immunology, or solid organ or 
hematopoietic stem cell transplant specialists) and the Medical Monitor should be consulted for 
additional guidance. 
Early disease recognition is critical, and systemic immune activation should be suspected if, in the 
absence of an alternative etiology, the patient meets two or more of the following criteria: 
• Hypotension that is refractory to aggressive IV fluid challenge (Vasopressor support may 
be required). 
• Respiratory distress that requires aggressive supportive care (Supplemental oxygen and 
intubation may be required). 
• Fever  38.5C. 
• Acute renal or hepatic failure. 
• Bleeding from coagulopathy. 
• Any of the following unexplained laboratory abnormalities (change from baseline):  
cytopenias (in two or more lineages), significant transaminitis, or coagulopathy. 
For patients with suspected systemic immune activation, an initial evaluation should include the 
following: 
• Hematology with peripheral smear. 
• PT, PTT, fibrinogen, and D-dimer. 
• Ferritin. 
• Soluble interleukin-2 receptor (soluble CD25). 
• Triglycerides. 
• AST, ALT, and direct bilirubin. 
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• LDH. 
• Complete neurologic and abdominal examination (assess for hepatosplenomegaly). 
Laboratory tests with normal results should be repeated frequently in patients for whom a high 
clinical suspicion of systemic immune activation exists. 
If neurologic abnormalities are present, consider cerebrospinal fluid analysis and/or an MRI of the 
brain. 
If cytopenias are present (Grade 2 in two or more lineages) or ferritin is 3000 ng/mL, the 
following evaluations should also be performed:   
• Bone marrow biopsy and aspirate (assess for evidence of hemophagocytosis). 
• Adenovirus, cytomegalovirus, Epstein-Barr virus, herpes-simplex virus, and human 
herpesvirus 6, 7, and 8 evaluations (for reactivated or active disease). 
Diagnostic criteria and recommended management for systemic immune activation are provided 
in Table 30.  The diagnostic criteria apply only when alternative etiologies have been excluded. 
An adverse event of systemic immune activation should be reported on the Adverse Event 
electronic Case Report Form if it meets the criteria for "consistent with systemic immune 
activation" or "probable systemic immune activation" as outlined in Table 30. 
Table 30 - Diagnostic Criteria and Recommended Management for Systemic Immune Activation  
Systemic Immune Activation Diagnostic Criteria  
(applicable only when alternative etiologies have been excluded) 
Major Criteria 
Minor Criteria 
• 
Fever 38.5C on more than one occasion 
• 
Ferritin 3000 ng/mL 
• 
Cytopenias (Grade 2 in two or more lineages) 
• 
Age-adjusted soluble interleukin-2 receptor elevated 
by 2 standard deviations 
• 
Severe (Grade 3) or progressive dysfunction in 
two or more organs 
• 
Decreased fibrinogen 
• 
Splenomegaly  
• 
Hemophagocytosis in bone marrow, spleen, or lymph 
nodes 
• 
Elevated -glutamyl transpeptidase (GGT) or liver 
function tests (AST, ALT, or direct bilirubin) 
• 
Elevated triglycerides 
• 
Elevated LDH 
• 
Decreased natural killer cell activity 
Diagnosis and Management of Systemic Immune Activation 
Number of Criteria 
Diagnosis 
Action to Be Taken 
4 major criteria 
Consistent with 
systemic immune 
activation 
• 
Permanently discontinue isatuximab and atezolizumab. 
• 
Consider treatment with an immunosuppressive agent (ie, cytokine 
inhibitors) and IV corticosteroids (ie, methylprednisolone 1 g once daily or 
equivalent, or dexamethasone 10 mg/m2 once daily if neurologic 
abnormalities are present). 
• 
Contact the Medical Monitor for additional recommendations. 
• 
Consider HLH-2004 protocol (65)if there is no clinical improvement. 
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3 major criteria 
OR 
2 major plus 3 minor 
criteria 
Probable 
systemic immune 
activation 
• 
Depending on clinical severity, follow guidelines for “Consistent with 
systemic immune activation” or “Possible systemic immune activation” 
diagnosis. 
• 
Clinical specialists and the Medical Monitor may be contacted for 
recommendations. 
2 major plus 2 minor 
criteria 
OR 
1 major plus 4 minor 
criteria 
Possible systemic 
immune activation 
• 
Withhold isatuximab and atezolizumab. 
• 
Consider treatment with IV corticosteroids. 
• 
Clinical specialists and the Medical Monitor may be contacted for 
additional recommendations. 
• 
Follow guidelines for “Consistent with systemic immune activation” 
diagnosis if there is no clinical improvement or if clinical worsening 
occurs. 
• 
If clinical improvement occurs, isatuximab and atezolizumab may be 
resumed following a benefit-risk assessment by the Medical Monitor. 
Notes:  Criteria are adapted from a Delphi Survey of 26 experts who provided helpful criteria in the positive diagnosis of hemophagocytic 
syndrome in adult patients (66). 
Grades are based on MedDRA and CTCAE. 
These recommendations do not replace clinical judgment and are intended as suggested guidance. 
10.22 APPENDIX 22: MANAGEMENT OF PATIENTS WITH HCV INFECTION  
Recommended management for recurrent HCV infection or an HCV flare are described below. 
In case of a hepatic AE, Investigator should exercise clinical judgment based on the symptoms 
and the condition of the individual patient.  This includes the characterization of an 
immune-related hepatic AE, by excluding differential diagnoses such as virologic flare (if 
applicable), biliary or vascular obstruction, infection, medications, and alcohol use.  Hepatology 
consultation is required per common standard of care in the sites with HCC treating expertise.  If 
the hepatic AE is deemed to be the result of a viral flare, common standard of care per site 
protocol should be followed.  Otherwise, if a hepatic AE is deemed to be the consequence of an 
immune-related mechanism, the detailed instructions articulated in Table 18 of the study protocol 
are to be followed. 
1. Recurrent HCV infection:  If the patient entered the study with an HCV RNA test of 
“Target not Detected” and has confirmed detectable HCV RNA (2 specimens, 1 week 
apart), then the patient has experienced a late HCV relapse or a recurrent infection. 
- 
Question the patient about use of injection or inhalation drugs, 
- 
At the time of first detection of HCV RNA, send a specimen for HCV genotyping, 
- 
Measure AST, ALT, ALP, total bilirubin, direct bilirubin, and INR weekly, 
- 
Measure HCV RNA levels every 2 weeks, 
- 
Therapy with HCV antiviral treatments should be strongly considered. 
2. HCV Flare: 
- 
At the time of first detection of HCV RNA, send a specimen for HCV genotyping, 
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- 
Measure AST, ALT, ALP, total bilirubin, direct bilirubin, and INR weekly, 
- 
Measure HCV RNA levels every 2 weeks, 
- 
Therapy with HCV antiviral treatments should be strongly considered. 
3. For both recurrent infection and HCV flare:  If ALT returns to normal or Grade 1 
(if normal at baseline), or to baseline grade (if Grade 2 at baseline) within 12 weeks, and 
the patient is clinically stable, the patient may restart study treatment. If these conditions 
are not met, then study treatment should be permanently discontinued. 
 
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11 
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Page 1
STATISTICAL ANALYSIS PLAN 
A Phase 1/2 open-label, multi-center, safety, preliminary efficacy and 
pharmacokinetic (PK) study of isatuximab (SAR650984) in combination with 
atezolizumab or isatuximab alone in patients with advanced malignancies 
SAR650984-ACT15377 
STATISTICIAN: 
 
Statistical Project Leader: 
 
DATE OF ISSUE: 12-Sep-2019 
Total number of pages: 
48 
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Statistical Analysis Plan  
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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN .................................................................................................................... 1 
TABLE OF CONTENTS .................................................................................................................................. 2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................................................................... 5 
1 
OVERVIEW AND INVESTIGATIONAL PLAN ................................................................................. 7 
1.1 
STUDY DESIGN AND RANDOMIZATION ...................................................................................... 7 
1.1.1 
Phase 1 (safety run-in) ..................................................................................................................... 7 
1.1.1.1 
Starting dose and de-escalation design ........................................................................................... 7 
1.1.1.2 
Dose limiting toxicity ......................................................................................................................... 8 
1.1.1.3 
Maximum tolerated dose and recommended Phase 2 dose ........................................................... 8 
1.1.2 
Phase 2 (efficacy signal search with a 2-stage design in each cohort)............................................ 8 
1.2 
OBJECTIVES ................................................................................................................................... 9 
1.2.1 
Primary objectives ............................................................................................................................ 9 
1.2.2 
Secondary objectives ..................................................................................................................... 10 
1.3 
DETERMINATION OF SAMPLE SIZE ........................................................................................... 10 
1.4 
STUDY PLAN ................................................................................................................................. 11 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL................................ 11 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN ..................... 11 
2 
STATISTICAL AND ANALYTICAL PROCEDURES ..................................................................... 12 
2.1 
ANALYSIS ENDPOINTS ................................................................................................................ 12 
2.1.1 
Demographic and baseline characteristics .................................................................................... 12 
2.1.2 
Prior or concomitant medications (other than anticancer therapies).............................................. 14 
2.1.3 
Efficacy endpoints .......................................................................................................................... 14 
2.1.3.1 
Primary efficacy endpoint(s) ........................................................................................................... 14 
2.1.3.2 
Secondary efficacy endpoint(s) ...................................................................................................... 15 
2.1.3.3 
Exploratory efficacy endpoint(s) ..................................................................................................... 16 
2.1.4 
Safety endpoints ............................................................................................................................. 17 
2.1.4.1 
Dose limiting toxicities (DLTs) ........................................................................................................ 18 
2.1.4.2 
Adverse events variables ............................................................................................................... 18 
2.1.4.3 
Infusion associated reactions ......................................................................................................... 19 
2.1.4.4 
Deaths ............................................................................................................................................ 19 
2.1.4.5 
Laboratory safety variables ............................................................................................................ 19 
2.1.4.6 
Vital signs variables........................................................................................................................ 20 
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2.1.4.7 
Electrocardiogram variables ........................................................................................................... 20 
2.1.4.8 
Clinical safety laboratory assessments .......................................................................................... 20 
2.1.4.9 
Immunogenicity variables ............................................................................................................... 21 
2.1.5 
Pharmacokinetic variables ............................................................................................................. 22 
2.1.6 
Biomarker endpoints ...................................................................................................................... 23 
2.1.6.1 
Microsatellite instability ................................................................................................................... 23 
2.1.6.2 
PD-L1 expression singleplex IHC .................................................................................................. 23 
2.1.6.3 
Cluster of differentiation 38 (CD38) expression singleplex IHC ..................................................... 23 
2.1.6.4 
Immune cell subpopulation tumor infiltration and markers co-expression multiplex 
immunofluorescence ...................................................................................................................... 24 
2.1.7 
Further therapy after discontinuation of investigational medicinal product administration 
during the study .............................................................................................................................. 24 
2.2 
DISPOSITION OF PATIENTS ....................................................................................................... 24 
2.2.1 
Randomization and drug dispensing irregularities ......................................................................... 25 
2.3 
ANALYSIS POPULATIONS ........................................................................................................... 25 
2.3.1 
All-treated population ..................................................................................................................... 25 
2.3.2 
DLT-evaluable population .............................................................................................................. 25 
2.3.3 
Pharmacokinetic population ........................................................................................................... 25 
2.3.4 
Biomarker Population ..................................................................................................................... 26 
2.3.5 
Immunogenicity population ............................................................................................................ 26 
2.3.6 
Response evaluable population ..................................................................................................... 26 
2.4 
STATISTICAL METHODS ............................................................................................................. 26 
2.4.1 
Demographics and baseline characteristics .................................................................................. 26 
2.4.2 
Prior or concomitant medications (other than anticancer therapies).............................................. 26 
2.4.3 
Anticancer therapies ...................................................................................................................... 27 
2.4.4 
Extent of investigational medicinal product exposure and compliance .......................................... 27 
2.4.4.1 
Extent of investigational medicinal product exposure .................................................................... 27 
2.4.4.2 
Isatuximab exposure ...................................................................................................................... 28 
2.4.4.3 
Atezolizumab exposure .................................................................................................................. 29 
2.4.5 
Analyses of efficacy endpoints ....................................................................................................... 31 
2.4.5.1 
Analysis of primary efficacy endpoint(s) ......................................................................................... 31 
2.4.5.2 
Analyses of secondary efficacy endpoints ..................................................................................... 31 
2.4.5.3 
Analyses of exploratory efficacy endpoints .................................................................................... 32 
2.4.5.4 
Multiplicity issues ............................................................................................................................ 32 
2.4.6 
Analyses of safety data .................................................................................................................. 32 
2.4.6.1 
Analyses of DLTs (Phase 1 only) ................................................................................................... 32 
2.4.6.2 
Analyses of adverse events ........................................................................................................... 32 
2.4.6.3 
Deaths ............................................................................................................................................ 34 
2.4.6.4 
Analyses of laboratory variables .................................................................................................... 35 
2.4.6.5 
Analyses of vital sign variables ...................................................................................................... 35 
2.4.6.6 
Analyses of electrocardiogram variables ....................................................................................... 36 
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2.4.6.7 
Analysis of Immunogenicity ............................................................................................................ 36 
2.4.7 
Analyses of pharmacokinetic variables .......................................................................................... 36 
2.4.7.1 
Cycle 1 non-compartmental analysis of isatuximab: following the 1st administration ..................... 36 
2.4.7.2 
Over treatment concentrations: Ctrough and Ceoi of isatuximab and atezolizumab ..................... 36 
2.4.7.3 
Immunogenicity impact on PK ........................................................................................................ 37 
2.4.7.4 
Over treatment: population PK approach of isatuximab and atezolizumab ................................... 37 
2.4.8 
Analyses of biomarker variables .................................................................................................... 38 
2.4.9 
Analyses of quality of life/health economics variables ................................................................... 38 
2.4.10 
Further therapy after discontinuation of investigational medicinal product administration 
during the study .............................................................................................................................. 38 
2.5 
DATA HANDLING CONVENTIONS .............................................................................................. 38 
2.5.1 
General conventions ...................................................................................................................... 38 
2.5.2 
Data handling conventions for secondary efficacy variables ......................................................... 38 
2.5.3 
Missing data ................................................................................................................................... 38 
2.5.4 
Windows for time points ................................................................................................................. 42 
2.5.5 
Unscheduled visits ......................................................................................................................... 42 
2.5.6 
Pooling of centers for statistical analyses ...................................................................................... 42 
2.5.7 
Statistical technical issues ............................................................................................................. 42 
3 
INTERIM ANALYSIS ..................................................................................................................... 43 
4 
DATABASE LOCK ........................................................................................................................ 44 
5 
SOFTWARE DOCUMENTATION.................................................................................................. 45 
6 
REFERENCES ............................................................................................................................... 46 
7 
LIST OF APPENDICES ................................................................................................................. 47 
APPENDIX A 
GENERIC RANGES FOR HEMATOLOGICAL AND BIOCHEMISTRY 
PARAMETERS .............................................................................................................................. 48 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
   
