Clinical trial NCT03367819
Conditions: Prostate Cancer Non-small Cell Lung Cancer
Keywords: Anti-CD38 monoclonal antibody
Sponsor: Sanofi
Start date: 2018-01-04; Completion date: 2021-03-10
Enrollment: 44 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Primary Objectives:

* To characterize the safety and tolerability of isatuximab in combination with REGN2810 in participants with metastatic, castration-resistant prostate cancer (mCRPC) who were naïve to anti-programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1)-containing therapy, or non-small cell lung cancer (NSCLC) who progressed on anti-PD-1/PD-L1-containing therapy, and to confirm the recommended Phase 2 dose (RP2D).
* To assess the response rate of isatuximab in combination with REGN2810 in participants with either mCRPC who were anti-PD-1/PD-L1 therapy naive, or NSCLC who progressed on anti-PD-1/PD-L1 therapy, or of isatuximab as single agent in participants with mCRPC.

Secondary Objectives:

* To evaluate the safety of the combination of isatuximab with REGN2810 or isatuximab monotherapy.
* To evaluate the immunogenicity of isatuximab and REGN2810.
* To characterize the pharmacokinetic (PK) profile of isatuximab single agent or in combination with REGN2810, and to characterize the PK of REGN2810 in combination with isatuximab.
* To assess overall efficacy of isatuximab in combination with REGN2810 or as a single agent.

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

Arms: arm 1: Isatuximab dose 1 and REGN2810 predefined dose arm 2: Participants with mCRPC will be given isatuximab dose determined in Phase 1 arm of study and REGN2810 predefined dose arm 3: Participants with mCRPC will be given isatuximab dose 2 arm 4: Participants with NSCLC will be given isatuximab dose determined in Phase 1 arm of study and REGN2810 predefined dose arm 5: Isatuximab dose 3 will be given in combination with REGN2810 predefined dose or isatuximab dose 3 will be given as monotherapy in participants with mCRPC arm 6: Isatuximab dose 3 will be given in combination with REGN2810 predefined dose
Interventions: intervention 1: Isatuximab SAR650984 intervention 2: Cemiplimab REGN2810
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: 


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NAMES AND ADDRESSES OF  
COORDINATING 
INVESTIGATOR 
 
Name: 
Address: 
 
 
Tel: 
Fax: 
E-mail: 
 
 
MONITORING TEAM’S 
REPRESENTATIVE 
 
Name: 
Address: 
 
 
 
Tel: 
Fax: 
E-mail: 
 
 
SPONSOR 
 
Company: 
Address: 
 
 
 
Tel: 
Fax: 
 
 
OTHER EMERGENCY 
TELEPHONE NUMBERS 
 
 
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE  
DOCUMENT HISTORY 
Document 
Country/countries 
impacted by 
amendment 
Date, Version 
Amended Clinical Trial Protocol 05 
All 
11-Jun-2019, Version 1 (electronic 1.0) 
Amended Clinical Trial Protocol 04 
All 
21-Nov-2018, Version 1 (electronic 1.0) 
Amended Clinical Trial Protocol 03 
All except UK 
23-Jul-2018, Version 1 (electronic 3.0) 
Amended Clinical Trial Protocol 04 (UK) 
UK 
23-Jul-2018, Version 1 (electronic 3.0) 
Protocol Amendment 04 
All 
23-Jul-2018, Version 1 (electronic 1.0) 
Amended Clinical Trial Protocol 02 
All except UK 
02-Apr-2018, Version 1 (electronic 2.0) 
Amended Clinical Trial Protocol 03 (UK) 
UK 
02-Apr-2018, Version 1 (electronic 2.0) 
Protocol Amendment 03 
All except UK 
02-Apr-2018, Version 1 (electronic 1.0) 
Amended Clinical Trial Protocol 02 (UK)  
UK 
03-Nov-2017, Version 1 (electronic 1.0) 
Protocol Amendment 02 (UK) 
UK 
03-Nov-2017, Version 1 (electronic 1.0) 
Amended Clinical Trial Protocol 01 
All 
05-Oct-2017, Version 1 (electronic 1.0) 
Protocol Amendment 01 
All 
05-Oct-2017, Version 1 (electronic 1.0) 
Clinical Trial Protocol 
All 
05-Sep-2017, Version 1 (electronic 1.0) 
 
Amended Protocol 05 (11 June 2019) 
This amended protocol (amendment 05) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
OVERALL RATIONALE FOR THE AMENDMENT 
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 
(i.e. 5 months), a revised duration of contraceptive measures of 6 months after the last study 
treatment is included to align with the REGN2810 requirement for operational simplicity.  
 
 
 
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Section # and Name 
Description of Change 
Brief Rationale 
1.3 & 1.4 Study Flowchart; 
and 12.5 Post treatment 
follow-up 
Pregnancy test is extended to monthly until 6 months 
after last dose of study treatment. 
Monthly pregnancy test is 
implemented until end of the 
extended contraception period. 
4.3.2 Schedule and dose of 
administration 
Re-estimation of isatuximab half-life of 28 days is 
included. 
Based on updated pharmacokinetic 
characterization of isatuximab. 
8.9.2 Contraceptive 
measures and pregnancy 
counseling 
Contraceptive measures are required to extend to 6 
months following the last dose of study treatment. 
5 months of contraception period 
after last dose of isatuximab is 
required based on updated 
pharmacokinetic analysis.  For 
operational simplicity and to be 
consistent with exclusion criterion 
E21, patients are required to 
maintain contraceptive measures up 
to 6 months after last dose of study 
treatment (aligned with requirement 
for REGN2810).  
 
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CLINICAL TRIAL SUMMARY  
COMPOUND: isatuximab 
(SAR650984) 
STUDY No: ACT15319 
TITLE 
A Phase 1/2 open-label, multi-center, safety, preliminary efficacy and 
pharmacokinetic (PK) study of isatuximab (SAR650984) in combination with 
REGN2810, or isatuximab alone, in patients with advanced malignancies 
INVESTIGATOR/TRIAL LOCATION 
Worldwide 
PHASE OF DEVELOPMENT 
Phase 1/2 
STUDY OBJECTIVE(S) 
 
Primary objective 
Phase 1 part: 
 
To characterize the safety and tolerability of isatuximab in 
combination with REGN2810 (cemiplimab) in patients with 
metastatic, castration resistant prostate cancer (mCRPC) who are 
naïve to anti-programmed cell death-1 (PD-1)/programmed cell 
death-ligand 1 (PD-L1)-containing therapy, or non-small cell lung 
cancer (NSCLC) who progressed on anti-PD-1/PD-L1-containing 
therapy, and to confirm the recommended Phase 2 dose (RP2D). 
Phase 2 part (applicable to Cohorts A-1, A-2, B, C, and D): 
 
To assess the response rate (RR) of isatuximab in combination with 
REGN2810 in patients with either mCRPC who are 
anti-PD-1/PD-L1 therapy-naïve, or NSCLC who progressed on 
anti-PD-1/PD-L1 therapy, or of isatuximab as single agent in 
patients with mCRPC. 
Secondary objectives 
 
To evaluate the safety of the combination of isatuximab with 
REGN2810 or isatuximab monotherapy. 
 
To evaluate the immunogenicity of isatuximab and REGN2810. 
 
To characterize the PK profile of isatuximab single agent or in 
combination with REGN2810, and to characterize the PK of 
REGN2810 in combination with isatuximab. 
 
To assess overall efficacy of isatuximab in combination with 
REGN2810 or single agent (tumor burden change, duration of 
response [DOR], disease control rate [DCR], and progression-free 
survival [PFS]). 
Exploratory objectives 
 
To explore the preliminary overall efficacy: Overall survival (OS), 
Time to response (TTR); for patients with mCRPC: prostate-specific 
antigen (PSA) RR, radiographic RR, duration of PSA response, 
duration of radiographic response, time to PSA response, time to 
radiographic response and time to PSA progression. 
 
To explore the preliminary overall efficacy of isatuximab in 
combination with REGN2810 in patients with mCRPC who progress 
on isatuximab monotherapy. 
 
To explore the relationship between clinical response and cluster of 
differentiation 38 (CD38) expression, PD-L1 expression and more 
broadly immune markers in tumor biopsy at baseline as potential 
predictive markers of response. 
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 
To explore tumor genetic markers at baseline including tumor 
mutational load and microsatellite instability (MSI) status as 
potential markers of response to anti-PD-1 therapy. 
 
To explore immune genetic markers in blood at baseline such as 
polymorphisms in FcγR receptors which are important for effector 
functions of isatuximab. 
 
To evaluate pharmacodynamic biomarkers in response to 
investigational medicinal product (IMP): immunophenotype to 
analyze the modulation of different immune cell populations in 
peripheral blood, immune markers in tumor, transcriptomic analysis 
in tumor and plasma or serum cytokine levels. 
 
A panel of tumor somatic mutations (ie, tumor mutational profile) will 
be analyzed at baseline and upon treatment in blood to explore 
potential mechanisms of escape in response to treatment. 
 
To perform PK/pharmacodynamics analysis if possible with any 
relevant pharmacodynamics markers mentioned above, and 
correlation with safety/efficacy endpoints. 
STUDY DESIGN 
This is a Phase 1/2 open-label, non-comparative, multi-center, safety, 
preliminary efficacy and PK study of isatuximab in combination with 
REGN2810 or isatuximab alone in patients with advanced malignancies. 
The study will be conducted in 3 parts: 
Phase 1 part (safety run-in): 
Patients with either mCRPC or NSCLC will be enrolled in the Phase 1 part. 
Starting dose is 350 mg Q3W for REGN2810 with isatuximab given 10 mg/kg 
once weekly (QW) for 3 weeks followed by once every 3 weeks (Q3W). Overall 
safety monitoring will be performed throughout the conduct of the study. 
Dose modification for Phase 1 part 
Dose level 
(DL) 
Isatuximab 
REGN2810 
Starting dose 
10 mg/kg 
QW × 3 ->Q3W 
350 mg 
Q3W 
Minus -1 
(DL-1) 
5 mg/kg 
QW × 3 ->Q3W 
350 mg 
Q3W 
The dose limiting toxicity (DLT) observation period is 1 cycle (21 days). All the 
adverse events (AEs) occurring during treatment, unless due to disease 
progression or  to a cause obviously unrelated to IMP, will be taken into 
consideration by the Sponsor and recruiting Investigators for the 
determination of the maximum tolerated dose and RP2D for the isatuximab 
and REGN2810 combination. 
At starting dose, DLTs will be assessed in the first 6 patients (1 cycle, 
21 days): 
 
If ≤1/6 patient has DLT, the starting dose will be the RP2D. 
 
If 2/6 patients have DLT, 6 additional patients will be enrolled at 
starting dose level: 
- 
If a total of 2/12 patients treated at starting dose have DLT, 
starting dose will be the RP2D. 
- 
If a total of ≥3/12 patients have DLT, dose will be  
de-escalated to dose level minus 1 (DL-1). 
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 
If ≥3/6 patients have DLT, dose will be de-escalated to DL-1. 
An additional 6 patients may be enrolled at DL-1: 
 
If ≤1/6 patient has DLT, DL-1 will be the RP2D. 
 
If 2/6 patients have DLT, 6 additional patients will be enrolled at 
DL-1: 
- 
If a total of 2/12 patients treated at DL-1 have DLT, DL-1 will 
be the RP2D. 
- 
If a total of ≥3/12 patients have DLT, an alternative 
dose/schedule might be considered from a safety viewpoint 
by the Sponsor after consulting with the Investigators who 
recruit patients for the Phase 1 part. 
IMP initiation in the Phase 1 part is to be staggered by at least 3 days. 
Following the identification of the RP2D, the Phase 2 part of the study will be 
initiated. 
The National Cancer Institute (NCI) common terminology criteria for adverse 
events (CTCAE) version 4.03 will be used to assess the severity of AEs. 
Causal relationships are to be determined by the Investigator. The DLTs will 
be confirmed by the Sponsor and recruiting Investigators. 
Dose limiting toxicity is defined as: 
All AEs specified below occurring during the first cycle of treatment, unless 
due to disease progression or to a cause obviously unrelated to IMP. The 
duration of the DLT observation period will be longer for patients 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. 
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 to 4 thrombocytopenia associated with clinically significant 
bleeding requiring clinical intervention. 
Non-hematological abnormalities 
 
Grade 4 non-hematologic AE. 
 
Grade ≥2 uveitis. 
 
Grade 3 non-hematological AE lasting >3 days despite optimal 
supportive care, except: 
- 
Grade 3 fatigue. 
- 
Allergic reaction/hypersensitivity attributed to isatuximab or 
REGN2810. 
- 
A Grade 3 or 4 laboratory abnormality that is not clinically 
significant per recruiting Investigators and Sponsor. 
 
Delay in initiation of Cycle 2 more than 14 days due to 
treatment-related laboratory abnormalities/AE. 
 
In addition, any other AE that the recruiting Investigators and 
Sponsor deem to be dose limiting, regardless of its grade, may also 
be considered as DLT. 
 
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Phase 2 part (efficacy signal search with Simon’s 2-stage design): 
The Phase 2 part may include up to 5 cohorts: 
Cohort A-1: mCRPC, isatuximab and REGN2810 combination therapy. 
Cohort A-2: mCRPC, isatuximab monotherapy. 
Cohort B: NSCLC, isatuximab and REGN2810 combination therapy. 
Possibly Cohort C: mCRPC, isatuximab and REGN2810 combination 
therapy, or isatuximab monotherapy without initial isatuximab weekly dosing. 
Possibly Cohort D: NSCLC, isatuximab and REGN2810 combination 
therapy without initial isatuximab weekly dosing. 
A Simon’s 2-stage design will be used in each cohort. Enrollment in Cohort 
A-2 will start only if the decision to proceed to Stage 2 in Cohort A-1 is made. 
The patients treated at the RP2D of isatuximab and REGN2810 in 
combination during Phase 1 will be included in the efficacy analysis together 
with patients of the same tumor type in Stage 1 of Phase 2. Based on the 
number of objective responses (observed at least 6 cycles after the last 
ongoing patient receives first dose of IMP) 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 
Investigators. 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. 
For patients with mCRPC, if it is decided to run Phase 2 Stage 2, an isatuximab 
monotherapy cohort will be initiated (Cohort A-2); patients with mCRPC will be 
randomly assigned in a 1:1 randomization ratio to Cohort A-1, isatuximab and 
REGN2810 combination therapy (Phase 2 Stage 2) or Cohort A-2, isatuximab 
monotherapy (Phase 2 Stage 1). The isatuximab single agent dose and 
schedule for cohort A-2 is 10 mg/kg QW for 3 weeks followed by Q3W. 
Based on the positive efficacy signal and the totality of data observed at the 
end of Phase 2 Stage 2, the Sponsor may decide to further study isatuximab 
10 mg/kg Q3W in combination with REGN2810 or isatuximab 10 mg/kg Q3W 
as monotherapy in patients with mCRPC (Cohort C) or isatuximab 10 mg/kg 
Q3W in combination with REGN2810 in patients with NSCLC (Cohort D). The 
schedule without the initial weekly dosing may be more practical for patients 
and health care providers. Objectives and study design considerations for 
Cohort C and Cohort D are the same as those for other cohorts in the same 
tumor type, respectively. The Sponsor may decide to test an isatuximab dose 
of 20 mg/kg in case of inadequate efficacy and PK results. 
Cross-over part (a subpart of Cohort A-2): 
Patients from Cohort A-2 who progress on isatuximab monotherapy may 
receive isatuximab plus REGN2810 if they still fulfill the eligibility criteria 
(except exclusion criteria #3 and #8). 
STUDY POPULATION  
Main selection criteria 
Main selection criteria 
Inclusion criteria: 
I 01. 
Signed written informed consent. 
I 02. 
≥18 years of age. 
I 03. 
Disease location amenable to mandatory tumor biopsy at baseline 
(unless clinically unfeasible* as per the Investigator and after 
obtaining written agreement from Sponsor representative, only for 
NSCLC cohort), and possibly at Cycle 2 Day 1. Fine needle 
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aspirates are not acceptable. Availability of a tissue specimen from 
core 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. *Clinically 
unfeasible: With a written opinion from the Investigator that 
performing a biopsy will put the wellbeing of the subject at an 
excessive risk due to the location of the lesion. 
I 04. 
Based on the Investigator’s judgment, at this time, chemotherapy is 
not the best treatment option for this specific patient. The eligibility 
of patient to take part in the study will be validated at the 
multidisciplinary collegial meeting in countries listed in Appendix I. 
For mCRPC patients (I05 to I11): 
I 05. 
Histologically confirmed adenocarcinoma of the prostate (excluding 
neuroendocrine differentiation and/or small cell features). 
I 06. 
Metastatic disease documented by bone lesion on bone scan, or by 
measurable soft tissue disease by computed tomography (CT) or 
magnetic resonance imaging (MRI). Patients whose disease spread 
is limited to regional pelvic lymph nodes are not eligible. 
I 07. 
Surgically or medically castrated, with testosterone levels of 
<50 ng/dL (<2.0 nM). Patients who have not had a bilateral 
orchiectomy must have started androgen deprivation therapy with 
gonadotropin-releasing hormone (GnRH) analogue ≥4 weeks prior 
to initiation of IMP and continue such therapy throughout the study. 
I 08. 
At least 1 but no more than 2 previous androgen receptor-targeted 
agents (abiraterone and enzalutamide). 
I 09. 
Received up to 2 previous taxane-based chemotherapy regimens as 
per local standard of care (for example, docetaxel followed by 
cabazitaxel), unless per investigator’s judgement a chemotherapy 
regimen is not appropriate for the specific patient. If the same 
taxane-based chemotherapy is used more than once, this will be 
considered as 1 regimen. 
I 10. 
No previous radium 223. 
I 11. 
Documentation of progressive disease (PD) as assessed by the 
Investigator with at least 1 of the following within 6 months prior to 
first dose of IMP per Prostate Cancer Clinical Trials Working 
Group 3 (PCWG3) criteria during or following the direct prior line of 
therapy: 
 
PSA progression defined by a minimum of 2 rising PSA levels with 
an interval of ≥1 week between each determination. The PSA value 
at the Screening visit should be ≥1 μg/L (1 ng/mL) if confirmed rise 
is the only indication of progression. Patients on systemic 
glucocorticoids for control of symptoms must have documented 
PSA progression while on systemic glucocorticoids before initiation 
of IMP. 
 
Radiographic progression of soft tissue disease by modified 
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 per 
PCWG3 recommendation. Previously normal (<1.0 cm) lymph 
nodes must have grown by ≥5 mm in the short axis from baseline or 
nadir and be ≥1.0 cm in the short axis to be considered to have 
progressed. If the node progresses to ≥1.5 cm in the short axis, it is 
measurable; nodes that have progressed to 1.0 cm to <1.5 cm are 
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pathologic, subject to clinical discretion, and are nonmeasurable. 
For existing pathologic adenopathy and other soft tissue disease, 
progression is defined per RECIST 1.1. 
 
Progression of bone metastasis is defined as 2 or more 
documented new bone lesions on a bone scan. Confirmation of 
ambiguous results by other imaging modalities (eg, CT or MRI) is 
obligatory if metastatic disease to bone is only defined by bone 
scan. 
For NSCLC patients (I12 to I16) : 
I 12. 
Histologically or cytologically confirmed diagnosis of Stage IIIB/IV or 
inoperable recurrent NSCLC. 
I 13. 
At least 1 measurable lesion per RECIST 1.1 criteria. Target lesions 
may be located in a previously irradiated field if there is documented 
radiographic disease progression in that site. 
I 14. 
One previous anti-PD-1/PD-L1 (nivolumab, pembrolizumab, 
atezolizumab, durvalumab, avelumab, or REGN2810) containing 
regimen as the most recent prior therapy to treat Stage IIIB/IV or 
inoperable recurrent NSCLC. An anti-PD-1/PD-L1 containing 
regimen is defined as either an anti-PD-1/PD-L1 monotherapy, or an 
anti-PD-1/PD-L1 agent administered in the same cycle as another 
systemic therapy. 
I 15. 
No more than 1 previous chemotherapy regimen to treat 
Stage IIIB/IV or inoperable recurrent NSCLC. 
I 16. 
Documentation of benefit (defined as complete response [CR], 
partial response [PR] or stable disease [SD] at ≥1 radiographic 
imaging scan) but subsequent progression per RECIST 1.1 during 
the anti-PD-1/PD-L1 containing regimen within 4 months prior to 
initiation of IMP. The site’s study team must have reviewed previous 
tumor assessments(including screening tumor imaging) to 
determine that radiographic progression has occurred per RECIST 
1.1 following initiation of the anti-PD-1/PD-L1 containing regimen. 
Exclusion criteria: 
E 01. 
Eastern Cooperative Oncology Group (ECOG) performance status 
of ≥2. 
E 02. 
Predicted life expectancy <3 months. 
E 03. 
Prior treatment with an agent (approved or investigational) that 
blocks CD38 (patients who joined a study with an anti-CD38 but 
have written confirmation they were on control arm are allowed). 
E 04. 
For patients with mCRPC, prior treatment with an agent (approved 
or investigational) that blocks the PD-1/PD-L1 pathway (patients 
who joined a study with an anti-PD-1/PD-L1 but have written 
confirmation they were on control arm are allowed). 
E 05. 
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 or 
other imaging modality 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 allowed. 
E 06. 
Symptomatic or impending cord compression. 
E 07. 
Prior solid organ or hematologic transplant. 
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E 08. 
Last dose of prior investigational agent within 28 days from 
initiation of IMP. 
E 09. 
Treatment-related immune-mediated (or immune-related) AEs 
from immune-modulatory agents (including but not limited to 
anti-PD-1/PD-L1 agents, anti-cytotoxic T-lymphocyte-associated 
protein 4 monoclonal antibodies, and PI3K δ inhibitors) that 
caused permanent discontinuation of the agent, or that were 
Grade 3 or 4 in severity, or that have not resolved to baseline at 
least 3 months prior to initiation of IMP. For other agents, 
treatment-related immune-mediated (or immune-related) AEs that 
were Grade 2 or above. 
E 10. 
Prior intravenous (IV) cytotoxic chemotherapy, antineoplastic 
biological therapy, major surgery, local prostatic intervention within 
21 days prior to initiation of IMP; oral cytotoxic chemotherapy, 
hormonal therapy, tyrosine kinase inhibitor therapy, or completed 
palliative radiotherapy within 14 days prior to initiation of IMP. 
E 11. 
Denosumab or bisphosphonate therapy initiation or dose/regimen 
adjustment within 28 days prior to initiation of IMP. Patients on a 
stable regimen are eligible and may continue their therapy without 
change. 
E 12. 
Comorbidity requiring corticosteroid therapy (>10 mg 
prednisone/day or equivalent) within 14 days of IMP initiation. 
Physiologic replacement doses are allowed even if they are 
>10 mg of prednisone/day or equivalent, as long as they are not 
being administered for immunosuppressive intent. Inhaled or 
topical steroids are permitted, provided that they are not for 
treatment of an autoimmune disorder. 
E 13. 
Significant cardiac dysfunction, New York Heart Association 
classification for chronic heart failure III-IV, symptomatic coronary 
artery disease, major clinically significant electrocardiogram (ECG) 
abnormality, significant ventricular arrhythmias; myocardial 
infarction within 6 months; unstable or poorly controlled angina 
pectoris. 
E 14. 
Ongoing AEs (excluding alopecia and fatigue) caused by any prior 
anti-cancer therapy ≥Grade 2 (NCI-CTCAE version 4.03). 
E 15. 
Active, known, or suspected autoimmune disease that has 
required systemic treatment in the past 2 years (ie, with use of 
disease modifying agents, corticosteroids or immunosuppressive 
drugs), except for replacement therapy (eg, thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or 
pituitary insufficiency, etc). 
E 16. 
History of or current interstitial lung disease or pneumonitis that 
requires oral or IV glucocorticoids to assist with management 
(radiation pneumonitis in the radiation field is permitted); history of 
thoracic radiation therapy of >30 Gy within 6 months of the first 
dose of trial treatment. 
E 17. 
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 18. 
Known uncontrolled infection with human immunodeficiency virus, 
known uncontrolled hepatitis B infection, active tuberculosis, or 
severe infection requiring parenteral antibiotic treatment. To 
control HBV infection, patients with positive HBsAg should have 
started anti-HBV therapy before initiation of IMP, and the 
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screening HBV viral load should be <2000 IU/mL (104 copies/mL).  
The anti-HBV therapy should continue throughout the treatment 
period. 
E 19. 
Known second malignancy either progressing or requiring active 
treatment within the last 3 years (except for basal cell carcinoma 
of the skin, squamous cell carcinoma of the skin, or in situ cervical 
cancer that has undergone potentially curative therapy). 
E 20. 
Inadequate organ and bone marrow function at the Screening visit: 
 
Absolute neutrophil count <1500 /uL (1.5 × 109/L). 
 
Platelets <100 × 10³ u/L (after at least 3 days without platelet 
transfusion). 
 
Hemoglobin <9 g/dL or <5.6 mmol/L (without transfusions within 
2 weeks of initiation of IMP). 
 
Total bilirubin >2 upper limit of normal (ULN). 
 
Aspartate aminotransferase and/or alanine aminotransferase 
>3 × ULN (or >5 × ULN for patients with liver metastases). 
 
Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 
(Modified Diet in Renal Disease Formula). 
E 21. 
Women of reproductive potential and male subjects with female 
partners of childbearing potential who are not willing to avoid 
pregnancy 2 weeks before and during the study treatment period 
and for 6 months following discontinuation of study treatment by 
using effective contraceptive methods such as: 
 
Diaphragm and spermicide PLUS male condom, or 
 
Intrauterine device PLUS male condom, or 
 
Medical method (such as hormonal contraceptive) PLUS male 
condom. 
 
A woman of productive potential is a woman who: 1) has achieved 
menarche at some time point, 2) has not undergone a hysterectomy 
or bilateral oophorectomy or 3) has not been naturally 
postmenopausal (amenorrhea following cancer therapy does not 
rule out childbearing potential) for at least 24 consecutive months 
(ie, has had menses at any time in the preceding 24 consecutive 
months). The choice of effective method is left to Investigator 
judgment, in accordance to local regulation. Sterilized or infertile 
subjects are exempted from the requirement to use of 
contraception. In order to be considered sterilized or infertile, 
subjects must have undergone surgical sterilization 
(vasectomy/bilateral tubectomy, hysterectomy, bilateral 
ovariectomy) or be a postmenopausal woman defined as 12 months 
or more with no menses prior to enrollment and 50 years of age. 
True abstinence is acceptable when this is in line with the preferred 
and usual lifestyle of the patient. Periodic abstinence (eg, calendar, 
ovulation, symptothermal, postovulation methods) and withdrawal 
are not acceptable methods of contraception. 
E 22. 
Pregnant or breastfeeding woman or woman who intends to 
become pregnant during the participation in the study. 
E 23. 
Known intolerance or hypersensitivity to any component of 
isatuximab and/or REGN2810. 
E 24. 
History or current evidence of any condition, therapy, or laboratory 
abnormality that might confound the results of the trial, interfere 
with the subject’s participation for the full duration of the trial, or is 
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not in the best interest of the subject to participate, in the opinion 
of the treating Investigator. 
E 25. 
Patients who will receive REGN2810: prior treatment with 
idelalisib. 
E 26. 
Known epidermal growth factor receptor (EGFR) sensitizing 
mutation, anaplastic lymphoma kinase (ALK) rearrangement, 
ROS1 rearrangement, or BRAF mutation for patients with  
non-squamous NSCLC. 
Re-screening once is allowed. 
Total expected number of patients 
In the Phase 1 part, approximately 6 (assuming 6 patients for the starting 
dose) to 24 (assuming 12 patients for the starting dose plus 12 patients for 
DL-1) DLT evaluable patients are expected to be enrolled. The actual sample 
size will vary depending on DLTs observed and the number of dose levels 
explored. 
In the Phase 2 part, approximately 134 patients are expected to be enrolled 
(assuming Cohort A-1, A-2 and B complete 2 stages), including approximately 
66 patients in Phase 2 Stage 1 and approximately 68 patients in 
Phase 2 Stage 2. The patients who are treated with RP2D in the Phase 1 part 
will be counted as Phase 2 part patients. If isatuximab 10 mg/kg Q3W in 
combination with REGN2810 or as monotherapy without the isatuximab 
10mg/kg QW for 3 weeks is to be tested in a mCRPC or NSCLC cohort, 49 or 
36 additional patients will be needed, respectively. 
Expected number of sites: 
Approximately 15 sites worldwide 
STUDY TREATMENT(s) 
 
Investigational medicinal 
product(s) 
Isatuximab (SAR650984) in combination with REGN2810 or alone 
Formulation 
Isatuximab: Drug product concentrated solution for infusion 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. 
REGN2810: Drug product concentrated solution 50 mg/mL in 10 mL vials with 
5.0 mL withdrawable, containing 10 mM histidine, 5% (w/v) sucrose, 
1.5% (w/v) L-proline, and 0.2% (w/v) polysorbate 80, pH 6.0. 
Route(s) of administration 
Isatuximab: IV infusion 
REGN2810: IV infusion 
Dose regimen 
Phase 1 part 
Starting dose: 
 
Isatuximab: 10 mg/kg weekly for 3 weeks (QW × 3), then every 
3 weeks (Q3W) (ie, on Day 1 of each 21-day cycle). 
 
REGN2810 (administrated before isatuximab): 350 mg Q3W,  
(ie, on Day 1 of each 21-day cycle). 
Dose -1 (may be implemented if 2/6 patients with DLT and then ≥3/12 with 
DLT or if ≥3/6 patients with DLT at starting dose): 
 
Isatuximab: 5 mg/kg QW × 3, then Q3W. 
 
REGN2810 (administrated before isatuximab): 350 mg Q3W. 
Phase 2 part 
Combination dose for the Phase 2 part will be determined based on safety 
data from the Phase 1 part. Monotherapy dose for the Phase 2 part will be the 
isatuximab RP2D. 
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Cross-over part 
The combination dose for the cross-over part is RP2D. 
Cohort C (may be implemented in the Phase 2 part if positive results are 
observed in mCRPC Cohort A-1 or Cohort A-2 Phase 2 Stage 2): 
 
Combination RP2D without initial isatuximab weekly dosing, OR 
 
Isatuximab 10 mg/kg Q3W. 
Cohort D (may be implemented in the Phase 2 part if positive results are 
observed in NSCLC Cohort B Phase 2 Stage 2): 
 
Combination RP2D without initial isatuximab weekly dosing. 
 
For the combination cohorts, REGN2810 will be administered first 
followed by isatuximab on Day 1 of each cycle. 
Noninvestigational medicinal 
product(s) 
 
 
All patients will receive following premedications to prevent or reduce 
infusion-associated reactions (IARs), 30 to 60 minutes prior to isatuximab 
infusion (no longer than 60 minutes). . Criteria for optional premedication for 
IARs 
 
If a patient develops 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. 
Formulation 
 
Acetaminophen (paracetamol) 650 to 1000 mg oral route. 
 
Ranitidine 50 mg IV or equivalent (other approved H2 antagonists 
[eg, cimetidine], oral proton pump inhibitors [eg, omeprazole, 
esomeprazole]). 
 