ADA: 
anti-drug antibodies  
ADI: 
actual dose intensity 
AEs: 
adverse events 
AESI: 
adverse events of special interest 
AFP: 
alpha-fetoprotein 
ALT: 
alanine aminotransferase 
AST: 
aspartate aminotransferase 
ATC: 
anatomic therapeutic category 
AUC: 
area under the curve 
BOR: 
best overall response 
BUN: 
blood urea nitrogen 
CD38: 
cluster of differentiation 38 
CR: 
complete response 
DCR: 
disease control rate 
DLT: 
dose limiting toxicity 
DoR: 
duration of response 
ECG: 
electrocardiogram 
ECOG: 
eastern cooperative oncology group 
eCRF: 
electronic case report form 
EOC: 
epithelial ovarian cancer 
EOT: 
end of treatment 
GBM: 
glioblastoma multiforme 
GCIG: 
gynaecologic cancer intergroup 
HCC: 
hepatocellular carcinoma 
IAR: 
infusion associated reaction 
IMP: 
investigational medicinal product 
INR: 
international normalized ratio 
iRANO: 
immunotherapy response assessment in neuro-oncology 
iRECIST: 
modified response evaluation criteria in solid tumors for immune-based 
therapies 
IV: 
intravenous 
LDH: 
lactate dehydrogenase 
MDRD: 
modified diet in renal disease 
MedDRA: 
medical dictionary for regulatory activities 
MTD: 
maximum tolerated dose 
NIMP: 
non-investigational medicinal product 
OS: 
overall survival 
PCSA: 
potentially clinically significant abnormality 
PFS: 
progression-free survival 
PFS-6: 
progression free survival rate at 6 months 
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PK: 
pharmacokinetic 
PR: 
partial response 
PT: 
preferred term 
PTT: 
partial thromboplastin time 
Q3W: 
once every 3 weeks 
QW: 
once weekly 
RANO: 
response assessment in neuro-oncology 
RBC: 
red blood cell 
RDI: 
relative dose intensity 
RECIST: 
response evaluation criteria in solid tumors 
ROI: 
region of interest 
RP2D: 
recommended phase 2 dose 
RR: 
response rate 
SAEs: 
serious adverse events 
SCCHN: 
squamous cell carcinoma of the head and neck 
SD: 
stable disease 
SOC: 
system organ class 
TEAE: 
treatment-emergent adverse event 
TSH: 
thyroid stimulating hormone 
TTP: 
time to progression 
TTR: 
time to response 
WHO-DD: 
world health organization-drug dictionary 
 
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1 
OVERVIEW AND INVESTIGATIONAL PLAN   
1.1 
STUDY DESIGN AND RANDOMIZATION 
This is a Phase 1/2 open-label, non-randomized, multi-center, safety, preliminary efficacy, and  
PK study of isatuximab in combination with atezolizumab, or isatuximab alone in participants 
with advanced malignancies. The study will be conducted in 2 phases. 
1.1.1 Phase 1 (safety run-in) 
Participants with hepatocellular carcinoma (HCC), squamous cell carcinoma of the head and neck 
(SCCHN), epithelial ovarian cancer (EOC), or glioblastoma multiforme (GBM) will be enrolled in 
Phase 1. 
1.1.1.1 Starting dose and de-escalation design 
Starting dose is isatuximab given 10 mg/kg once weekly (QW) for 3 weeks followed by once 
every 3 weeks (Q3W) with atezolizumab at 1200 mg once every 3 weeks (Q3W). Dose 
de-escalation will be performed if necessary as defined in Table 1 below: 
Table 1 - Dose modification for Phase 1 
Dose level (DL) 
Isatuximab 
Atezolizumab 
Starting dose 
10 mg/kg 
QW × 3 ->Q3W 
1200 mg 
Q3W 
Minus -1 
(DL-1) 
5 mg/kg 
QW × 3 ->Q3W 
1200 mg 
Q3W 
Abbreviations: DL: Dose level; QW: once weekly, Q3W: once every 3 weeks. 
At the starting dose, up to approximately 8 patients will be treated and decision will be based on 
the DLTs assessed in the first 6 DLT-evaluable participants (1 cycle, 21 days): 
 If ≤1/6 participant has DLT, the starting dose will be the recommended Phase 2 dose 
(RP2D). 
 If 2/6 participants have DLT, 6 additional participants will be enrolled at starting dose 
level: 
- 
If a total of 2/12 participants treated at starting dose have DLT, starting dose will be 
the RP2D, 
- 
If a total of ≥3/12 participants have DLT, dose will be de-escalated to dose level minus 
1 (DL-1). 
 If ≥3/6 participants have DLT, dose will be de-escalated to DL-1. 
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An additional 6 participants may be enrolled at DL-1: 
 If ≤1/6 participant has DLT, DL-1 will be the RP2D. 
 If 2/6 participants have DLT, 6 additional participants will be enrolled at DL-1: 
- 
If a total of 2/12 participants treated at starting dose have DLT, DL-1 will be the 
RP2D, 
- 
If a total of ≥3/6 or ≥3/12 participants have DLT, an alternative dose/schedule might be 
considered from a safety viewpoint by the Sponsor. 
Investigational medicinal product (IMP) initiation in each patient treated in Phase 1 is to be 
staggered by at least 3 days. 
1.1.1.2 Dose limiting toxicity 
Dose limiting toxicity (DLT) is defined in Section 4.1.1 in the protocol. 
1.1.1.3 Maximum tolerated dose and recommended Phase 2 dose 
Any DLT observed during Cycle 1, and also overall safety including all the AEs occurring during 
treatment, unless due to disease progression or an obviously unrelated cause, will be taken into 
consideration by a Study Committee for the determination of the maximum tolerated dose (MTD) 
and RP2D for the isatuximab and atezolizumab combination. 
The MTD is defined as the highest dose level at which no more than 1 out of 6 participants 
(starting dose or DL-1) or 2 out of 12 participants (starting dose) experience an IMP related DLT. 
The RP2D is defined as the dose selected for the Phase 2 portion. 
1.1.2 Phase 2 (efficacy signal search with a 2-stage design in each cohort) 
Phase 2 may include up to 6 cohorts: Cohorts A, B, C, and D-1 will be initiated in parallel, while 
other cohorts of the same tumor type will be open depending on results observed at the end of 
Stage 2 of the corresponding initial tumor type cohort. 
 Cohort A: HCC, isatuximab and atezolizumab combination. 
 Cohort B: SCCHN, isatuximab and atezolizumab combination. 
 Cohort C: EOC, isatuximab and atezolizumab combination. 
 Cohort D-1: GBM, isatuximab and atezolizumab combination. 
 Possibly Cohort D-2: GBM, isatuximab monotherapy. 
 Possibly Cohort E: isatuximab and atezolizumab combination in participants with one 
tumor type (HCC, SCCHN, EOC, or GBM), or isatuximab monotherapy (GBM only), 
without initial isatuximab weekly dosing. 
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A 2-stage design will be used in each cohort. Enrollment in Cohort D-2 may start only if clinical 
benefit is observed in Cohort D-1 at the end of Phase 2 Stage 2. 
The participants treated at the RP2D of isatuximab and atezolizumab in combination during  
Phase 1 will be included in the efficacy analysis together with participants of the same tumor type 
in Phase 2 Stage 1. Based on the predefined number of objective responses in participants with 
SCCHN, HCC, EOC, or the predefined PFS-6 in participants with GBM, as well as any other 
relevant data observed within a treatment cohort in Phase 2 Stage 1, the study will proceed with 
Phase 2 Stage 2. After enrollment completion of Phase 2 Stage 1, if efficacy results do not warrant 
initiation of Stage 2, enrollment will be paused until sufficient results or analyses warrant 
initiation of Phase 2 Stage 2. In the case of inadequate efficacy for a cohort at interim analyses, the 
Sponsor will notify study sites regarding modification or termination of study 
procedures/scheduled activities for patients in that specific cohort. 
For participants with GBM, if clinical benefit is observed in Cohort D-1 at the end of  
Phase 2 Stage 2, an isatuximab monotherapy cohort may be initiated (Cohort D-2). Participants 
with GBM will be enrolled into Cohort D-2, isatuximab monotherapy (Phase 2 Stage 1). The 
isatuximab single agent dose and schedule for Cohort D-2 will be determined based on results 
from Cohort D-1. 
Based on the positive efficacy signal and the totality of data observed within a treatment cohort at 
end of Phase 2 Stage 2, the Sponsor may decide to further study in the same indication either 
isatuximab Q3W in combination with atezolizumab, or isatuximab Q3W as monotherapy in 
participants with GBM. This schedule without the initial weekly dosing may be more practical for 
participants and health care providers. Objectives and study design considerations for these 
cohorts are the same as those for other cohorts in the same tumor type, respectively. 
1.2 
OBJECTIVES 
1.2.1 Primary objectives 
Phase 1: 
 To characterize the safety and tolerability of isatuximab in combination with atezolizumab 
in participants with unresectable hepatocellular carcinoma (HCC), platinum-refractory 
recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN), 
platinum-resistant/refractory epithelial ovarian cancer (EOC), or recurrent glioblastoma 
multiforme (GBM), and to determine the recommended Phase 2 dose (RP2D). 
Phase 2: 
 To assess response rate (RR) of isatuximab in combination with atezolizumab in 
participants with HCC or SCCHN or EOC. 
 To assess the progression free survival rate at 6 months (PFS-6) of isatuximab in 
combination with atezolizumab, or as a single agent in participants with GBM. 
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1.2.2 Secondary objectives 
 To evaluate the safety (in Phase 2) profile of isatuximab monotherapy (GBM only), or in 
combination with atezolizumab.  
 To evaluate the immunogenicity of isatuximab and atezolizumab. 
 To characterize the pharmacokinetic (PK) profile of isatuximab single agent (GBM only) 
and atezolizumab in combination with isatuximab. 
 To assess overall efficacy of isatuximab in combination with atezolizumab, or single agent 
(GBM only). 
1.3 
DETERMINATION OF SAMPLE SIZE 
Phase 1 
Approximately 6 (assuming 6 participants for the starting dose) to 24 (assuming 12 participants 
for the starting dose, and 12 participants for DL-1) DLT evaluable participants are expected to be 
enrolled. The actual sample size will vary depending on DLTs observed and the number of dose 
levels explored. Participants who are not evaluable for DLT assessment in Phase 1 may be 
replaced. 
Phase 2 
Phase 2 of the study is to evaluate initial anti-tumor activity based on tumor response using 
response evaluation criteria in solid tumors (RECIST) 1.1 criteria (1) for HCC, SCCHN and EOC, 
and response assessment in neuro-oncology (RANO) criteria (2) for GBM. The efficacy 
evaluation is based on 2-stage design with 85% power at 5% one-sided alpha level for each of the 
participant cohorts, respectively. 
The assumption of RR, the required sample sizes, and the number of responders at each stage are 
provided in Table 2 for HCC, SCCHN and EOC: 
Table 2 - Sample size calculation for HCC, SCCHN and EOC 
Indication 
H0 
H1 
Sample size 
Number (%) of responses 
to reject H0 
Stage 1 
Final 
Stage 1 
Final 
HCC & 
SCCHN 
15% 
30% 
26 
59 
≥5 (19.2%) 
≥14 (23.7%) 
EOC 
20% 
40% 
17 
37 
≥4 (23.5%) 
≥12 (32.4%) 
Abbreviations: H0=null hypothesis; H1=alternative hypothesis; HCC=hepatocellular carcinoma; SCCHN=squamous cell carcinoma of the 
head and neck; EOC=epithelial ovarian cancer. 
Note: Based on the number of objective responses and the totality of data observed within a treatment cohort in Phase 2 Stage 1, the 
Sponsor may decide to advance such a treatment cohort to Phase 2 Stage 2 after consulting with Study Committee. 
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The assumption of PFS-6, the required sample sizes, and PFS-6 at each stage are provided  
in Table 3 for GBM: 
Table 3 - Sample size calculation for GBM 
Indication 
H0 
H1 
Sample size 
Number (%) of responses 
to reject H0 
Stage 1 
Final 
Stage 1 
Final 
GBM 
20% 
35% 
31 
65 
>19.4% 
>27.7% 
Abbreviations: H0=null hypothesis; H1=alternative hypothesis; GBM=glioblastoma multiforme. 
Note: Based on the PFS-6 and the totality of data observed within a treatment cohort in Phase 2 Stage 1, the Sponsor may decide to advance 
such a treatment cohort to Phase 2 Stage 2 after consulting with Study Committee. 
Participants who received the recommended dose regimen in Phase 1 will be also included in 
Phase 2 Stage 1 (eg, if 6 HCC participants were enrolled in Phase 1, only 20 HCC participants 
will be needed to complete the Phase 2 Stage 1 HCC cohort). 
In Phase 2, approximately 285 participants are expected to be enrolled (assuming Cohort A, B, C, 
D-1, and D-2 complete 2 stages), including approximately 131 in Phase 2 Stage 1 and 
approximately 154 participants in Phase 2 Stage 2. The participants who are treated with RP2D in 
Phase 1 will be counted as Phase 2 participants. 
If isatuximab Q3W in combination with atezolizumab or as monotherapy (GBM only) without the 
isatuximab QW for 3 weeks is to be tested in HCC, SCCHN, EOC, or GBM, 65 additional 
participants are expected to be enrolled. As a consequence, a total of up to 350 participants may be 
enrolled. 
1.4 
STUDY PLAN 
The complete study plan is presented in Section 1.2 of the protocol. 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL  
The statistical section of the protocol was never changed in an amendment. 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN 
Not applicable. 
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2 
STATISTICAL AND ANALYTICAL PROCEDURES 
Patients treated at the RP2D in Phase 1 will be included in the analysis with patients of the same 
tumor type in Phase 2. If the RP2D is the starting dose, all data from the patients in Phase 1 will 
be summarized together with the data from the patients of the same tumor type in Phase 2 except 
for the DLT analysis.  
Data from HCC, SCCHN, EOC, and GBM cohorts (Cohorts A, B, C, D-1, and D-2) in Phase 2 
will be analyzed and reported separately by cohort. Data from the cohort E will be summarized 
separately unless otherwise noted. 
2.1 
ANALYSIS ENDPOINTS 
2.1.1 Demographic and baseline characteristics 
The baseline value is defined as the last assessment for this parameter before first administration 
of study treatments unless otherwise noted. 
All baseline safety and efficacy parameters (apart from those listed below) will be presented along 
with summary statistics in the safety and efficacy sections (Section 2.4.5 and Section 2.4.6). 
Demographic characteristics 
Demographic variables include race (American Indian or Alaska Native, Asian, Black or African 
American, Native Hawaiian or Other Pacific Islander, White, Not reported, Unknown), ethnicity 
(Hispanic or Latino, Not Hispanic or Latino, Not reported, Unknown), age in years, weight (kg), 
height (cm), eastern cooperative oncology group (ECOG) performance status (for patients with 
HCC or SCCHN or EOC) and Karnofsky performance status (for patients with GBM) at baseline.  
Medical or surgical history 
Medical or surgical history includes relevant history of previous or associated pathologies other 
than the tumor.  
This information will be coded using the version of Medical Dictionary for Regulatory Activities 
(MedDRA) currently in effect at Sanofi at the time of database lock. 
Disease characteristics at diagnosis 
The following disease characteristics at initial diagnosis will be described: 
 Time from initial diagnosis to first study treatment administration (in years). 
 Histology (diagnosis as collected in electronic case report form [eCRF]). 
 Disease Location. 
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 Histopathology type (as collected in eCRF). 
 Stage of the disease (as collected in eCRF, for patients with SCCHN and EOC). 
Disease characteristics at study entry - HCC 
The following disease characteristics at study entry will be described: 
 BCLC stage. 
 Child-Pugh score. 
 Progression on OR intolerance to other therapy. 
 Extrahepatic metastases. 
 Vascular invasion. 
Disease characteristics at study entry - SCCHN 
The following disease characteristics at study entry will be described: 
 Tumor recurrence or PD within 6 months of last platinum-based therapy. 
 HPV status. 
Disease characteristics at study entry - EOC 
The following disease characteristics at study entry will be described: 
 Disease resistant/refractory to platinum chemotherapy. 
 BRCA1 status. 
 BRCA2 status. 
Disease characteristics at study entry - GBM 
The following disease characteristics at study entry will be described: 
 IDH gene mutated. 
 MGMT gene methyled. 
 Surgeries undergone (complete resection, partial resection, biopsy only, other). 
Prior anticancer therapies 
Prior anti-cancer treatments are collected by regimen in the eCRF. The following variables will be 
summarized for each cohort (HCC, SCCHN, EOC, or GBM): 
 Number of prior regimens (by category). 
 Prior surgery related to disease: number (%) of patients with any prior surgery by type of 
procedure (Preferred Term). 
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In addition, for EOC cohort, prior PARP inhibitor will be summarized by category (0, 1 or >1). 
Any technical details related to computation, dates, and imputation for missing dates are described 
in Section 2.5.  
2.1.2 Prior or concomitant medications (other than anticancer therapies) 
All medications will be coded using the World Health Organization-Drug Dictionary (WHO-DD), 
using the version currently in effect at Sanofi at the time of database lock. 
 Prior medications are those the patient used prior to first study treatment administration. 
Prior medications can be discontinued before first dosing or can be ongoing during 
treatment phase.   
 Concomitant medications are any treatments received by the patient concomitantly to the 
study treatment from first administration to the last administration + 30 days. A given 
medication can be classified both as a prior medication and as a concomitant medication.  
 Post-treatment medications are those the patient took in the period running from the day 
after the last study treatment administration + 30 days up to the end of the study. 
Infusion associated reaction (IAR) medications 
As defined in Section 6.6.4 of the study protocol, patients were to routinely receive 
premedications prior to isatuximab infusion to reduce the risk and severity of hypersensitivity 
reactions commonly associated with monoclonal antibodies. Premedications are defined in the 
protocol as non-investigational medicinal product(s). Premedications are reported on a specific 
eCRF page. 
Any technical details related to computation, dates, imputation for missing dates are described  
in Section 2.5. 
2.1.3 Efficacy endpoints 
2.1.3.1 Primary efficacy endpoint(s) 
The primary efficacy endpoint for the Phase 2 part of the study is RR for patients with HCC or 
SCCHN or EOC and is PFS-6 for patients with GBM.  
For patients with HCC or SCCHN or EOC, the RR is defined as the proportion of patients with 
complete response and partial response as best overall response (BOR), assessed by investigators 
per RECIST 1.1 criteria, relative to the total number of patients in the analysis population. The 
confirmation of complete or partial response is required to determine BOR. BOR will be derived 
per RECIST 1.1 criteria using disease assessments performed from the first dose of treatment 
through the study excluding any assessments performed after the cut-off date or following the 
initiation of a further anticancer treatment. Clinical deterioration will not be considered as 
progression in the primary analysis of RR. 
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For patients with GBM, the PFS-6 is defined as the PFS rate at 6 months (assessed by 
Investigators per RANO criteria). 
2.1.3.2 Secondary efficacy endpoint(s) 
The secondary efficacy endpoints are: 
 Tumor burden change: Tumor burden change is defined as the best percent-change from 
baseline in a sum of the diameters (longest for non-nodal lesion, short axis for nodal 
lesions) for all target lesions. 
 Area under the curve (AUC) of percent-change from baseline in tumor burden is defined as 
the area under the percent-change from baseline versus time curve calculated using the 
trapezoidal method from the date of the first post-baseline assessment to the date of the 
last assessment. 
 The time-adjusted AUC of percent-change from baseline in tumor burden is defined as 
AUC of percent-change from baseline in tumor burden divided by the duration of the 
assessment. 
 Disease control rate (DCR): DCR is defined as the sum of the complete response (CR), 
partial response (PR) and stable disease (SD) rates. CR, PR, and SD are assessed by 
Investigator (per RECIST 1.1 criteria for HCC or SCCHN or EOC patients; per RANO 
criteria for GBM patients). 
 Duration of response (DoR): DoR is defined as the time from the date of first response (PR 
or CR whichever is first) that is subsequently confirmed to the first date that recurrent or 
progressive disease progression is objectively documented, or the date of death, whichever 
occurs first. Disease progression refers to radiographic disease progression. The RECIST 
1.1 criteria will be followed for assessment of radiographic disease progression in patients 
with HCC or SCCHN or EOC and the RANO criteria will be followed in patients with 
GBM. In the absence of disease progression or death before the analysis cut-off date or the 