Diphenhydramine 25 to 50 mg IV or equivalent (eg, cetirizine, 
promethazine, dexchlorpheniramine according to local approval and 
availability. Intravenous route is preferred for at least the first 
4 infusions). 
 
Methylprednisolone 100 mg IV or equivalent. 
 
Montelukast 10 mg orally or equivalent 
(Non-investigational products will be locally sourced and formulations may 
vary). 
Route(s) of administration 
See above 
Dose regimen 
 
 
Premedications will be administered 30 to 60 minutes prior to isatuximab 
infusion (no more than 60 minutes prior). 
When isatuximab and REGN2810 are to be administrated on the same day, 
the administration sequence is: premedications, followed by REGN2810, 
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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ENDPOINT(S) 
 
Primary endpoint: 
Phase 1 part: 
Safety and tolerability will be assessed based on DLTs (in Cycle 1), 
AEs/serious adverse events (SAEs), DLTs, and laboratory abnormalities. 
Phase 2 part: 
RR (for the definition, please refer to “Response evaluation definition for 
the primary efficacy endpoint” below). 
Secondary endpoints: 
 
Safety and tolerability will be assessed based on AEs/SAEs and 
laboratory abnormalities. 
 
Immunogenicity: Anti-drug antibody (ADA) against isatuximab and 
against REGN2810. 
 
PK evaluation using non-compartmental analysis for both 
compounds using serum concentrations for REGN2810 and plasma 
concentrations for isatuximab (except cross-over part). 
 
Preliminary overall efficacy: Tumor burden change, DOR, DCR, and 
PFS. 
Exploratory endpoints: 
 
For patients with mCRPC and patients with NSCLC, the following 
endpoints will be summarized: 
- 
OS and TTR. 
 
For patients with NSCLC, the following endpoint will be 
summarized: 
- 
Objective response rate (ORR) by modified Response 
Evaluation Criteria in Solid Tumors for immune-based 
therapies (iRECIST). 
 
For patients with mCRPC, the following endpoints will be 
summarized: 
- 
PSA response rate: PSA response is defined as a ≥50% 
decline from baseline and this decline must be confirmed to be 
sustained by a second PSA value obtained 4 or more weeks 
later. 
- 
Radiographic response rate. 
- 
Duration of PSA response. 
- 
Duration of radiographic response. 
- 
Time to PSA response. 
- 
Time to radiographic response. 
- 
Time to PSA progression. 
 
Preliminary overall efficacy of isatuximab in combination with 
REGN2810 in patients with mCRPC who progress on isatuximab 
monotherapy. 
 
To explore 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 as potential predictive markers of response. 
 
To explore tumor and immune genetic markers at baseline: tumor 
mutational load and MSI status in tumor as well as tumor mutational 
profile and immune genetic determinants in blood. 
 
To evaluate pharmacodynamic biomarkers in response to IMP: 
immunophenotype in peripheral blood, immune contexture in tumor 
and plasma or serum cytokine levels. 
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 
A panel of tumor somatic mutations (ie, tumor mutational profile) will 
be analyzed at baseline and upon treatment in plasma cell free 
DNA from peripheral blood. 
 
Determination of exposure-response relationships with efficacy, 
safety, and biomarkers, if possible. 
Response evaluation definition for the primary efficacy endpoint: 
 
In NSCLC: assessed and objective responses are confirmed by 
Investigators using RECIST 1.1. 
 
In mCRPC: response will be defined per PCWG3 criteria on the 
basis of the following outcomes (if any of these occur, patients will 
be considered to have responded): 
- 
Radiographic objective response assessed and confirmed by 
the Investigators. 
- 
PSA decline of ≥50% (confirmed by a second PSA test). 
ASSESSMENT SCHEDULE 
Please see Section 1.3 and Section 1.4 (study flowcharts) and Section 1.5 
(PK/pharmacodynamics flowcharts) for additional details. 
STATISTICAL CONSIDERATIONS 
 
Determination of the sample size 
Phase 1 part 
Approximately 6 (assuming 6 patients for the starting dose) to 24 (assuming  
12 patients for the starting dose plus 12 patients for DL-1) DLT evaluable 
patients are expected to be enrolled. The actual sample size will vary depending 
on DLTs observed and the number of dose levels explored. Patients who are 
not evaluable for DLT assessment in the Phase 1 part may be replaced. 
Phase 2 part 
The Phase 2 part of the study is to evaluate initial anti-tumor activity based on 
tumor response using RECIST 1.1 criteria for NSCLC and PCWG3 criteria for 
mCRPC. The efficacy evaluation is based on Simon’s 2-stage design with 
90% power at 5% 1-sided alpha level for each of the patient cohorts of 
mCRPC and NSCLC patients respectively. 
The assumption of RR, the required sample sizes, and the number of 
responders at each stage are provided below: 
Indication 
H0 
H1 
Sample size 
Number (%) of 
responses to reject H0 
Stage 1 
Final 
Stage 1 
Final 
mCRPC 
(Combo) 
10% 
26% 
23 
49 
≥3 (13.0%) 
≥9 (18.4%) 
mCRPC 
(Single) 
10% 
26% 
23 
49 
≥3 (13.0%) 
≥9 (18.4%) 
NSCLC  
 (Combo) 
5% 
22% 
20 
36 
≥2 (10.0%) 
≥5 (13.9%) 
Abbreviations: H0=null hypothesis; H1=alternative hypothesis; mCRPC=metastatic, 
castration-resistant prostate cancer; NSCLC=non-small cell lung 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 Investigators. 
Patients who received the RP2D in Phase 1 will be also included in Phase 2 
Stage 1 (eg, if 6 NSCLC patients were enrolled in Phase 1, only 14 NSCLC 
patients will be needed to complete the Phase 2 Stage 1 NSCLC cohort). 
 
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Analysis populations 
All-treated/safety population: For both Phase 1 and Phase 2 parts of the 
study, the All-treated/safety population will include all patients who have given 
their informed consent and received at least 1 dose (even incomplete) of 
treatments either isatuximab or REGN2810. 
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 population: The DLT evaluable population is defined as 
patients in the Phase 1 part receiving the planned doses of isatuximab and 
REGN2810 during Cycle 1, and who completed the DLT observation period 
after the first IMP administration as per Section 9.1.1, unless they discontinue 
the study treatment(s) due to DLT. The dose recommended for Phase 2 will 
be determined on the DLT evaluable population. 
ADA evaluable population: The ADA evaluable population will include all 
patients from the all-treated population with at least 1 non-missing ADA result 
after the first dose of study treatment. 
PK population: The PK population will include all patients from the all-treated 
population with at least 1 drug concentration after the first dose of study 
treatment. 
Pharmacodynamic population: The pharmacodynamic population will include 
all patients from the all-treated population with at least 1 pharmacodynamic 
marker result after the first dose of study treatment. 
Cross-over population: The cross-over population is defined as patients in 
Cohort A-2 who progressed on isatuximab monotherapy and received 
isatuximab in combination with REGN2810. 
Response evaluable population: The response evaluable population will 
include all patients who fulfill all 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. 
General statistical approach 
Data from mCRPC and NSCLC cohorts in the Phase 2 part will be analyzed 
and reported separately by cohort. Data from the Cohort A-2 cross-over part 
will be summarized separately unless otherwise noted. 
Analysis of efficacy endpoints: 
Primary efficacy endpoint (Phase 2): 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. 
Analysis of secondary efficacy endpoints: 
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 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 methods. 
DCR (complete response + partial response + stable disease) will be 
summarized with descriptive statistics. 
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Analysis of safety endpoints: 
In the Phase 1 part, the DLTs will be listed by patient using the DLT evaluable 
population. 
The treatment emergent adverse events (TEAEs) will be coded according to 
Medical Dictionary for Regulatory Activities. AEs and laboratory abnormalities 
will be graded according to the NCI-CTCAE version 4.03. 
Number (%) of patients experiencing TEAEs by primary system organ class 
and preferred term will be summarized by CTCAE grade (all grades and 
Grade ≥3) for the all-treated/safety population. Same table will be prepared 
for drug related TEAEs, TEAEs leading to treatment discontinuation, serious 
TEAEs and TEAEs with fatal outcome. 
Number (%) of patients 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/safety population. 
The immunogenicity for isatuximab and REGN2810 will be summarized. The 
impact of positive immune response will be evaluated on efficacy, PK, and 
safety endpoints when relevant. 
Analysis of PK endpoints: 
Descriptive statistics (mean, geometric mean, median, and standard 
deviation, coefficient of variation, and minimum and maximum) on 
concentrations and PK parameters will be provided for both REGN2810 and 
isatuximab. 
Analysis of pharmacodynamics endpoints: 
Findings from pharmacodynamics markers will be descriptively summarized 
and tabulated. 
Interim analysis 
An interim analysis will be performed for each cohort after the first 23 patients 
for mCRPC cohorts or the first 20 patients for NSCLC cohort(s) in the Phase 
2 part have completed 6 cycles. The interim analysis may be conducted 
earlier if the required number of responses for proceeding to Phase 2 Stage 2 
is achieved. 
Planned date for analysis cut-off: 
For each cohort, the analysis cut-off date for the primary analysis of RR will 
be 6 months after the last patient’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 will be updated. 
Planned date for study cut-off: 
The study cut-off is planned at 12 months after the last ongoing patient 
initiates IMP, 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 earliest. 
DURATION OF STUDY PERIOD (per 
patient)  
The duration of the study for a patient will include a screening period (up to 
28 days), a treatment period (up to 2 years), a safety follow-up period 
(90 days or until negative ADA testing if ADA test is positive or inconclusive at 
Day 90), and a survival phone call follow-up period (until death or study 
cut-off). 
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Treatment period: The cycle duration is 21 days. Patients will continue 
treatment until disease progression confirmed by imaging 4 weeks after initial 
evidence of progression (radiographic progression of mCRPC defined by 
bone scan should be confirmed by a second bone scan 6 weeks later also 
using the 2+2 rule [at least 2 new lesions on first post-treatment scan, with at 
least 2 additional lesions on the next scan]) providing they are clinically 
stable, unacceptable AEs, patient’s decision, 2 years of IMP treatment without 
documented PD, or administrative reasons. Patients with PSA progression in 
the absence of radiographic progression should continue IMP. 
Safety follow-up period: After treatment discontinuation, patients will return 
to the study site 30 days (±7 days) after the last dose of IMP, or when the 
patient receives another anti-cancer therapy, whichever is earlier, for end of 
treatment (EOT) assessments. In addition, there will be an extended safety 
follow-up period for 90 days after the last dose of IMP for ADA assessment 
and for safety assessment. If REGN2810 or isatuximab ADA testing is 
positive or inconclusive during post treatment follow-up, ADA testing will be 
repeated every 3 months until negative. 
Patients who discontinue the study treatment without PD will be followed 
every 90 days for disease assessment until confirmation of PD or start of 
treatment with another anti-cancer therapy, or until study cut-off date, 
whichever comes first. 
Survival phone call follow-up period: The further follow-up schedule 
beyond 90 days after last dose of IMP is according to the disease progression 
status: 
Patients who discontinue study treatment due to PD: phone call follow-up will 
be done every 90 days from the date of last IMP administration until death or 
study cut-off date. 
Patients who discontinue the study treatment without PD, and without PD 
confirmed during the safety follow-up period: will be followed every 90 days 
for disease assessment until confirmation of PD or start of treatment with 
another anti-cancer therapy, or until study cut-off date, whichever occurs first. 
After PD patient will be followed by phone call until death or study cut-off date. 
Patients who are still on study treatment after study cut-off date: will continue 
to receive study treatment and will undergo planned study procedures (except 
PK and ADA) until confirmation PD, or start with another anti-cancer therapy, 
or treatment period ended, whichever comes first. 
Cross-over: The patients in Cohort A-2 treated with isatuximab monotherapy 
who experience PD will be permitted to cross over to isatuximab in 
combination with REGN2810 for up to 2 years after progression on 
isatuximab monotherapy. Safety and efficacy assessments for these patients 
during the cross-over period are the same as the assessments in the Phase 2 
part. 
The Sponsor has the right to terminate the study at 1 or more sites for any 
reason. 
 
 
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1 
FLOWCHARTS  
1.1 
DESIGN DIAGRAM  
Figure 1 - Overall study schema  
 
 
Cohort C and/or Cohort D may be initiated per Section 6.3. No randomization will be needed. 
a Patients from Cohort A-2 who progress on isatuximab monotherapy may receive isatuximab plus REGN2810 if they still fulfill the eligibility criteria (except exclusion criteria #3 and #8). 
Abbreviations: DLT=dose limiting toxicity; mCRPC=metastatic, castration-resistant prostate cancer; N=number of patients; NSCLC=non-small cell lung cancer; R=randomization. 
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1.2 
STUDY TREATMENT ADMINISTRATION  
Cohort 
IMP 
Cycle 1 
Cycle 2 
Cycle 3 and subsequent cycles 
D1 
D8 
D15 
D1 
D8 
D15 
D1 
D8 
D15 
Phase 1 and Phase 2 Cohort A-1 
and Cohort B 
Isatuximab 
X 
X 
X 
X 
 
 
X 
 
 
REGN2810 
X 
 
 
X 
 
 
X 
 
 
Phase 2 Cohort A-2 
Isatuximab 
X 
X 
X 
X 
 
 
X 
 
 
Phase 2 Cohort Ca 
Isatuximab 
X 
 
 
X 
 
 
X 
 
 
REGN2810 (may not be administered 
if isatuximab monotherapy is chosen 
for further study) 
X 
 
 
X 
 
 
X 
 
 
Phase 2 Cohort Db 
Isatuximab 
X 
 
 
X 
 
 
X 
 
 
REGN2810 
X 
 
 
X 
 
 
X 
 
 
a Depending on the positive efficacy signal and the totality of data observed at the end of Phase 2 Stage 2, the Sponsor may decide to further study isatuximab 10 mg/kg Q3W in combination with REGN2810 or as 
monotherapy (without isatuximab initial weekly dosing) in patients with mCRPC. 
b Depending on the positive efficacy signal and the totality of data observed at the end of Phase 2 Stage 2, the Sponsor may decide to further study isatuximab 10 mg/kg Q3W in combination with REGN2810 
(without isatuximab initial weekly dosing) in patients with NSCLC. 
Abbreviations: mCRPC=metastatic, castration resistant prostate cancer; NSCLC=non-small cell lung cancer; Q3W=once every 3 weeks. 
 
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1.3 
STUDY FLOWCHART FOR PHASE 1, PHASE 2 COHORTS A-1, A-2, B AND CROSS-OVER PART  
Evaluationa 
Screening/ Baseline 
Cycle 1b 
Subsequent Cyclesb 
End of Treatment (EOT)  
Post treatment safety follow-up 
periodc 
Survival follow-upc 
D-28 to D1 
D1 
D8 
D15 
D1 
30 (±7) days after last 
IMP admin 
At 60 (±7) days 
after last IMP 
admin 
At 90 (±7) days 
after last IMP 
admin 
Beyond 90 (±7) days 
after last IMP admin 
Informed Consent / Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
Demography, Medical/Surgical and Disease 
Historyd 
X 
 
 
 
 
 
 
 
 
Physical Examinatione 
X 
X 
X 
X 
X 
X 
X 
X 
 
Weight/Height (at baseline only)f  
X 
X 
X 
X 
X 
X 
 
 
 
Vital Signsg 
X 
X 
X 
X 
X 
X 
X 
X 
 
Performance Status (ECOG) 
X 
X 
X 
X 
X 
X 
 
 
 
12-Lead ECGh 
X 
As clinically indicated 
 
 
 
Laboratory Assessments: 
Pregnancy Testi 
X (within 7 days prior to first 
dose) 
X 
 
 
X 
X 
X 
Xi 
 
Blood Chemistryj 
X 
Xk 
X 
X 
X 
X 
X 
X 
 
Hematologyl 
X 
Xk 
X 
X 
X 
X 
X 
X 
 
Coagulationm 
X 
As clinically indicated 
 
 
 
Testosterone level 
X 
 
 
 
 
 
 
 
 
Blood typing interference testn 
X 
 
 
 
Cycle 2 only 
 
 
 
 
Urinalysiso 
X 
Xk 
As clinically indicated 
X 
X 
X 
 
PKp 
See PK/pharmacodynamics Flow-Chart 
ADAq 
See PK/pharmacodynamics Flow-Chart 
Exploratory biomarkers:  
Tumor biopsy for IHC analyses: CD38, PD-L1, 
immune contexturer 
X 
 
 
 
X (Cycle 2 Day 1, unless clinically 
unfeasible and after discussion with 
Sanofi Medical Monitor) 
 
 
 
 
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Evaluationa 
Screening/ Baseline 
Cycle 1b 
Subsequent Cyclesb 
End of Treatment (EOT)  
Post treatment safety follow-up 
periodc 
Survival follow-upc 
D-28 to D1 
D1 
D8 
D15 
D1 
30 (±7) days after last 
IMP admin 
At 60 (±7) days 
after last IMP 
admin 
At 90 (±7) days 
after last IMP 
admin 
Beyond 90 (±7) days 
after last IMP admin 
Tumor biopsy for transcriptomic analysiss 
X 
 
 
 
X (Cycle 2 Day 1, unless clinically 
unfeasible and after discussion with 
Sanofi Medical Monitor) 
 
 
 
 
Tumor biopsy for genomic characterization (tumor 
mutational load and MSI status)t 
X 
 
 
 
 
 
 
 
 
Blood sample for tumor mutational load controlu  
X 
 
 
 
 
 
 
 
 
Blood sample for immune genetic markersv  
 
X 
 
 
 
 
 
 
 
Tumor genetic markers (blood)w  
 
X 
 
 
X (Cycle 2 and Cycle 3 only) 
X 
 
 
 
Immunophenotyping (blood)x  
 
X 
 
 
X (Cycle 2, Cycle 3, then every other 
cycle) 
X 
X 
 
 
Plasma or serum cytokines (blood)y  
X 
X 
 
 
X (Cycle 2, Cycle 3, then every other 
cycle) 
X 
X 
 
 
Disease Assessment 
- 
CT/MRIz 
X 
 
 
 
X (repeat every 9 weeks) 
X 
X 
- 
PSA assessmentaa 
X 
Xk 
 
 
X (repeat every 9 weeks) 
X 
X 
- 
Bone scanbb 
X 
 
 
 
X (repeat every 9 weeks) 
X 
X 
Isatuximab Administrationcc 
 
X 
X 
X 
X 
 
 
 
REGN2810 Administrationcc 
 
X 
 
 
X 
 
 
 
AE/SAE Assessmentdd 
X 
Continuously throughout study period 
X (ongoing related AEs, ongoing SAEs, new related AE/SAEs) 
Prior/Concomitant Medication 
X (within 28 days prior to first 
dose) 
Continuously throughout study period 
X (related to AE/SAEs) 
 
New anticancer therapy 
 
 
 
 
 
X 
X 
X 
Survival status 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
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a Evaluation: Assessments to be performed prior to study treatment and prior to premedication administration unless otherwise indicated. Inform consent should be signed before any study specific procedures. It 
can be signed more than 28 days prior to enrollment/randomization. Screening time indicates the time frame in which study procedures used to support eligibility have to be done prior to enrollment/randomization. 
b Cycle: A cycle is 21 days. The treatment window is ±1 day for each of the weekly administrations and ±2 day for each of the Q3W administrations. A dose is deemed to have been delayed if the treatment is 
≥2 days beyond the theoretical day of treatment for weekly dose, and ≥3 days beyond the theoretical day of treatment for Q3W dose. The window for blood chemistry, hematology, urinalysis, PSA assessment 
(Cycle 1 Day 1 only), and biomarker blood draw is within 1 day prior to IMP administration (where applicable) for Cycle 1 and beyond. 
c Follow-up: Patients who discontinue the study treatment without PD will be followed every 90 days for disease assessment until confirmation of PD or start of treatment with another anti-cancer therapy, or until 
study cut-off date, whichever comes first. The further follow-up schedule beyond 90 days after last dose of IMP is according to the disease progression status: 
Patients who discontinue study treatment due to PD: phone call follow-up will be done every 90 days from the date of last IMP administration until death or study cut-off date. 
Patients who discontinue the study treatment without PD, and without PD confirmed during the safety follow-up period: will be followed every 90 days for disease assessment until confirmation of PD or 
start of treatment with another anti-cancer therapy, or until study cut-off date, whichever occurs first. After PD patients will be followed by phone call until death or study cut-off date. 
d Demography: Includes age, gender, and race. Medical/Surgical History: Includes relevant history of previous/associated pathologies and smoking status. Disease History: Includes stage at diagnosis and at 
study entry, and previous anti-tumor therapy (type, duration, reason for discontinuation and response to the therapy). In addition, results of additional procedures (such as EGFR mutation test, ALK, ROS1 fusion 
detection etc for patients with NSCLC) performed as part of standard of care to assess disease status are also to be collected. The transfusion service should be made aware that the patient is receiving an 
anti-CD38 treatment (isatuximab). During the study treatment period the transfusion service should follow the recommendations issued in the AABB bulletin in case a blood red cells transfusion is needed. The web 
link to the AABB bulletin will be indicated on the study patient card (see Appendix E). Patients should keep together their study patient card with their blood type card throughout the duration of the study treatment. 
e Physical Examination: To be performed at screening (<7 days prior to first dose), prior to study treatment administration, at the EOT visit and during follow-up. Consists of examination of major body systems, 
including neurological, digestive, respiratory (signs and symptoms, respiratory rate), lymph node examination. Only main diagnoses will be reported in the e-CRF as AEs or medical history. Signs and symptoms 
related to either mCRPC or NSCLC ongoing at baseline will be recorded in medical history and will be reported in AE page in case they worsen or become serious during study treatment. Laboratory abnormalities 
at baseline will be recorded in laboratory pages. 
f 
Weight/Height: Height is required at baseline only. Weight is required at Screening, prior to starting infusion and at the EOT visit. 
g Vital Signs: Vital signs including blood pressure, heart rate, temperature, and respiration rate are required at Screening. The measurements will also be performed at the EOT visit, and post treatment follow up 
visits at 60 and 90 days after last treatment. For all patients, vital signs should be obtained prior to the start of each isatuximab infusion, 1 hour after the start of the infusion, at the end of infusion, and if clinically 
indicated during the infusion. 
h 12-Lead ECG: Single (not triplet). To be performed at Screening and then as clinically indicated. 
i 
Pregnancy Test: Women of child bearing potential must have a negative serum pregnancy test result within 7 days prior to first IMP administration. A pregnancy test (serum or urine) is to be done on Day 1 of 
each cycle prior to the study treatment, at the EOT visit, and every 30 (± 7) days until 6 months after the last dose of study treatment. 
j 
Blood Chemistry: To be done at Screening, then prior to premedication and IMP administration, at the EOT visit, during follow-up and as clinically indicated. Biochemistry should be performed every 7 days in 
case of Grade 3/4 abnormalities. Blood chemistry includes: AST, ALT, bilirubin (total and direct), ALP, LDH, sodium, potassium, chloride, bicarbonate/carbon dioxide, calcium, magnesium, phosphate, uric acid, 
urea or BUN, serum creatinine, eGFR (MDRD formula; Appendix H), glucose (fasting), albumin and total protein. TSH will be assessed at baseline, every second cycle, EOT, during follow-up visits (60 and 90 days 
after last treatment); free T4 will be assessed if TSH is outside of the normal range. 
k Blood chemistry, hematology, PSA and urinalysis assessments are not required to be repeated prior to Cycle 1 Day 1 if the screening laboratory assessments were performed within 3 days prior to first IMP 
administration. 
l 
Hematology: To be done at Screening, then prior to premedication and IMP administration, at the EOT visit, during follow-up and as clinically indicated. Hematology includes: Hemoglobin, hematocrit, RBC, WBC 
with differential, and platelet counts. If Grade 4 neutropenia, assess ANC every 2 to 3 days until ANC 0.5 × 109/L and at least weekly thereafter until ANC 1.0 × 109/L. Blood group card to be obtained before 
study entry. 
m Coagulation: To be done at Screening and then as clinically indicated. Coagulation includes: prothrombin time or INR and activated PTT. 
n Blood typing interference test: at screening: blood type (if not already done) and phenotype (according to the site protocol). Recommended phenotype includes Rh system (C/c and E/e), Kell system (K/k); Duffy 
system (Fya/Fyb); Kidd system (Jka/Jkb); MNS system (M/N, S/s), and indirect antiglobulin test (indirect Coombs test). On Cycle 2 Day 1 and before each transfusion: IAT (indirect Coombs test or antibody 
screen). Blood type card will be kept by the patient with the study card. Blood transfusions are to be recorded in the e-CRF. The blood bank needs to be informed that the patient is receiving a treatment with an 
anti-CD38 and a potential interference with the Coombs test is possible. 
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o Urinalysis: Quantitative or semi-quantitative (according to site practice and if such method can provide absolute numeric value of the parameters) urinalysis (includes RBC, protein, glucose, pH, ketones, bilirubin, 
leucocytes, nitrates and specific gravity) to be done at baseline, Cycle 1 Day 1, EOT, during follow-up and during the treatment period if hematuria is observed or clinically indicated – Dipstick (qualitative) will be 
performed on Day 1 of each new cycle if clinically indicated. 
p Pharmacokinetics: Isatuximab and REGN2810. See PK/pharmacodynamics flow chart. 
q ADA: Isatuximab and REGN2810. See PK/pharmacodynamics flow chart. 
r 
Tumor biopsy for IHC analysis of CD38, PD-L1, and immune contexture: 1 tumor biopsy procedure per time point is required (fine needle aspirate is not acceptable, core needle or excisional biopsies, or 
resected tissue are required): at baseline (mandatory, details please refer to Section 7.2 I 03) and Cycle 2 Day 1 (unless clinically unfeasible and after discussion with Sponsor Medical Monitor).  Adequate archival 
pre-treatment tumor tissue sample may replace mandatory baseline biopsy if sample was obtained at the time of or after progression of immediate previous line of anti-cancer treatment, and can be performed 
more than 28 days from Day 1 as long as it is performed after progression to prior therapy. Refer to lab manual for description of adequate archival tumor tissue. On-treatment biopsy at Cycle 2 Day 1 maybe 
obtained within 7 days prior to IMP administration on Cycle 2 Day 1 (after IMP administration on C1D15 wherever applicable). From this tumor biopsy procedure, the priority is to prepare tumor core biopsies for 
IHC analysis, at least 1 tumor core biopsy is required but 2 tumor core biopsies are preferable. If additional tumor material is available, the additional tumor core biopsies are detailed below for transcriptomic 
analysis (at baseline and Cycle 2 Day 1) and genomic characterization (at baseline). 
s  Tumor biopsy for transcriptomic analysis: At baseline and Cycle 2 Day 1, if enough tumor material is available after sampling for IHC, 1 additional tumor core biopsy will be collected from the same biopsy 
procedure for transcriptomic analysis. 
t 
Tumor biopsy for genomic characterization: At baseline, if enough tumor material is available after sampling for IHC and transcriptomic analysis, 2 additional tumor core biopsies will be collected as follows: 
1 for tumor mutational load and 1 for MSI status. 
u Blood used as a control for tumor mutational load: a sample of peripheral blood will be drawn at baseline as a control for the tumor mutational load assessment in tumor core biopsy. 
v Immune genetic markers: a sample of peripheral blood for genetic markers will be drawn at Cycle 1 Day 1, prior to IMP administration. 
w Tumor genetic markers: a sample of peripheral blood will be drawn at Cycle 1 Day 1, Cycle 2 Day 1 and Cycle 3 Day 1 prior to IMP administration, and at the EOT visit. 
x Immunophenotyping: a sample of peripheral blood will be drawn at Cycle 1 Day 1, Cycle 2 Day 1 and Cycle 3 Day 1 and then on Day 1 prior to IMP administration of each odd cycle starting from Cycle 5 (eg 
Cycle 5, Cycle 7, Cycle 9, Cycle 11, etc), at the EOT visit, and at follow-up (60 days after last IMP administration). 
y Plasma or serum cytokine concentration: A sample of peripheral blood will be drawn at baseline and Cycle 1 Day 1, Cycle 2 Day 1, Cycle 3 Day 1 and then on Day 1 prior to IMP administration at each odd 
cycle starting from Cycle 5 (ie, Cycle 5, Cycle 7, Cycle 9, Cycle 11 etc), at the EOT visit and at follow-up (60 days after last IMP administration).  
z Tumor assessment: CT or MRI of the chest, abdomen, pelvis and any other locations with suspicion or evidence of disease involvement is to be performed in all patients at screening (diagnostic quality scans 
performed as part of routine clinical management within 28 days prior to IMP initiation are acceptable). Repeat every 9 weeks starting at the end of Cycle 3 (63 ±7 days; disease assessment timing should follow 
calendar days and should not be adjusted for delays in cycle start), whenever disease progression is suspected, at the EOT visit (if not performed in the past 30 days) and during follow-up (if discontinue IMP 
without PD, repeat every 90 days), using the same method for each assessment. If tumor assessment status is partial or complete response, changes in tumor measurements must be confirmed by repeat 
assessments that should be performed no less than 4 weeks after the criteria for response are first met. Initial evidence of progression should be confirmed no less than 4 weeks later, see Section 6.7.1. Tumor 
assessment is not needed for patients who start another anti-cancer treatment regimen. Study sites must retain disease assessment images, as Sponsor may decide to collect these images for possible 
Independent Central Review in the future. 
aa PSA assessment: For patients with mCRPC, to be performed at baseline (within 14 days before initiation of IMP). Repeat at Cycle 1 Day 1, every 9 weeks starting at the end of Cycle 3 (63 ±7 days; disease 
assessment timing should follow calendar days and should not be adjusted for delays in cycle start), at the EOT visit (if not performed in the past 30 days) and during follow-up (if discontinue IMP without PD, 
repeat every 90 days). PSA responses are to be confirmed no less than 4 weeks later. PSA assessment is not needed for patients who start another anti-cancer treatment regimen. 
bb Bone scan: Mandatory for patients with mCRPC (diagnostic quality scans performed as part of routine clinical management within 6 weeks prior to IMP initiation are acceptable). Repeat every 9 weeks at the end 
of Cycle 3 (63 ±7 days; disease assessment timing should follow calendar days and should not be adjusted for delays in cycle start), at the EOT visit (if not performed in the past 30 days) and during follow-up (if 
discontinue IMP without PD, repeat every 90 days). If progression is defined by bone scan only, the bone scan should be repeated no less than 6 weeks to confirm the progression, see Section 6.7.1. In case of 
doubtful lesions on bone scan, bone-centered X-ray or MRI scan should be performed to confirm the nature of those lesions (metastatic or not). Study sites must retain disease assessment images, as Sponsor 
may decide to collect these images for possible Independent Central Review in the future. 
cc REGN2810/Isatuximab Administration: At the start of each treatment cycle, the patient’s weight will be determined. REGN2810 administration is only applicable in cohorts receiving isatuximab in combination 
with REGN2810. 
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dd AE/SAE assessment: All AEs, including adverse events of new onset as well as worsening of baseline signs and symptoms are to be reported from the signing of the informed consent to 30 days following the last 
administration of study treatment. After the 30 day all ongoing related non-serious AEs, ongoing SAE and new related AE/SAEs are to be followed to resolution or stabilization. Stabilization is defined as an AE 
ongoing without any change for at least 3 months. Severity will be graded according to NCI-CTCAE version 4.03. 
Cross-over part: patients in Cohort A-2 who progressed on isatuximab monotherapy are allowed to enter the cross-over part if clinically stable at the discretion of the Investigators. The screening period for the 
cross-over part is up to 28 days from PD confirmation. All screening processes for the patients in the Phase 1 and Phase 2 parts are to be conducted before combination IMP initiation for the cross-over part, except 
informed consent, demography, medical/surgical and disease history, and height. Tumor biopsy at cross-over screening is required unless clinically unfeasible and after discussion with the Sanofi Medical Monitor. 
On-treatment biopsy at Cycle 2, Day 1 (≤7 days; after IMP administration on C1D15 wherever applicable, prior to IMP administration on Cycle 2 Day 1) of the cross-over part is optional (fine needle aspirate is not 
acceptable). Patients who are included in the cross over part should be evaluated as Cohort A-1 and Cohort B (except PK). Patients who do not meet the cross-over part eligibility criteria should be followed up for 
safety and survival. 
Abbreviations: ADA=anti-drug antibodies; AE=adverse event; ALK=anaplastic lymphoma kinase; ALP=alkaline phosphatase; ALT=alanine aminotransferase; ANC=absolute neutrophil count; AST=aspartate 
aminotransferase; BUN=blood urea nitrogen; C=Cycle; CD38=cluster of differentiation 38; CR=complete remission; CRF=case report form; D=Day; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology 
Group; e-CRF=electronic case report form; EOT=end-of-treatment; FFPE=formalin-fixed, paraffin embedded; FUP=follow-up visit; IAT=indirect antiglobulin test; IFN=interferon; IHC=immunohistochemistry; 
IL=interleukin; IMP=investigational medicinal product; INR=international normalized ratio; LDH=lactate dehydrogenase; mCRPC=metastatic, castration resistant prostate cancer; MDRD=Modification of Diet in Renal 
Disease Study; MSI=microsatellite instability; NSCLC=non-small cell lung cancer; PD=progressive disease; PD-L1=programmed cell death ligand 1; PK=pharmacokinetic; PR=partial remission; PS=performance 
status; PSA=prostate-specific antigen; PT=prothrombin time; PTT=partial thromboplastin time; Q3W=every 3 weeks; RBC=red blood cell count; SAE=serious adverse event; TNF=tumor necrosis factor; TSH=thyroid 
stimulating hormone; WBC=white blood cell. 
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1.4 
STUDY FLOWCHART FOR COHORT C AND COHORT D  
The alternative schedule may be implemented as an additional cohort in the Phase 2 part in 1 indication when positive results are observed in 
Phase 2 Stage 2 for such indication. 
Evaluationa 
Screening/ Baseline 
Cycle 1b 
Subsequent Cyclesb 
End of Treatment (EOT)  
Post treatment safety follow-up 
periodc 
Survival 
follow-upc 
D-28 to D1 
D1 
D1 
30 days after last IMP 
admin 
At 60 days after 
last IMP admin 
At 90 days after 
last IMP admin 
Beyond 90 days 
after last IMP 
administration 
Informed Consent / Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
Demography, Medical/Surgical and Disease 
Historyd 
X 
 