date of initiation of a further anticancer treatment, the DoR will be censored at the date of 
the last valid response assessment not showing disease progression performed prior to 
initiation of a further anticancer treatment or the analysis cut-off date, whichever is earlier. 
DoR will not be calculated for patients who do not achieve a response. 
Progression-free survival (PFS): PFS is defined as the time from first study treatment 
administration to the date of first documented radiographic progression (HCC, SCCHN, 
EOC per RECIST 1.1; GBM per RANO) or the date of death from any cause, whichever 
occurs first.  
For patients who did not experience documented radiographic progression or death before 
the analysis cut-off date or the date of initiation of new anticancer treatment, PFS will be 
censored at the date of the last valid disease assessment not showing radiographic 
progression performed prior to initiation of a further anticancer treatment or the analysis 
cut-off date, whichever comes first. In addition, patient without PFS event (death or 
documented radiographic progression) and without any valid post-baseline disease 
assessments will be censored at the date of first treatment (Day 1). 
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 RR (GBM only): RR for GBM patients is defined as the proportion of patients with 
complete response and partial response as best overall response, assessed by Investigators 
using RANO criteria. The confirmation of complete or partial response is required to 
determine BOR. BOR will be derived per RANO criteria using disease assessments 
performed from the first dose of treatment through the study excluding any assessments 
performed after the cut-off date or following the initiation of a further anticancer treatment. 
2.1.3.3 Exploratory efficacy endpoint(s) 
For patients with HCC, SCCHN, and EOC, the following endpoints will be summarized: 
 RR, DCR, DoR, and PFS by modified Response Evaluation Criteria in Solid Tumors for 
immune-based therapies (iRECIST) (3). Definitions are similar to the ones in primary and 
secondary efficacy endpoints, except using iRECIST criteria instead of RECIST 1.1. Based 
on iRECIST, progressive disease should be confirmed on a second examination done at 
least 4 weeks apart to exclude pseudo progression. Once confirmed, the date of 
progression is the date of initial documented disease progression. 
 Time to response (TTR): TTR is defined as the time from first study treatment 
administration to the first response (PR or CR whichever is first) that is subsequently 
confirmed (by RECIST 1.1 and iRECIST respectively). 
 Time to progression (TTP): TTP is defined as the time from first study treatment 
administration to the date of first documented disease progression (by RECIST 1.1 and 
iRECIST respectively). Confirmation of progression is required by iRECIST. The date of 
progression is the date of initial documented disease progression.  
 For patients who did not experience progression before the analysis cut-off date or the date 
of initiation of new anticancer treatment, TTP will be censored at the date of the last valid 
disease assessment not showing disease progression performed prior to initiation of a 
further anticancer treatment or the analysis cut-off date, whichever comes first. In addition, 
patient without disease progression and without any valid post-baseline disease 
assessments will be censored at the date of first treatment (Day 1). 
 Overall survival (OS): OS is defined as the time from first study treatment administration 
to death from any cause. Patients without death prior to the analysis cut-off date will be 
censored at the last date the patient was known to be alive or the cut-off date, whichever 
comes first. 
For patients with HCC, the following endpoint will also be summarized: 
 Alpha-fetoprotein (AFP) reduction from baseline and relation with clinical response:  
% reduction and absolute reduction from baseline will be summarized for patients with 
clinical benefits (ie, patients with SD>6 months in the responder group) and others, 
respectively. Duration of SD is defined as the time from the date of first treatment to the 
date of first disease progression or death due to any cause, whichever occurs first. 
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For patients with EOC, the following endpoint will also be summarized: 
 CA125 response by Gynaecologic Cancer Intergroup (GCIG) criteria and relation with 
clinical response. Patients should have a pre-treatment CA-125 of at least twice the ULN 
in order to be considered for CA-125 response. A CA-125 response would be obtained the 
moment the CA-125 is reduced by 50% and this should be confirmed with a consecutive 
CA-125 assessment not earlier than 28 days after the previous one, with however the date 
of the first 50% reduction to be the reference date for the CA-125 response. Patients are 
not evaluable by CA-125 if they have received mouse antibodies or if there has been 
medical and/or surgical interference with their peritoneum or pleura during the previous  
28 days.  
For patients with GBM, the following endpoints will be summarized: 
 RR, DCR, DoR, and PFS by Immunotherapy Response Assessment in Neuro-Oncology 
(iRANO) (4). Definitions are similar to the ones in primary and secondary efficacy 
endpoints, except using iRANO criteria instead of RANO. 
By iRANO, if it is ≤6 months after the initiation of immunotherapy, then a repeat scan is 
required to confirm radiographic progression. The minimum time interval for confirmation 
of progression is ≥3 months, and a new lesion dose not define PD. 
By iRANO, if it is >6 months after the initiation of immunotherapy, then the confirmation 
of radiographic progression is not required, and a new lesion defines PD. 
 OS-6: OS-6 is defined as the overall survival rate at 6 months. 
 TTR and TTP (by RANO and iRANO). Definitions are similar to the ones for patients 
with HCC, SCCHN, and EOC, except using RANO and iRANO criteria. 
 OS: Definition is same as OS for patients with HCC, SCCHN, and EOC. 
2.1.4 Safety endpoints 
The safety analysis will be based on the reported adverse events (AEs) and other safety 
information, such as clinical laboratory data, vital signs, weight, electrocardiogram (ECG), 
Eastern Cooperative Oncology Group (ECOG) performance status (for patients with HCC or 
SCCHN or EOC) and Karnofsky performance status (for patients with GBM). 
Observation period  
The observation period starts from the time when the patient gives informed consent and is 
divided into 3 periods: 
 The pre-treatment period is defined as the time informed consent is signed until the first 
dose of study treatments administration. 
 The treatment-emergent adverse event (TEAE) period is defined as the time from the 
first dose of study treatments up to 30 days after last dose of study treatments. 
 The post-treatment period is defined as the time starting from 31 days after the last dose 
of study treatments to the end of the study (as defined in the protocol). 
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2.1.4.1 Dose limiting toxicities (DLTs) 
For the Phase 1 part dose limiting toxicities will be listed by patient using the DLT evaluable 
population. 
2.1.4.2 Adverse events variables 
AEs (including serious adverse events [SAEs] and AEs of special interest [AESIs]) will be 
collected from the time of signed informed consent until the end of study. 
Adverse event observation period 
 Pre-treatment AEs are defined as any adverse event reported during the pre-treatment 
period. 
 TEAEs are adverse events that developed or worsened or became serious during the 
TEAE period. 
 Post-treatment AEs are adverse events that developed or worsened or became serious 
during the post-treatment period. 
All AEs (including SAEs and AESIs) will be graded according to NCI-CTCAE v4.03 and coded 
to a lower-level term, preferred term (PT), high-level term, high-level group term and associated 
primary system organ class (SOC) using the version of MedDRA currently in effect at Sanofi at 
the time of database lock. 
Adverse events of special interest 
Specific analyses will be performed for the following AEs: 
 DLTs. 
 Grade ≥2 acute IARs with isatuximab.  
 Any grade IARs with atezolizumab. 
 Grade ≥3 immune-related TEAEs. 
 Any grade of the following TEAEs with atezolizumab: pneumonitis, colitis, 
endocrinopathies (diabetes mellitus, pancreatitis, adrenal insufficiency, hyperthyroidism, 
and hypophysitis), systemic lupus erythematosus, neurologic disorders (Guillain-Barré 
syndrome, myasthenic syndrome, myasthenia gravis, and meningoencephalitis), nephritis, 
ocular toxicities, myositis, myopathies, vasculitis, and autoimmune hemolytic anemia. 
 Grade ≥2 cardiac disorders with atezolizumab. 
 Pregnancy of a female patient entered in a study as well as pregnancy occurring in a 
female partner of a male patient entered in a study with IMP/non-investigational medicinal 
product (NIMP). 
 Symptomatic overdose (serious or non-serious) with isatuximab/NIMP. 
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2.1.4.3 Infusion associated reactions 
Infusion associated reactions (IARs) typically occur within 24 hours from the start of each 
isatuximab/atezolizumab infusion. 
Whenever possible, a diagnosis of the IAR (eg, Cytokine release syndrome, infusion related 
reaction, anaphylactic reaction, or any other teams chosen by the investigator) will be reported by 
the investigator in a specific AE page. In addition, symptoms of the IARs will be reported on a 
separate eCRF form. 
IARs will be analyzed based on the investigator reported term collected in the specific AE pages. 
2.1.4.4 Deaths 
The deaths will be summarized as follows: 
 Deaths in TEAE period: includes all deaths occurring from the first IMP up to the end of 
treatment + 30 days. 
 Deaths in post-treatment period: includes all deaths occurring after the end of TEAE 
period up to study closure. 
2.1.4.5 Laboratory safety variables 
Clinical laboratory data consists of blood and urine analysis including hematology, biochemistry 
and urinalysis. Clinical laboratory values will be converted into standard international units that 
will be used in all listings and tables. 
Parameters measured on the day of the first study treatment infusion will be considered as part of 
the baseline measurements. 
For laboratory safety variables, the treatment period is defined as the time from the first dose of 
study treatment (irrespective of treatment) administration to the last dose of study treatments  
+ 30 days. 
Blood and urine samples for clinical laboratories parameters will be taken as defined in the study 
flow charts and as clinically indicated. The laboratory parameters will be classified as follows:   
 Hematology  
- 
Hemoglobin and coagulation: hemoglobin, hematocrit, red blood cell (RBC) count, 
platelet counts, prothrombin time or international normalized ratio (INR) and activated 
partial thromboplastin time (PTT). 
- 
White blood cells (WBCs): leukocytes, neutrophils, lymphocytes, monocytes, 
basophils, eosinophils. 
 Biochemistry 
- 
Metabolism: fasting glucose, total protein, 
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- 
Electrolytes: sodium, potassium, chloride, calcium, albumin, magnesium, phosphate, 
bicarbonate/carbon dioxide, 
- 
Renal function: uric acid, serum creatinine, estimated creatinine clearance by 
modified diet in renal disease (MDRD) formula, urea or blood urea nitrogen (BUN), 
- 
Liver parameters: alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
alkaline phosphatase, total and direct bilirubin, lactate dehydrogenase (LDH). 
- 
Hormonal: thyroid stimulating hormone (TSH) and free T4. 
 Urinalysis  
- 
Quantitative or semi-quantitative urinalysis: RBC, protein, glucose, pH, leukocytes. 
2.1.4.6 Vital signs variables 
Vital signs include: weight, temperature, pulse rate, systolic and diastolic blood pressure, and 
respiratory rate. Oxygen saturation is assessed for patients with SCCHN only.  
Weight is required at Screening, prior to starting infusion and at the EOTvisit. Temperature, pulse 
rate, respiratory rate, and blood pressure will be performed at screening, at Cycle 1 Day 1, Day 8 
and Day 15, and Cycle N Day 1 - just before starting infusion of IMPs, during infusion, and at the 
end of infusion, at EOT visit, and at post treatment follow-up visits at 60 and 90 days after last 
treatment.  
Thus, parameters measured pre-infusion on the day of the first study treatment infusion will be 
considered as part of the baseline measurements.  
For a given parameter, a patient (respectively a cycle) will be considered as evaluable if at least 
one measure of this parameter is available during the on-treatment period. 
2.1.4.7 Electrocardiogram variables 
12-lead ECG assessments will be described as normal or abnormal. 
2.1.4.8 Clinical safety laboratory assessments 
All protocol-required laboratory assessments, as defined in Section 10.3 of the protocol, will be 
performed and to the Schedule of Activities 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 eCRF. Remaining 
laboratory tests are reported in eCRF pages for Hematology and Biochemistry. 
All laboratory tests with values considered clinically significantly abnormal during participation in 
the study or 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.  
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2.1.4.9 Immunogenicity variables 
Anti-drug antibodies (ADA) against isatuximab and atezolizumab will be collected according to 
the pharmacokinetics/pharmacodynamics (PK/PD) flowcharts in Section 1.3 of the protocol.  
ADA attributes 
Pre-existing ADA is defined as ADA reactive with the biotherapeutic present in subjects before 
treatment (or before initiation of the clinical study). 
Treatment boosted ADA is defined as pre-existing ADAs that were boosted to a higher level 
following administration of biotherapeutic (ie, any time after the initial drug administration) the 
ADA titer is significantly higher than the baseline titer. A low serial dilution schema (2-fold or  
3 fold) should be applied during titration. A difference in titer values of two titer steps between 
treatment or follow-up sample and its baseline sample is considered significant. For examples, at 
least a 4-fold increase in titers for 2- fold serial dilution schema (or 9-fold increase in titers for 
3- fold serial dilution schema). If no titer could be determined for a positive sample, the titer will 
be reported as the minimal required dilution of the assay. 
Treatment-induced ADA is defined as ADAs developed de novo (seroconversion) following 
administration of the biotherapeutic (ie, formation of ADAs any time after the initial drug 
administration in a subject without pre-existing ADAs). If the baseline ADA sample is missing or 
non-reportable and at least one reportable ADA sample is available during the treatment 
(including follow-up period) the baseline sample will be considered as “negative” for data 
analysis. This is considered being a conservative approach for ADA assessment. 
Subject status 
Among evaluable population for immunogenicity (described in Section 2.3.5), following patient 
status will be defined: 
 ADA-positive subject: A subject with at least one treatment induced or treatment boosted 
ADA-positive sample at any time during the treatment or follow-up observation period.  
 ADA-negative subject: Subject without any treatment induced or treatment boosted 
ADA-positive sample during the treatment or follow-up observation period. 
 ADA-inconclusive subject: A subject who cannot irrefutably be classified as  
ADA negative (eg, all post baseline samples inconclusive). 
Overview of the ADA response 
Two main categories can be reported for the epidemiology of an ADA immune response: ADA 
prevalence and ADA incidence: 
 ADA prevalence defines the proportion of all subjects tested positive for ADAs (including 
preexisting antibodies, treatment boosted ADAs and treatment induced ADAs) at any point 
in time. 
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 In contrast the term ADA incidence only defines the proportion of subjects found to either 
have seroconverted (treatment induced ADAs) or boosted their pre-existing ADA response 
during the study. Only evaluable subjects (described in Section 2.3.5) are considered for 
computing ADA incidence. 
Kinetics of the immune response 
 Onset of ADA: refers to the time period between the initial drug administration and the 
first instance of treatment induced ADAs. The use of real-elapsed days should be used for 
the calculations. The “median time to ADA development” and the quartiles Q1 and Q3 
should be reported. 
 Duration of ADA: ADA duration will be calculated as the date of last treatment induced 
ADA sample minus date of first treatment induced or treatment boosted ADA sample +1; 
ADA duration will be calculated only for patients with at least two ADA positive samples. 
Median duration of an induced ADA response and the quartiles Q1 and Q3 should be 
reported. 
 Transient ADA response is defined by: 
- 
Treatment induced ADA detected only at one sampling time point during the treatment 
or follow-up observation period  (excluding the last sampling time point), OR 
- 
Treatment induced ADA detected at two or more sampling time points during the 
treatment (including follow-up period if any), where the first and last ADA-positive 
samples (irrespective of any negative samples in between) are separated by a period 
less than 16 weeks, and the patient’s last sampling time point is ADA negative. 
 Persistent ADA response is defined by: 
- 
Treatment induced ADA detected at two or more sampling time points during the 
treatment (including follow-up period if any), where the first and last ADA-positive 
samples are separated by at least 16 weeks (irrespective of any negative samples in 
between).  
 Indeterminate ADA is defined by: 
- 
Treatment induced ADA detected only at the last sampling time point, OR 
- 
The last two samples being ADA-positive and separated by a period of less than  
16 weeks. 
Treatment-boosted ADAs are excluded from the analysis of ADA kinetics. 
2.1.5 Pharmacokinetic variables  
PK analysis will be done separately for isatuximab and atezolizumab.  
The PK sampling times for isatuximab and atezolizumab were provided in the PK/PD flowchart in 
Section 1.3 of the protocol. 
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 
For isatuximab only: the following PK parameters (listed in Table 4) will be calculated 
with PKDMS software (Pharsight) V3.0, using non-compartmental method from 
isatuximab concentrations after the first administration on Cycle 1.  The parameters will 
include, but may not be limited to the following: 
Table 4 - List of pharmacokinetic parameters and definitions 
Parameters 
Analyte 
Definition 
 
Atezolizumab 
Isatuximab 
 
Ceoi 
X 
X 
Concentration observed at the end of intravenous (IV) infusion 
Cmax 
X 
X 
Maximum concentration observed 
tmax 
X 
X 
Time to reach Cmax 
Clast  
X 
X 
Last concentration observed above the lower limit of quantification 
tlast 
X 
X 
Time of Clast 
AUC0-7d 
X 
 
Area under the concentration versus time curve calculated using the 
trapezoidal method over the dosing interval (21 days)  
 
 
For isatuximab and atezolizumab: Ctrough defined as sample collected just before treatment 
administration and Ceoi will be measured over the study period.   
In addition, populations PK approaches may be used for both compounds and PK 
estimates may be used to conduct exploratory exposure-response analyses for safety and 
efficacy and PK/PD analyses for relevant biomarkers. If done, the data generated will be 
reported in stand-alone report(s).  
2.1.6 Biomarker endpoints  
2.1.6.1 Microsatellite instability 
Microsatellite instability will be analyzed on tumor samples collected at screening or baseline: 
 
Results will be of the form of MSI-H (ie, high microsatellite instability) or no-MSI-H  
(ie, low microsatellite instability or microsatellite stable). 
2.1.6.2 PD-L1 expression singleplex IHC 
PD-L1 expression on tumor and immune cells will be assessed using tumor tissue (freshly 
collected tumor biopsy or archival tissue) biopsy at Screening/Baseline and (unless clinically 
unfeasible) at C2D1. 
2.1.6.3 Cluster of differentiation 38 (CD38) expression singleplex IHC 
CD38 expression on tumor and immune cells will be assessed using tumor tissue (freshly 
collected tumor biopsy or archival tissue) biopsy at Screening/Baseline and (unless clinically 
unfeasible) at C2D1. 
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2.1.6.4 Immune cell subpopulation tumor infiltration and markers co-expression 
multiplex immunofluorescence 
Immune cell subpopulation tumor infiltration and markers co-expression on different cell 
sub-populations will be assessed on tumor tissue (freshly collected tumor biopsy or archival tissue) 
biopsy at Screening/Baseline and (unless clinically unfeasible) at C2D1. Cell sub-populations will 
be determined by multiplex Immunofluorescence based on the expression of 12 different cell 
markers. The results will be provided per region of interest (ROI) and the number of cell 
sub-populations will be provided for 3 regions (total, within tumor, outside tumor). 
Per cell sub-population, an average of the results provided per ROI will be calculated for the 
totality of tumor tissue. 
2.1.7 Further therapy after discontinuation of investigational medicinal product 
administration during the study 
Further therapies after discontinuation of study treatment will be collected on a specific eCRF 
page. The following information will be collected: drug/medication (brand or generic name), start 
date and end date (if available)/ongoing (otherwise). 
2.2 
DISPOSITION OF PATIENTS 
Patient disposition will be summarized by cohort based on the analysis population defined 
in Section 2.3.  
Screened patients are defined as any patients who signed the study informed consent. 
Enrolled patients are screened patients who are planned to receive the study treatment, ie, for 
whom the investigator ticked “Yes” to the question “Will the patient continue into the study?” at 
the end of the screening period.  
For patient study status, the total number of patients for each of the following categories will be 
presented in the clinical study report using a flow-chart diagram or a summary table: 
 Screened patients. 
 Enrolled patients. 
 Enrolled and not treated patients. 
 Enrolled and treated patients. 
 Patients still on treatment. 
 Patients completed treatment. 
 Patients who discontinued the study treatments period and reasons for permanent 
discontinuation. 
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The number and percentage of patients in analysis population (defined in Section 2.3) will be 
provided in a summary table. 
A summary of the reasons for definitive and premature treatment discontinuation for either 
treatment will be provided.  Definitive treatment discontinuation is defined as the discontinuation 
of all the study treatments. Premature treatment discontinuation (only for cohorts with the 
combination therapy) is defined as the discontinuation of one of the study treatments but the other 
one continued. Listing of the reasons for treatment discontinuation will be provided. 
The number (%) of patients treated by country and center will be summarized using the all-treated 
population (defined in Section 2.3). 
All critical or major deviations potentially impacting efficacy and safety analyses will be 
summarized by cohort separately.  Critical or major protocol deviations will be listed. 
2.2.1 Randomization and drug dispensing irregularities 
This is an open-label, non-randomized study; therefore, randomization and dispensing 
irregularities are not applicable.  
2.3 
ANALYSIS POPULATIONS 
2.3.1 All-treated population 
For both Phase 1 and Phase 2 parts of the study, the all-treated population will include all patients 
who signed the study informed consent and received at least 1 dose (even incomplete) of the study 
treatments, either isatuximab or atezolizumab. 
This population is the primary population for the analyses of efficacy and safety parameters except 
for DLT evaluation. All analyses using this population will be based on the dose level actually 
received in the first cycle. 
2.3.2 DLT-evaluable population  
The DLT evaluable population is defined as patients in the Phase 1 part receiving the planned 
doses of isatuximab and atezolizumab during Cycle 1, and who completed the DLT observation 
period after the first IMP administration as per Section 4.1.1 from protocol, unless they 
discontinue the study treatment(s) due to DLT. The dose recommended for Phase 2 will be 
determined on the DLT evaluable population. 
2.3.3 Pharmacokinetic population 
The PK population will be defined independently for isatuximab and atezolizumab, and include 
patients from the all treated population who received at least one dose of the drug even if 
incomplete with at least one reportable concentration after the study drug administration (whatever 
the cycle and even if dosing is incomplete). 
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2.3.4 Biomarker Population 
The biomarker population will include all treated patients who submitted at least one baseline 
biomarker sample.       
2.3.5 Immunogenicity population 
The immunogenicity population will be defined independently for isatuximab and atezolizumab, 
and include subjects from the all treated population who received at least one dose of the drug 
even if incomplete with at least one sample, taken post-baseline after drug administration during 
the treatment or follow-up observation period, with a reportable result (positive, negative or 
inconclusive).  
2.3.6 Response evaluable population 
The response evaluable population will include all patients in the all-treated population who 
fulfilled all inclusion and exclusion criteria with an evaluable baseline assessment and at least one 
evaluable post-baseline disease assessment during the treatment period. 
2.4 
STATISTICAL METHODS 
Continuous data will be summarized using number of available data, mean, standard deviation, 
median, minimum and maximum for each dose level (if applicable). Categorical and ordinal data 
will be summarized using number and percentage of patients. 
Data listings will be provided separately by cohort and sorted by patient number, unless otherwise 
specified. 
2.4.1 Demographics and baseline characteristics 
Demographics and baseline characteristics will be summarized on the all-treated population.  
Parameters described in Section 2.1.1 will be summarized using descriptive statistics. 
The medical and surgical history will be summarized according to the SOC and PT (SOC will be 
sorted according to the internationally agreed order and PT by overall decreasing frequency).  
Disease characteristics at diagnosis and at study entry will be described. 
2.4.2 Prior or concomitant medications (other than anticancer therapies) 
The prior, concomitant and post medications will be presented for the all-treated population. The 
anti-cancer therapy will be presented separately.  
Medications will be summarized according to the WHO-DD dictionary, considering the first digit 
of the anatomic therapeutic category (ATC) class and the first 3 digits of the ATC class 
(therapeutic category).  All ATC codes corresponding to a medication will be summarized, and the 
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patients will be counted once in each ATC category (anatomic or therapeutic) linked to the 
medication. Therefore the patients may be counted several times for the same medication.  
The tables for medications (prior, concomitant and post-treatment) will be sorted by decreasing 
frequency of ATC followed by all other therapeutic classes based on the overall incidence.  In case 
of equal frequency regarding ATCs, alphabetical order will be used. 
IAR medications 
Number (%) of patients with IAR medications as defined in Section 2.1.2 will be provided. 
2.4.3 Anticancer therapies 
Prior anti-cancer treatments will be summarized for the all-treated population. Number (%) of 
patients with the anti-cancer treatments described in Section 2.1.1 will be summarized.  
2.4.4 Extent of investigational medicinal product exposure and compliance  
The extent of study treatment exposure will be assessed and summarized on the all-treated 
population. 
2.4.4.1 Extent of investigational medicinal product exposure 
The overall extent of exposure will be assessed as: 
 Overall number of cycles started. 
 Duration of overall exposure (weeks): defined as (last day of last cycle - first day of first 
cycle)/7. The first day of first cycle is defined as the date of the first dose of study 
treatments. The last day of last cycle is defined as the later date among the following: 
- 
Date of the last dose of isatuximab + 7 days if the last cycle is a QW cycle or date of 
the last dose of isatuximab + 21 days if the last cycle is a Q3W, 
- 
Date of the last dose of atezolizumab + 21 days. 
Total number of cycles started, number of cycles started by patient as a continuous variable and by 
category (ie, number [%] of patients receiving at least 1 cycle, at least 2 cycles, etc), duration of 
overall exposure will be summarized using descriptive statistics. 
To describe overall dose modification, the cycle delay will be summarized. A cycle is considered 
as delayed if the start date of cycle - 21 - the start date of the previous cycle is >3 days. The cycle 
start date is defined as the earlier date of isatuximab or atezolizumab administration within a 
cycle. Cycle delay is not defined for the first cycle. 
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Cycle delay will be summarized at both the patient and cycle levels as follows: 
 Patient level: 
- 
Number of patients treated, 
- 
Number (%) of treated patients with at least 1 cycle delayed,  
- 
Number (%) of treated patients with a cycle delayed between 4 and 7 days, 
- 
Number (%) of treated patients with a cycle delayed between 8 and 14 days, 
- 
Number (%) of treated patients with a cycle delayed more than 14 days. 
 Cycle level: 
- 
Number of cycles started, 
- 
Number (%) of cycles delayed, 
- 
Number (%) of cycles delayed between 4 and 7 days, 
- 
Number (%) of cycles delayed between 8 and 14 days, 
- 
Number (%) of cycles delayed more than 14 days. 
2.4.4.2 Isatuximab exposure 
The isatuximab exposure will be summarized as follows: 
 Total number of cycles started. 
 Number of cycles started by patient as a continuous variable and by category. 
 Duration of isatuximab exposure (weeks) is defined as: 
- 
(Date of the last dose of isatuximab + 7 days - date of the first dose of isatuximab)/7 if 
the last cycle is a QW cycle, 
- 
(Date of the last dose of isatuximab + 21 days - date of the first dose of isatuximab)/7 
if the last cycle is a Q3W cycle. 
 Actual dose (mg/kg): is defined as the actual dose (mg) administered divided by the body 
weight at the time. 
 Cumulative dose (mg/kg): the cumulative dose is the sum of all actual doses (mg/kg) of 
isatuximab given from the first to the last administration. 
 Actual dose intensity (ADI, mg/kg/week): is defined as the cumulative dose (mg/kg) 
divided by the duration of isatuximab exposure (weeks).  
 Relative dose intensity (RDI, %): 
k)
(mg/kg/wee
Intensity 
 