 
 
 
 
 
Physical Examinatione 
X 
X 
X 
X 
X 
X 
 
Weight/Height(at baseline only)f 
X 
X 
X 
X 
 
 
 
Vital Signsg 
X 
X 
X 
X 
X 
X 
 
Performance Status (ECOG) 
X 
X 
X 
X 
 
 
 
12-Lead ECGh 
X 
As clinically indicated 
 
 
 
Laboratory Assessments: 
Pregnancy Testi 
X (within 7 days prior to first 
dose) 
X 
X 
X 
X 
Xii 
 
Blood Chemistryj 
X 
Xk 
X 
X 
X 
X 
 
Hematologyl 
X 
Xk 
X 
X 
X 
X 
 
Coagulationm 
X 
As clinically indicated 
 
 
 
Testosterone level 
X 
 
 
 
 
 
 
Blood typing interference testn 
X 
 
Cycle 2 only 
 
 
 
 
Urinalysiso 
X 
Xk 
As clinically indicated 
X 
X 
X 
 
PKp 
See PK/pharmacodynamics Flow-Chart 
ADAq 
See PK/pharmacodynamics Flow-Chart 
Exploratory biomarkers:  
Tumor biopsy for IHC analyses: CD38, PD-L1, 
immune contexturer 
X 
 
X (Cycle 2 Day 1, unless clinically 
unfeasible and after discussion with 
Sanofi Medical Monitor) 
 
 
 
 
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Evaluationa 
Screening/ Baseline 
Cycle 1b 
Subsequent Cyclesb 
End of Treatment (EOT)  
Post treatment safety follow-up 
periodc 
Survival 
follow-upc 
D-28 to D1 
D1 
D1 
30 days after last IMP 
admin 
At 60 days after 
last IMP admin 
At 90 days after 
last IMP admin 
Beyond 90 days 
after last IMP 
administration 
Tumor biopsy for transcriptomic analysiss 
X 
 
X (Cycle 2 Day 1, unless clinically 
unfeasible and after discussion with 
Sanofi Medical Monitor) 
 
 
 
 
Tumor biopsy for genomic characterization 
(tumor mutational load and MSI status)t 
X 
 
 
 
 
 
 
Blood sample for tumor mutational load controlu 
X 
 
 
 
 
 
 
Blood sample for immune genetic markersv 
 
X 
 
 
 
 
 
Tumor genetic markers (blood) w 
 
X 
X (Cycle 2 and Cycle 3 only) 
X 
 
 
 
Immunophenotyping (blood)x  
 
X 
X (Cycle 2, Cycle 3, then every other 
cycle) 
X 
X 
 
 
Plasma or serum cytokines (blood)y 
X 
X 
X (Cycle 2, Cycle 3, then every other 
cycle) 
X 
X 
 
 
Disease Assessment 
 
 
 
 
 
 
 
- 
CT/MRIz 
X 
X 
X (repeat every 9 weeks) 
X 
X 
- 
PSA assessmentaa 
X 
Xk 
X (repeat every 9 weeks) 
X 
X 
- 
Bone scanbb 
X 
X 
X (repeat every 9 weeks) 
X 
X 
Isatuximab Administrationcc 
 
X 
X 
 
REGN2810 Administrationcc 
 
X 
X 
 
 
 
AE/SAE Assessmentdd 
X 
Continuously 
throughout study 
period 
X (ongoing related AEs, ongoing SAEs, 
new related AE/SAEs) 
 
 
 
Prior/Concomitant Medication 
X (within 28 days prior to first 
dose) 
Continuously throughout study period 
X (related to AE/SAEs) 
 
New anticancer therapy 
 
X 
X 
X 
Survival status 
 
 
 
X 
 
 
 
 
 
 
 
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a Evaluation: Assessments to be performed prior to study treatment and prior to premedication administration unless otherwise indicated. Inform consent should be signed before any study specific procedures. It 
can be signed more than 28 days prior to enrollment/randomization. Screening time indicates the time frame in which study procedures used to support eligibility have to be done prior to enrollment/randomization. 
b Cycle: A cycle is 21 days. The treatment window is ±2 day for each of the Q3W administrations. A dose is deemed to have been delayed if the treatment is ≥3 days beyond the theoretical day of treatment for 
Q3W dose. The reason for dose delay will be captured. The window for blood chemistry, hematology, urinalysis, PSA assessment (Cycle 1 Day 1 only), and biomarker blood draw is within 1 day prior to IMP 
administration (where applicable) for Cycle 1 and beyond. 
c Follow-up: Patients who discontinue the study treatment without PD will be followed every 90 days for disease assessment until confirmation of PD or start of treatment with another anti-cancer therapy, or until 
study cut-off date, whichever comes first. The further follow-up schedule beyond 90 days after last dose of IMP is according to the disease progression status: 
Patients who discontinue study treatment due to PD: phone call follow-up will be done every 90 days from the date of last IMP administration until death or study cut-off date. 
Patients who discontinue the study treatment without PD, and without PD confirmed during the safety follow-up period: will be followed every 90 days for disease assessment until confirmation of PD or 
start of treatment with another anti-cancer therapy, or until study cut-off date, whichever occurs first. After PD patients will be followed by phone call until death or study cut-off date. 
d Demography: Includes age, gender, and race. Medical/Surgical History: Includes relevant history of previous/associated pathologies and smoking status. Disease History: Includes stage at diagnosis and at 
study entry, and previous anti-tumor therapy (type, duration, reason for discontinuation and response to the therapy). In addition, results of additional procedures (such as EGFR mutation test, ALK, ROS1 fusion 
detection etc for patients with NSCLC) performed as part of standard of care to assess disease status are also to be collected. The transfusion service should be made aware that the patient is receiving an 
anti-CD38 treatment (isatuximab). During the study treatment period the transfusion service should follow the recommendations issued in the AABB bulletin in case a blood red cells transfusion is needed. The web 
link to the AABB bulletin will be indicated on the study patient card (see Appendix E). Patients should keep together their study patient card with their blood type card throughout the duration of the study treatment. 
e Physical Examination: To be performed at screening (<7 days prior to first dose), prior to study treatment administration, at the EOT visit and during follow-up. Consists of examination of major body systems, 
including neurological, digestive, respiratory (signs and symptoms, respiratory rate), lymph node examination. Only main diagnoses will be reported in the e-CRF as AEs or medical history. Signs and symptoms 
related to either mCRPC or NSCLC ongoing at baseline will be recorded in medical history and will be reported in AE page in case they worsen or become serious during study treatment. Laboratory abnormalities 
at baseline will be recorded in laboratory pages. 
f 
Weight/Height: Height is required at baseline only. Weight is required at Screening, prior to starting infusion and at the EOT visit. 
g Vital Signs: Vital signs including blood pressure, heart rate, temperature, and respiration rate are required at Screening. The measurements will also be performed at the EOT visit, and post treatment follow up 
visits at 60 and 90 days after last treatment. For all patients, vital signs should be obtained prior to the start of each isatuximab infusion, 1 hour after the start of the infusion, at the end of infusion, and if clinically 
indicated during the infusion. 
h 12-Lead ECG: Single (not triplet). To be performed at Screening and then as clinically indicated. 
i 
Pregnancy Test: Women of child bearing potential must have a negative serum pregnancy test result within 7 days prior to first IMP administration. A pregnancy test (serum or urine) is to be done on Day 1 of 
each cycle prior to the study treatment, at the EOT visit, and every 30 (± 7) days until 6 months after the last dose of study treatment. 
j 
Blood Chemistry: To be done at Screening, then prior to premedication and IMP administration, at the EOT visit, during follow-up and as clinically indicated. Biochemistry should be performed every 7 days in 
case of Grade 3/4 abnormalities. Blood chemistry includes: AST, ALT, bilirubin (total and direct), ALP, LDH, sodium, potassium, chloride, bicarbonate/carbon dioxide, calcium, magnesium, phosphate, uric acid, 
urea or BUN, serum creatinine, eGFR (MDRD formula; Appendix H), glucose (fasting), albumin and total protein. TSH will be assessed at baseline, every second cycle, EOT, during follow-up visits (60 and 90 days 
after last treatment); free T4 will be assessed if TSH is outside of the normal range. 
k Blood chemistry, hematology, urinalysis and PSA assessments are not required to be repeated prior to Cycle 1 Day 1 if the screening laboratory assessments were performed within 3 days prior to first IMP 
administration. 
l 
Hematology: To be done at Screening, then prior to premedication and IMP administration, at the EOT visit, during follow-up and as clinically indicated. Hematology includes: Hemoglobin, hematocrit, RBC, WBC 
with differential, and platelet counts. If Grade 4 neutropenia, assess ANC every 2 to 3 days until ANC 0.5 × 109/L and at least weekly thereafter until ANC 1.0 × 109/L. Blood group card to be obtained before 
study entry. 
m Coagulation: To be done at Screening and then as clinically indicated. Coagulation includes: prothrombin time or INR and activated PTT. 
n Blood typing interference test: at screening: blood type (if not already done) and phenotype (according to site protocol). Recommended phenotype includes Rh system (C/c and E/e), Kell system (K/k), Duffy 
system (Fya/Fyb), Kidd system (Jka/Jkb), MNS system (M/N, S/s), and indirect antiglobulin test (indirect Coombs test). On Cycle 2, Day 1 and before each transfusion: IAT (indirect Coombs test or antibody 
screen). Blood type card will be kept by the patient with the study card. Blood transfusions are to be recorded in the e-CRF. The blood bank needs to be informed that the patient is receiving a treatment with an 
anti-CD38 and a potential interference with the Coombs test is possible. 
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o Urinalysis: Quantitative or semi-quantitative (according to site practice and if such method can provide absolute numeric value of the parameters) urinalysis (includes RBC, protein, glucose, pH, ketones, bilirubin, 
leucocytes, nitrates and specific gravity) to be done at baseline, Cycle 1 Day 1, EOT, during follow-up and during the treatment period if hematuria is observed or clinically indicated – Dipstick (qualitative) will be 
performed on Day 1 of each new cycle if clinically indicated. 
p Pharmacokinetics: Isatuximab and REGN2810. See PK/pharmacodynamics flow chart. 
q ADA: Isatuximab and REGN2810. See PK/pharmacodynamics flow chart. 
r 
Tumor biopsy for IHC analysis of CD38, PD-L1, and immune contexture: 1 tumor biopsy procedure per time point is required (fine needle aspirate is not acceptable, core needle or excisional biopsies, or 
resected tissue are required): at baseline (mandatory, details please refer to Section 7.2, I 03) and Cycle 2 Day 1 (unless clinically unfeasible and after discussion with Sponsor Medical Monitor).  Adequate archival 
pre-treatment tumor tissue sample may replace mandatory baseline biopsy if sample was obtained at the time of or after progression of immediate previous line of anti-cancer treatment, and can be performed 
more than 28 days from Day 1 as long as it is performed after progression to prior therapy. Refer to lab manual for description of adequate archival tumor tissue. On-treatment biopsy at Cycle 2 Day 1 maybe 
obtained within 7 days prior to IMP administration on Cycle 2 Day 1 (after IMP administration on C1D15 wherever applicable). From this tumor biopsy procedure, the priority is to prepare tumor core biopsies for 
IHC analysis, at least 1 tumor core biopsy is required but 2 tumor core biopsies are preferable. If additional tumor material is available, the additional tumor core biopsies are detailed below for transcriptomic 
analysis (at baseline and Cycle 2 Day 1) and genomic characterization (at baseline). 
s Tumor biopsy for transcriptomic analysis: At baseline and Cycle 2 Day 1, if enough tumor material is available after sampling for IHC, 1 additional tumor core biopsy will be collected from the same biopsy 
procedure for transcriptomic analysis. 
t 
Tumor biopsy for genomic characterization: At baseline, if enough tumor material is available after sampling for IHC and transcriptomic analysis, 2 additional tumor core biopsies will be collected as follows: 
1  for tumor mutational load and 1 for MSI status. 
u Blood used as a control for tumor mutational load: a sample of peripheral blood will be drawn at baseline as a control for the tumor mutational load assessment in tumor core biopsy. 
v Immune genetic markers: a sample of peripheral blood for genetic markers will be drawn at Cycle 1 Day 1, prior to IMP administration. 
w Tumor genetic markers: a sample of peripheral blood will be drawn at Cycle 1 Day 1, Cycle 2 Day 1 and Cycle 3 Day 1 prior to IMP administration, and at the EOT visit. 
x Immunophenotyping: a sample of peripheral blood will be drawn at Cycle 1 Day 1, Cycle 2 Day 1 and Cycle 3 Day 1 and then on Day 1 prior to IMP administration of each odd cycle starting from Cycle 5 (eg, 
Cycle 5, Cycle 7, Cycle 9, Cycle 11, etc), at the EOT visit, and at follow-up (60 days after last IMP administration). 
y Plasma or serum cytokine concentration: A sample of peripheral blood will be drawn at baseline and Cycle 1 Day 1, Cycle 2 Day 1, Cycle 3 Day 1 and then on Day 1 prior to IMP administration at each odd 
cycle starting from Cycle 5 (ie, Cycle 5, Cycle 7, Cycle 9, Cycle 11 etc), at the EOT visit and at follow-up (60 days after last IMP administration). 
z Tumor assessment: CT or MRI of the chest, abdomen, pelvis and any other locations with suspicion or evidence of disease involvement is to be performed in all patients at screening (diagnostic quality scans 
performed as part of routine clinical management are acceptable). Repeat every 9 weeks starting at the end of Cycle 3 (63 ±7 days; disease assessment timing should follow calendar days and should not be 
adjusted for delays in cycle start), whenever disease progression is suspected, at the EOT visit (if not performed in the past 30 days) and during follow-up (if discontinue IMP without PD, repeat every 90 days), 
using the same method for each assessment. If tumor assessment status is partial or complete response, changes in tumor measurements must be confirmed by repeat assessments that should be performed no 
less than 4 weeks after the criteria for response are first met. Initial evidence of progression should be confirmed no less than 4 weeks later, see Section 6.7.1. Tumor assessment is not needed for patients who 
start another anti-cancer treatment regimen. Study sites must retain disease assessment images, as Sponsor may decide to collect these images for possible Independent Central Review in the future. 
aa PSA assessment: For patients with mCRPC, to be performed at baseline (within 14 days before initiation of IMP). Repeat at Cycle 1 Day 1, every 9 weeks starting at the end of Cycle 3 (63 ±7 days; disease 
assessment timing should follow calendar days and should not be adjusted for delays in cycle start), at the EOT visit (if not performed in the past 30 days) and during follow-up (if discontinue IMP without PD, 
repeat every 90 days). PSA responses are to be confirmed no less than 4 weeks later. PSA assessment is not needed for patients who start another anti-cancer treatment regimen. 
bb Bone scan: For patients with mCRPC, bone scan performed within 6 weeks prior to first study dose is allowed at baseline. Repeat every 9 weeks starting at the end of Cycle 3 (63 ±7 days; disease assessment 
timing should follow calendar days and should not be adjusted for delays in cycle start), at the EOT visit (if not performed in the past 30 days) and during follow-up (if discontinue IMP without PD, repeat every 90 
days). If progression is defined by bone scan only, the bone scan should be repeated no less than 6 weeks to confirm the progression, see Section 6.7.1. In case of doubtful lesions on bone scan, bone-centered 
X-ray or MRI scan should be performed to confirm the nature of those lesions (metastatic or not). Study sites should retain disease assessment images, as Sponsor may decide to collect these images for possible 
Independent Central Review in the future. 
cc REGN2810/Isatuximab Administration: At the start of each treatment cycle, the patient’s weight will be determined. REGN2810 administration is only applicable in cohort(s) receiving isatuximab in combination 
with REGN2810. 
dd AE/SAE assessment: All AEs, including adverse events of new onset as well as worsening of baseline signs and symptoms are to be reported from the signing of the informed consent to 30 days following the last 
administration of study treatment. After the 30 day all ongoing related non-serious AEs, ongoing SAE and new related AE/SAEs are to be followed to resolution or stabilization. Stabilization is defined as an AE 
ongoing without any change for at least 3 months. Severity will be graded according to NCI-CTCAE version 4.03. 
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Abbreviations: ADA=anti-drug antibodies; AE=adverse event; ALK=anaplastic lymphoma kinase; ALP=alkaline phosphatase; ALT=alanine aminotransferase; ANC=absolute neutrophil count; AST=aspartate 
aminotransferase; BUN=blood urea nitrogen; C=Cycle; CD38=cluster of differentiation 38; CR=complete remission; CRF=case report form; D=Day; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology 
Group; e-CRF=electronic case report form; EOT=end-of-treatment; FFPE=formalin-fixed, paraffin embedded; FUP=follow-up visit; IAT=indirect antiglobulin test; IFN=interferon; IHC=immunohistochemistry; 
IL=interleukin; IMP=investigational medicinal product; INR=international normalized ratio; LDH=lactate dehydrogenase; mCRPC=metastatic, castration resistant prostate cancer; MDRD=Modification of Diet in Renal 
Disease Study; MSI=microsatellite instability; NSCLC=non-small cell lung cancer; PD=progressive disease; PD-L1=programmed cell death ligand 1; PK=pharmacokinetic; PR=partial remission; PS=performance 
status; PSA=prostate-specific antigen; PT=prothrombin time; PTT=partial thromboplastin time; Q3W=every 3 weeks; RBC=red blood cell count; SAE=serious adverse event; TNF=tumor necrosis factor; TSH=thyroid 
stimulating hormone; WBC=white blood cell. 
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1.5 
PHARMACOKINETICS/PHARMACODYNAMICS FLOWCHART  
1.5.1 For Phase 1 part, Stage 1 Phase 2 part of Cohort A-1 and Cohort B (not applicable for the patients with NSCLC who are enrolled 
for Phase 2 Stage 1 after implementation of Amendment #5 at individual sites)  
Study Phase 
Treatment Phase 
Post 
treatment 
Cycle 
Cycle 1 
Cycle 3 
Cycle 4 
Subsequent  
Cycles 
Follow-up 
period 
Day within cycle 
D1 
D4 
D8 
D15 
D22 (Cycle 2 Day 1) 
D1 
D1 
D1 
90 ±7 days 
after last 
study 
treatment 
Sample RNT (h) 
Ref: REGN2810 SOI 
SOI 
EOI 
EOI 
+4h 
-  
72h 
168h 
336h 
-  
504h  
(SOI) 
EOI 
-  
SOI 
EOI 
SOI 
EOI 
-  
- 
SOI 
- 
- 
Sample Time 
windowa 
[-24h, SOI] 
[-5 
min, 
EOI] 
±30  
min 
-  
±5h 
±24h 
±48h 
-  
[-24h, 
SOI] 
[-5 min, 
EOI] 
 - 
[-24h, 
SOI] 
[-5 min, 
EOI] 
[-24h, 
SOI] 
[-5 
min, 
EOI] 
 - 
-  
[-24h, 
SOI] 
- 
- 
Sample RNT (h) 
Ref: Isatuximab SOI 
SOI 
- 
EOI 
EOI 
+ 4h 
72h 
168h 
(SOI) 
SOI 
EOI 
SOI 
- 
EOI 
SOI 
- 
SOI 
 
EOI 
EOI 
+1h 
SOI 
 
- 
Sample Time 
windowa 
 - 
- 
±10  
min 
±30 
 min 
±5h 
[-24h, 
SOI] 
[-24h, 
SOI] 
±10 
 min 
-  
- 
±10 
 min 
-  
- 
 - 
- 
±10 
 min 
±10  
min 
 - 
- 
- 
IMP administration (IV infusion) 
REGN2810 
X-------X 
 
 
 
 
 
 
X-------X 
 
X-------X 
X-------X 
 
 
X 
 
 
Isatuximab 
 
X-------X 
 
 
X 
X-------X 
 
X-------X 
 
X 
 
X-------X 
 
 
X 
 
Pharmacokineticsb 
REGN2810 
Sample ID 
S00f 
S01d 
S02e 
- 
S03  
S04  
S05 
- 
S06f,g 
S07d 
- 
S00f 
S01d 
S00f 
S01d 
- 
- 
S00f 
- 
SF00 
Isatuximabh 
Sample ID 
P00c 
- 
P01i 
P02 
P03 
P04j,
k 
P05j 
P06i 
P07c,j 
- 
P08i 
P00c,j 
- 
P00c,j 
- 
P01i 
P02 
P00c,j, 
h  
- 
- 
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Study Phase 
Treatment Phase 
Post 
treatment 
Cycle 
Cycle 1 
Cycle 3 
Cycle 4 
Subsequent  
Cycles 
Follow-up 
period 
Day within cycle 
D1 
D4 
D8 
D15 
D22 (Cycle 2 Day 1) 
D1 
D1 
D1 
90 ±7 days 
after last 
study 
treatment 
Immunogenicity (ADA)l 
REGN2810m 
AS00f,m  
- 
AS01f,
m 
- 
- 
- 
AS00f,
m 
- 
ASF00n 
Isatuximabh,o  
AP00c,o 
- 
AP01c,
o 
- 
- 
AP00c,
o 
- 
AP00c,
o 
- 
- 
AP00c, 
h ,o 
- 
APF00h, p 
 
a Time windows targeted for PK/pharmacodynamics and ADA sampling. 
b Refer to the laboratory manual for sample collection, processing and shipping. REGN2810 PK samples to be collected: Cycle 1 predose (corresponding to SOI) and actual end of infusion (ie, EOI), EOI+ 4h, 72h, 
168h, 336h, and 504h (predose second administration) after start of first dose; EOI of second administration (Day 22 [Day 1 of Cycle 2]); then Cycles 3 and 4: predose and EOI; subsequent cycles: predose and at 
90 days after last study treatment administration; isatuximab PK samples to be collected: Cycle 1 predose and EOI, EOI+ 4h, 72h and 168h (predose second administration, Day 8 of Cycle 1) after start of first 
dose; Cycle 1 Day 15 and Cycle 1 Day 22 (corresponding to Cycle 2 Day 1): predose and EOI; then Cycle 3 Day 1 predose; Cycle 4 Day 1 predose, EOI, EOI+ 1h; subsequent cycles Day 1 predose. For the 
patients with NSCLC who are enrolled for Phase 2 Stage 1 after implementation of Amendment #5 at individual sites, no PK samples for REGN2810 and isatuximab will be collected. 
c Predose sample: isatuximab PK or ADA assessment could be drawn at the same time just before REGN2810 administration. 
d Sample collected just before (within 5 minutes) the actual end of infusion of REGN2810. 
e Sample collected for REGN2810 could be drawn at the same time as the end of infusion sample of isatuximab. 
f 
REGN2810 sample collected strictly before the start of REGN2810 infusion.  
g S06 sample must be collected even if the second infusion of REGN2810 is not done or delayed 
h Isatuximab PK and ADA samples to be collected each cycle until the last study treatment for PK and until follow-up for ADA or at the cut-off date, whichever comes first. However, collection can be stopped earlier 
or reduced upon notification from the Sponsor based on the updated knowledge of isatuximab immunogenicity and PK. 
i 
Sample collected just before actual end of infusion of isatuximab. 
j 
Predose sample for isatuximab collected strictly before the start of isatuximab infusion. 
k P04 sample must be collected even if the patient withdraws the study without receiving the second administration of isatuximab. 
l 
After start of study treatment, if 1 drug is prematurely discontinued, ADA samples for this drug will be collected on Day 1 of the 2 next cycles. If ADA test at the second cycle is positive or inconclusive, ADA testing 
will be repeated every 3 months until negative. The ADA sample collection for other drug should be done as planned. 
m During the treatment phase, the ADA samples for REGN2810 must be collected before REGN2810 treatment administration at each time point: Cycle 1 Day1, Cycle 1 Day 22 (predose Cycle 2), and on Day 1 
every 3 cycles afterwards (ie, Cycle 5, Cycle 8, Cycle 11, Cycle 14 etc). In response to AEs of special interest, such as anaphylaxis or hypersensitivity, ADA samples closer to the event may be collected, based on 
the judgment of the Investigator and/or medical monitor. For the patients with NSCLC who are enrolled for Phase 2 Stage 1 after implementation of Amendment #5 at individual sites, no REGN2810 ADA samples 
will be collected. 
n During the posttreatment follow-up period REGN2810 ADA samples are collected at 90 ±7 days after last study treatment and every 3 months thereafter until the sample is negative (ASF01, ASF02…). 
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o During the treatment phase, the ADA samples for isatuximab must be collected before isatuximab treatment administration on Day 1 of each Cycle (could be drawn at the same time just before REGN2810 
administration). ADA samples are not collected at Cycle 1 Day 8 or Cycle 1 Day 15. For the patients with NSCLC who are enrolled for Phase 2 Stage 1 after implementation of Amendment #5 at individual sites, no 
isatuximab ADA samples will be collected. 
p During the posttreatment follow-up period isatuximab ADA samples are collected at 90 ±7 days after last study treatment and every 3 months thereafter until the sample is negative (APF01, APF02…). 
Abbreviations: AB=antibody; ADA=anti-drug antibody; AP=antibody plasma (for isatuximab); AS=antibody serum (for REGN2810); EOI=end of IV infusion; IMP=investigational medicinal product; P=Plasma; 
PD=pharmacodynamics; PK=pharmacokinetics; RNT=relative nominal time; S=Serum; SOI=start of IV infusion. 
 