Dose
 
Planned
 
k)
(mg/kg/wee
 
ADI
100
. 
Planned dose intensity (mg/kg/week) corresponds to the planned dose (mg/kg) multiplied 
by the theoretical total number of doses during the started cycles (3 for QW cycle and 1 for 
Q3W cycle) and divided by the theoretical cycle duration (weeks), ie, 3 weeks per cycle 
started. 
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The total number of cycles started, number of cycles started by patients as a continuous variable 
and by category (ie, number [%] of patients receiving at least 1 cycle, at least 2 cycles, etc), 
duration of isatuximab exposure, cumulative dose, ADI and RDI will be summarized by 
descriptive statistics. 
The following variables will be derived to describe dose delay and modification: 
 Dose delay within Cycle 1: a dose is deemed as delayed within Cycle 1 if the actual start 
date of the infusion is ≥2 days beyond the theoretical day of treatment for weekly dose. 
Dose delay does not apply to the first infusion of Cycle 1. 
 Infusion interruption: an infusion is considered to be interrupted (as collected on eCRF) if 
the isatuximab administration is stopped during an infusion before it is completed 
regardless of whether it is further restarted or not. 
 Dose omission: a dose is considered omitted if the dose is not administered for the 
scheduled visit and there are dose(s) administered afterwards.  
Dose delay and modification will be summarized at the patient and infusion levels as follows: 
 Patient level: 
- 
Number (%) of patients with at least 1 dose delay within cycle, 
- 
Number (%) of patients with at least 1 dose omission, 
- 
Number (%) of patients with at least 1 infusion interrupted, 
- 
Number (%) of patients with at least 1 infusion interrupted and re-started, 
- 
Number (%) of patients with at least 1 infusion interrupted and not re-started. 
 Infusion level: 
- 
Number of isatuximab infusions, 
- 
Number (%) of infusions interrupted, 
- 
Number (%) of infusions interrupted and re-started, 
- 
Number (%) of infusions interrupted and not re-started, 
- 
Number (%) of infusions interrupted more than once, 
- 
Number (%) of infusions interrupted at 1st infusion, 2nd infusion, subsequent 
infusions, 
- 
Time from infusion start to first interruption in minutes summarized as a continuous 
variable and by category (<5 minutes, 5-10 minutes, etc). 
2.4.4.3 Atezolizumab exposure 
The atezolizumab exposure will be summarized as follows: 
 Total number of cycles started. 
 Number of cycles started by patient as a continuous variable and by category. 
 Duration of atezolizumab exposure (weeks) is defined as (Date of the last dose of 
atezolizumab + 21 days - Date of the first dose of atezolizumab)/7. 
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 Actual dose (mg): is defined as actual dose administered. 
 Cumulative dose (mg): the cumulative dose is the sum of all actual atezolizumab doses. 
 ADI (mg/week): is defined the cumulative dose (mg) divided by the duration of 
atezolizumab exposure (weeks). 
 RDI (%): 
(mg/week)
Intensity 
 
Dose
 
Planned
 
(mg/week)
 