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1.5.2 For Phase 2 part of Cohort A-2, Stage 2 Phase 2 part of Cohort A-1 and Cohort B (tests for REGN2810 are not applicable for 
Cohort A-2, tests for PK are not applicable for cross-over part)  
Study phase 
Treatment phase 
Post 
treatment 
Cycle 
Cycle 1 
Cycle 3 
Cycle 4 
Subsequent cycles 
Follow-up 
period 
Day within cycle 
D1 
D8 
D15 
D22 (Cycle 2 Day 1) 
D1 
D1 
D1 
90 ±7 
days after 
last study 
treatment 
Sample RNT (h) 
Ref: REGN2810 SOI 
SOI 
EOI 
EOI+4h 
- 
168h 
336h 
- 
504h 
(SOI) 
EOI 
- 
SOI 
EOI 
SOI 
EOI 
- 
SOI 
- 
- 
Sample Time windowa 
[-24h, 
SOI] 
[-5 
min,EOI] 
±30 
min 
- 
±24h 
±48h 
- 
[-24h, 
SOI] 
[-5 
min,EOI] 
- 
[-24h, 
SOI] 
[-5 
min,EOI] 
[-24h, 
SOI] 
[-5 
min,EOI] 
- 
[-24h, 
SOI] 
- 
- 
Sample RNT (h) 
Ref: Isatuximab SOI 
SOI 
- 
EOI 
EOI+1h 
168h 
(SOI) 
SOI 
EOI 
SOI 
- 
EOI 
SOI 
- 
SOI 
- 
EOI 
SOI 
- 
- 
Sample Time windowa 
- 
- 
±10 
min 
±10 
min 
[-24h, 
SOI] 
[-24h, 
SOI] 
±10 
min 
- 
- 
±10 
min 
- 
- 
- 
- 
±10 
min 
- 
- 
- 
IMP administration (IV infusion) 
REGN2810 
X-------X 
 
 
 
         X-------X 
 
X-------X 
X-------X 
 
X 
 
 
Isatuximab 
 
X-------X 
 
X 
X-------X 
 
X-------X 
 
X-------X 
 
X-------X 
 
X 
 
Pharmacokineticsb 
REGN2810 
Sample ID 
S00f 
S01d 
S02e 
- 
S03 
S04 
- 
S05f,g 
S06d 
- 
S00f 
S01d 
S00f 
S01d 
- 
S00f 
- 
SF00 
Isatuximabh 
Sample ID 
P00c 
- 
P01i 
P02 
P03j,k  
P04j 
P05i 
P06c,j  
- 
P07i 
P00c,j  
- 
P00c,j  
- 
P01i 
P00c, 
h,j  
- 
- 
Immunogenicity (ADA)l  
REGN2810m 
AS00f,m  
- 
AS01f,m 
- 
- 
- 
AS00f,m 
- 
ASF00n 
Isatuximabh,o 
AP00c,o  
- 
AP01c,o  
- 
- 
AP00c,o 
- 
AP00c,o 
- 
- 
AP00c, 
h ,o  
- 
APF00h,p  
 
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Amended Clinical Trial Protocol No. 05  
11-Jun-2019 
SAR650984-ACT15319 - isatuximab 
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Property of the Sanofi Group - strictly confidential 
Page 36 
a Time windows targeted for PK/pharmacodynamics and ADA sampling. 
b Refer to the laboratory manual for sample collection, processing and shipping. REGN2810 PK samples to be collected: Cycle 1 predose (corresponding to SOI) and actual end of infusion (ie, EOI), EOI+ 4h, 168h, 
336h, and 504h (predose second administration [Day 1 of Cycle 2]) after start of first dose; EOI of second administration (Day 22 [Day 1 of Cycle 2]); then Cycles 3 and 4: predose and EOI; subsequent cycles: 
predose and at 90 days after the last study treatment administration; isatuximab PK samples to be collected: Cycle 1 predose and EOI, EOI+ 1hand 168h (predose second administration, Day 8 of Cycle 1) after 
start of first dose; Cycle 1 Day 15 and Cycle 1 Day 22 (corresponding to Cycle 2 Day 1): predose and EOI; then Cycle 3 Day 1 predose; Cycle 4 Day 1: predose and EOI; subsequent cycles: Day 1 predose. 
c Predose sample: isatuximab PK or ADA assessment could be drawn at the same time just before REGN2810 administration. 
d Sample collected just before (within 5 minutes) the actual end of infusion of REGN2810. 
e Sample collected for REGN2810 could be drawn at the same time as the end of infusion sample of isatuximab. 
f 
REGN2810 sample collected strictly before the start of REGN2810 infusion. 
g S05 sample must be collected even if the second infusion of REGN2810 is not done or delayed. 
h Isatuximab PK and ADA samples to be collected each cycle until the last study treatment for PK and until follow-up for ADA or at the cut-off date, whichever comes first. However, collection can be stopped earlier 
or reduced upon notification from the Sponsor based on the updated knowledge of isatuximab immunogenicity and PK. 
i 
Sample collected just before actual end of infusion of isatuximab. 
j 
Predose sample for isatuximab collected strictly before the start of isatuximab infusion. 
k P03 sample must be collected even if the patient withdraws the study without receiving the second administration of isatuximab. 
l 
After start of study treatment, if 1 drug is prematurely discontinued, ADA samples for this drug will be collected on Day 1 of the 2 next cycles. If ADA test at the second cycle is positive or inconclusive, ADA testing 
will be repeated every 3 months until negative. The ADA sample collection for other drug should be done as planned. 
m During treatment phase, the ADA samples for REGN2810 must be collected before REGN2810 treatment administration at each time point: Cycle 1 Day1, Cycle 1 Day 22 (predose Cycle 2), and on Day 1 every 
3 cycles afterwards (ie, Cycle 5, Cycle 8, Cycle 11, Cycle 14 etc). In response to AEs of special interest, such as anaphylaxis or hypersensitivity, ADA samples closer to the event may be collected, based on the 
judgment of the Investigator and/or medical monitor. 
n During posttreatment follow-up period REGN2810 ADA samples are collected at 90 ±7 days after last study treatment and every 3 months thereafter until sample is negative (ASF01, ASF02…). 
o During treatment phase, the ADA samples for isatuximab must be collected before isatuximab treatment administration on Day 1 of each Cycle (could be drawn at the same time just before REGN2810 
administration). ADA samples are not collected at Cycle 1 Day 8 or Cycle 1 Day 15. 
p During posttreatment follow-up period isatuximab ADA samples are collected at 90 ±7 days after last study treatment and every 3 months thereafter until sample is negative (APF01, APF02…). 
Abbreviations: AB=antibody; ADA=anti-drug antibody; AP=antibody plasma (for REGN2810); AS=antibody serum (for isatuximab); EOI=end of IV infusion; P=plasma; PD=pharmacodynamic; PK=pharmacokinetic; 
RNT=relative nominal time; S=serum; SOI=start of IV infusion. 
 
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1.5.3 For Cohort C and Cohort D (tests for REGN2810 are not applicable for Cohort C if isatuximab monotherapy is administered)  
Study phase 
Treatment phase 
Post 
treatment 
Cycle 
Cycle 1 
 
Cycle 3 
Cycle 4 
Subsequent cycles 
Follow-up 
period 
Day within cycle 
D1 
D4 
D8 
D15 
D22 (Cycle 2 Day 1) 
D1 
D1 
D1 
90 ±7 
days after 
last study 
treatment 
Sample RNT (h) 
Ref: REGN2810 SOI 
SOI 
EOI 
EOI+4h 
- 
72h 
168h 
336h 
504h 
(SOI) 
EOI 
- 
SOI 
EOI 
SOI 
EOI 
- 
- 
SOI 
- 
- 
Sample Time 
windowa 
[-24h, 
SOI] 
[-5 
min,EOI] 
±30 
min 
- 
±5h 
±24h 
±48h 
[-24h, 
SOI] 
[-5 min, 
EOI] 
- 
[-24h, 
SOI] 
[-5 
min,EOI] 
[-24h, 
SOI] 
[-5 
min,EOI] 
- 
- 
[-24h, 
SOI] 
- 
- 
Sample RNT (h) 
Ref: Isatuximab SOI 
SOI 
- 
EOI 
EOI+4h 
72h 
168h 
336h 
- 
504h 
(SOI) 
EOI 
SOI 
- 
SOI 
- 
EOI 
EOI+1h 
SOI 
- 
- 
Sample Time 
windowa 
- 
- 
±10 
min 
±30 
min 
±5h 
±24h 
±48h 
- 
- 
±10 
min 
- 
- 
- 
- 
±10 
min 
±10 
min 
- 
- 
- 
IMP administration (IV infusion) 
REGN2810 
X-------X 
 
       X-------X 
X-------X 
        X-------X 
 
X 
 
 
Isatuximab 
 
X-------X 
 
X-------X 
 
X 
 
X-------X 
 
 
X 
 
Pharmacokineticsb 
REGN2810 
Sample ID 
S00f 
S01d 
S02e 
- 
S03 
S04 
S05 
S06f,g  
S07d 
- 
S00f 
S01d 
S00f 
S01d 
- 
- 
S00f 
- 
SF00 
Isatuximabh 
Sample ID 
P00c 
- 
P01i 
P02 
P03 
P04 
P05 
 P06c, 
j,k  
- 
P07i 
P00c,j 
- 
P00c,j  
- 
P01i 
P02 
P00c,j  
- 
- 
Immunogenicity (ADA)l  
REGN2810m 
AS00f,m  
- 
AS01f,m 
- 
- 
- 
AS00f m  
- 
ASF00n  
Isatuximabh,o  
AP00c,o  
- 
AP01c,o  
- 
- 
AP00c,o 
- 
AP00c,o 
- 
- 
AP00c,h,o  
- 
APF00h,p 
 
VV-CLIN-0507776 2.0


Amended Clinical Trial Protocol No. 05  
11-Jun-2019 
SAR650984-ACT15319 - isatuximab 
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Property of the Sanofi Group - strictly confidential 
Page 38 
a Time windows targeted for PK/pharmacodynamics and ADA sampling. 
b Refer to laboratory manual for sample collection, processing and shipping. REGN2810 PK samples to be collected: Cycle 1 predose (corresponding to SOI) and actual end of infusion (ie, EOI), EOI+ 4h, 72h, 168h, 
336h, and 504h (predose second administration [Day 1 of Cycle 2]) after start of first dose; EOI of second administration (Day 22 [Day 1 of Cycle 2]); then Cycles 3 and 4: predose and EOI; subsequent cycles: 
predose and at 90 days after the last study treatment administration); isatuximab PK samples to be collected: Cycle 1 predose and EOI, EOI+ 4h, 72h, 168h, 336h and 504h (predose second administration, Day 1 
Cycle 2); Cycle 1 Day 22 (corresponding to Day 1 of Cycle 2): EOI; then Cycle 3 Day 1: predose; Cycle 4 Day 1: predose, EOI, EOI+ 1h; subsequent cycles Day 1 predose. 
c Predose sample: isatuximab PK or ADA assessment could be drawn at the same time just before REGN2810 administration. 
d Sample collected just before (within 5 minutes) the actual end of infusion of REGN2810. 
e Sample collected for REGN2810 could be drawn at the same time as the end of infusion sample of isatuximab. 
f 
REGN2810 sample collected strictly before the start of REGN2810 infusion. 
g S06 sample must be collected even if the second infusion of REGN2810 is not done or delayed. 
h Isatuximab PK and ADA samples to be collected each cycle until the last study treatment for PK and until follow-up for ADA or at the cut-off date, whichever comes first. However, collection can be stopped earlier 
or reduced upon notification from the Sponsor based on the updated knowledge of isatuximab immunogenicity and PK. 
i 
Sample collected just before actual end of infusion of isatuximab. 
j 
Predose sample for isatuximab collected strictly before the start of isatuximab infusion. 
k P06 sample must be collected even if the patient withdraws from the study without receiving the second administration of isatuximab. 
l 
After start of study treatment, if 1 drug is prematurely discontinued, ADA samples for this drug will be collected on Day 1 of the 2 next cycles. If ADA test at the second cycle is positive or inconclusive, ADA testing 
will be repeated every 3 months until negative. The ADA sample collection for other drug should be done as planned. 
m During treatment phase, the ADA samples for REGN2810 must be collected before REGN2810 treatment administration at each time points: Cycle 1 Day1, Cycle 1 Day 22 (predose Cycle 2), and on Day 1 every 
3 cycles afterwards (ie, Cycle 5, Cycle 8, Cycle 11, Cycle 14 etc). In response to AEs of special interest, such as anaphylaxis or hypersensitivity, ADA samples closer to the event may be collected, based on the 
judgment of the Investigator and/or medical monitor. 
n During posttreatment follow-up period REGN2810 ADA samples are collected at 90 ±7 days after last study treatment and every 3 months thereafter until sample is negative (ASF01, ASF02…). 
o During treatment phase, the ADA samples for isatuximab must be collected before isatuximab treatment administration at each time (could be drawn at the same time just before REGN2810 administration). ADA 
samples are not collected at Cycle 1 Day 8 or Cycle 1 Day 15. 
p During posttreatment follow-up period isatuximab ADA samples are collected at 90 ±7 days after last study treatment and every 3 months thereafter until sample is negative (APF01, APF02…). 
Abbreviations: AB=antibody; ADA=anti-drug antibody; AP=antibody plasma (for isatuximab); AS=antibody serum (for REGN2810); EOI=end of IV infusion; P=plasma, PK=pharmacokinetic; RNT=relative nominal time; 
S=serum; SOI=start of IV infusion. 
 
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Amended Clinical Trial Protocol No. 05  
11-Jun-2019 
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Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 39 
2 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE .................................................................. 3 
1 
FLOWCHARTS .............................................................................................................................. 20 
1.1 
DESIGN DIAGRAM........................................................................................................................ 20 
1.2 
STUDY TREATMENT ADMINISTRATION .................................................................................... 21 
1.3 
STUDY FLOWCHART FOR PHASE 1, PHASE 2 COHORTS A-1, A-2, B AND CROSS-
OVER PART .................................................................................................................................. 22 
1.4 
STUDY FLOWCHART FOR COHORT C AND COHORT D ......................................................... 27 
1.5 
PHARMACOKINETICS/PHARMACODYNAMICS FLOWCHART ................................................. 32 
1.5.1 
For Phase 1 part, Stage 1 Phase 2 part of Cohort A-1 and Cohort B (not applicable for the 
patients with NSCLC who are enrolled for Phase 2 Stage 1 after implementation of 
Amendment #5 at individual sites) ................................................................................................. 32 
1.5.2 
For Phase 2 part of Cohort A-2, Stage 2 Phase 2 part of Cohort A-1 and Cohort B (tests for 
REGN2810 are not applicable for Cohort A-2, tests for PK are not applicable for cross-over 
part) ................................................................................................................................................ 35 
1.5.3 
For Cohort C and Cohort D (tests for REGN2810 are not applicable for Cohort C if 
isatuximab monotherapy is administered) ..................................................................................... 37 
2 
TABLE OF CONTENTS ................................................................................................................ 39 
2.1 
LIST OF TABLES ........................................................................................................................... 47 
2.2 
LIST OF FIGURES ......................................................................................................................... 48 
3 
LIST OF ABBREVIATIONS .......................................................................................................... 49 
4 
INTRODUCTION AND RATIONALE ............................................................................................. 52 
4.1 
INTRODUCTION ............................................................................................................................ 52 
4.1.1 
Cluster of differentiation 38 ............................................................................................................ 52 
4.1.2 
Programmed cell death 1 protein ................................................................................................... 52 
4.1.3 
Solid tumors ................................................................................................................................... 53 
4.1.3.1 
Non-small cell lung cancer ............................................................................................................. 53 
4.1.3.2 
Metastatic, castration resistant prostate cancer ............................................................................ 54 
4.2 
DESCRIPTION OF INVESTIGATIONAL MEDICINAL PRODUCT ............................................... 55 
4.2.1 
Isatuximab ...................................................................................................................................... 55 
4.2.1.1 
Clinical data .................................................................................................................................... 55 
4.2.2 
REGN2810 ..................................................................................................................................... 56 
4.2.2.1 
Clinical data .................................................................................................................................... 56 
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4.3 
RATIONALE ................................................................................................................................... 56 
4.3.1 
Study rationale ............................................................................................................................... 56 
4.3.2 
Schedule and dose of administration ............................................................................................. 59 
4.4 
BENEFIT/RISK ASSESSMENT ..................................................................................................... 60 
4.4.1 
Benefits .......................................................................................................................................... 60 
4.4.1.1 
Non-small cell lung cancer ............................................................................................................. 60 
4.4.1.2 
Metastatic, castration resistant prostate cancer ............................................................................ 60 
4.4.2 
Potential and identified risks .......................................................................................................... 60 
4.4.2.1 
Isatuximab ...................................................................................................................................... 60 
4.4.2.2 
REGN2810 ..................................................................................................................................... 61 
4.4.3 
Potential risk related to the combination ........................................................................................ 62 
4.4.4 
Preventative measures to minimize the risk of the combination .................................................... 62 
4.4.5 
Conclusion ..................................................................................................................................... 64 
5 
STUDY OBJECTIVES ................................................................................................................... 65 
5.1 
PRIMARY OBJECTIVES ............................................................................................................... 65 
5.2 
SECONDARY OBJECTIVES ......................................................................................................... 65 
5.3 
EXPLORATORY OBJECTIVES ..................................................................................................... 65 
6 
STUDY DESIGN ............................................................................................................................ 67 
6.1 
DESCRIPTION OF THE STUDY ................................................................................................... 67 
6.2 
PHASE 1 PART (SAFETY RUN-IN) .............................................................................................. 67 
6.2.1 
Starting dose and de-escalation design ......................................................................................... 67 
6.2.2 
Maximum tolerated dose ................................................................................................................ 68 
6.3 
PHASE 2 PART (EFFICACY SIGNAL) .......................................................................................... 68 
6.4 
CROSS-OVER PART (A SUBPART OF COHORT A-2) ............................................................... 69 
6.5 
RETREATMENT OF PATIENTS ................................................................................................... 70 
6.6 
DOSE DELAYS/MODIFICATIONS ................................................................................................ 70 
6.6.1 
General rules .................................................................................................................................. 70 
6.6.2 
Dose delay and dose omission ...................................................................................................... 71 
6.6.3 
Dose modifications ......................................................................................................................... 71 
6.6.4 
General guidelines for the management of immune-related adverse events ................................ 72 
6.6.5 
General guidelines for the management of infusion-associated reactions .................................... 73 
6.7 
DURATION OF STUDY PARTICIPATION .................................................................................... 75 
6.7.1 
Duration of study participation for each patient ............................................................................. 75 
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6.7.2 
Determination of end of clinical trial (all patients) .......................................................................... 77 
6.8 
INTERIM ANALYSIS ...................................................................................................................... 77 
6.9 
STUDY COMMITTEES .................................................................................................................. 77 
7 
SELECTION OF PATIENTS .......................................................................................................... 78 
7.1 
NUMBER OF PATIENTS ............................................................................................................... 78 
7.2 
INCLUSION CRITERIA .................................................................................................................. 78 
7.3 
EXCLUSION CRITERIA ................................................................................................................ 80 
8 
STUDY TREATMENTS ................................................................................................................. 83 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT ............................................................................... 83 
8.1.1 
Isatuximab (SAR650984) ............................................................................................................... 83 
8.1.1.1 
Pharmaceutical form ...................................................................................................................... 83 
8.1.1.2 
Dose of drug per administration ..................................................................................................... 83 
8.1.1.3 
Preparation, reconstitution and administration .............................................................................. 83 
8.1.2 
REGN2810 (SAR439684) .............................................................................................................. 84 
8.1.2.1 
Pharmaceutical form ...................................................................................................................... 84 
8.1.2.2 
Dose of drug per administration ..................................................................................................... 84 
8.1.2.3 
Preparation, reconstitution and administration .............................................................................. 84 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCT(S) .................................................................. 84 
8.2.1 
Acetaminophen (paracetamol) ....................................................................................................... 85 
8.2.2 
Ranitidine or equivalent ................................................................................................................. 85 
8.2.3 
Diphenhydramine or equivalent ..................................................................................................... 85 
8.2.4 
Methylprednisolone or equivalent .................................................................................................. 85 
8.2.5 
Montelukast .................................................................................................................................... 85 
8.3 
DOSING SEQUENCE .................................................................................................................... 85 
8.3.1 
Study treatment .............................................................................................................................. 85 
8.3.1.1 
Rate and duration of infusion ......................................................................................................... 87 
8.4 
BLINDING PROCEDURES ............................................................................................................ 87 
8.5 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP .............................................. 87 
8.6 
INVESTIGATIONAL MEDICINAL PRODUCT PACKAGING AND LABELING ............................. 88 
8.6.1 
Isatuximab ...................................................................................................................................... 88 
8.6.2 
REGN2810 ..................................................................................................................................... 88 
8.7 
STORAGE CONDITIONS AND SHELF LIFE ................................................................................ 88 
8.7.1 
Isatuximab ...................................................................................................................................... 88 
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8.7.2 
REGN2810 ..................................................................................................................................... 88 
8.8 
RESPONSIBILITIES ...................................................................................................................... 89 
8.8.1 
Treatment accountability and compliance...................................................................................... 89 
8.8.2 
Return and/or destruction of treatments ........................................................................................ 89 
8.9 
CONCOMITANT TREATMENT ..................................................................................................... 90 
8.9.1 
Prohibited concomitant treatments ................................................................................................ 90 
8.9.2 
Contraceptive measures and pregnancy counseling ..................................................................... 91 
9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT .............................................. 92 
9.1 
SAFETY ......................................................................................................................................... 92 
9.1.1 
Dose-limiting toxicities (Phase 1 only) ........................................................................................... 92 
9.1.2 
Adverse events .............................................................................................................................. 93 
9.1.3 
Laboratory safety variables ............................................................................................................ 93 
9.1.4 
Clinical examinations ..................................................................................................................... 93 
9.1.5 
Immunogenicity .............................................................................................................................. 93 
9.1.6 
Other safety endpoints ................................................................................................................... 94 
9.2 
PHARMACOKINETIC EVALUATION ............................................................................................ 94 
9.2.1 
Sampling time ................................................................................................................................ 94 
9.2.2 
Pharmacokinetic sample handling procedure ................................................................................ 94 
9.2.3 
Bioanalytical Methods .................................................................................................................... 94 
9.2.4 
Pharmacokinetic parameters ......................................................................................................... 95 
9.2.4.1 
Non-compartmental analysis ......................................................................................................... 95 
9.2.4.2 
Population approach ...................................................................................................................... 95 
9.3 
BIOMARKERS ............................................................................................................................... 96 
9.4 
SAMPLES BLOOD VOLUME ........................................................................................................ 97 
9.5 
FUTURE USE OF SAMPLES ........................................................................................................ 97 
9.6 
EFFICACY ..................................................................................................................................... 98 
9.6.1 
Primary endpoint ............................................................................................................................ 98 
9.6.2 
Secondary endpoints ..................................................................................................................... 99 
9.6.3 
Exploratory endpoints .................................................................................................................... 99 
10 
PATIENT SAFETY ....................................................................................................................... 101 
10.1 
SAFETY ENDPOINTS ASSESSED IN THIS TRIAL ................................................................... 101 
10.2 
SAFETY INSTRUCTIONS ........................................................................................................... 101 
10.3 
ADVERSE EVENTS MONITORING ............................................................................................ 101 
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10.4 
DEFINITIONS OF ADVERSE EVENT AND SERIOUS ADVERSE EVENT ................................ 101 
10.5 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING ........................ 102 
10.5.1 
Adverse events ............................................................................................................................ 102 
10.5.2 
Timely handling of certain adverse events .................................................................................. 103 
10.5.3 
Follow-up ...................................................................................................................................... 103 
10.5.4 
Treatment discontinuation due to non-serious adverse event ..................................................... 103 
10.5.5 
Adverse event of special interest ................................................................................................. 104 
10.5.6 
Laboratory abnormalities ............................................................................................................. 105 
10.5.7 
Guidelines for reporting product complaints (IMP/NIMP) ............................................................ 105 
10.6 
OBLIGATIONS OF THE SPONSOR ........................................................................................... 105 
11 
HANDLING OF PATIENT TEMPORARY AND PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION .................................... 106 
11.1 
PERMANENT TREATMENT DISCONTINUATION WITH INVESTIGATIONAL MEDICINAL 
PRODUCT(S) ............................................................................................................................... 106 
11.1.1 
List of criteria for permanent treatment discontinuation ............................................................... 106 
11.1.2 
Handling of patients after permanent treatment discontinuation ................................................. 107 
11.2 
REPLACEMENT OF PATIENTS ................................................................................................. 107 
12 
STUDY PROCEDURES .............................................................................................................. 108 
12.1 
VISIT SCHEDULE ........................................................................................................................ 108 
12.2 
BASELINE EVALUATION ............................................................................................................ 108 
12.3 
TREATMENT PERIOD ................................................................................................................ 110 
12.3.1 
Cycle 1 (Day 1, Day 8 and Day 15) ............................................................................................. 110 
12.3.2 
Subsequent cycles (Day 1) .......................................................................................................... 112 
12.4 
END OF TREATMENT................................................................................................................. 114 
12.5 
POST TREATMENT FOLLOW-UP .............................................................................................. 115 
12.5.1 
Safety follow-up period ................................................................................................................ 115 
12.5.2 
Survival follow-up period .............................................................................................................. 116 
12.5.3 
Post overall survival study cut-off date ........................................................................................ 117 
12.6 
CROSS-OVER PERIOD .............................................................................................................. 118 
13 
STATISTICAL CONSIDERATIONS ............................................................................................ 119 
13.1 
DETERMINATION OF SAMPLE SIZE ......................................................................................... 119 
13.2 
PATIENT DESCRIPTION ............................................................................................................ 120 
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13.2.1 
Disposition of patients .................................................................................................................. 120 
13.2.2 
Protocol deviations ....................................................................................................................... 120 
13.3 
ANALYSIS POPULATIONS ......................................................................................................... 120 
13.3.1 
All-treated/safety population ........................................................................................................ 120 
13.3.2 
Patients evaluable for dose-limiting toxicity assessment ............................................................. 120 
13.3.3 
Pharmacokinetic population ......................................................................................................... 121 
13.3.4 
Pharmacodynamic population ...................................................................................................... 121 
13.3.5 
Anti-drug antibody evaluable population ...................................................................................... 121 
13.3.6 
Cross-over population .................................................................................................................. 121 
13.3.7 
Response evaluable population ................................................................................................... 121 
13.4 
STATISTICAL METHODS ........................................................................................................... 121 
13.4.1 
Demographics and baseline characteristics ................................................................................ 122 
13.4.2 
Extent of investigational medicinal product exposure .................................................................. 122 
13.4.3 
Prior/concomitant medication/therapy.......................................................................................... 122 
13.4.4 
Analyses of efficacy variables ...................................................................................................... 122 
13.4.4.1 Analysis of primary efficacy endpoint........................................................................................... 123 
13.4.4.2 Analysis of secondary efficacy endpoints .................................................................................... 123 
13.4.5 
Analyses of safety data ................................................................................................................ 123 
13.4.5.1 Dose-limiting toxicities.................................................................................................................. 123 
13.4.5.2 Analyses of adverse events ......................................................................................................... 123 
13.4.5.3 Deaths .......................................................................................................................................... 125 
13.4.5.4 Clinical laboratory evaluations ..................................................................................................... 125 
13.4.5.5 Vital signs ..................................................................................................................................... 125 
13.4.5.6 Immunogenicity ............................................................................................................................ 125 
13.4.6 
Analyses of pharmacokinetic variables ........................................................................................ 126 
13.4.7 
Analyses of pharmacodynamic variables..................................................................................... 126 
13.5 
INTERIM ANALYSIS .................................................................................................................... 126 
14 
ETHICAL AND REGULATORY CONSIDERATIONS ................................................................. 127 
14.1 
ETHICAL AND REGULATORY STANDARDS ............................................................................ 127 
14.2 
INFORMED CONSENT ............................................................................................................... 127 
14.3 
HEALTH AUTHORITIES AND INSTITUTIONAL REVIEW BOARD/INDEPENDENT 
ETHICS COMMITTEE (IRB/IEC) ................................................................................................. 127 
15 
STUDY MONITORING................................................................................................................. 129 
15.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S) ..................................................................... 129 
15.2 
RESPONSIBILITIES OF SPONSOR ........................................................................................... 129 
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15.3 
SOURCE DOCUMENT REQUIREMENTS .................................................................................. 130 
15.4 
USE AND COMPLETION OF CASE REPORT FORMS AND ADDITIONAL REQUESTS ......... 130 
15.5 
USE OF COMPUTERIZED SYSTEMS ........................................................................................ 130 
16 
ADDITIONAL REQUIREMENTS ................................................................................................. 131 
16.1 
CURRICULUM VITAE.................................................................................................................. 131 
16.2 
RECORD RETENTION IN STUDY SITES(S) ............................................................................. 131 
16.3 
CONFIDENTIALITY ..................................................................................................................... 131 
16.4 
PROPERTY RIGHTS ................................................................................................................... 132 
16.5 
DATA PROTECTION ................................................................................................................... 132 
16.6 
INSURANCE COMPENSATION .................................................................................................. 132 
16.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES ............................... 133 
16.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE .......................................................................................................................................... 133 
16.8.1 
By the Sponsor ............................................................................................................................. 133 
16.8.2 
By the Investigator ....................................................................................................................... 134 
16.9 
CLINICAL TRIAL RESULTS ........................................................................................................ 134 
16.10 
PUBLICATIONS AND COMMUNICATIONS ............................................................................... 134 
17 
CLINICAL TRIAL PROTOCOL AMENDMENTS ........................................................................ 135 
18 
BIBLIOGRAPHIC REFERENCES ............................................................................................... 136 
19 
APPENDICES .............................................................................................................................. 141 
APPENDIX A 
PROSTATE CANCER CLINICAL TRIALS WORKING GROUP 3 CRITERIA FOR 
PROGRESSION .......................................................................................................................... 142 
APPENDIX B  
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS VERSION 1.1 ................... 146 
APPENDIX C 
EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE STATUS 
SCALE ......................................................................................................................................... 154 
APPENDIX D  
MODIFIED RESPONSE EVALUATION CRITERIA IN SOLID TUMORS FOR 
IMMUNE-BASED THERAPEUTICS ............................................................................................ 155 
APPENDIX E 
CLUSTER OF DIFFERENTIATION 38 BLOOD TEST INTERFERENCE GUIDELINE 
AABB2016 .................................................................................................................................... 157 
APPENDIX F 
NATIONAL CANCER INSTITUTE COMMON TERMINOLOGY CRITERIA FOR 
ADVERSE EVENTS..................................................................................................................... 161 
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APPENDIX G 
RECOMMENDED DOSE MODIFICATION OR DISCONTINUATION AND 
SUPPORTIVE CARE GUIDELINES FOR SPECIFIC REGN2810 DRUG-RELATED 
ADVERSE EVENTS..................................................................................................................... 162 
APPENDIX H 
MODIFICATION OF DIET IN RENAL DISEASE (MDRD) EQUATION ............................. 174 
APPENDIX I 
MULTIDISCIPLINARY COLLEGIAL MEETING REQUIREMENT ...................................... 175 
APPENDIX J 
PROTOCOL AMENDMENT HISTORY .............................................................................. 176 
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2.1 
LIST OF TABLES  
Table 1 - Dose modification for Phase 1 ....................................................................................................... 67 
Table 2 - Isatuximab and REGN2810 dose modification guidelines ............................................................. 72 
Table 3 - General guidelines for immune-related adverse events ................................................................ 73 
Table 4 - Infusion-associated reaction management .................................................................................... 75 
Table 5 - Bioanalytical methods for immune response assessment ............................................................. 94 
Table 6 - Bioanalytical methods for isatuximab and REGN2810 pharmacokinetic analysis ......................... 95 
Table 7 - List of pharmacokinetic parameters and definitions ....................................................................... 95 
Table 8 - Sample size calculation ................................................................................................................ 119 
Table 9 - Response evaluation definitions for ACT15319 ........................................................................... 142 
Table 10 - Prostate Cancer Clinical Trials Working Group 3 criteria for progression at trial entry by disease 
manifestation ............................................................................................................................................... 143 
Table 11 - Prostate Cancer Clinical Trials Working Group 3 criteria for progression during study............. 144 
Table 12 - Response criteria ....................................................................................................................... 149 
Table 13 - Response in patients with target disease .................................................................................. 151 
Table 14 - Response in patients with non-target disease only.................................................................... 152 
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) ............................ 155 
Table 16 - Assessment of timepoint response using modified Response Evaluation Criteria in Solid Tumors 
for immune-based therapies (iRECIST) ...................................................................................................... 156 
Table 17 - Colitis adverse event management ............................................................................................ 162 
Table 18 - Endocrine adverse event management ..................................................................................... 165 
Table 19 - Pneumonitis adverse event management .................................................................................. 166 
Table 20 - Renal adverse event management ............................................................................................ 168 
Table 21 - Dermatologic adverse event management ................................................................................ 170 
Table 22 - Hepatitis adverse event management ....................................................................................... 171 
Table 23 - Ophthalmology (uveitis) adverse event management ............................................................... 172 
Table 24 - Nausea and vomiting adverse event management ................................................................... 173 
 
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2.2 
LIST OF FIGURES  
Figure 1 - Overall study schema ................................................................................................................... 20 
Figure 2 - Cluster of differentiation 38 H-scores (3 × (% cells 3+) + 2 × (% cells 2+) + 1 × (% cells 1+) in 
treatment naive prostate adenocarcinoma .................................................................................................... 57 
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................................................................................................................................................................ 58 
 