ADI
100
, where the planned dose  
intensity (mg/week) is 400 mg/week for Q3W schedule. 
The total number of cycles started, number of cycles started by patients as a continuous variable 
and by category (ie, number [%] of patients receiving at least 1 cycle, at least 2 cycles, etc), 
duration of atezolizumab exposure, cumulative dose, ADI and RDI will be summarized by 
descriptive statistics. 
The following variables will be derived to describe dose delay and modification: 
 Infusion interruption: An infusion will be considered to be interrupted (as collected on 
eCRF) if the atezolizumab administration is stopped during an infusion before it is 
completed regardless of whether it is further restarted or not. 
 Dose omission: a dose is considered omitted if the dose is not administered for the 
scheduled visit and there are positive dose(s) afterwards. 
Dose delay and modification will be summarized at the patient and infusion levels as follows: 
 Patient level: 
- 
Number (%) of patients with at least 1 dose omission, 
- 
Number (%) of patients with at least 1 infusion interrupted, 
- 
Number (%) of patients with at least 1 infusion interrupted and re-started, 
- 
Number (%) of patients with at least 1 infusion interrupted and not re-started. 
 Infusion level: 
- 
Number of atezolizumab infusions, 
- 
Number (%) of infusions interrupted, 
- 
Number (%) of infusions interrupted and re-started, 
- 
Number (%) of infusions interrupted and not re-started, 
- 
Number (%) of infusions interrupted more than once, 
- 
Number (%) of infusions interrupted at 1st infusion, 2nd infusion, subsequent 
infusions, 
- 
Time from infusion start to first interruption in minutes summarized as a continuous 
variable and by category (<5 minutes, 5-10 minutes, etc). 
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2.4.5 Analyses of efficacy endpoints 
All efficacy analysis will be performed using the all-treated population. In addition, efficacy 
analysis will be performed using the response evaluable population. 
For each cohort, the analysis cut-off date for the primary analysis (RR for HCC, SCCHN, and 
EOC; PFS-6 for GBM) will be 6 months after the last participant’s first treatment in the cohort.  
The analysis cut-off date for secondary efficacy endpoints including DoR and PFS will be 
12 months after the last participant’s first treatment in the cohort. The primary analysis of RR in 
the cohort for HCC, SCCHN, and EOC, and of PFS-6 in the cohort for GMB will be updated. In 
case of inadequate efficacy for a cohort at interim analyses, the Sponsor may decide not to update 
primary nor perform secondary analyses for that cohort. 
2.4.5.1 Analysis of primary efficacy endpoint(s) 
For HCC, SCCHN and EOC, RR will be summarized with descriptive statistics. A 90% 2-sided 
confidence interval will be computed using Clopper-Pearson method. BOR will be summarized 
descriptively. 
For GBM, PFS-6 will be summarized using Kaplan-Meier method. 
2.4.5.2 Analyses of secondary efficacy endpoints 
The analyses of secondary efficacy endpoints include: 
 Tumor burden change: the best percent-change from baseline in tumor burden will be 
summarized and presented graphically for patients with measurable disease at baseline. In 
addition, a summary of the AUC and the time-adjusted AUC of percent-change from 
baseline in tumor burden will also be provided as an exploratory analysis.  
 DCR: DCR (complete response + partial response + stable disease) will be summarized 
with descriptive statistics. 
 DoR: Kaplan-Meier estimates such as median and Kaplan-Meier curves will be provided 
for patients who achieved a response (PR or CR). 
 PFS: the PFS will be analyzed using the Kaplan-Meier method. The Kaplan-Meier 
estimates of the 25th, 50th and 75th percentiles and the 95% confidence intervals of 
median will also be computed. The Kaplan-Meier curves will be plotted. In addition, PFS 
at 6 months will also be provided.  
 RR (GBM only): RR for GBM patients will be summarized with descriptive statistics. 
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2.4.5.3 Analyses of exploratory efficacy endpoints 
RR and DCR by iRECIST for patients with HCC, SCCHN and EOC, as well as by iRANO for 
GBM patients, will be summarized with descriptive statistics.  
For patients with HCC, SCCHN and EOC, Kaplan-Meier method will be used to analyze DoR and 
PFS by iRECIST, TTR and TTP by RECIST 1.1 and iRECIST respectively, and OS. 
For patients with GBM, Kaplan-Meier method will be used to analyze DoR and PFS by iRANO, 
TTR and TTP by RANO and iRANO respectively, OS-6, and OS. 
In addition, AFP reduction from baseline for HCC patients and CA125 response for EOC patients 
will be summarized with descriptive statistics. 
2.4.5.4 Multiplicity issues 
Not applicable. 
2.4.6 Analyses of safety data 
The all-treated population will be used for all safety analyses except for the DLT analysis in  
Phase 1, which will be performed based on the DLT-evaluable population.  
2.4.6.1 Analyses of DLTs (Phase 1 only) 
The DLTs will be listed by patient using the DLT-evaluable population in Phase 1. 
2.4.6.2 Analyses of adverse events 
The primary focus of adverse event reporting will be on treatment-emergent adverse events. 
Pre-treatment and post-treatment adverse events will be described separately.  
If an AE date of onset (occurrence, worsening, or becoming serious) is incomplete, an imputation 
algorithm will be used to classify the AE as pretreatment, treatment-emergent, or post-treatment.  
The algorithm for imputing date of onset will be conservative and will classify an AE as treatment 
emergent unless there is definitive information to determine it is pretreatment or post-treatment.  
Details on classification of adverse events with missing or partial onset dates are provided  
in Section 2.5.3.  
Regarding treatment discontinuation, following definitions will be used: 
 Premature treatment discontinuation is defined when 1 of the IMPs is permanently 
discontinued, subjects will continue receiving the other IMP until study treatment 
permanent discontinuation. 
 Definitive treatment discontinuation is defined as the discontinuation of all the study 
drugs.  
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The severity grade will be taken into account in the summary. For patients with multiple 
occurrences of the same AE, the maximum (worst) severity grade by period of observation will be 
used. Summaries will be provided for all grades and for Grade ≥3 (including Grade 5). Missing 
grades handling is provided in Section 2.5.3.  
Sorting within tables should ensure the same presentation for the set of all AEs for each 
observation period (pre-treatment, treatment-emergent and post-treatment). For that purpose, 
tables of all TEAEs by SOC and PT will be sorted by the internationally agreed SOC order and 
decreasing frequency of PTs within SOCs. This order will define the presentation order for all 
other tables unless otherwise specified.  
Overall summary of TEAEs 
An overall summary of TEAEs will be provided.  The number (%) of patients who experience any 
of the following will be provided: 
 TEAE. 
 TEAE of Grade ≥3. 
 TEAE of Grade 5. 
 Serious TEAE. 
 Treatment-related TEAEs (any grade). 
 Treatment-related TEAEs of Grade ≥3. 
 Serious treatment-related TEAEs. 
 TEAE leading to definitive study treatment discontinuation. 
 TEAE leading to premature discontinuation of isatuximab. 
 TEAE leading to premature discontinuation of atezolizumab. 
 AESI. 
 AESI of Grade ≥3. 
Analysis of all TEAEs 
The number (%) of patients experiencing TEAEs by primary SOC and PT will be summarized by 
grade (all grades and Grade ≥3).  Similar tables will be presented for treatment-related TEAEs, 
serious TEAEs, and TEAEs leading to definitive/premature discontinuation. 
TEAEs with an incidence ≥5% will be summarized by PT for all grades and Grade ≥3.   
Listings of serious TEAEs, TEAEs leading to definitive or premature treatment discontinuation 
will be provided. 
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Infusion associated reactions (IARs) 
IAR analysis will include all adverse events regardless of relationship to isatuximab, atezolizumab 
or NIMP. The IARs will be summarized as follow: 
 Number (%) of patients experiencing IARs according to investigator reported AEs 
presented by primary SOC and PT will be summarized by grade. 
 Description of the IAR diagnoses (using the diagnosis reported and excluding symptoms). 
- 
Number (%) of patients action taken, 
- 
Number (%) of patients with only 1, ≥1, ≥2, ≥3, ≥4 and ≥5 episodes, 
- 
Number (%) of patients with first occurrence of IAR at the first infusion and 
subsequent infusions, 
- 
Number (%) of patients with IAR at the first and subsequent infusions, 
- 
Number (%) of patients with at least two episodes of IRs at the same infusion, 
- 
Day of onset from infusion, 
- 
Duration (in days). 
 Number of patients with symptoms of IARs (as reported by investigator) by SOC and PT. 
Analysis of adverse events of special interest 
A listing of patients with at least one AESI described in Section 2.1.4.2 will be provided.  
Analysis of pre-treatment and post-treatment adverse events  
The following analysis will be provided by grade (all grades and Grade ≥3).   
 All pre-treatment AEs by primary SOC and PT, showing the number (%) of patients with 
at least 1 pre-treatment AE, sorted by the internationally agreed SOC order and decreasing 
incidence of PTs within each SOC. 
 All post-treatment AEs by primary SOC and PT, showing the number (%) of patients with 
at least 1 post-treatment AE, sorted by the internationally agreed SOC order and 
decreasing incidence of PTs within each SOC. 
2.4.6.3 Deaths 
The following summaries of deaths will be generated: 
 Number (%) of patients who died by study period (on-treatment, post-treatment) and 
reasons for death (disease progression, AE, other). 
 TEAEs with fatal outcome (on the AE eCRF page as reported by the Investigator), TEAEs 
that started as non-fatal during treatment period but became fatal during post-treatment 
period, and TEAEs with fatal outcome during the post-treatment period summarized by 
SOC and PT. 
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2.4.6.4 Analyses of laboratory variables  
Each laboratory test result will be graded by CTCAE criteria (version 4.03), when applicable. For 
hematological parameters and for some biochemistry parameters, Sanofi sponsor generic normal 
ranges will be used for the grading of laboratory abnormalities (see list of parameters in Table 7 
and Table 8). For other biochemistry parameters (eg, for hepatic parameters), grading will be 
derived using the local laboratory normal ranges. 
The number (%) of patients with abnormal laboratory tests at baseline and during the on-treatment 
period will be presented by all grades and each grade. For patients with multiple occurrences of 
the same laboratory variable during the on-treatment period, 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.  
When appropriate, the summary table will present the frequency of patients with any grade of 
abnormal laboratory tests and with Grade 3-4 abnormal laboratory tests. 
2.4.6.5 Analyses of vital sign variables 
The incidence of vital signs potentially clinically significant abnormality (PCSA) (Table 5) any 
time during the on-treatment period will be summarized by treatment group irrespective of the 
baseline level and/or according to the following baseline status categories:  
 Normal/missing. 
 Abnormal according to PCSA criterion or criteria. 
Table 5 - Potentially clinically significant abnormalities criteria for vital signs 
Parameter 
PCSA 
HR 
≤50 bpm and decrease from baseline ≥20 bpm 
≥120 bpm and increase from baseline≥20 bpm 
SBP 
≤95 mmHg and decrease from baseline ≥20mmHg 
≥160 mmHg and increase from baseline ≥20 mmHg 
DBP 
≤45 mmHg and decrease from baseline ≥10 mmHg 
≥110 mmHg and increase from baseline ≥10 mmHg 
Weight 
≥5% increase from baseline  
≥5% decrease from baseline 
Temperature and respiratory rate will be summarized at baseline and end of treatment. A listing of 
patients with at least one PCSA will be provided. 
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2.4.6.6 Analyses of electrocardiogram variables 
A listing of patients with ECG results will be provided.  
2.4.6.7 Analysis of Immunogenicity 
Immunogenicity analysis will be done separately for isatuximab and atezolizumab.  
Number of evaluable patients, number (%) of pre-existing ADA and negative patients at baseline, 
number (%) of boosted and induced patients (either transient, persistent or indeterminate) will be 
reported, along with descriptive statistics of titer, by cohort and possibly overall. Prevalence and 
incidence will also be presented. 
In addition, for positive ADA patients, time to onset, duration of ADA response, and the 
characterization of the immune response (transient, persistent, indeterminate) will be provided.  
An individual data listing with ADA samples status (positive, negative or inconclusive), the titer if 
applicable, date of first/last dose, duration of exposure, study period, cycle/day, time point and 
date/time of sampling along with Ctrough value of the drug will be provided for all patients.  
The impact on safety and efficacy endpoints may be further explored by graphical methods or 
descriptively, depending on the ADA prevalence. 
2.4.7 Analyses of pharmacokinetic variables  
2.4.7.1 Cycle 1 non-compartmental analysis of isatuximab: following the 
1st administration 
Following the first administration, individual concentrations and PK parameters of drug will be 
listed and summarized by descriptive statistics (such as the number of observations, arithmetic and 
geometric mean, median, SD, SEM, CV%, minimum, and maximum) by cohort and overall. 
Individual and mean concentration profiles over time will be plotted by cohort and overall under 
the responsibility of Sanofi, Pharmacokinetic, Dynamic and Metabolism (PKDM), Translational 
Medicine and Early Development (TMED) department.  
2.4.7.2 Over treatment concentrations: Ctrough and Ceoi of isatuximab and atezolizumab  
Ctrough defined as a sample collected before dosing, in a time window of 6 to 8 days after the 
previous infusion for the QW administration and in a time window of 18 to 24 days after the 
previous infusion for the Q3W administration (always before administration) will be included in 
the descriptive analysis irrespectively of interruption of infusion. However Ctrough drawn outside 
time collection window described in the protocol PK flowchart or collected after a dose deviation 
higher than ±50% from intended dose will be excluded from the analyses.  
Ceoi (only for isatuximab) collected after a dose deviation higher than ±50% from intended dose 
will be excluded from the analyses. 
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Individual Ctrough and Ceoi (only for isatuximab) will be listed and summarized with same 
descriptive statistics as above by cohort and overall.  
Mean (±SE) of Ctrough and Ceoi (only for isatuximab) will be plotted over treatment phase by 
cohort and overall for isatuximab and for atezolizumab. 
Individual Ctrough ratio and Ceoi ratio (described in Table 6) will be listed and summarized by 
descriptive statistics by cohort and overall as described above.  
Table 6 - Ctrough and Ceoi ratio 
Analyte 
Ctrough 
Ceoi 
Isatuximab 
C2D1 vs C1D1 T168h 
C2D1 vs C1D1 
C4D1 vs C1D1 T168h 
C4D1 vs C1D1 
Atezolizumab 
C4D1 vs C2D1  
NA 
 
C8D1 vs C2D1 
NA 
NA = Not applicable. 
2.4.7.3 Immunogenicity impact on PK  
Immunogenicity impact on PK analysis may be explored, depending on the ADA prevalence.  
A descriptive statistics of Ctrough as described above will be provided at each cycle in the subset 
of negative patients by cohort and overall where positive or inconclusive patients will be 
observed.  
A graphical representation of individual Ctrough profile will be provided throughout the course of 
treatment by cohort and possibly overall where positive or inconclusive patients will be observed. 
Positive patients profile will be highlighted (eg, color or bold) and the concentration of isatuximab 
and atezolizumab at the same time as ADA positive result will be notified.  
2.4.7.4 Over treatment: population PK approach of isatuximab and atezolizumab  
In addition, populations PK approaches may be used for both compounds and PK estimates may 
be used to conduct exploratory exposure-response analyses for safety and efficacy and PK/PD 
analyses for relevant biomarkers. If done, the data generated will be reported in stand-alone 
report(s). 
These analyses, if applicable, will be described in the Population Analysis Plan (PAP) which will 
be issued separately from this Statistical Analysis Plan. 
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2.4.8 Analyses of biomarker variables  
The biomarker variables may be summarized by clinical group (eg, SD >6 months vs. others) and 
overall depending on availability of assessable tumor biopsy samples. Graphics will be provided 
as appropriate. The biomarker variables include, but not limited to, the following variables: 
 CD38 expression. 
 PDL1 expression. 
Additional biomarker analysis may be conducted in an exploratory manner. Additional analysis, 
not specified in the protocol but related to the drug action and/or effect of  
isatuximab/ Atezolizumab, may be conducted on remaining samples pending evolving literature. 
2.4.9 Analyses of quality of life/health economics variables 
Not applicable. 
2.4.10 Further therapy after discontinuation of investigational medicinal product 
administration during the study 
A listing of further therapy after discontinuation of investigational medicinal product 
administration during the study may be provided. 
2.5 
DATA HANDLING CONVENTIONS 
2.5.1 General conventions 
The following formulas will be used for computation of parameters. 
Estimated glomerular filtration (eGRF) using the equation of MDRD formula: 
American)
African 
 
if 
(1.212
 x 
Female)
 
if 
(0.742
 x 
(Age)
 x 
 
(Scr)
 x 
175
 
GFR
-0.203
-1.154

 
with serum creatinine in mg/dL and age in year. 
Corrected calcium formula: 
Corrected Calcium (mmol/L) = Serum Calcium (in mmol/L) + 0.8 (4 - serum albumin [in g/dL]) 
2.5.2 Data handling conventions for secondary efficacy variables 
Not applicable. 
2.5.3 Missing data 
The analyses and summaries of continuous and categorical variables will be based on observed 
data only. Percentages will be calculated using as denominator the number of patients with 
non-missing observation in the considered population. When relevant, the number of patients with 
missing data is presented. 
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When incomplete or missing dates were found in the eCRF, attempts were made to retrieve the 
complete date, especially for dates within the month prior to first dose. However, if some dates 
remain incomplete, the following rules will be applied: 
Handling of disease characteristics missing/partial dates 
 If the day is missing, it will be estimated by 1. 
 If the month is missing, it will be estimated by 1 (only for medical history variables). 
 If the year is missing, no estimation will be performed. 
Handling of medication missing/partial dates  
No imputation of medication (other than anti-cancer therapies) start/end dates or times will be 
performed. If a medication date or time is missing or partially missing and it cannot be determined 
whether it was taken prior or concomitantly, it will be considered a prior, concomitant, and 
post-treatment medication. 
For prior anti-cancer therapies, following rules will be applied: 
Missing/partial start date will be imputed as follows: 
 If year and month exist, day is missing, impute as the first day of the month. 
 If only year exists, month and day are missing, impute as the first day of the year. 
 If year, month, and day are all missing, no imputation will be applied. 
Missing/partial end date will be imputed in a two-step approach as follows: 
 Step 1: Use the following rule to impute end date: 
- 
If year and month exist, day is missing, impute as the first day of the month, 
- 
If only year exists, month and day are missing, impute as the first day of the year, 
- 
If year, month, and day are all missing, no imputation will be applied. 
 Step 2: If imputed end date is earlier than start date, set the imputed end date the same as 
start date. 
Imputation of incomplete date for post anti-cancer treatment start date  
For post anti-cancer treatments, if the medication start date is missing, it will be imputed as 
follows: 
 If the medication start day and month are missing and the medication start year is the same 
as treatment end year, the medication start date will be set equal to treatment end date + 1. 
 If the medication start day and month are missing and the medication start year is after the 
treatment end year, the medication start day and month will each be set to 01. 
 If the medication start day is missing and medication start year and month is the same as 
the treatment end year and month, the medication start day will be set equal to the 
treatment end day + 1. 
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 If the medication start day is missing and medication start month is before the treatment 
end month and the medication start year is the same as treatment end year, the medication 
start day will be set to 01. 
 If the medication start day is missing and the medication start month is after the treatment 
end month and the medication start year is the same as treatment end year, the medication 
start day will be set to 01. 
 If the medication start day is missing and the medication start month is not missing and the 
medication start year is after the treatment end year, the medication start day will be set to 
01. 
 If the medication start day, start month and start year is missing, the medication start date 
will be set equal to the treatment end date + 1. 
No imputation will be done for the missing/partial end date. 
Handling of adverse events with missing or partial date of onset 
Missing or partial adverse event onset dates (occurrence or becoming serious) will be imputed so 
that if the partial adverse event onset date information or visit number does not indicate that the 
adverse event started prior to treatment or after the treatment-emergent adverse event period, the 
adverse event will be classified as treatment-emergent. In case of AEs worsening during the study, 
the emergence will also be based on the cycle of worsening. No imputation of adverse event end 
dates will be performed. These data imputations are for categorization purpose only and will not 
be used in listings. No imputation is planned for date of adverse event resolution.   
Handling of death with missing or partial date of death 
The imputation for missing or partial death date will proceed as follows: 
 If the death day is missing and the death month and year are the same as the last month and 
year the patient was last known to be alive, the death day will be set equal to the last day 
the patient was known to be alive + 1. 
 If the death day is missing and the death month is after the month the patient was last 
known to be alive and the death year is the same as the year the patient was last known to 
be alive, the death day will be set to 01. 
 If the death day and month are missing and the death  year is the same as the year the 
patient was last known to be alive, the death date will be set equal to the date the patient 
was last known to be alive + 1. 
 If the death day and month are missing and the death year is after the year the patient was 
last known to be alive, the death day and month will both be set to 01. 
If the date the patient was last known to be alive is partial or missing, no imputation for missing or 
partial death date will be performed. The last date the patient was known to be alive is the last of: 
date of last dose, date of last visit performed (when the patient is known to be alive according to 
subject vital status), date of last laboratory assessment, and date of last vital signs. 
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Handling of AEs with missing grade 
If the grade is missing for one of the treatment emergent occurrences of an AE, the maximal 
severity on the remaining occurrences will be considered. If the severity is missing for all the 
occurrences, no imputation will be done and missing grades will be summarized in the “all 
grades” category. 
Handling of missing assessment of relationship of adverse events to investigational medicinal 
product  
If the assessment of the relationship to the regimen is missing, then the relationship to the regimen 
has to be assumed and the adverse event considered as such in the frequency tables of possibly 
related adverse events, but no imputation should be done at the data level. No imputation will be 
done for relationship to NMIP. 
Handling of parameters expressed as inequality or approximation 
For some parameters (such as laboratory parameters), if the value is expressed as “<xx”, “≤xx, 
half of the numeric portion of the entry or limit of quantification will be used in calculations. 
Handling of missing date/time in duration of infusion calculation 
When both atezolizumab and isatuximab are given to a patient on the same visit: 
 Missing atezolizumab end date/time will be imputed by isatuximab start date/time  
(if available). 
 Missing isatuximab start date/time will be imputed by atezolizumab end date/time  
(if available). 
Other types of missing date/time will not be imputed, and data will be excluded from the analysis 
of duration of infusion.  
Handling of other missing dates 
Incomplete date of cancer diagnosis:  
 If the day of the cancer diagnosis is missing, the date will be imputed to the first day of the 
month. 
 If day and month of the cancer diagnosis are missing, no imputation will be done. 
Incomplete date of progression for the last prior regimen:  
 If the day of the progression for the last prior regimen is missing, the date will be imputed 
to the end day of the month. 
 If day and month of the progression for the last prior regimen are missing, no imputation 
will be done. 
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Incomplete date of prior surgery:  
 If the day of the last prior surgery is missing, the date will be imputed to the end day of the 
month. 
 If day and month of the last prior surgery are missing, no imputation will be done. 
Incomplete date of prior radiotherapy: 
 If the day of the last prior radiotherapy is missing, the date will be imputed to the end day 
of the month. 
 If day and month of the last prior radiotherapy are missing, no imputation will be done. 
2.5.4 Windows for time points 
Laboratory data 
A protocol planned laboratory test is considered to have occurred during a cycle if the date of 
sampling is after (>) the first day of the cycle, but prior to or equal (≤) to the first day of the next 
cycle. For unscheduled tests, a test is considered to have occurred during a cycle if the date of 
sampling is equal to or after (≥) the first day of the cycle, but prior (<) to the first day of the next 
cycle. 
2.5.5 Unscheduled visits 
Unscheduled visit measurements of laboratory data, vital signs and ECG will be used for 
computation of worst values and/or grades on treatment. Unscheduled visits prior to first 
administration will be also used for computation of baseline except if they are not collected on the 
day of first administration. 
2.5.6 Pooling of centers for statistical analyses 
Data from all sites will be pooled together for analyses. 
2.5.7 Statistical technical issues 
Not applicable. 
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3 
INTERIM ANALYSIS 
An IA for each cohort will be performed for HCC, SCCHN, EOC, and GBM cohorts after the last 
participants remaining in the treatment period among the first 26, 26, 17 and 31 participants, 
respectively, in Phase 2 have completed approximately 6 months of study treatment or 
permanently discontinued both atezolizumab and isatuximab, whichever comes first. The IA may 
be conducted earlier if the required number of responses for proceeding to Phase 2 Stage 2 is 
achieved for HCC, SCCHN, and EOC cohorts. 
The analysis will include the following parameters/analyses (defined in Section 2.1): RR for 
patients with HCC or SCCHN or EOC, PFS-6 for patients with GBM, demographics and baseline 
characteristics, prior or concomitant medication, AEs (TEAE, death, SAE, TEAE leading to 
discontinuation, IAR, AESI), and laboratory variables (abnormality of hematological and 
chemistry test).  If needed, more data will be analyzed to inform the futility decision including 
additional efficacy, PK, and biomarker.  
 
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4 
DATABASE LOCK 
The database will be locked when clinical review of the database has been completed and all 
critical queries have been resolved. 
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5 
SOFTWARE DOCUMENTATION 
All summaries and statistical analyses will be generated using SAS® Version 9.4 or higher. 
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6 
REFERENCES 
1. Eisenhauer EA, Therasse P, Bogaerts J Schwartz LH, Sargent D, Ford R et al. New response 
evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer. 
2009;45:228-47. 
2. Wen PY, Macdonald DR, Reardon DA, Cloughesy TF, Sorensen AG, Galanis E et al. Updated 
Response Assessment Criteria for High-Grade Gliomas:  Response Assessment in Neuro-
Oncology Group. J Clin Oncol. 2010;28(11):1963-72. 
3. Seymour L, Bogaerts J, Perrone A, Ford R, Schwartz LH, Mandrekar S, et al. iRECIST: 
guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol. 
2017;18:e143-52. 
4. Okada H, Weller M, Huang R, Finocchiaro G, Gilbert M, Wick W et al. Immunotherapy 
Response Assessment in Neuro-Oncology (iRANO):  a report of the RANO working group. 
Lancel Oncol. 2015;16(15):e534-42. 
5. Alexander Kratz, Maryjane Ferraro, Patrick M. Sluss and Kent B. Lewandrowski, MD. 
Laboratory reference values. 
 
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7 
LIST OF APPENDICES 
 
Appendix A 
Generic ranges for hematological and biochemistry parameters 
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Appendix A 
Generic ranges for hematological and biochemistry parameters 
Table 7 - Generic ranges for hematological parameters 
Test 
Gender 
Unit 
Lower/Upper limit of normal 
Hemoglobin 
F 
g/L 
120 - 160 
Hemoglobin 
M 
g/L 
135 - 175 
Lymphocytes 
109/L 
1 - 2 
Neutrophils 
109/L 
1.8 - 3.15 
Platelets 
109/L 
150 - 350 
Leukocytes 
 
109/L 
4.5 - 11 
Eosinophils 
109/L 
0 - 0.4 
Basophils 
109/L 
0 - 0.15 
Monocytes 
109/L 
0.18 - 0.5 
Hematocrit 
M 
Ratio 
0.41 -0.53 
Hematocrit 
F 
Ratio 
0.36 - 0.46 
Erythrocytes 
F 
1012/L 
4 - 5.2 
Erythrocytes 
M 
1012/L 
4.5 -5.9 
INR 
 
ratio 
0.8 -1.2 
Based on Kratz et al. (5) 
Table 8 - Generic ranges for biochemistry parameters 
Test 
Unit 
Lower – Upper limit of normal 
Albumin 
g/L 
35 - 55 
BUN 
mmol/L 
3.6 - 7.1 
Calcium 
mmol/L 
2.2 - 2.6 
Chloride 
mmol/L 
80 - 115 
Corrected calcium 
mmol/L 
2.2 - 2.6 
Glucose 
mmol/L 
3.9 - 7 
Bicarbonate (HCO3) 
mmol/L 
22 - 29 
Carbon dioxide 
mmol/L 
21 - 30 
Potassium 
mmol/L 
3.5 - 5 
Magnesium 
mmol/L 
0.8 - 1.2 
Sodium 
mmol/L 
136 - 145 
Phosphate 
mmol/L 
1 - 1.4 
Protein 
g/L 
55 - 80 
Urea 
mmol/L 
3.6 - 7.1 
 
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