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3 
LIST OF ABBREVIATIONS  
 
ADA: 
anti-drug antibody 
AE: 
adverse event 
AESI: 
adverse event of special interest 
ALP: 
alkaline phosphatase 
ALT: 
alanine aminotransferase 
ANC: 
absolute neutrophil count 
AST: 
aspartate aminotransferase 
ATC: 
Anatomincal Therapeutic Chemical 
AUC: 
area under the curve 
BUN: 
blood urea nitrogen 
CD38: 
cluster of differentiation 38 
CR: 
complete response 
CRF: 
case report form 
CSCC: 
cutaneous squamous cell carcinoma 
CT: 
computed tomography 
CTCAE: 
common terminology criteria for adverse events 
CTLA-4: 
cytotoxic T-lymphocyte-associated protein 4 
DL-1: 
dose level minus 1 
DLT: 
dose limiting toxicity 
DOR: 
duration of response 
DRF: 
discrepancy resolution form 
ECG: 
electrocardiogram 
ECOG: 
Eastern Cooperative Oncology Group 
e-CRF: 
electronic case report form 
eGFR: 
estimated glomerular filtration rate 
EOT: 
end of treatment 
FDA: 
Food and Drug Administration 
FDG-PET: 
fluorodeoxyglucose-positron emission tomography 
FFPE: 
formalin-fixed, paraffin-embedded 
GCP: 
good clinical practice  
GnRH: 
gonadotropin-releasing hormone 
IARs: 
infusion associated reactions 
IECs: 
institutional ethics committees 
IHC: 
immunohistochemistry 
IL: 
interleukin 
IMP: 
investigational medicinal product 
INR: 
international normalized ratio 
irAEs: 
immune-related adverse events 
IRBs: 
institutional review boards 
iRECIST: 
modified Response Evaluation Criteria in Solid Tumors for immune‑based 
therapies 
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ITSM: 
immunoreceptor tyrosine-based switch motif 
IV: 
intravenous 
mCRPC: 
metastatic, castration resistant prostate cancer 
MDRD: 
Modified Diet in Renal Disease 
MedDRA: 
Medical Dictionary for Regulatory Activities 
MM: 
multiple myeloma 
MRI: 
magnetic resonance imaging 
MSI: 
microsatellite instability 
MTD: 
maximum tolerated dose 
NCI: 
National Cancer Institute 
NE: 
not evaluable 
NGS: 
next-generation sequencing 
NIMPs: 
non-investigational medicinal products 
NK: 
natural killer 
NSCLC: 
non-small cell lung cancer 
ORR: 
objective response rate 
OS: 
overall survival 
PCSA: 
potentially clinically significant abnormality 
PCWG3: 
Prostate Cancer Clinical Trials Working Group 3 
PD: 
progressive disease 
PD-1: 
programmed cell death 1 
PD-L1: 
programmed cell death-ligand 1 
PD-L2: 
programmed cell death-ligand 2 
PFS: 
progression-free survival 
PI 3-K: 
phosphatidylinositol 3-kinase 
PK: 
pharmacokinetics 
PR: 
partial response 
PSA: 
prostate-specific antigen 
PT: 
preferred term 
PTT: 
partial thromboplastin time 
Q2W: 
once every 2 weeks 
Q3W: 
once every 3 weeks 
QW: 
once weekly 
RBC: 
red blood cell 
RECIST: 
modified Response Evaluation Criteria in Solid Tumors 
RP2D: 
recommended Phase 2 dose 
RRs: 
response rates 
SAE: 
serious adverse event 
SAP: 
Statistical Analysis Plan 
SD: 
stable disease 
SOC: 
system organ class 
TEAE: 
treatment-emergent adverse event 
TSH: 
thyroid stimulating hormone 
TTR: 
time to response 
ULN: 
upper limit of normal 
VGPR: 
very good partial response 
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WBC: 
white blood cell 
WOCBP: 
woman of childbearing potential 
 
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4 
INTRODUCTION AND RATIONALE  
4.1 
INTRODUCTION  
4.1.1 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). Cluster of differentiation 38 functions as a receptor 
binding to CD31 and is involved in cell adhesion and signal transduction. Cluster of 
differentiation 38 is also an ecto-enzyme catalyzing the synthesis and hydrolysis of cyclic 
adenosine-diphosphate-ribose from nicotinamide adenine dinucleotide to adenosine 
diphosphate-ribose (1). Adenosine diphosphate-ribose can be further converted into adenosine, a 
multifunctional immunosuppressive nucleoside that binds to different specific receptors expressed 
by immune effector cells (2). 
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, CD38 
expression has been shown. 
4.1.2 Programmed cell death 1 protein  
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades (3). The programmed cell death 1 (PD-1) 
receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune control (4). 
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 (5) and in complex with its ligands 
were first resolved (6, 7) 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 (8). 
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 
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ZAP70, which are involved in the CD3 T cell signaling cascade (9). The mechanism by which 
PD-1 down-modulates T cell responses is similar to, but distinct from that of CTLA-4 (10). 
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 (11). Expression has 
also been shown during thymic development on CD4-CD8- (double negative) T cells (12) as well 
as subsets of macrophages (13) and dendritic cells (14). The ligands for PD-1 (PD-L1 and PD-L2) 
are constitutively expressed or can be induced in a variety of cell types (15). Programmed cell 
death-ligand 1 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 (15). 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 (16, 17) which, via its interaction 
with the PD-1 receptor on tumor-specific T cells, plays a critical role in immune evasion by 
tumors (18). As a consequence, the PD-1/PD-L1 pathway is an attractive target for therapeutic 
intervention in cancer (19). 
Five anti-PD-1 and anti-PD-L1 antibodies, nivolumab, pembrolizumab, atezolizumab, avelumab 
and durvalumab, are now approved in multiple indications including lung cancer  
(20, 21, 22, 23, 24, 25, 26, 27). 
4.1.3 Solid tumors  
4.1.3.1 Non-small cell lung cancer  
Despite remarkable advances in targeted therapy, advanced lung cancer patients have not 
experienced a significant improvement in survival rates. Lung cancer has been shown to be 
responsive to checkpoint blockade therapy (28, 29). Checkpoint signals such as PD-1/PD-L1 
dampen T cell activation and allow tumors to escape the adaptive immune response. Response 
rates (RRs) in patients with pretreated, advanced non-small cell lung cancer (NSCLC) were much 
higher and more durable with PD-1 blockade therapy compared to standard-of-care, cytotoxic 
chemotherapy. Therefore, PD-1 inhibitors such as nivolumab, pembrolizumab and atezolizumab 
(20, 21, 22, 23) were rapidly approved for both squamous and non-squamous lung cancer in the 
pretreated population. Recently pembrolizumab was also approved, either as a monotherapy, or in 
combination with pemetrexed and carboplatin, as first-line treatment of patients with a subset of 
metastatic NSCLC (24, 25). 
However, the majority of patients with NSCLC who respond to PD-1/PD-L1 inhibition will 
eventually progress. This leaves an unmet need for a large and growing population, especially 
those patients without actionable oncogenic driver mutations who are not eligible for subsequent 
chemotherapy. A recent preclinical study from researchers at MD Anderson suggested that CD38 
may be involved in the resistance to anti-PD-1 in a NSCLC in vivo model (30, 31). 
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In this study (ACT15319), the efficacy endpoints for patients with NSCLC are selected based on 
modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (Appendix B ;32) and 
modified Response Evaluation Criteria in Solid Tumors for immune-based therapies (iRECIST) 
(Appendix D;33). 
4.1.3.2 Metastatic, castration resistant prostate cancer  
The prognosis for patients with castration resistant prostate cancer with disseminated metastatic 
spread remains poor. For the men who have metastatic prostate cancer at the time of diagnosis, 
their 5-year survival, although improved from 2 decades ago, is still only 28.2% (34). For men 
with metastatic, castration resistant prostate cancer (mCRPC), the median overall survival (OS) in 
recent Phase 3 studies has ranged from 12.2 to 34.7 months (35, 36, 37, 38, 39). The approved 
androgen deprivation therapy and chemotherapy have demonstrated significant improvements in 
OS but ultimately metastatic prostate cancer remains incurable. The current standard of care for 
this population is cabazitaxel. From limited retrospective studies, the best clinical response of 
partial response (PR) may be as high as 25% to 30% (40, 41, 42, 43). 
Targeting the immune system represents an appealing option for the development of anti-cancer 
treatment. The cancer vaccine sipuleucel-T has been approved in the USA for use in mCRPC. A 
preliminary analysis of a Phase 2 trial which studied the efficacy of pembrolizumab in patients 
with mCRPC progressing on enzalutamide, demonstrated 4 of 20 patients had achieved a 
confirmed prostate-specific antigen (PSA) reduction ≥50%. Two of the 4 PSA responders had 
measurable disease achieved a durable PR (44, 45). In another Phase 2 study, in PD-L1 positive 
patients with mCRPC who failed or were unable to receive standard of care therapy, 13% of the 
patients had a confirmed PR with median duration of response of 59 weeks. Stable disease (SD) 
rate was 39% (46). These data indicate PD-1 inhibitors may have activity in a subset of patients 
with mCRPC. 
Cluster of differentiation 38 is expressed on prostate adenocarcinoma. Based on preclinical 
studies indicating that isatuximab induced antibody-dependent cellular-mediated cytotoxicity can 
be enhanced through the inhibition of PD-1, the combination therapy of isatuximab and 
REGN2810 (an anti-PD-1 antibody currently in clinical development) may provide another option 
for the treatment of patients with mCRPC who have failed or are not eligible for standard of 
care (47). 
In this study (ACT15319), the primary efficacy endpoint for patients with mCRPC are selected 
based on PCWG3 guidance (Appendix A;48) and similarly with TOPARP, which led to the 
breakthrough designation of olaparib in prostate cancer by the US Food and Drug Administration 
(FDA) in 2016 (49). 
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4.2 
DESCRIPTION OF INVESTIGATIONAL MEDICINAL PRODUCT  
4.2.1 Isatuximab  
Isatuximab (SAR650984) is a monoclonal antibody 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 (50). 
4.2.1.1 Clinical data  
At the cut-off date of 05 January 2017, a total of 323 patients were treated with isatuximab in 
7 ongoing studies: TED10893, TCD11863, TCD14079, TCD13983, TED14154, TED14095, and 
EFC14335. All patients had hematological malignancy. The Phase 1 portion of the TED10893 
study (monotherapy; relapsed/refractory multiple myeloma [MM] and other hematological 
malignancies) and TCD11863 were completed. 
For TED10893 (Phase 1, monotherapy; relapsed/refractory MM and other hematological 
malignancies), a total of 89 patients with CD38+ hematological malignancies were treated with 
isatuximab. Median time on treatment was 10.1 weeks (2 to 16 weeks) and 8 patients remained on 
therapy at the analysis cut-off date. In patients with MM (N = 84), the median age was 64 years 
(40 to 81 years). The median time from diagnosis to first isatuximab dosing was 5.8 years (1.2 to 
22.8 years). Median number of prior lines of therapies was 5.0 (1 to 13); 94.0% previously 
received lenalidomide, 40.5% previously received pomalidomide, 98.8% previously received 
bortezomib, and 42.9% previously received carfilzomib. Objective response rate (ORR) according 
to Investigator assessment European Society for Blood and Marrow Transplantation criteria 
among the 84 MM treated-patients was 20.2% (1 complete response [CR], 16 PR). Clinical 
benefit response (≥minimal response) was 26.2% and best response was SD in 42.9% of the MM 
treated-patients. The minimal response or better occurred at all dose levels ≥1 mg/kg. In patients 
treated at doses ≥10 mg/kg in dose escalation and expansion cohorts (n = 63), ORR was 23.8% 
(n = 15/63), and the clinical benefit response was 30.2% (n = 19/63). In patients treated at 
10 mg/kg once every 2 weeks (Q2W) in the high-risk cohort (n = 18), ORR was 16.7% (n = 3/18) 
and clinical benefit response was 27.8% (n = 5/18). 
Study TCD11863 evaluated the combination of isatuximab with standard doses of lenalidomide 
and dexamethasone. Two schedules of isatuximab administration were evaluated, Q2W and once 
weekly (QW)/Q2W. Fifty-seven patients were enrolled in this study. The first part of the trial 
evaluated 3 doses of isatuximab 3, 5, and 10 mg/kg using the Q2W schedule of administration; 
among the patients treated at 10 mg/kg (n = 24), the ORR was 62.5% with a PR rate of 20.8%, 
very good partial response (VGPR) of 33.3% and stringent complete response of 8.3%. Among 
the patients treated in the second part of the trial (QW/Q2W schedule), the ORR was 50% for both 
10 mg/kg (n = 12) and 20 mg/kg (n = 10) QW/Q2W. At 10 mg/kg QW/Q2W, best overall 
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response was PR for 2 patients and VGPR for 4 patients, whereas at the 20 mg/kg QW/Q2W dose, 
all responses were VGPR. 
Safety data are detailed in Section 4.4.2.1. Please refer to the isatuximab Investigator’s Brochure 
for more information on the current safety and efficacy of isatuximab. 
4.2.2 REGN2810  
REGN2810 (cemiplimab) is a high affinity hinge-stabilized IgG4P human antibody to the PD-1 
receptor (PDCD1, CD279) that blocks PD-1/PD-L1-mediated T cell inhibition. REGN2810 
displayed a robust, dose-dependent suppression of MC38.Ova tumors in the syngeneic mouse 
tumor model. The nonclinical activity of REGN2810 is similar to 2 in-house generated anti-PD-1 
comparator antibodies with identical amino acid sequence to nivolumab and pembrolizumab 
(based on publically available sequence data). 
4.2.2.1 Clinical data  
Cumulatively, as of 20 January 2017, 459 patients have been treated with REGN2810 either as 
monotherapy or in combination with radiotherapy and/or other cancer therapy in the 3 ongoing 
studies. A total of 287 patients (62.5%) experienced at least 1 treatment-related adverse event 
(AE) of which 62 patients (13.5%) experienced Grade 3 or higher treatment-related AEs. 
Thirty-five patients (7.6%) experienced treatment-related serious adverse events (SAE). 
Efficacy data are available from the ongoing first in human study with REGN2810 
(Study R2810-ONC-1423) in patients with advanced solid malignancies, which includes tumor 
types known to respond poorly to PD-1/PD-L1 blockade. Preliminary efficacy has been observed 
in NSCLC cohorts in R2810-ONC-1423, with an overall RR of 27.2% and a disease control rate 
of 69.1%. All RRs are by Investigator assessments. 
Safety data are detailed in Section 4.4.2.2. Please refer to the REGN2810 Investigator’s Brochure 
for more information on the current safety and efficacy of REGN2810. 
4.3 
RATIONALE  
4.3.1 Study rationale  
Anti-PD-1 monoclonal antibodies have changed the landscape of cancer therapy. Nivolumab and 
pembrolizumab were granted accelerated approval by the US FDA in 2014. Despite their success, 
optimal outcomes for many patients will require combination therapies. Numerous clinical studies 
are currently evaluating anti-PD-1 antibodies in combination with chemotherapy, targeted 
therapies and other immunotherapies in patients with solid tumors and hematological 
malignancies. 
Cluster of differentiation 38 expression is well documented in hematological cancers, including 
MM, lymphomas and leukemias. In solid tumors, CD38 is found expressed on the tumor cells of 
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treatment naïve prostate adenocarcinoma and glioblastoma biopsies (Sanofi report NCB16V1). 
Therefore isatuximab monotherapy cohort will be initiated in patients with prostate 
adenocarcinoma upon positive signal of isatuximab and REGN2810 combination Phase 2 Stage 1. 
Figure 2 shows the H-scores for CD38 in tumor tissues from prostate adenocarcinoma patients at 
different stages of the disease (Gleason score 6 to 10). H-scores in normal prostate tissues (N) are 
also shown. 
Figure 2 - Cluster of differentiation 38 H-scores (3 × (% cells 3+) + 2 × (% cells 2+) + 1 × (% cells 1+) 
in treatment naive prostate adenocarcinoma  
 
Abbreviations: GS=Gleason score; N=normal prostate tissues. 
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 (51). 
E) CD38 expressing mouse tumor cells inhibit the proliferation of autologous T cells (47). 
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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 (Figure 3) 
(30, 31). 
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. 
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B) Isatuximab restores T cell function inhibited by regulatory T cells (47). 
C) Isatuximab induces activation of NK cells and increases their cytolytic activity. 
D) Isatuximab increases macrophage phagocytic activity and M1 polarization. 
Isatuximab single agent has shown clinical response in relapsed/refractory MM patients and in 
combination with immuno-modulatory agents. Although isatuximab has not been tested in solid 
tumors, we hypothesize, based on the immunomodulatory activities described above, that 
isatuximab may contribute reshaping the tumor immune-environment and will enhance the 
activity of anti-PD-1 therapy (or antibody). 
4.3.2 Schedule and dose of administration  
REGN2810 is administered as an intravenous (IV) infusion every 3 weeks at 350 mg dose. 
A flat IV REGN2810 dose of 350 mg once every 3 weeks (Q3W) was selected, based on 
population pharmacokinetics (PK) modeling and simulation, as it is expected to provide exposure 
that closely replicates that observed in patients (mean weight: 80 kg) for the 3 mg/kg Q2W IV 
regimen in the ongoing first-in-human study R2810-ONC-1423 (NCT02383212). Simulations of 
REGN2810 exposure in 1000 patients using population PK analyses indicated that: 
 
A 350 mg Q3W dose in patients resulted in similar (20% difference) Ctrough, AUC12 weeks, 
and Cmax as compared to the 3 mg/kg Q2W dose in the first-in-human patient population 
(80 kg), and exceeded those observed at the 1 mg/kg Q2W dose. 
 
The variability in REGN2810 exposure (coefficient of variation) was similar for 
body-weight adjusted doses as compared to flat doses. 
Given the similar predicted exposure for 350 mg Q3W when compared to the 3 mg/kg Q2W 
regimen, a similar efficacy/safety profile is also expected. Therefore, the 350 mg Q3W IV dose of 
REGN2810 is being proposed across the REGN2810 program. 
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 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 internal 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 prostate cancer compared to MM (ie, less target-mediated drug 
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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 will be tested 
as the loading period may not be necessary to ensure activity. 
4.4 
BENEFIT/RISK ASSESSMENT  
4.4.1 Benefits  
4.4.1.1 Non-small cell lung cancer  
Please refer to Section 4.1.3.1. 
4.4.1.2 Metastatic, castration resistant prostate cancer  
Please refer to Section 4.1.3.2. 
4.4.2 Potential and identified risks  
4.4.2.1 Isatuximab  
As of 05 January 2017, 323 patients have received isatuximab across 5 ongoing or completed 
Phase 1/2 clinical studies conducted in patients with MM or other hematological malignancies 
(319 patients with MM). Isatuximab has been investigated either as monotherapy or in 
combination with conventional treatment regimens in MM. The safety profile of isatuximab 
monotherapy has been best characterized in 186 patients (including 181 patients with MM) from 
study TED10893 (Phase 1 and Phase 2), where the most common treatment emergent AEs, 
excluding the AEs corresponding to laboratory abnormalities, include infusion-associated 
reactions (IARs), fatigue, nausea, upper respiratory infection, cough, back pain and diarrhea. 
Infusion reactions occurred in 49.4% and 51.5% of the patients from TED10893 Phase 1 
(concluded) and Phase 2 Stage 1 (ongoing), respectively. 
The infusion-associated reactions (IARs) associated with isatuximab in patients who are 
administered appropriate primary prophylaxis (see also Section 4.4.4) 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. Primary prophylaxis routinely administered to 
all the patients consists of 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. 
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In the event of a mild or moderate IAR, the isatuximab infusion should be interrupted and may 
subsequently resume after recovery at a slower infusion rate under close monitoring and with 
supportive care, as needed. Prior to restarting the infusion, patients may receive additional 
medication based on medical judgment; recommended medications consist of diphenhydramine 
25 mg IV and methylprednisolone 100 mg IV (or equivalent). In case of a severe hypersensitivity 
reaction, however, treatment with isatuximab is to be immediately and permanently discontinued. 
In addition to the occurrence of infusion reactions, cytokine release syndrome described above, 
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). 
To investigate the potential for immunogenicity, anti-drug antibodies (ADAs) are systematically 
tested across the isatuximab program, using a validated PandA method (DOH1297). As of 
30 September 2016, 285 patients (2747 samples) from studies TED10893 (Phase 1 and Phase 2 
Stage 1), TED14154, TCD10479, TCD11863, and TCD13983 have been evaluated for ADAs. 
Isatuximab induced ADAs in 4.2% of the patients (12/285 patients), with 8 patients from study 
TED10893 Phase 1 and 4 patients from study TCD11863 being found positive for ADAs. Among 
the 12 patients with positive ADA status, 8 had transiently positive ADA (positive ADA at 1 time 
point), 1 patient had transiently non-treatment induced positive ADA (positive ADA at baseline), 
2 patients had persistently positive ADA (positive ADA titers in samples from 2 separate time 
points), and 1 patient had pending status (transient versus persistent) depending on subsequent 
time points to be analyzed. Monitoring of ADAs will continue in current and future clinical trials. 
4.4.2.2 REGN2810  
The safety profiles of the known anti-PD-1 agents are similar and most notably include a range of 
AEs considered as immune-related adverse events (irAEs) listed in the REGN2810 Investigator’s 
Brochure. The most commonly observed treatment-related irAEs associated with these 
monoclonal antibodies are: fatigue, pyrexia, chills, infusion reactions, skin rash, diarrhea/colitis, 
endocrine toxicities, hepatic toxicities (mainly asymptomatic elevations in aspartate 
aminotransferase [AST] and alanine aminotransferase [ALT] levels), pneumonitis, uveitis, 
interstitial nephritis, pancreatitis and neurologic syndromes (52, 53). Increasing use and an 
understanding of how to manage the adverse reactions associated with these agents appears to be 
have lessened the morbidity as well as the mortality associated with severe irAEs (53). 
Cumulatively, as of 20 January 2017, 459 patients have been treated with REGN2810 either as 
monotherapy or in combination with radiotherapy and/or other cancer therapy in the 3 ongoing 
studies. Below are summary from the 2 studies in solid tumors (REGN2810 is being evaluated in 
two Phase 1 clinical studies: R2810-ONC-1423 and R1979 ONC-1504), and one Phase 2 clinical 
study: R2810-ONC-1540. 
R2810-ONC-1423 is a first-in-human repeat dose study with REGN2810 as single therapy and in 
combination with other anti-cancer therapies in patients with advanced malignancies. As of 
20 January 2017, a total of 353 patients have been enrolled and treated with different dose levels 
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(1 mg/kg Q2W, 3 mg/kg Q2W, 10 mg/kg Q2W, and 200 mg Q2W) of REGN2810 as 
monotherapy as well as in combination with hypofractionated radiation therapy and/or 
cyclophosphamide or in combination with hypofractionated radiation therapy, cyclophosphamide 
and granulocyte macrophage colony-stimulating factor or in combination with chemotherapy 
agents (low dose carboplatin plus docetaxel, low dose docetaxel, full dose carboplatin plus 
paclitaxel or carboplatin plus pemetrexed); in 2 NSCLC Expansion Cohorts (21 and 22) 
REGN2810 is given at 3 mg/kg Q3W in combination with chemotherapy. Among 353 patients, 
the most common treatment-emergent adverse events (TEAEs) occurring in 10% or more of all 
patients were fatigue (n = 105, 29.7%), nausea (n = 84, 23.8%), decreased appetite (n = 56, 
15.9%), anemia (n = 53, 15.0%), constipation (n = 52, 14.7%), arthralgia (n = 45, 12.7%), 
diarrhoea (n = 45, 12.7%), dyspnea (n = 45, 12.7%), cough (n = 43, 12.2%), pyrexia (n = 40, 
11.3%), vomiting (n = 40, 11.3%), asthenia (n = 37, 10.5%) and back pain (n = 37, 10.5%). 
R2810-ONC-1540 is a Phase 2, non-randomized, 2-group, multicenter study of REGN2810 at a 
dose of 3 mg/kg Q2W for patients with advanced cutaneous squamous cell carcinoma (CSCC). 
The study has 2 groups. Group 1 is for patients with metastatic (nodal or distant) CSCC. Group 2 
is for patients with unresectable locally advanced CSCC. As of 20 January 2017, a total of 
53 patients have been enrolled and treated with 3 mg/kg REGN2810 in this study. Thirty-two 
patients were enrolled in the metastatic CSCC group and 21 patients in the unresectable locally 
advanced CSCC group. The most common TEAEs occurring in 10% or more of all patients 
included fatigue (n = 13, 24.5%), nausea (n = 7, 13.2%) and decreased appetite (n = 6, 11.3%). 
4.4.3 Potential risk related to the combination  
Based on the available pre-clinical and clinical data from each individual drug, the potentially 
overlapping adverse drug reactions anticipated with the isatuximab and REGN2810 combination 
consist of fatigue, diarrhea, and infusion related reactions, which are all manageable. 
4.4.4 Preventative measures to minimize the risk of the combination  
To minimize the risk of IARs, all the patients 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 
commonly observed with monoclonal antibodies. In an attempt to further mitigate the incidence 
and severity of IARs, it is recommended that the initial infusion rate 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 a mild or moderate hypersensitivity reaction, the isatuximab infusion should be 
interrupted and may subsequently resume after recovery, at a slower infusion rate, under close 
monitoring and with supportive care as needed. Prior to restarting the infusion, patients may 
receive additional medication per the judgment of the Investigator; recommended medications 
consist of diphenhydramine 25 mg IV and methylprednisolone 100 mg IV (or equivalent). In the 
event of a severe hypersensitivity reaction, treatment with isatuximab is to be immediately and 
permanently discontinued.  
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For all patients, vital signs should be obtained prior to the start of each isatuximab infusion, 
1 hour after the start of the infusion, at the end of infusion, and if clinically indicated during the 
infusion. 
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 treatment emergent adverse events related to 
REGN2810, the exclusion criteria in the Study ACT15319 include: 
 
Active, known, or suspected autoimmune disease that has required systemic treatment in 
the past 2 years (ie, with use of disease modifying agents, corticosteroids or 
immunosuppressive drugs), except for replacement therapy (eg, thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc). 
 
Treatment-related immune-mediated (or immune-related) AEs from immune-modulatory 
agents (including but not limited to anti-PD-1/PD-L1 agents, anti-CTLA-4 monoclonal 
antibodies, and PI3K δ inhibitors) 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 investigational medicinal product (IMP). 
 
Comorbidity requiring corticosteroid therapy (>10 mg prednisone/day or equivalent) 
within 14 days of IMP initiation. Physiologic replacement doses are allowed even if they 
are >10 mg of prednisone/day or equivalent, as long as they are not being administered for 
immunosuppressive intent. Inhaled or topical steroids are permitted, provided that they are 
not for treatment of an autoimmune disorder. 
 
History of or current interstitial lung disease or pneumonitis that requires oral or IV 
glucocorticoids to assist with management (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. 
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 measures that will continue to be 
implemented to minimize the risks in study patients. 
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General guidelines for the management of irAEs, including some specific irAEs such as colitis, 
endocrine AEs, pneumonitis, renal AEs, dermatologic AEs, hepatitis, ophthalmologic AEs  
(eg, uveitis) are also provided in the study protocol. 
4.4.5 Conclusion  
Overall, the anticipated benefit/risk ratio of isatuximab in combination with REGN2810 supports 
the conduct of study ACT15319 in patients with mCRPC and NSCLC. 
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5 
STUDY OBJECTIVES  
5.1 
PRIMARY OBJECTIVES  
Phase 1: 
 
To characterize the safety and tolerability of isatuximab in combination with REGN2810 
in patients with mCRPC who are naïve to anti-PD-1/PD-L1-containing therapy naive, or 
NSCLC who progressed on anti-PD-1/PD-L1-containing therapy, and to confirm the 
recommended Phase 2 dose (RP2D). 
Phase 2 (applicable to Cohorts A-1, A-2, B, C, and D): 
 
To assess the RR of isatuximab in combination with REGN2810 in patients with either 
mCRPC who are anti-PD-1/PD-L1 therapy naive, or NSCLC who progressed on 
anti-PD-1/PD-L1 therapy, or of isatuximab as single agent in patients with mCRPC. 
5.2 
SECONDARY OBJECTIVES  
 
To evaluate the safety of the combination of isatuximab with REGN2810 or isatuximab 
monotherapy. 
 
To evaluate the immunogenicity of isatuximab and REGN2810. 
 
To characterize the PK profile of isatuximab single agent or in combination with 
REGN2810, and to characterize the PK of REGN2810 in combination with isatuximab. 
 
To assess overall efficacy of isatuximab in combination with REGN2810 or single agent 
(tumor burden change, duration of response [DOR], disease control rate [DCR], and 
progression-free survival [PFS]). 
5.3 
EXPLORATORY OBJECTIVES  
 
To explore the preliminary overall efficacy: OS, time to response (TTR); for patients with 
mCRPC: PSA RR, radiographic RR, duration of PSA response, duration of radiographic 
response, time to PSA response, time to radiographic response and time to PSA 
progression. 
 
To explore the preliminary overall efficacy of isatuximab in combination with REGN2810 
in patients with mCRPC who progress on isatuximab monotherapy. 
 
To explore the relationship between clinical response and CD38 expression, PD-L1 
expression and more broadly immune markers in tumor biopsy at baseline as potential 
predictive markers of response. 
 
To explore tumor genetic markers at baseline including tumor mutational load and 
microsatellite instability (MSI) status as potential markers of response to anti-PD-1 
therapy. 
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 
To explore immune genetic markers in blood at baseline such as polymorphisms in FcγR 
receptors which are important for effector functions of isatuximab. 
 
To evaluate pharmacodynamic biomarkers in response to investigational medicinal 
product: immunophenotype to analyze the modulation of different immune cell 
populations in peripheral blood, immune markers in tumor, transcriptome in tumor and 
plasma or serum cytokine levels. 
 
A panel of tumor somatic mutations (ie, tumor mutational profile) will be analyzed at 
baseline and upon treatment in blood to explore potential mechanisms of escape in 
response to treatment. 
 
To perform PK/pharmacodynamics analysis if possible with any relevant 
pharmacodynamics markers mentioned above, and correlation with safety/efficacy 
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6 
STUDY DESIGN  
6.1 
DESCRIPTION OF THE STUDY  
This is an open-label, multi-center, non-comparative, Phase 1/2 study to evaluate the safety, 
preliminary efficacy and PK of isatuximab in combination with REGN2810 or isatuximab alone 
in patients with advanced malignancies. 
The study will be conducted in up to 3 parts: 
 
The Phase 1 part (safety run-in) is to characterize the safety and tolerability of isatuximab 
in combination with REGN2810 and to confirm the RP2D. 
 
The Phase 2 part (efficacy signal search with Simon’s 2-stage design) is to assess the 
preliminary efficacy of isatuximab in combination with REGN2810 or isatuximab alone. 
 
Cross-over part (a subpart of Cohort A-2) in which patients who progress on isatuximab 
monotherapy may receive isatuximab plus REGN2810 if they still fulfill the eligibility 
criteria (except exclusion criteria #3 and #8). 
Isatuximab and REGN2810 are defined in this protocol as “study treatments”. 
6.2 
PHASE 1 PART (SAFETY RUN-IN)  
Patients with either mCRPC or NSCLC will be enrolled in the Phase 1 part. There is no minimum 
patient number requirement for either tumor type. 
6.2.1 Starting dose and de-escalation design  
The starting dose is selected based on past and ongoing clinical trials. Starting dose is 350 mg 
Q3W for REGN2810 with isatuximab given 10 mg/kg QW for 3 weeks followed by Q3W. Dose 
de-escalation will be performed if necessary as defined in Table 1 below: 
Table 1 - Dose modification for Phase 1  
Dose level 
Isatuximab 
REGN2810 
Starting dose 
10 mg/kg 
QW × 3->Q3W 
350 mg 
Q3W 
Minus 1 (DL-1) 
5 mg/kg 
QW × 3->Q3W 
350 mg 
Q3W 
Abbreviations: DL=dose level; QW=once weekly; Q3W=once every 3 weeks. 
At the starting dose, dose limiting toxicity (DLT) will be assessed in the first 6 patients  
(1 cycle; 21 days): 
 
If ≤1/6 patient has DLT, the starting dose will be the RP2D. 
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 
If 2/6 patients have DLT, 6 additional patients will be enrolled at starting dose level: 
- 
If a total of 2/12 patients treated at starting dose have DLT, starting dose will be the 
RP2D. 
- 
If a total of ≥3/12 patients have DLT, dose will be de-escalated to dose level minus  
1 (DL-1). 
 
If ≥3/6 patients have DLT, dose will be de-escalated to DL-1. 
An additional 6 patients may be enrolled at DL-1; if ≤1/6 patient has DLT, DL-1 will be the 
RP2D. At DL-1, if ≥2/6 patients have DLT, an alternative dose/schedule might be considered 
from a safety viewpoint by the Sponsor after consulting with the Investigators who recruit patients 
for the Phase 1 part. If 2/6 patients have DLT, 6 additional patients will be enrolled at DL-1; if a 
total of 2/12 patients treated at DL-1 have DLT, DL-1 will be the RP2D.  If a total of ≥3/12 
patients have DLT, an alternative dose/schedule might be considered from a safety viewpoint by 
the Sponsor after consulting with the Investigators who recruit patients for the Phase 1 part. 
The DLT observation period is 1 cycle (21 days). The duration of the DLT observation period will 
be longer for patients 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. All AEs during treatment, 
unless due to disease progression or to a cause obviously unrelated to IMP, will be taken into 
consideration by the Sponsor and recruiting Investigators for the determination of the maximum 
tolerated dose (MTD) and RP2D. 
IMP initiation of patients in the Phase 1 part is to be staggered by ≥3 days. 
The National Cancer Institute (NCI) common terminology criteria for adverse events (CTCAE) 
version 4.03 (Appendix F) will be used to assess the severity of AEs. Causal relationship is to be 
determined by the Investigator. The DLTs will be confirmed by the Sponsor and recruiting 
Investigators. 
6.2.2 Maximum tolerated dose  
The MTD is defined as the highest dose level at which no more than 1 out of 6 patients (starting 
dose or DL-1) or 2 out of 12 patients (starting dose) experience an IMP related DLT. The RP2D is 
defined as the dose selected for the Phase 2 portion. The Sponsor and recruiting investigators will 
review the overall data observed to decide MTD and RP2D for the isatuximab and REGN2810 
combination. 
6.3 
PHASE 2 PART (EFFICACY SIGNAL)  
The Phase 2 part may include up to 5 cohorts (see design diagram in Section 1.1): 
 
Cohort A-1: mCRPC, isatuximab and REGN2810 combination therapy. 
 
Cohort A-2: mCRPC, isatuximab monotherapy. 
 
Cohort B: NSCLC, isatuximab and REGN2810 combination therapy. 
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 
Possibly Cohort C: mCRPC, isatuximab and REGN2810 combination therapy, or 
isatuximab monotherapy without initial isatuximab weekly dosing. 
 
Possibly Cohort D: NSCLC, isatuximab and REGN2810 combination therapy without 
initial isatuximab weekly dosing. 
A Simon’s 2-stage design will be used in each cohort. Enrollment in Cohort A-2 will start only if 
the decision to proceed to Phase 2 Stage 2 in Cohort A-1 is made. 
The patients treated at the RP2D of isatuximab and REGN2810 in combination during Phase 1 
will be included in the efficacy analysis together with patients of the same tumor type in Stage 1 
of Phase 2. Based on the number of objective responses (observed at least 6 cycles after the last 
ongoing patient receives first dose of IMP) 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 Investigators. After enrollment completion of Phase 2 Stage 1, if 
efficacy results do not warrant initiation of Stage 2, enrolment will be paused until sufficient 
results or analyses warrant initiation of Phase 2 Stage 2. 
For patients with mCRPC, if it is decided to run Phase 2 Stage 2, an isatuximab monotherapy 
cohort will be initiated for this population (Cohort A-2); patients with mCRPC will be randomly 
assigned in a 1:1 randomization ratio to enter Cohort A-1, isatuximab and REGN2810 
combination (Phase 2 Stage 2) or Cohort A-2, isatuximab monotherapy (Phase 2 Stage 1). The 
isatuximab single agent dose and schedule for cohort A-2 is 10 mg/kg QW for 3 weeks followed 
by Q3W. 
Based on the efficacy signal and the totality of data observed within a tumor type at end of 
Phase 2 Stage 2, the Sponsor may decide to further study isatuximab 10 mg/kg Q3W in 
combination with REGN2810 or isatuximab as a monotherapy in patients with mCRPC 
(Cohort C) or isatuximab 10 mg/kg Q3W in combination with REGN2810 in patients with 
NSCLC (Cohort D), without the isatuximab doses of 10 mg/kg QW for 3 weeks. The schedule 
without the initial weekly dosing may be more practical for patients and health care providers. 
Objectives and study design considerations for Cohort C and Cohort D are the same as those for 
other cohorts in the same tumor type. The Sponsor may decide to test an isatuximab dose of 
20 mg/kg in case of inadequate efficacy and PK results. 
6.4 
CROSS-OVER PART (A SUBPART OF COHORT A-2)  
Patients from Cohort A-2 who progress on isatuximab monotherapy may receive isatuximab plus 
REGN2810 at the discretion of the Investigators and if they still fulfill the eligibility criteria 
(except exclusion criteria #3 and #8). The screening period for the cross-over part is 28 days from 
PD confirmation. 
All screening processes for the patients in the Phase 1 and Phase 2 parts are to be conducted 
before combination IMP initiation for the cross-over part, except informed consent, demography, 
medical/surgical and disease history, and weight/height. Tumor biopsy at cross-over screening is 
required unless clinically unfeasible and after discussion with the Sanofi Medical Monitor. On 
treatment biopsy at Cycle 2, Day 1 (≤7 days; after IMP administration on C1D15 wherever 
applicable, prior to IMP administration on Cycle 2 Day 1) of the cross-over part is optional (fine 
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needle aspirate is not acceptable). Patients who are included in the cross-over part should be 
evaluated as Cohort A-1 and Cohort B (except PK). 
Patients who do not meet the cross-over part eligibility criteria should be followed up for safety 
and survival. 
6.5 
RETREATMENT OF PATIENTS  
The patient 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 patient 
will continue treatment until disease progression confirmed by imaging 4 weeks after initial 
evidence of progression (or 6 weeks for bone progression in mCRPC in Appendix A) as detailed 
in Section 6.7.1, unacceptable AE, patient’s decision, 2 years of uninterrupted delivery of IMP 
without documented PD, or administrative reasons. 
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 toxicity 
including DLT, in order for patients to be retreated, see Section 6.6 and Appendix G for 
retreatment recommendations. 
6.6 
DOSE DELAYS/MODIFICATIONS  
6.6.1 General rules  
Dose modifications are permitted according to the guidelines described in this section. 
Dose modifications different from those stated in the protocol should only be made in consultation 
with the Sponsor unless required for immediate patient safety. 
Dose adjustment, dose delay (ie, delay of either isatuximab or REGN2810 within a cycle for 
combination cohorts), cycle delay (ie, delay of both IMPs for combination cohorts, or delay of 
isatuximab for monotherapy cohorts), or dose omission (ie, omission of either isatuximab or 
REGN2810 within a cycle for combination cohorts) are permitted in case of toxicity. Dose 
adjustments will be made according to the worst grade of toxicity observed within a cycle. If a 
patient experiences several toxicities and there are conflicting recommendations, the most 
conservative dose adjustment recommended should be followed. Once a dose has been decreased, 
intra-patient re-escalation back to the previous dose level is not permitted. 
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. 
If 1 of the 2 drugs (REGN2810 or isatuximab) is prematurely permanently discontinued, the other 
drug can be continued until disease progression confirmed by imaging 4 weeks after initial 
evidence of progression (or 6 weeks for bone progression in mCRPC in Appendix A) as detailed 
in Section 6.7.1, unacceptable AE, patient’s decision, 2 years of uninterrupted delivery of IMP 
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without documented PD, or administrative reasons. The end of treatment (EOT) assessment in this 
case will be 30 days after the date of the last IMP administration. 
All changes to study treatment administration must be recorded in the electronic case report form 
(e-CRF). 
6.6.2 Dose delay and dose omission  
Within a cycle, the treatment window is ±1 day for each of the weekly 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 dose, and 
≥3 days beyond the theoretical day of treatment for Q3W dose. The patient will receive the next 
infusion after recovery of the toxicity as described in Section 6.6.3. 
Patients may have dose delay, cycle delay, or dose omission if toxicity occurs and he/she does not 
recover according to following rules: 
 
In Cycle 1 (for weekly administration of isatuximab) if toxicity occurs and the patient 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 toxicity occurs and the patient does not recover on the day of 
planned infusion or within the following 14 days, either infusion of isatuximab or 
REGN2810 may be omitted for combination cohort.  
 
In case of cycle delay or dose omissions for the recovery of toxicity, the following rules 
should be followed for restart or discontinue the treatment: 
- 
In case of a cycle delay up to 14 days or a dose omission, it is per Investigator’s 
decision to restart the study treatment. 
- 
After a cycle delay of >14 days and ≤84 days, or 2 to 4 consecutive dose omissions, 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, the IMP will be 
prematurely discontinued. 
6.6.3 Dose modifications  
Guidelines for isatuximab and REGN2810 dose modifications and treatment discontinuation due 
to hematological and non-hematological adverse reactions in general are outlined in Table 2. 
See Section 6.6.4 and Appendix G for guidance for irAEs correlated with REGN2810, and 
Section 6.6.5 for IARs correlated with isatuximab and REGN2810. 
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Table 2 - Isatuximab and REGN2810 dose modification guidelines  
Toxicity 
NCI CTCAE V4.03 
Isatuximab dose 
management 
REGN2810 Dose 
management 
Action and Guidelines 
Hematological toxicity 
Grade 1, 2, 3 
No change 
Patient should be given 
supportive care and 
monitored closely. 
Grade 3 thrombocytopenia 
lasting >7 days or 
associated with bleeding 
Delay the cycle until bleeding is controlled and platelet 
>50,000/mm3. Restart treatment with same dose and schedule. 
Patient should be given 
supportive care and 
monitored closely. 
Permanent discontinuation of 
study treatment should be 
considered if toxicity does not 
resolve within 84 days of last 
infusion. 
Grade 4 
Delay the cycle until ANC >1000/mm3, and platelet >50 000/mm3. 
Restart with same dose and schedule. 
Grade 4 lymphopenia: no change in dose 
Febrile neutropenia and/or 
neutropenic infection 
Delay the cycle until fever and infection recover and 
ANC >1000/mm3. Restart with same dose and schedule. 
Non-hematological toxicity (other than irAE and IAR) 
Grade 1 
No change 
N/A 
Grade 2 (except alopecia) 
Delay the cycle until improves to Grade ≤1 or baseline. 
Restart treatment at same dose and schedule 
It is up to the Investigator’s 
judgment whether to restart 
the treatment of isatuximab 
and REGN2810 if the cycle 
delay is within 14 days. 
If the cycle delay is longer 
than 14 days, before 
restarting the treatment, the 
Investigator must discuss with 
Sponsor; if it is determined 
that it is to the best interest of 
the patient, the treatment may 
be restarted. 
If the cycle delay is longer 
than 84 days, the treatment 
must be discontinued. 
Grade 3 
Grade 4 
Permanently discontinue treatment for treatment related AEs 
Immune-related AE: see Table 3 and Appendix G for dose modification and patient management guideline 
Infusion-Associated Reaction: see Table 4 for IAR management guideline 
Abbreviations: AE=adverse event; ANC=absolute neutrophil count; DL-1=dose level minus 1; IAR=infusion-associated reaction; 
irAE=immune-related adverse event. 
6.6.4 General guidelines for the management of immune-related adverse events  
Investigators must be extremely vigilant and be ready to intervene early in the management of 
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, renal AE, dermatologic AE, hepatitis, ophthalmologic AE [uveitis]), plus 
nausea and vomiting is provided in Appendix G. 
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 
General guidance is provided in Table 3. 
 
If a patient experiences several irAEs which involve different recommendations, the most 
conservative recommendation should be followed. 
The recommendations provided in Table 3 and Appendix G should be seen as guidelines, and the 
treating physician should exercise clinical judgment based on the symptoms and condition of the 
individual patient. 
Table 3 - General guidelines for immune-related adverse events  
Severity 
Withhold/restart 
/discontinue 
isatuximab treatment 
Withhold/restart/discontinue 
REGN2810 treatment 
Supportive care 
Grade 1 
No action 
Provide symptomatic treatment. 
Grade 2 
No action 
May delay or omit the dose until 
Grade ≤1 
Consider systemic corticosteroids 
(Prednisone 0.5 to 1 mg/kg/day or 
equivalent) in addition to appropriate 
symptomatic treatment. 
Grade 3  
Grade 4 
Delay the cycle until when toxicity improves to Grade ≤1 or baseline. 
Discontinue prematurely REGN2810 if unable to reduce 
corticosteroid dose to <10 mg per day prednisone equivalent within 
84 days of toxicity. 
For any Grade 3-4 immune-related 
adverse event, if symptoms worsen 
or do not improve on adequate 
corticosteroids (prednisone 1 to 
2 mg/kg/day or equivalent) within 48 
to 72 hours), consider additional 
immunosuppressive agents (to be 
selected from agents such as: 
infliximab, cyclophosphamide, 
cyclosporine and mycophenolate 
mofetil). Referral of the patient to a 
specialized unit for assessment and 
treatment should be considered. 
 
Any patient currently receiving REGN2810 who was previously treated with a 
phosphatidylinositol 3-kinase (PI3K) inhibitor and who develops stomatitis or mucositis should 
temporarily suspend study treatment. If this or any other irAE occurs among these patients, the 
sponsor should be informed as soon as possible to discuss further management of the patient. An 
irAE of any grade in a patient previously treated with a PI3K inhibitor should be reported as an 
adverse event of special interest (AESI). 
6.6.5 General guidelines for the management of infusion-associated reactions  
Patients should routinely receive premedications prior to isatuximab infusion as detailed in 
Section 8.2 to reduce the risk and severity of IARs commonly observed with monoclonal 
antibodies. 
Infusion-associated reactions (which include NCI-CTCAE, version 4.03 terms 
“allergic/hypersensitivity reactions” and “cytokine release syndrome/acute infusion reaction”) 
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typically occur within 24 hours from the start of the infusion. If an IAR is observed, patients must 
also be informed of the potential risk of recurrent allergic reactions at subsequent infusions. 
Summary of IAR management is provided in Table 4. 
Patients who experience Grade 2 IARs may resume REGN2810/isatuximab infusion after 
temporary interruption, under close monitoring and with therapy as needed. Patients 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 to Grade ≤1, the infusion may be restarted: 
 
For REGN2810, the infusion should be restarted at half the original infusion rate. 
 
For isatuximab, the infusion should be restarted at half the original infusion rate, see 
Section 8.3.1.1 for 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. 
Patients with Grade 3 or 4 IAR must have REGN2810 and/or isatuximab permanently 
discontinued and appropriate therapy should be administered: 
 
If a Grade 3 or higher IAR occurs during REGN2810 infusion, REGN2810 should be 
permanently discontinued. The patient can continue treatment with isatuximab. 
 
If a Grade 3 or higher IAR occurs after the start of isatuximab infusion, the patient should 
permanently discontinue treatment with both REGN2810 and isatuximab. 
The infusion reaction and the therapy administered must be documented in the case report form 
(CRF). 
Grade 2 or higher IARs must be reported as AESI (see Section 10.5.5). Study personnel should 
consult the Medical Monitor for further guidance regarding re-treatment of patients with infusion 
reactions and regarding issues of premedication management (eg, alternative medications for 
patients allergic or intolerant to premedication agents) or to determine if locally used equivalent 
medications are acceptable. 
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Table 4 - Infusion-associated reaction management  
Infusion related reaction grading 
(NCI-CTCAE v4.03 criteria) 
Recommendation 
Mild 
Grade 1 
Infusion interruption or intervention not indicated 
Continuation of REGN2810/isatuximab infusion is per the 
judgment of the Investigator following close direct monitoring of 
the patient’s clinical status. 
REGN2810/isatuximab infusion may be stopped at any time if 
deemed necessary. If stopped, IAR will be classified as 
Grade 2 as per NCI-CTCAE definition. 
Moderate 
Grade 2 
Therapy or infusion interruption indicated but responds 
promptly to symptomatic treatment (eg, antihistamines, 
NSAIDS, narcotics, IV fluids); prophylactic medications 
indicated for ≤24 hours) 
Stop REGN2810/isatuximab infusion. Give additional 
medication(s) with IV diphenhydramine 25 mg (or equivalent) 
and/ or IV methylprednisolone 100 mg (or equivalent) as 
needed. REGN2810a/Isatuximabb may be resumed only after 
patient recovery, with close monitoring. 
 
Severe or Life-threatening 
Grade 3: Prolonged (eg, not rapidly responsive to symptomatic 
medication and/or brief interruption of infusion); recurrence of 
symptoms following initial improvement; hospitalization 
indicated for clinical sequelae 
 
Grade 4: Life-threatening consequences; urgent intervention 
indicated 
Stop REGN2810/isatuximab infusion. Give additional 
medication(s) with diphenhydramine 25 mg IV (or equivalent) 
and/ or IV methylprednisolone 100 mg (or equivalent) and/or 
epinephrine as needed. 
If IAR occurred during REGN2810 infusion, permanently 
discontinue REGN2810. Continue treatment with isatuximab. 
If IAR occurred after the start of isatuximab infusion, 
permanently discontinue both REGN2810 and isatuximab. 
a REGN2810: The prepared infusion bag should be kept no more than 8 hours at room temperature, or no more than 24 hours at 5°C (with an 
acceptable operating range of 2°C to 8°C refrigerator). 
b Isatuximab: the infusion should be completed within 16 hours from the end of infusion preparation or a new infusion should be prepared with 
the remaining dose to be administered the same day. 
Abbreviations: AE=adverse event; CTCAE=common terminology criteria for adverse events; IAR=infusion-associated reaction; IFN=interferon; 
IL=interleukin; IV=intravenous; NCI=National Cancer Institute; TNF=tumor necrosis factor. 
6.7 
DURATION OF STUDY PARTICIPATION  
6.7.1 Duration of study participation for each patient  
The duration of the study for a patient will include a period of screening of up to 28 days, a 
treatment period (up to 2 years), a safety follow-up period (90 days or until ADA is negative, if 
ADA test is positive or inconclusive at Day 90), and a survival phone call follow-up period. 
Treatment period: The cycle duration is 21 days. Patients will continue treatment until disease 
progression confirmed by imaging 4 weeks after initial evidence of progression (or 6 weeks for 
bone progression in mCRPC in Appendix A), unacceptable AEs, patient’s decision, 2 years of 
uninterrupted delivery of IMP without documented progressive disease (PD), or administrative 
reasons. 
Patients who have apparent radiographic progression by CT/MRI per RECIST v1.1 or bone scan 
per PCWG3 criteria are allowed to continue until PD is confirmed providing: 
 
Absence of clinical symptoms or signs indicating clinically significant disease 
progression;  
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 
No decline in performance status;  
 
Absence of rapid disease progression or threat to vital organs or critical anatomical sites 
[eg, CNS metastasis, respiratory failure due to tumor compression, spinal cord 
compression] requiring urgent alternative medical intervention; 
 
No significant, unacceptable or irreversible toxicities related to study treatment. 
Safety follow-up period: After treatment discontinuation, patients will return to the study site 
30 days (±7 days) after the last dose of IMP, or when the patient receives another anti-cancer 
therapy, whichever is earlier, for end-of-treatment assessments. In addition, there will be an 
extended safety follow-up period for 90 days after the last dose of IMP for ADA assessment and 
for safety assessment. If ADA test is positive or inconclusive, ADA testing will be repeated every 
3 months until negative. All ongoing related AEs, ongoing SAEs and new related AE/SAEs will 
also be followed up. 
Patients who discontinue the study treatment without PD will be followed every 90 days for 
disease assessment until confirmation of PD or start of treatment with another anti-cancer therapy, 
or until study cut-off date, whichever comes first 
Survival phone call follow-up period: The further follow-up schedule beyond 90 days after last 
dose of IMP is according to the disease progression status: 
 
Patients who discontinue study treatment due to PD: phone call follow-up will be done 
every 90 days from the date of last IMP administration until death or study cut-off date. 
 
Patients who discontinue the study treatment without PD, and without PD confirmed 
during the safety follow-up period: will be followed every 90 days for disease 
assessment until confirmation of PD or start of treatment with another anti-cancer therapy, 
or until study cut-off date, whichever occurs first. After PD patients will be followed by 
phone call until death or study cut-off date. 
 
Patients who are still on study treatment after study cut-off date: will continue to 
receive study treatment and will undergo planned study procedures (except PK and ADA) 
until confirmation PD, or start with another anti-cancer therapy, or treatment period ended, 
whichever comes first. 
Cross-over: The patients in Cohort A-2 treated with isatuximab monotherapy who experience PD 
will be permitted to cross over to isatuximab in combination with REGN2810 for up to 2 years 
after progression on isatuximab monotherapy. Safety and efficacy assessments for these patients 
during the cross-over period are the same as the assessments in the Phase 2 part. 
For post OS study cut-off date please refer to Section 12.5.3. 
Sponsor has the right to terminate the study at 1 or more sites for any reason. 
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6.7.2 Determination of end of clinical trial (all patients)  
The study cut-off is planned at 12 months after the last ongoing patient initiates IMP, 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 earliest. 
6.8 
INTERIM ANALYSIS  
Refer to Section 13.5 for details of the interim analysis. 
6.9 
STUDY COMMITTEES  
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, at the end of Stage 1 and 
2 of each tumor cohort, and ad hoc as required. 
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 first data review 
meeting) and make appropriate recommendations regarding the conduct of Phase 2 of this study.  
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7 
SELECTION OF PATIENTS  
7.1 
NUMBER OF PATIENTS  
Refer to Section 13.1. 
7.2 
INCLUSION CRITERIA  
I 01. Signed written informed consent. 
I 02. ≥18 years of age. 
I 03. Disease location amenable to mandatory tumor biopsy at baseline (unless clinically 
unfeasible* as per the Investigator and after obtaining written agreement from sponsor 
representative, only for NSCLC cohort), and possibly at Cycle 2 Day 1. Fine needle 
aspirates are not acceptable. Availability of a tissue specimen from core 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. *Clinically unfeasible: 
With a written opinion from the investigator that performing a biopsy will put the 
wellbeing of the subject at an excessive risk due to the location of the lesion. 
I 04. Based on the Investigator’s judgment, at this time, chemotherapy is not the best treatment 
option for this specific patient. The eligibility of patient to take part in the study will be 
validated at the multidisciplinary collegial meeting in countries listed in Appendix I. 
For mCRPC patients (I05 to I11): 
I 05. Histologically confirmed adenocarcinoma of the prostate (excluding neuroendocrine 
differentiation and/or small cell features). 
I 06. Metastatic disease documented by bone lesion on bone scan, or by measurable soft tissue 
disease by computed tomography (CT) or magnetic resonance imaging (MRI). Patients 
whose disease spread is limited to regional pelvic lymph nodes are not eligible. 
I 07. Surgically or medically castrated, with testosterone levels of <50 ng/dL (<2.0 nM). 
Patients who have not had a bilateral orchiectomy must have started androgen deprivation 
therapy with gonadotropin-releasing hormone (GnRH) analogue ≥4 weeks prior to 
initiation of IMP and continue such therapy throughout the study. 
I 08. At least 1 but no more than 2 previous androgen receptor-targeted agents (abiraterone and 
enzalutamide). 
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I 09. Received up to 2 previous taxane-based chemotherapy regimens as per local standard of 
care (for example, docetaxel followed by cabazitaxel), unless per investigator’s judgement 
a chemotherapy regimen is not appropriate for the specific patient. If the same  
taxane-based chemotherapy is used more than once, this will be considered as 1 regimen. 
I 10. No previous radium 223. 
I 11. Documentation of PD as assessed by the Investigator with at least 1 of the following within 
6 months prior to first dose of IMP per Prostate Cancer Clinical Trials Working Group 3 
(PCWG3) criteria (Appendix A) during or following the direct prior line of therapy. 
 
Prostate-specific antigen progression defined by a minimum of 2 rising PSA levels with an 
interval of ≥1 week between each determination. The PSA value at the Screening visit 
should be ≥1 μg/L (1 ng/mL) if confirmed rise is the only indication of progression. 
Patients on systemic glucocorticoids for control of symptoms must have documented PSA 
progression while on systemic glucocorticoids before initiation of IMP. 
 
Radiographic progression of soft tissue disease by RECIST 1.1 per PCWG 
recommendation (Appendix B ). Previously normal (<1.0 cm) lymph nodes must have 
grown by ≥5 mm in the short axis from baseline or nadir and be ≥1.0 cm in the short axis 
to be considered to have progressed. If the node progresses to ≥1.5 cm in the short axis, it 
is measurable; nodes that have progressed to 1.0 cm to <1.5 cm are pathologic, subject to 
clinical discretion, and are nonmeasurable. For existing pathologic adenopathy and other 
soft tissue disease, progression is defined per RECIST 1.1. 
 
Progression of bone metastasis is defined as 2 or more documented new bone lesions on a 
bone scan. Confirmation of ambiguous results by other imaging modalities (eg, CT or 
MRI) is obligatory if metastatic disease to bone is only defined by bone scan. 
For NSCLC patients (I12 to I16): 
I 12. Histologically or cytologically confirmed diagnosis of Stage IIIB/IV or inoperable 
recurrent NSCLC. 
I 13. At least 1 measurable disease per RECIST 1.1 criteria. Target lesions may be located in a 
previously irradiated field if there is documented radiographic disease progression in that 
site. 
I 14. One previous anti-PD-1/PD-L1 (nivolumab, pembrolizumab, atezolizumab, durvalumab, 
avelumab, or REGN2810) containing regimen as the most recent prior therapy to treat 
Stage IIIB/IV or inoperable recurrent NSCLC. An anti-PD-1/PD-L1 containing regimen is 
defined as either an anti-PD-1/PD-L1 monotherapy, or an anti-PD-1/PD-L1 agent 
administered in the same cycle as another systemic therapy. 
I 15. No more than 1 previous chemotherapy regimen to treat Stage IIIB/IV or inoperable 
recurrent NSCLC. 
I 16. Documented benefit (defined as CR, PR or SD at ≥1 radiographic imaging scan) but 
subsequent progression per RECIST 1.1 during the PD-1/PD-L1 containing regimen 
within 4 months prior to initiation of IMP. The site's study team must have reviewed 
previous tumor assessments (including screening tumor imaging) to determine that 
radiographic progression has occurred per RECIST 1.1 following initiation of the  
anti-PD-1/PD-L1 containing regimen. 
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7.3 
EXCLUSION CRITERIA  
Patients who have met all the above inclusion criteria listed in Section 7.2 will be screened for the 
following exclusion criteria: 
E 01. Eastern Cooperative Oncology Group (ECOG) performance status of ≥2 (Appendix C). 
E 02. Predicted life expectancy <3 months. 
E 03. Prior treatment with an agent (approved or investigational) that blocks CD38 (patients who 
joined a study with an anti-CD38 but have written confirmation they were on control arm 
are allowed). 
E 04. For patients with mCRPC, prior treatment with an agent (approved or investigational) that 
blocks the PD-1/PD-L1 pathway (patients who joined a study with an anti-PD-1/PD-L1 but 
have written confirmation they were on control arm are allowed). 
E 05. 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 or other imaging modality 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 allowed. 
E 06. Symptomatic or impending cord compression. 
E 07. Prior solid organ or hematologic transplant. 
E 08. Last dose of prior investigational agent within 28 days from initiation of IMP. 
E 09. Treatment-related immune-mediated (or immune-related) AEs from immune-modulatory 
agents (including but not limited to anti-PD-1/PD-L1 agents, anti-CTLA-4 monoclonal 
antibodies, and PI3K δ inhibitors) that caused permanent discontinuation of the agent, or 
that were Grade 3 or 4 in severity, or that have not resolved to baseline at least 3 months 
prior to initiation of IMP. For other agents, treatment-related immune-mediated (or 
immune-related) AEs that were Grade 2 or above. 
E 10. Prior IV cytotoxic chemotherapy, antineoplastic biological therapy, major surgery, local 
prostatic intervention within 21 days prior to initiation of IMP; oral cytotoxic 
chemotherapy, hormonal therapy, tyrosine kinase inhibitor therapy, or completed palliative 
radiotherapy within 14 days prior to initiation of IMP. 
E 11. Denosumab or bisphosphonate therapy initiation or dose/regimen adjustment within  
28 days prior to initiation of IMP. Patients on a stable regimen are eligible and may 
continue their therapy without change. 
E 12. Comorbidity requiring corticosteroid therapy (>10 mg prednisone/day or equivalent) 
within 14 days of IMP initiation. Physiologic replacement doses are allowed even if they 
are >10 mg of prednisone/day or equivalent, as long as they are not being administered for 
immunosuppressive intent. Inhaled or topical steroids are permitted, provided that they are 
not for treatment of an autoimmune disorder. 
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E 13. Significant cardiac dysfunction, New York Heart Association classification for chronic 
heart failure III-IV, symptomatic coronary artery disease, major clinically significant 
electrocardiogram (ECG), significant ventricular arrhythmias; myocardial infarction within 
6 months; unstable or poorly controlled angina pectoris. 
E 14. Ongoing AEs (excluding alopecia and fatigue) caused by any prior anti-cancer therapy 
≥Grade 2 (NCI-CTCAE version 4.03). 
E 15. Active, known or suspected autoimmune disease that has required systemic treatment in 
the past 2 years (ie, with use of disease modifying agents, corticosteroids or 
immunosuppressive drugs), except for replacement therapy (eg, thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency). 
E 16. History of or current interstitial lung disease or pneumonitis that requires oral or IV 
glucocorticoids to assist with management (radiation pneumonitis in the radiation field is 
permitted); history of thoracic radiation therapy of >30 Gy within 6 months of the first 
dose of trial treatment. 
E 17. 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 18. Known uncontrolled infection with human immunodeficiency virus, known uncontrolled 
hepatitis B infection, active tuberculosis, or severe infection requiring parenteral antibiotic 
treatment. To control HBV infection, patients with positive HBsAg should have started 
anti-HBV therapy before initiation of IMP, and the screening HBV viral load should be 
<2000 IU/mL (104 copies/mL).  The anti-HBV therapy should continue throughout the 
treatment period. 
E 19. Known second malignancy either progressing or requiring active treatment within the last 
3 years (except for basal cell carcinoma of the skin, squamous cell carcinoma of the skin, 
or in situ cervical cancer that has undergone potentially curative therapy). 
E 20. Inadequate organ and bone marrow function at the Screening visit: 
 
Absolute neutrophil count (ANC) <1500 u/L (1 × 109/L). 
 
Platelets <100 × 10³ u/L (after at least 3 days without platelet transfusion). 
 
Hemoglobin <9 g/dL or <5.6 mmol/L (without transfusions within 2 weeks of initiation of 
IMP). 
 
Total bilirubin >2 upper limit of normal (ULN). 
 
AST and/or ALT >3 × ULN (or >5 × ULN for patients with liver metastases). 
 
Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 (Modified Diet in Renal 
Disease [MDRD] Formula; Appendix H). 
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E 21. Women of reproductive potential and male subjects with female partners of childbearing 
potential who are not willing to avoid pregnancy 2 weeks before and during the study 
treatment period and for 6 months following discontinuation of study treatment by using 
effective contraceptive methods such as: 
 
Diaphragm and spermicide PLUS male condom, or 
 
Intrauterine device PLUS male condom, or 
 
Medical method (such as hormonal contraceptive) PLUS male condom. 
 
A woman of productive potential is a woman who: 1) has achieved menarche at some time 
point, 2) has not undergone a hysterectomy or bilateral oophorectomy or 3) has not been 
naturally postmenopausal (amenorrhea following cancer therapy does not rule out 
childbearing potential) for at least 24 consecutive months (ie, has had menses at any time 
in the preceding 24 consecutive months). The choice of effective method is left to 
Investigator judgment, in accordance to local regulation. Sterilized or infertile subjects are 
exempted from the requirement to use of contraception. In order to be considered sterilized 
or infertile, subjects must have undergone surgical sterilization (vasectomy/bilateral 
tubectomy, hysterectomy, bilateral ovariectomy) or be a postmenopausal woman defined 
as 12 months or more with no menses prior to enrollment and 50 years of age. True 
abstinence is acceptable when this is in line with the preferred and usual lifestyle of the 
patient. Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation 
methods) and withdrawal are not acceptable methods of contraception. 
E 22. Pregnant or breastfeeding woman or woman who intends to become pregnant during the 
participation in the study. 
E 23. Known intolerance or hypersensitivity to any component of isatuximab and/or REGN2810. 
E 24. History or current evidence of any condition, therapy or laboratory abnormality that might 
confound the results of the trial, interfere with the subject’s participation for the full 
duration of the trial or is not in the best interest of the subject to participate, in the opinion 
of the treating Investigator. 
E 25. Patients who will receive REGN2810: prior treatment with idelalisib. 
E 26. Known epidermal growth factor (EGFR) sensitizing mutation, anaplastic lymphoma kinase 
(ALK) rearrangement, ROS1 rearrangement, or BRAF mutation for patients with  
non-squamous NSCLC. 
Re-screening once is allowed. 
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8 
STUDY TREATMENTS  
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT  
8.1.1 Isatuximab (SAR650984)  
8.1.1.1 Pharmaceutical form  
The drug product is 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, 0.02% (w/v) 
polysorbate 80 and pH 6.0 buffer. 
Isatuximab is supplied as a sterile, non-pyrogenic, injectable, and colorless, 20 mg/mL 
concentrate for solution for infusion that may contain white to off-white particulates and is 
packaged in 30 mL glass vials fitted with elastomeric closure. Each vial contains a nominal 
content of 500 mg of isatuximab. The fill volume has been established to ensure removal of 
25 mL. 
For administration to patients, the appropriate volume of isatuximab will be diluted in an infusion 
bag of 0.9% sodium chloride solution or 5% dextrose solution. The final infusion volume 
corresponding to the dose of isatuximab will be administered for a period of time that will depend 
on dose administered and on the amount of protein given per hour. 
8.1.1.2 Dose of drug per administration  
The starting dose of isatuximab is 10 mg/kg (see Section 6.2.1). 
8.1.1.3 Preparation, reconstitution and administration  
Isatuximab concentrate for solution for infusion will be diluted in an infusion bag with 
0.9% sodium chloride solution or 5% dextrose solution to achieve the appropriate drug 
concentration for infusion. 
Infusion via a central line is preferred if available. In case of patients with local intolerance after 
peripheral IV infusion, the decision to use a central line is left to the Investigator. The final 
infusion volume corresponding to the dose of isatuximab will be administered by IV infusion for 
the period of time that depends on total dose administered. 
Prior to dosing, each patient's dose will be individually prepared by the study pharmacist and 
labeled with the protocol number, patient number, and treatment description. The patient’s weight 
should be measured prior to each treatment to allow calculation of the isatuximab dose. 
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For infusion, an IV tubing administration set with a 0.20 μm in-line filter will be used; if an 
in-line filter is unavailable, a 0.20 μm filter unit may be attached to the administration set before 
administration. Further details are provided in the Pharmacy Manual. 
8.1.2 REGN2810 (SAR439684)  
8.1.2.1 Pharmaceutical form  
REGN2810 drug product is presented as a concentrate for solution for infusion of 50 mg/mL in 
10 mL vials with 5.0 mL withdrawable, containing 10 mM histidine, 5% (w/v) sucrose, 
1.5% (w/v) L-proline, and 0.2% (w/v) polysorbate 80, at pH 6.0. 
8.1.2.2 Dose of drug per administration  
The starting dose of REGN2810 is 350 mg per administration (see Section 6.2.1). 
8.1.2.3 Preparation, reconstitution and administration  
REGN2810 concentrate for solution for infusion will be diluted in an infusion bag with 
0.9% sodium chloride solution to achieve the appropriate drug concentration for infusion. 
Infusion via a central line is preferred if available. In case of patients with local intolerance after 
peripheral IV infusion, the decision to use a central line is left to the Investigator. The final 
infusion volume corresponding to the dose of REGN2810 will be administered by IV infusion for 
the period of time that will depend on total dose administered. 
Prior to dosing, each patient's dose will be individually prepared by the study pharmacist and 
labeled with protocol number, patient number, and treatment description.  
For infusion, an IV tubing administration set with a 0.20 μm in-line filter will be used; if an 
in-line filter is unavailable, a 0.20 μm filter unit may be attached to the administration set before 
administration. Further details are provided in the Pharmacy Manual. 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCT(S)  
Patients should routinely receive premedication 30 to 60 minutes prior to the start of the 
isatuximab infusion (no longer than 60 minutes) to reduce the risk and severity of IARs 
commonly observed with monoclonal antibodies.  See Section 4.4.4 for additional information on 
premedication requirements. 
 
The recommended premedication agents are listed below:Acetaminophen (paracetamol) 
650 to 1000 mg, taken orally. 
 
Ranitidine 50 mg IV or equivalent. 
 
Diphenhydramine 25 to 50 mg IV or equivalent. 
 
Methylprednisolone 100 mg IV or equivalent. 
 
Montelukast 10 mg orally or equivalent 
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Non-investigational products will be locally sourced and formulations may vary. Investigators 
must follow the Summary of Product Characteristics/Package Inserts in terms of contraindications 
for non-investigational medicinal products (NIMPs). 
8.2.1 Acetaminophen (paracetamol)  
Commercial supplies of acetaminophen or equivalent will be used for this study. Please refer to 
the package insert for further details as regards to formulation, storage and handling purposes. 
8.2.2 Ranitidine or equivalent  
Ranitidine is presented as a solution for IV infusion. Commercial supplies of ranitidine or 
equivalent will be used for this study. Please refer to the package insert for further details as 
regards to formulation, storage and handling purposes. Equivalents are other approved H2 
antagonists (eg, cimetidine), oral proton pump inhibitors (eg, omeprazole, esomeprazole). 
8.2.3 Diphenhydramine or equivalent  
Diphenhydramine is presented as a solution for IV infusion. Commercial supplies of 
diphenhydramine or equivalent will be used for this study. Please refer to the package insert for 
further details as regards to formulation, storage and handling purposes. Equivalents are, eg, 
cetirizine, promethazine, dexchlorpheniraminem according to local approval and availability. 
Intravenous route is preferred for at least the first 4 infusions. 
8.2.4 Methylprednisolone or equivalent  
Methylprednisolone is presented as a solution for IV infusion. Commercial supplies of 
methylprednisolone or equivalent will be used for this study. Please refer to the package insert for 
further details as regards to formulation, storage and handling purposes. 
8.2.5 Montelukast  
Commercial supplies of montelukast will be used for the study. Please refer to the package insert 
for further details as regards to formulation, storage and handling purposes. 
8.3 
DOSING SEQUENCE  
8.3.1 Study treatment  
All patients will receive isatuximab in combination with REGN2810 for Phase 1 (safety run-in) 
and isatuximab only or isatuximab in combination with REGN2810 for Phase 2 (efficacy signal). 
Emergency equipment and medication for the treatment of IARs (eg, antihistamines, 
bronchodilators, IV saline, corticosteroids, acetaminophen, and/or epinephrine) must be available 
for immediate use. 
A table showing planned study treatment administration is provided in Section 1.2. 
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Phase 1 and Phase 2 Cohort A-1 and B: 
On Day 1 of each cycle (C1 to Cn) patients will receive: 
 
Premedications as described in Section 8.2 
followed by 
 
REGN2810 infusion over 30 minutes 
followed by 
 
Isatuximab IV infusion over approximately 2 to 4 hours. 
In Cycle 1 Day 8 and 15, patients will receive: 
 
Premedications as described in Section 8.2 
followed by 
 
Isatuximab IV infusion over approximately 2 to 4 hours. 
Phase 2 Cohort A-2 
On Day 1 of each cycle (C1 to Cn) patients will receive: 
 
Premedications as described in Section 8.2 
followed by 
 
Isatuximab IV infusion over approximately 2 to 4 hours. 
In Cycle 1 Day 8 and 15, patients will receive: 
 
Premedications as described in Section 8.2 
followed by 
 
Isatuximab IV infusion over approximately 2 to 4 hours. 
Phase 2 Cohort C 
On Day 1 of each cycle (C1 to Cn) patients will receive: 
 
Premedications as described in Section 8.2 
followed by 
 
REGN2810 infusion over 30 minutes (not applicable if isatuximab monotherapy is 
administered) 
followed by 
 
Isatuximab IV infusion over approximately 2 to 4 hours. 
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Phase 2 Cohort D 
On Day 1 of each cycle (C1 to Cn) patients will receive: 
 
Premedications as described in Section 8.2 
followed by 
 
REGN2810 infusion over 30 minutes  
followed by 
 
Isatuximab IV infusion over approximately 2 to 4 hours. 
8.3.1.1 Rate and duration of infusion  
The duration of infusion for REGN2810 350 mg is 30 minutes per administration. 
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. 
Guidelines for patients who develop IARs are provided in Section 6.6.5. 
8.4 
BLINDING PROCEDURES  
This is an open-label study; therefore, blinding procedures are not applicable. 
8.5 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP  
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. 
Patients who received the RP2D in Phase 1 and new patients will then enter the Phase 2 part of 
Cohort A-1 and Cohort B depending on the type of tumor. If the decision is made to initiate the 
mCRPC Cohort A-1 Phase 2 Stage 2, an isatuximab monotherapy cohort (Cohort A-2) will be 
initiated for patients with mCRPC. Patients with mCRPC will be randomly assigned in a 
1:1 randomization ratio to Cohort A-1 (Phase 2 Stage 2; isatuximab plus REGN2810 combination 
therapy) or Cohort A-2 (Phase 2 Stage 1; isatuximab monotherapy). 
Study treatment should be initiated within 3 working days after enrollment. 
If the decision is to initiate Cohort C and/or Cohort D, patients will be assigned depending on the 
type of tumor. 
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8.6 
INVESTIGATIONAL MEDICINAL PRODUCT PACKAGING AND LABELING  
8.6.1 Isatuximab  
Isatuximab is packaged in 30 mL glass vials fitted with elastomeric closure. Packaging is in 
accordance with the administration schedule. 
The content of the labeling is in accordance with the local regulatory specifications and 
requirements. 
8.6.2 REGN2810  
REGN2810 is packaged in USP Type 1 clear glass, 10 mL vial with 20 mm gray chlorobutyl 
rubber stopper with FluroTec® coating and 20 mm red flip-off seal. Packaging is in accordance 
with the administration schedule. 
The content of the labeling is in accordance with the local regulatory specifications and 
requirements. 
8.7 
STORAGE CONDITIONS AND SHELF LIFE  
8.7.1 Isatuximab  
Investigators or other authorized persons (eg, pharmacists) are responsible for storing isatuximab 
in a secure and safe place with restricted access in accordance with local regulations, labeling 
specifications, policies, and procedures. 
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. 
8.7.2 REGN2810  
Investigators or other authorized persons (eg, pharmacists) are responsible for storing REGN2810 
in a secure and safe place with restricted access in accordance with local regulations, labeling 
specifications, policies, and procedures. 
Control of REGN2810 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. 
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REGN2810 is to be stored at +2°C to +8°C (36°F to 46°F), is not to be frozen, and 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. 
8.8 
RESPONSIBILITIES  
The Investigator, the hospital pharmacist, or other personnel allowed to store and dispense the 
IMP will be responsible for ensuring that the IMP used in the clinical trial is securely maintained 
as specified by the Sponsor and in accordance with applicable regulatory requirements. 
The IMP will be dispensed in accordance with the Investigator's prescription and it is the 
Investigator's responsibility to ensure that an accurate record of IMP issued and returned is 
maintained. 
Any quality issue noticed with the receipt or use of an IMP (deficiency in condition, appearance, 
pertaining documentation, labeling, expiration date, etc) should 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 IMP and eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP to a third party, allows the IMP to be 
used other than as directed by this clinical trial protocol, or dispose of IMP in any other manner. 
8.8.1 Treatment accountability and compliance  
Administration of the IMP will be supervised by the Investigator or Subinvestigator. 
The person responsible for drug dispensing is required to maintain adequate records of the IMP. 
These records (eg, drug movement form) include the date the IMP is received from the Sponsor, 
dispensed to the patient 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 patient will record precisely the date and the 
time of the drug administration to the patient. 
8.8.2 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 
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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. 
8.9 
CONCOMITANT TREATMENT  
A concomitant medication is any treatment received by the patient concomitantly to any study 
treatment(s). The administration of concomitant medication should be performed according to the 
relevant Summary of Product Characteristics/Package Inserts and potential contraindication 
should be avoided. 
All treatments being taken by the patient 28 days prior to the first study treatment, at any time 
during the study in addition to the IMP are regarded as concomitant treatments and the type, dose 
and route of administration must be documented on the appropriate pages of the e-CRF. 
Concomitant medications should be kept to a minimum during the study. However, if these are 
considered necessary for the patient's welfare and are unlikely to interfere with the IMP, they may 
be given at the discretion of the Investigator and recorded in the e-CRF. 
Supportive treatment as medically indicated for the patient’s well-being may be prescribed at the 
Investigator’s discretion. Every medication or treatment taken by the patient during the trial and 
the reason for its administration must be recorded in the e-CRF. 
8.9.1 Prohibited concomitant treatments  
 
Concurrent treatment with any other anti-neoplasm therapy not specified in the protocol, 
including immunotherapy, hormonal therapy (except GnRH analogue which should 
continue throughout the study), targeted therapy or biological therapies, or other 
investigational drug or curative radiotherapy. However, palliative radiotherapy may be 
given to control pain. 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. 
 
Subjects with a condition requiring systemic treatment with either corticosteroids (>10 mg 
daily prednisone equivalent) or other immunosuppressive medications within 14 days of 
randomization. Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg 
daily prednisone equivalent, are permitted in the absence of active autoimmune disease. 
 
Live vaccines should be avoided. However, given the increased risk of infection, routine 
vaccinations are recommended for the patients and their contacts. Prophylactic vaccination 
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. 
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 
Denosumab or bisphosphonate therapy initiation or dose/regimen adjustment is not 
permitted. Patients on a stable regimen may continue their therapy without change. 
 
Systemic use of interferon. 
8.9.2 Contraceptive measures and pregnancy counseling  
Females of child bearing potential or male patients with female partners of childbearing potential 
shall be required to use effective contraceptive methods (double barrier method, intrauterine 
device, oral contraception or abstinence) 2 weeks prior to first study treatment, while on therapy 
and for 6 months following the last dose of study treatment. 
A woman is considered of childbearing potential (WOCBP), ie, fertile, following menarche and 
until becoming postmenopausal unless permanently sterile. 
The following highly effective methods of contraception are accepted: 
 
Sexual abstinence. 
 
Diaphragm and spermicide PLUS male condom, or, 
 
Intrauterine device PLUS male condom, or, 
 
Medical method (such as hormonal contraceptive) PLUS male condom. 
The choice of effective method is left to Investigator judgment, in accordance to local regulation. 
Sterilized or infertile patients are exempt from the requirement to use of contraception. In order to 
be considered sterilized or infertile, patients must have undergone surgical sterilization 
(vasectomy/bilateral tubectomy, hysterectomy, bilateral ovariectomy) or be a postmenopausal 
woman defined as 12 months or more with no menses prior to enrollment and 50 years of age. 
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9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT  
9.1 
SAFETY  
The primary objective of the Phase 1 part of this study and a secondary endpoint in the Phase 2 
part of the study is to characterize the safety and tolerability of isatuximab in combination with 
REGN2810 in patients with mCRPC who are anti-PD-1/PD-L1 therapy naïve, or with NSCLC 
and who progressed on anti-PD-1 therapy, and determine the RP2D. Overall safety monitoring 
will be performed throughout the whole conduct of the study. 
The safety profile will be assessed from the findings of physical examination (preferably by the 
same physician in each center), laboratory tests and reports of AEs, etc, and will be based on 
incidence, severity (as graded in the NCI-CTCAE version 4.03), and cumulative nature of TEAEs 
(defined as AEs that develop or worsen in grade or become serious during the on-treatment 
period) and of AEs. 
9.1.1 Dose-limiting toxicities (Phase 1 only)  
Potential DLTs are defined all AEs specified below occurring during the first cycle of treatment, 
unless due to disease progression or to a cause obviously unrelated to IMP. The duration of the 
DLT observation period will be longer for patients 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. 
Hematological abnormalities are defined as any of the following: 
 
Grade 4 neutropenia for ≥7 consecutive days. 
 
Grade 3 to 4 neutropenia complicated by fever (temperature ≥38.5°C on more than 
1 occasion) or by microbiologically or radiographically documented infection. 
 
Grade 3 to 4 thrombocytopenia associated with clinically significant bleeding requiring 
clinical intervention. 
Non-hematological abnormalities 
 
Grade 4 non-hematologic AE. 
 
Grade ≥2 uveitis. 
 
Grade 3 non-hematological AE lasting >3 days despite optimal supportive care, except: 
- 
Grade 3 fatigue. 
- 
Allergic reaction/hypersensitivity attributed to isatuximab or REGN2810. 
- 
Grade 3 or 4 laboratory abnormality that is not clinically significant per recruiting 
Investigator and Sponsor. 
 
Delay in initiation of Cycle 2 >14 days due to treatment related laboratory 
abnormalities/AE. 
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In addition, any other AE that the recruiting Investigators and Sponsor deem to be dose limiting, 
regardless of its grade, may also be considered as DLT. 
At the end of Cycle 1, each patient must be assessed by the Investigator to determine if he or she 
experienced a DLT. This information must be recorded on the appropriate e-CRFs, and an 
electronic DLT notification (either DLT or not) will be sent to the Sponsor, before a subsequent 
cycle may begin. 
Potential and IMP-related DLTs will be considered as AESIs. As such, Investigators are required 
to report them to the Sponsor within 24 hours of the Investigator becoming aware of each AE. The 
Investigator will attach the DLT-specific CRF page to the transmitted DLT/AESI form or will 
complete the specific DLT form in the e-CRF. 
The reported potential DLTs will be reviewed by the Sponsor and recruiting Investigators in order 
to determine their relationship to the IMP and confirm them as DLTs. 
9.1.2 Adverse events  
Adverse events will be collected from the signing of the study informed consent form to 30 days 
after the last IMP administration. Beyond 30 days after last IMP administration all ongoing 
non-serious AEs, ongoing SAEs and new treatment-related AEs/SAEs are to be followed to 
resolution or stabilization. Adverse events encountered before the start of isatuximab and 
REGN2810 treatment or later than 30 days after the last IMP administration will be summarized 
separately. 
All AEs will be graded according to the NCI-CTCAE version 4.03, and will be coded to a 
“Preferred Term” (PT) and associated primary “System Organ Class” (SOC) using the Medical 
Dictionary for Regulatory Activities (MedDRA). Adverse events will be summarized and 
analysed with respect to the type, frequency, severity, seriousness, relatedness, and outcome. 
The general and study-specific safety criteria are presented in Section 10. 
9.1.3 Laboratory safety variables  
Please refer to “Study Procedures” Section 12. 
9.1.4 Clinical examinations  
Please refer to “Study Procedures” Section 12. 
9.1.5 Immunogenicity  
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. 
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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. 
The REGN2810 and isatuximab ADA sampling times for blood collection can be found in the PK 
Flow Chart. (Section 1.5). Bioanalytical methods used for immunogenicity assessments are 
summarized in Table 5. 
Table 5 - Bioanalytical methods for immune response assessment  
Analyte 
Anti-isatuximab antibody 
Anti-REGN2810 antibody 
Matrix 
Plasma 
Serum 
Analytical technique 
PandA method 
Non-quantitative bridging immunoassay 
Site of bioanalysis 
Covance Harrogate (UK) 
Regeneron Pharmaceuticals, Inc. 
(Tarrytown, NY) 
 
9.1.6 Other safety endpoints  
Please refer to “Study Procedures” Section 12. 
9.2 
PHARMACOKINETIC EVALUATION  
9.2.1 Sampling time  
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. 
The REGN2810 and isatuximab PK sampling times for blood collection can be found in the PK 
Flow Chart (Section 1.5). 
9.2.2 Pharmacokinetic sample handling procedure  
Detailed instructions for sample preparation and shipping for REGN2810 and isatuximab ADA 
will be provided to the study sites in a separate Laboratory Manual. 
9.2.3 Bioanalytical Methods  
Bioanalytical methods are summarized in Table 6. 
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Table 6 - Bioanalytical methods for isatuximab and REGN2810 pharmacokinetic analysis  
Analyte 
Isatuximab 
REGN2810 
Matrix: 
Plasma 
Serum 
Analytical technique: 
Immunoassay 
Immunoassay 
Site of bioanalysis: 
Covance 
(Harrogate, UK) 
Regeneron Pharmaceuticals, Inc. 
(Tarrytown, NY) 
9.2.4 Pharmacokinetic parameters  
9.2.4.1 Non-compartmental analysis  
Pharmacokinetic parameters will be calculated with PKDMS software (Pharsight), using 
non-compartmental methods, from isatuximab plasma and REGN2810 serum concentrations. The 
parameters will include, but may not be limited to, the following: 
Table 7 - List of pharmacokinetic parameters and definitions  
Parameters 
Analyte 
Definition 
 
REGN2810 
Isatuximab 
 
Ceoi 
X 
X 
Concentration observed at the end of intravenous infusion 
Cmax 
X 
X 
Maximum concentration observed after the first infusion 
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 
Ctrough 
X 
X 
Concentration observed just before treatment administration during 
repeated dosing 
AUC0-21d 
X 
 
Area under the concentration versus time curve calculated using the 
trapezoidal method over the dosing interval (21 days) after the first 
administration 
AUC0-7d or 
AUC0-21d 
 
X 
Area under the concentration versus time curve calculated using the 
trapezoidal method over the dosing interval (7 days and for cohorts C and 
D: 21 days) after the first administration 
 
9.2.4.2 Population approach  
Population PK approaches may be used for both compounds and more precisely to analyze the 
isatuximab plasma concentration-time profiles from Phase 2 Stage 2. If done, the data generated 
will be reported in a standalone report(s). 
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9.3 
BIOMARKERS  
 
Tumor biopsies will be collected at baseline* and during screening period for the 
cross-over part* for the following biomarker analyses: 
- 
CD38, PD-L1 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 next-generation sequencing 
(NGS) (RNAseq) on RNAlater preserved tumor if enough tumor material is available 
or by Nanostring on available FFPE tumor sample. 
- 
Tumor mutational load on RNAlater preserved tumor core biopsy and MSI status on 
snap frozen preserved tumor core biopsy if enough tumor material is available  
(for both analyses) or on FFPE tumor core biopsy. The techniques used could be, for 
example, NGS (DNA exome sequencing or Pentaplex). For the DNA exome 
sequencing, a sample of peripheral blood will be taken as a control and will not be 
used to determine the likelihood of the patient or his/her family members developing a 
disease. 
- 
Blood DNA for tumor mutational load control will not be used to determine sequences 
of other genes, nor will these analyses be used to determine the likelihood of the 
patient or his/her family members developing a disease. 
*Tumor biopsy at baseline or provision of adequate archival pre-treatment tumor 
tissue sample is mandatory (details please refer to Section 7.2 I 03). Tumor biopsy at 
cross-over screening is required unless clinically unfeasible and after discussion with 
the Sanofi Medical Monitor. 
 
Peripheral blood samples will be collected at baseline for the following biomarker 
analyses: 
- 
Immune genetic determinants (including FcγR III polymorphism) will be analyzed. 
Blood DNA for Immune genetic determinants will not be used to determine the 
likelihood of the patient or his/her family members developing a disease. 
 
Tumor biopsies will be collected at baseline** and during treatment (including cross-over 
period treatment)**, for the following pharmacodynamics biomarker analyses: 
- 
CD38 positive cells and immune-contexture (such as T cells, B cells, activating or 
inhibitory receptors) by IHC or Fluorescent Multiplex IHC in 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. 
** Tumor biopsy at baseline or provision of adequate archival pre-treatment tumor 
tissue sample is mandatory (details please refer to Section 7.2 I 03). Tumor biopsy at 
cross-over screening is required unless clinically unfeasible and after discussion with 
the Sanofi Medical Monitor. During treatment (including cross-over period treatment), 
tumor biopsies will be taken at Cycle 2 Day 1 (≤7 days; after IMP administration on 
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C1D15 wherever applicable, prior to IMP administration on Cycle 2 Day 1), unless 
clinically unfeasible and after discussion with Sanofi Medical Monitor. On-treatment 
biopsy at Cycle 2, Day 1 (≤7 days; after IMP administration on C1D15 wherever 
applicable, prior to IMP administration on Cycle 2 Day 1) of the cross-over part is 
optional. 
 
Peripheral blood samples will be collected at baseline and during treatment (including 
cross-over period), for the following pharmacodynamics biomarker analyses: 
- 
Immunophenotyping to assess the immunomodulatory effects of isatuximab and 
REGN2810. More particularly, immune cell subsets (such as B cells, T cells, NK cells, 
macrophages, neutrophils and regulatory cells), as well as immune regulatory markers 
(such as activating and inhibitory receptors) will be characterized by flow cytometry. 
For prostate cancer, the neutrophil lymphocyte ratio will be determined from this 
immunophenotyping analysis and correlated with clinical response, as a potential 
marker of response. 
- 
Tumor mutational profile (ie, somatic mutations in genes such as KRAS, for NSCLC) 
will be analyzed in plasma cell free DNA and followed as a potential marker of 
resistance to treatment. Subtractive mutation analysis will be performed with germline 
DNA data to identify tumoral specific variations. 
- 
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 by enzyme-linked immunosorbent assay-based techniques. 
During treatment, peripheral blood samples will be taken: 
- 
For immunophenotyping and peripheral blood cytokine dosage at Day 1 of each cycle 
during the first 3 cycles and then every other cycle and at EOT and 60 days (±7 days) 
after last-IMP administration. 
- 
For tumor mutational profile at Day 1 of each cycle during the first 3 cycles and then 
every other cycle and at EOT. 
Additional analysis, not specified in the protocol but related to the drug action and/or effect of 
isatuximab/REGN2810, may be conducted on remaining samples pending evolving literature. 
9.4 
SAMPLES BLOOD VOLUME  
The volume of blood to be collected during Cycle 1 and further cycles will be provided to the 
study sites in a separate Laboratory Manual. 
9.5 
FUTURE USE OF SAMPLES  
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 but 
in a stand-alone report, if applicable. 
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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, subject 
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 16.3 and Section 16.5). These samples may 
be 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. 
9.6 
EFFICACY  
9.6.1 Primary endpoint  
The primary endpoint for the Phase 2 part of the study is RR. The RECIST 1.1 criteria 
(Appendix B ) will be followed for assessment of tumor response in patients with NSCLC (54). 
The PCWG3 criteria (Appendix A) will be followed for the assessment of tumor response in 
patients with mCRPC (48). For patients with mCRPC, response will be defined by radiographic 
objective response assessed and confirmed by the Investigators and/or a PSA decline of ≥50% 
from baseline that is subsequently confirmed per PCWG3 criteria (Appendix A). The PSA decline 
must be confirmed to be sustained by a second PSA value obtained 4 or more weeks later. 
The following disease assessment procedures will be performed at screening (for eligibility) and 
again at Cycle 1 Day 1 (if needed) prior to study treatment administration (baseline for response 
assessment) and then as detailed below: 
 
Tumor imaging: performed at screening (diagnostic quality scans performed as part of 
routine clinical management are acceptable) and then repeated every 9 weeks starting at 
the end of Cycle 3 (63 ±7 days; disease assessment timing should follow calendar days and 
should not be adjusted for delays in cycle start), whenever disease progression is 
suspected, at the EOT visit (if not performed in the past 30 days) and during follow-up (if 
discontinue IMP without PD), using the same method (CT or MRI) for each assessment. If 
tumor assessment status is partial or complete response, changes in tumor measurements 
must be confirmed by repeat assessments that should be performed no less than 4 weeks 
after the criteria for response are first met. 
 
Prostate-specific antigen assessment for patients with mCRPC: performed at baseline 
(within 14 days before initiation of IMP). Repeat at Cycle 1 Day 1 and every 9 weeks 
starting at the end of Cycle 3 (63 ±7 days; disease assessment timing should follow 
calendar days and should not be adjusted for delays in cycle start), at the EOT visit (if not 
performed in the past 30 days) and during follow-up (if discontinue IMP without PD). 
PSA responses are to be confirmed no less than 4 weeks later. 
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9.6.2 Secondary endpoints  
Secondary efficacy endpoints are: 
 
Tumor burden change: 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. 
In addition, the area under the curve (AUC) and the time-adjusted AUC of percent-change 
from baseline in a sum of the diameter for all target lesions will also be summarized in an 
exploratory fashion. 
 
Duration of response: defined as the time from the date of first response (PR or CR in 
radiographic objective response, or PSA decline ≥50% for patients with mCRPC) that is 
subsequently confirmed to the date of first disease progression or death, whichever occurs 
first. The RECIST 1.1 criteria (Appendix B ) will be followed for assessment of tumor 
response in patients with NSCLC and the PCWG3 criteria (Appendix A) will be followed 
for the assessment of tumor response in patients with mCRPC. Disease progression 
includes radiographic disease progression or unequivocal clinical progression. For patients 
with mCRPC, radiographic progression includes progression by PCWG3 modified 
RECIST 1.1 for soft tissue and/or PCWG3 defined progression by bone scan. 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 and the analysis cut-off date, whichever is earlier. DOR will 
not be calculated for patients who do not achieve a response. 
 
Progression-free survival: defined as the time from first study treatment administration to 
the date of first documentation of PD (RECIST 1.1 for patients with NSCLC and PCWG3 
criteria for patients with mCRPC) or the date of death from any cause. The same censoring 
rules as DOR will be used. 
 
Disease control rate (DCR): defined as the proportion of patients with confirmed complete 
response (CR) or partial response (PR) or stable disease (SD), as assessed by Investigator 
relative to the total number of patients in the analysis population. 
9.6.3 Exploratory endpoints  
Exploratory efficacy endpoints are: 
 
Overall survival: 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. 
 
Time to response: defined as the time from first study treatment administration to the first 
response (PR or CR in radiographic objective response, or PSA decline ≥50% for patients 
with mCRPC) that is subsequently confirmed (RECIST 1.1 for patients with NSCLC and 
PCWG3 criteria for patients with mCRPC). 
For patients with NSCLC, exploratory efficacy endpoint also includes: 
 
ORR by iRECIST (Appendix B ) for patients with NSCLC. 
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For patients with mCRPC (to be assessed per PCWG3 criteria), exploratory efficacy endpoints 
also include: 
 
PSA RR: PSA response is defined as a PSA decline of ≥50% from baseline that is 
subsequently confirmed. 
 
Radiographic RR: radiographic response is defined as radiographic objective response 
assessed and confirmed by investigator. 
 
Duration of PSA response: defined as the time from the date of the PSA first decline of 
≥50% from baseline that is subsequently confirmed to the date of first confirmed PSA 
progression or death, whichever occurs first. PSA progression for patients who have 
achieved a ≥50% decrease from baseline is defined as at least a 25% increase and an 
absolute increase of ≥2 ng/mL above the nadir (the lowest PSA value on study). The same 
censoring rules as for DOR will be used. 
 
Duration of radiographic response: defined as the time from the date of the first 
radiographic response (PR or CR) that is subsequently confirmed to the date of first 
radiographic progression or death, whichever occurs first. The same censoring rules as for 
DOR will be used. 
 
Time to PSA response: defined as the time from first study treatment administration to the 
first PSA response that is subsequently confirmed. 
 
Time to radiographic response: defined as the time from first study treatment 
administration to the first radiograph response that is subsequently confirmed. 
 
Time to PSA progression: defined as the time from first study treatment administration to 
the date of first confirmed PSA progression. For patients who have achieved a ≥50% 
decrease from baseline, PSA progression is defined as at least a 25% increase and an 
absolute increase of ≥2 ng/mL above the nadir (the lowest PSA value on study). For 
patients without a PSA decrease of this magnitude or no decrease at all, PSA progression 
is defined as at least a 25% increase and an absolute increase of ≥2 ng/mL above the 
baseline. Death from prostate cancer or any other cause without prior evidence of PSA 
progression will not count as an event. If no event exists, then time to PSA progression 
will be censored at the last scheduled PSA assessment on study or date of death, 
whichever occurs first. 
 
To explore 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 as potential predictive markers of response. 
 
To explore tumor and immune genetic markers at baseline: tumor mutational load and 
MSI status in tumor as well as tumor mutational profile and immune genetic determinants 
in blood. 
 
To evaluate pharmacodynamic biomarkers in response to IMP: immunophenotype in 
peripheral blood, immune contexture in tumor and plasma or serum cytokine levels. 
 
A panel of tumor somatic mutations (ie, tumor mutational profile) will be analyzed at 
baseline and upon treatment in plasma cell free DNA from peripheral blood. 
 
Determination of exposure-response relationships with efficacy, safety, and biomarkers, if 
possible. 
 
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10 
PATIENT SAFETY  
10.1 
SAFETY ENDPOINTS ASSESSED IN THIS TRIAL  
Refer to Section 9.1 for definition of safety criteria, parameters to be analyzed and method of 
sample collection. 
10.2 
SAFETY INSTRUCTIONS  
The safety of the patients in this clinical trial is primarily dependent on the clinical Investigator’s 
monitoring and assessment of their patients. Please refer to Section 9.1.2. 
10.3 
ADVERSE EVENTS MONITORING  
All AEs will be managed and reported in compliance with all applicable regulations, and included 
in the final clinical study report. 
10.4 
DEFINITIONS OF ADVERSE EVENT AND SERIOUS ADVERSE EVENT  
An Adverse Event is any untoward medical occurrence in a patient or clinical investigation 
patient administered with a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment. 
A Serious Adverse Event is any untoward medical occurrence that at any dose: 
 
Results in death or; 
 
Is life-threatening or; 
Note: The term “life-threatening” in the definition of “serious” refers to an event in which 
the patient 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. 
 
Requires inpatient hospitalization or prolongation of existing hospitalization or; 
 
Results in persistent or significant disability/incapacity or; 
 
Is a congenital anomaly/birth defect; 
 
Is a medically important event: 
Medical and scientific judgment should be exercised in deciding whether expedited 
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 
patient or may require intervention to prevent 1 of the other outcomes listed in the 
definition above. 
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Note: The following list of medically important events is intended to serve as a guideline for 
determining which conditions are to be considered medically important events. The list is not 
intended to be exhaustive: 
 
Intensive treatment in an emergency room or at home for: 
- 
Allergic bronchospasm. 
- 
Blood dyscrasias (ie, agranulocytosis, aplastic anemia, bone marrow aplasia, 
myelodysplasia, pancytopenia, etc). 
- 
Convulsions (seizures, epilepsy, epileptic fit, absence, etc). 
 
Development of drug dependence or drug abuse. 
 
Suicide attempt or any event suggestive of suicidality. 
 
Syncope, loss of consciousness (except if documented as a consequence of blood 
sampling). 
 
Bullous cutaneous eruptions. 
 
Cancers diagnosed during the study or aggravated during the study, if judged 
unusual/significant by the Investigator. 
10.5 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING  
10.5.1 Adverse events  
All AEs regardless of seriousness or relationship to the IMP, spanning from the signature of the 
informed consent form (ie, occurring during the baseline period even in the absence of any 
administration of IMP), up to 30 days following the last administration of study treatment, are to 
be recorded on the corresponding page(s) included in the e-CRF. 
Whenever possible, a diagnosis or single syndrome should be reported instead if symptoms. The 
Investigator should specify the date of onset, intensity, action taken with respect to IMP, 
corrective treatment/therapy given, additional investigations performed, outcome, and his/her 
opinion as to whether there is a reasonable possibility that the AE was caused by the IMP. 
Vital signs or ECG abnormalities are to be recorded as AEs only if they are symptomatic and/or 
requiring corrective treatment and/or lead to treatment discontinuation and/or modification of 
dosing and/or fulfill a seriousness criterion and/or are defined as AESIs (see Section 10.5.5). 
Laboratory abnormalities are to be recorded as AEs only if they lead to treatment discontinuation 
and/or modification of dosing and/or fulfill a seriousness criterion and/or are defined as AESIs 
(see Section 10.5.5). 
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10.5.2 Timely handling of certain adverse events  
In the case of an SAE, AESI, pregnancy report, or an overdose, the Investigator or any designees 
must immediately: 
 
ENTER (within 24 hours) the information related to the SAE in the appropriate screens of 
the e-CRF; the system will automatically send e-notification to the monitoring team after 
approval of the Investigator within the e-CRF or after a standard delay. 
 
SEND (preferably by fax or e-mail) the photocopy of all examinations carried out and the 
dates on which these examinations were performed, to the representative of the monitoring 
team. Care should be taken to ensure that the patient's identity is protected and the 
patient’s identifiers in the clinical trial are properly mentioned on any copy of source 
document provided to the Sponsor. For laboratory results, include the laboratory normal 
ranges. 
 
All further data updates should be recorded in the e-CRF as appropriate, and further 
documentation as well as additional information (for laboratory data, concomitant 
medication, patient status) should be sent (by fax or e-mail) to the monitoring team within 
24 hours of knowledge. In addition, any effort should be made to further document each 
SAE that is fatal or life threatening within the week (7 days) following initial notification. 
 
A back-up plan is used (using paper flow) when the e-CRF system does not work. 
10.5.3 Follow-up  
 
The Investigator should take all appropriate measures to ensure the safety of the patients, 
notably he/she should follow-up the outcome of any AEs (clinical signs, laboratory values 
or other, etc) until the return to normal or stabilization of the patient's condition. Ongoing 
related AEs at the end of study treatment will be followed until resolution or stabilization. 
 
In case of any SAE/AESI, the patient must be followed up until clinical recovery is 
complete and laboratory results have returned to normal, or until outcome has been 
stabilized. This may imply that follow-up may continue after the patient has discontinued 
study treatment or has left the clinical trial and that additional investigations may be 
requested by the monitoring team; 
 
In case of any AE or AESI brought to the attention of the Investigator at any time after the 
end of the study for the patient and considered by him/her to be caused by the IMP with a 
reasonable possibility, should be reported to the monitoring team. 
10.5.4 Treatment discontinuation due to non-serious adverse event  
In the case of a treatment discontinuation due to a non-serious AE: 
 
ENTER (within 24 hours) the information related to treatment discontinuation due to a 
non-SAE in the appropriate screens of the e-CRF (AE with the box "action taken with 
IMP" ticked "permanently discontinued", together with the EOT form with reason that 
should be ticked "AE"); the system will automatically send the notification to the 
monitoring team after approval of the Investigator within the e-CRF or after a standard 
delay. 
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10.5.5 Adverse event of special interest  
An AESI is an AE (serious or nonserious) of scientific and medical concern specific to the 
isatuximab program, 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 
the study by protocol amendment. 
Dose limiting toxicities (as defined in Section 9.1.1) are considered as 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 event. The Investigator will attach the DLT-specific CRF page to the 
DLT/AESI form. 
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 IARs. An IAR occurs typically within 24 hours from the start of the infusion. 
 
Grade ≥3 immune-related TEAEs. 
 
Immune-related AEs of any grade in a patient previously treated with a PI3K 
inhibitor (only applicable for patients who receive REGN2810). 
 
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/NIMP. 
Pregnancy occurring in a female patient entered in the clinical trial or in a female partner of a 
male patient entered in the clinical trial. It will be qualified as an SAE only if it fulfills 1 of the 
seriousness criteria (see Section 10.4), 
- 
In the event of pregnancy in a female participant, treatment with the 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. 
 
Symptomatic overdose (serious or non-serious) with IMP/NIMP (see Section 10.5.2). 
- 
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, 
- 
REGN2810 symptomatic overdose:  accidental or intentional overdose of at least 2 
times the intended dose of study drug within the intended therapeutic window, if 
associated with an AE, 
- 
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, 
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- 
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 
e-CRF. 
Of note, asymptomatic overdose has to be reported as a standard AE. 
10.5.6 Laboratory abnormalities  
Laboratory abnormalities should be monitored, documented, and managed according to the 
related flowchart (see Section 1.3). Laboratory values will be reported in the appropriate pages of 
e-CRF. 
Laboratory abnormalities should be reported as AEs, only in case they lead to an action on study 
treatment, if they are serious, or they meet the definition of AESIs (see Section 10.5.1). 
10.5.7 Guidelines for reporting product complaints (IMP/NIMP)  
Any defect in the IMP/NIMP must be reported as soon as possible by the Investigator to the 
monitoring team that will complete a product complaint form within required timelines. 
Appropriate information (eg, samples, labels or documents like pictures or photocopies) related to 
product identification and to the potential deficiencies may need to be gathered. The Investigator 
will assess whether or not the quality issue has to be reported together with an AE or SAE. 
10.6 
OBLIGATIONS OF THE SPONSOR  
During the course of the study, the Sponsor will report in an expedited manner: 
 
All SAEs that are unexpected and are at least reasonably related to the IMP (ie, suspected 
unexpected serious adverse reactions), to the regulatory authorities, institutional ethics 
committees (IECs)/institutional review boards (IRBs) as appropriate and to the 
Investigators. 
 
All SAEs that are expected and at least reasonably related to the IMPs to the regulatory 
authorities, according to local regulations. 
 
The AESIs (eg, DLT) to those regulatory authorities who require such reporting. 
Adverse events that are considered expected are specified in the reference safety information as 
specified in the current IB of each of the 2 IMPs. 
The Sponsor will report all the safety observations made during the conduct of the trial in the 
clinical study report. 
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11 
HANDLING OF PATIENT TEMPORARY AND PERMANENT 
TREATMENT DISCONTINUATION AND OF PATIENT STUDY 
DISCONTINUATION  
Pregnancy will lead to definitive treatment discontinuation in all cases. 
11.1 
PERMANENT TREATMENT DISCONTINUATION WITH INVESTIGATIONAL 
MEDICINAL PRODUCT(S)  
11.1.1 List of criteria for permanent treatment discontinuation  
Patients may withdraw from treatment with IMP if they decide to do so, at any time and 
irrespective of the reason, or this may be done at the discretion of the Investigator. All efforts 
should be made to document the reason(s) for discontinuation and this should be documented in 
the e-CRF. 
Treatment with the IMP should be discontinued in any of the following cases: 
 
At the patient’s request, at any time and irrespective of the reason (patient’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. Patient’s decision for 
treatment should be distinguished from patient’s decision for follow-up visits and from 
patient’s decision for non-patient 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. Patients 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 patient 
should withdraw consent in writing and, if the patient or the patient’s representative 
refuses or is physically unavailable, the site should document any case of patient’s 
decision. 
 
If, in the Investigator’s opinion, continuation of the study treatment would be detrimental 
to the patient’s well-being, such as: 
- 
Confirmation of disease progression (per Section 6.7.1). 
- 
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). 
 
Patient is lost to follow-up. 
 
Completion of the 2 year treatment period. 
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If patients are clinically stable, and possibly deriving clinical benefit from therapy with minimal 
toxicity, the patient will be maintained on treatment for the maximum period of time defined in 
Section 6.7. 
11.1.2 Handling of patients after permanent treatment discontinuation  
All permanent treatment discontinuation must be recorded by the Investigator in the appropriate 
screen of e-CRF when considered as confirmed. After study treatment is discontinued, patients 
should complete a visit 30 days after the last administration of the IMP as described in 
Section 12.4. 
Patients who have been withdrawn from the study treatment cannot be re-entered into the study. 
Patients 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. 
11.2 
REPLACEMENT OF PATIENTS  
During the Phase 1 part of the study, a patient may be considered not evaluable for DLT and may 
be replaced at the same dose level as described in Section 6.2.2. 
Patients treated in the Phase 2 part of the study who are withdrawn from study treatment will not 
be replaced. 
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12 
STUDY PROCEDURES  
12.1 
VISIT SCHEDULE  
During the course of the study, all patients entering the study must be evaluated according to the 
schedule outlined in the flow charts in Section 1 and described below. The results of the 
evaluation will be recorded in the e-CRF pages until the patient is not followed anymore. After 
the baseline visit, all eligible patients included in the study will return to the site for a study visit 
on Day 1, Day 4, Day 8 and Day 15 of Cycle 1 (note: patients in Phase 2 Cohort A-2, Stage 2 
Phase 2 of Cohort A-1 and Cohort B will not return for study visit at Cycle 1 Day 4) and on Day 1 
of all subsequent cycles. An EOT visit will be performed 30 days after the last administration of 
the IMP (see flow chart for investigations to be performed). 
There will be an extended safety follow-up period for 90 days after the last dose of IMP for ADA 
assessment and safety assessment. If REGN2810 or isatuximab ADA testing is positive or 
inconclusive, ADA testing will be repeated every 3 months until negative. 
Patients who discontinue study treatment without PD will be followed every 90 days for disease 
assessment until confirmation of PD or start of treatment with another anti-cancer therapy, or until 
study cut-off date, whichever comes first. 
The further follow-up schedule beyond 90 days after last dose of IMP treatment is according to 
the disease progression status: 
 
Patients who discontinue study treatment due to PD: phone call follow-up will be done 
every 90 days from the date of last IMP administration until death or study cut-off date. 
 
Patients who discontinue the study treatment without PD, and without PD confirmed 
during the safety follow-up period: will be followed every 90 days for disease 
assessment until confirmation of PD or start of treatment with another anti-cancer therapy, 
or until study cut-off date, whichever occurs first. After PD, patients will be followed by 
phone call until death or study cut-off date. 
 
Patients who are still on study treatment after study cut-off date: will continue to 
receive study treatment and will undergo planned study procedures (except PK and ADA) 
until confirmation PD, or start with another anti-cancer therapy, or treatment period ended, 
whichever comes first. 
12.2 
BASELINE EVALUATION  
The pretreatment examinations are to be performed within 28 days prior to the first administration 
of the IMP. All of the inclusion criteria (and none of the exclusion criteria) must be met (see 
Section 7). Patients from Cohort A-2 who progress on isatuximab monotherapy may enter 
cross-over part if they still fulfill the eligibility criteria (except exclusion criteria E 03 and E 08). The 
informed consent form must be signed by the patient before any study-specific procedure can be 
performed. Re-screening once is allowed. 
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The following procedures are to be performed/assessed at this visit. 
 
Signed informed consent (not applicable for cross-over part baseline evaluation). 
 
Demography: includes age, gender and race (not applicable for cross-over part baseline 
evaluation). 
 
Medical/surgical history: includes history of previous/associated pathologies and smoking 
status (not applicable for cross-over part baseline evaluation). 
 
Disease history: includes stage at diagnosis and at study entry, previous anti-tumor therapy 
(type, duration, reason for discontinuation and response to) and the results of any 
additional procedures performed as part of standard of care to assess disease status, such 
as EGFR mutation test, anaplastic lymphoma kinase, ROS1 fusion detection etc for 
patients with NSCLC (not applicable for cross-over part baseline evaluation). 
 
Physical examination: to be performed <7 days prior to first dose of IMP. Includes 
examination of major body systems (neurological, digestive, respiratory [signs and 
symptoms, respiratory rate] and lymph node examination). 
 
Height and weight (not applicable for cross-over part baseline evaluation). 
 
Vital signs: includes blood pressure, heart rate, temperature, and respiration rate. 
 
Performance status (ECOG). 
 
12-lead ECG (single). 
 
Adverse event/SAEs, including AEs of new onset as well as worsening baseline signs and 
symptoms, occurring after signed informed consent for all patients. 
 
Prior/concomitant medication within 28 days prior to first dose of IMP. 
Laboratory assessments 
 
Serum pregnancy test: WOCBP must have a negative serum pregnancy test result within 
7 days prior to the first dose IMP administration (local laboratory). 
 
Blood chemistry: includes AST, ALT, bilirubin (total and direct), alkaline phosphatase 
(ALP), LDH, sodium, potassium, chloride, bicarbonate/carbon dioxide, calcium, 
magnesium, phosphate, uric acid, urea or blood urea nitrogen (BUN), serum creatinine, 
eGFR (MDRD formula; Appendix H), glucose (fasting), albumin, total protein, thyroid 
stimulating hormone (TSH), and free T4 if TSH is outside of the normal range (local 
laboratory). 
 
Hematology: includes hemoglobin, hematocrit, red blood cell (RBC) count, white blood 
cell (WBC) count with differential, and platelet counts. If Grade 4 neutropenia, assess 
ANC every 2 to 3 days until ANC ≥0.5 × 109/L and at least weekly thereafter until 
ANC ≥1.0 × 109/L (local laboratory). 
 
Coagulation: includes prothrombin time or international normalized ratio (INR) and 
activated partial thromboplastin time (PTT) (local laboratory). 
 
Testosterone level (local laboratory). 
 
Blood typing interference test (local laboratory). 
 
Quantitative or semi-quantitative urinalysis: includes RBC, protein, glucose, pH, ketones, 
bilirubin, leucocytes, nitrates and specific gravity (local laboratory). 
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Exploratory biomarkers (central laboratory, please refer to study flowchart in Section 1) 
 
Tumor biopsy for IHC, CD38, PD-L1, immune contexture. 
 
Tumor biopsy for transcriptomic analysis. 
 
Tumor biopsy for genomic characterization (tumor mutational load and MSI status). 
 
Blood sample for tumor mutational load. 
 
Blood sample for plasma or serum cytokines. 
Disease assessment 
 
Tumor imaging: CT or MRI scan of the chest, abdomen, pelvis and any other locations 
with suspicion or evidence of disease involvement (the same method of assessment should 
be used throughout the study). The initial tumor imaging will be performed within 28 days 
screening period (as close as possible to initiation of IMP). Scans performed as part of 
routine clinical management are acceptable for use as the screening scan if they are of 
diagnostic quality and performed within 28 days before IMP initiation. 
- 
mCRPC: Measureable lesion per RECIST 1.1 per local reading is not mandatory. 
- 
NSCLC: Patients with NSCLC must have at least 1 radiographically measurable lesion 
per RECIST 1.1 per local reading. 
 
Prostate-specific antigen assessment for patients with mCRPC (local laboratory). 
 
Bone scan for patients with mCRPC: The initial scan will be performed within 28 days 
screening period (as close as possible to initiation of IMP). Scans performed as part of 
routine clinical management are acceptable for use as the screening scan if they are of 
diagnostic quality and performed within 6 weeks before IMP initiation. In case of doubtful 
lesions on bone scan, bone-centered X-ray or MRI scan should be performed to confirm 
the nature of those lesions (metastatic or not). 
All patients who signed the study informed consent form will be assigned a patient number. Each 
patient will receive an incremental identification number corresponding to his/her 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. A written confirmation of each 
eligible patient identification and treatment dose level will be forwarded to the Investigator. 
12.3 
TREATMENT PERIOD  
12.3.1 Cycle 1 (Day 1, Day 8 and Day 15)  
The treatment window is ±1 day for each of the QW administrations and ±2 days for each of the 
Q3W administrations. The following procedures are to be performed/assessed on Day 1, Day 8 
and Day 15 prior to study treatment administration unless specified otherwise: 
 
Physical examination: includes examination of major body systems (neurological, 
digestive, respiratory [signs and symptoms, respiratory rate] and lymph node 
examination). 
 
Body weight prior to starting infusion. 
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 
Vital signs including blood pressure, heart rate, temperature, and respiration rate, prior to 
starting infusion of IMP, every hour during infusion, and at the end of infusion, and if 
clinically indicated during the infusion. 
 
Performance status (ECOG). 
 
All AEs/SAEs throughout the cycle, including AEs of new onset as well as worsening of 
baseline signs and symptoms. 
 
Concomitant medications from registration and used throughout the cycle. 
 
Study treatment administration: REGN2810 on Cycle 1 Day 1 (only in cohorts receiving 
isatuximab and REGN2810 combination); isatuximab on Cycle 1 Day 1, Cycle 1 Day 8 
and Cycle 1 Day 15 (isatuximab is not administered on Cycle 1 Day 8 and Cycle 1 Day 15 
in Cohort C and Cohort D). 
Laboratory assessments  
 
Serum or urine pregnancy test: WOCBP must have a negative serum pregnancy test result 
within 7 days prior to first IMP administration. A pregnancy test (serum or urine, local 
laboratory) is to be done on Day 1 of each cycle prior to the study treatment. Pregnancy 
test is not required at Cycle 1 Day 8 or Cycle 1 Day 15. 
 
Blood chemistry: includes AST, ALT, bilirubin (total and direct), ALP, LDH, sodium, 
potassium, chloride, bicarbonate/carbon dioxide, calcium, magnesium, phosphate, uric 
acid, urea or BUN, serum creatinine, eGFR (MDRD formula; Appendix H), glucose 
(fasting), albumin, total protein, TSH, and free T4 if TSH is outside of the normal range. 
To be performed every 7 days in cases of Grade 3 or Grade 4 abnormalities. Blood 
chemistry assessments are not required to be repeated prior to Cycle 1 Day 1 if 
performed ≤3 days prior to first study treatment administration at Screening (local 
laboratory). 
 
Hematology: includes hemoglobin, hematocrit, RBC, WBC with differential, and platelet 
counts. If Grade 4 neutropenia, assess ANC every 2 to 3 days until ANC ≥0.5 × 109/L and 
at least weekly thereafter until ANC ≥1.0 × 109/L. Hematology assessments are not 
required to be repeated prior to Cycle 1 Day 1 if performed ≤3 days prior to first 
study treatment administration at Screening (local laboratory). 
 
Quantitative or semi-quantitative urinalysis on Day 1: includes RBC, protein, glucose, pH, 
ketones, bilirubin, leucocytes, nitrates and specific gravity. To be repeated if hematuria is 
observed or clinically indicated. Urinalysis assessments are not required to be repeated 
prior to Cycle 1 Day 1 if performed ≤3 days prior to first study treatment 
administration at Screening Dipstick (qualitative) will be performed on Day 1 of each 
new cycle if clinically indicated (local laboratory). 
 
Blood sample collection for PK and ADA evaluation (see Section 1.5). 
Exploratory biomarkers (central laboratory, please refer to study flowchart in Section 1) 
 
Blood sample for immune genetic markers (Day 1 only). 
 
Blood sample for tumor genetic markers (Day 1 only). 
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 
Blood sample for immunophenotyping (Day 1 only). 
 
Blood sample for plasma or serum cytokines (Day 1 only). 
Disease assessment 
 
Prostate-specific antigen assessment on Day 1 for patients with mCRPC. PSA 
assessments are not required to be repeated prior to Cycle 1 Day 1 if performed 
≤3 days prior to first study treatment administration at Screening (local laboratory). 
If clinically indicated only 
 
12-lead ECG (single). 
 
Coagulation: includes prothrombin time or INR and activated PTT (local laboratory). 
 
Qualitative urinalysis (dipstick) on Day 1 (local laboratory). 
 
Any other examinations that are clinically indicated. 
12.3.2 Subsequent cycles (Day 1)  
The treatment window is ±2 days for each of the Q3W administrations. The following procedures 
are to be performed/assessed on Day 1 prior to study treatment administration unless 
specified otherwise: 
 
Physical examination: includes examination of major body systems (neurological, 
digestive, respiratory [signs and symptoms, respiratory rate] and lymph node 
examination). 
 
Body weight. 
 
Vital signs including blood pressure, heart rate, temperature, and respiration rate, prior to 
starting infusion of IMP, every hour during infusion, and at the end of infusion, and if 
clinically indicated during the infusion.  
 
Performance status (ECOG). 
 
All AEs/SAEs throughout the cycle, including AEs of new onset as well as worsening of 
baseline signs and symptoms. 
 
Concomitant medications used throughout the cycle. 
 
Study treatment administration: REGN2810 on Day 1 (only in cohorts receiving 
isatuximab and REGN2810 combination); isatuximab on Day 1. 
Laboratory assessments 
 
Serum or urine pregnancy test for WOCBP: a pregnancy test is to be done on Day 1 of 
each cycle prior to the study treatment (local laboratory). 
 
Blood chemistry: includes AST, ALT, bilirubin (total and direct), ALP, LDH, sodium, 
potassium, chloride, bicarbonate/carbon dioxide, calcium, magnesium, phosphate, uric 
acid, urea or BUN, serum creatinine, eGFR (MDRD formula; Appendix H), glucose 
(fasting), albumin, total protein, TSH (every second cycle), and free T4 if TSH is outside 
of the normal range. To be performed every 7 days in cases of Grade 3 or Grade 4 
abnormalities (local laboratory). 
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 
Hematology: includes hemoglobin, hematocrit, RBC, WBC with differential, and platelet 
counts. If Grade 4 neutropenia, assess ANC every 2 to 3 days until ANC ≥0.5 × 109/L and 
at least weekly thereafter until ANC ≥1.0 × 109/L (local laboratory). 
 
Blood typing interference test on Cycle 2, Day 1 only (local laboratory). 
 
Blood sample collection for PK and ADA evaluation (see Section 1.5, central laboratory). 
Exploratory biomarkers (central laboratory, please refer to study flowchart in Section 1) 
 
Tumor biopsy for IHC, CD38, PD-L1, immune contexture at Cycle 2 Day 1 (≤7 days; after 
IMP administration on C1D15 wherever applicable, prior to IMP administration on Cycle 
2 Day 1), only if clinically feasible. 
 
Tumor biopsy for transcriptomic analysis at Cycle 2 Day 1 (≤7 days; after IMP 
administration on C1D15 wherever applicable, prior to IMP administration on Cycle 2 
Day 1), only if clinically feasible. 
 
Blood sample for tumor genetic markers (Cycle 2 Day 1 and Cycle 3 Day 1 only). 
 
Blood sample for immunophenotyping (Cycle 2 Day 1, Cycle 3 Day 1, then on Day 1 prior 
to IMP administration at each odd numbered cycle starting from Cycle 5). 
 
Blood sample for plasma or serum cytokines (Cycle 2 Day 1, Cycle 3 Day 1, then on 
Day 1 prior to IMP administration at each odd numbered cycle starting from Cycle 5). 
Disease assessment 
 
Tumor imaging: CT or MRI scan every 9 weeks starting at the end of Cycle 3 (63 ±7 days) 
and whenever disease progression is suspected (the same method of assessment should be 
used throughout the study). Tumor imaging timing should follow calendar days and should 
not be adjusted for delays in cycle starts. 
If initial evidence of RECIST 1.1 defined progression is documented, patients could 
continue treatment while waiting for PD confirmation scan 4 weeks after providing the 
patients are clinically stable as detailed in Section 6.7.1. When treatment is continued 
beyond RECIST 1.1 defined tumor progression, subsequent imaging assessments should 
be based upon iRECIST criteria (Appendix D). 
For patients with mCRPC, bone lesions are not considered “non-measurable” lesion pre 
RECIST 1.1. Bone lesions will be assessed by bone scan only.   
 
Prostate-specific antigen assessment every 9 weeks starting at the end of Cycle 3 (63 
±7 days) for patients with mCRPC. Patients with PSA progression (Appendix A) in the 
absence of radiographic progression should continue IMP (local laboratory). 
 
Bone scan for patients with mCRPC, every 9 weeks starting at the end of Cycle 3 (63 
±7 days). In cases of PD based on bone scan only, the bone scan should be repeated after 
6 weeks to confirm the progression using the 2+2 rule (2 new lesions on first scan, with at 
least 2 additional lesions on the confirmatory scan; refer to Appendix A) as detailed in 
Section 6.7.1. In case of doubtful lesions on bone scan, bone-centered X-ray or MRI scan 
should be performed to confirm the nature of those lesions (metastatic or not). 
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If clinically indicated only 
 
12-lead ECG (single). 
 
Coagulation: includes prothrombin time or INR and activated PTT (local laboratory). 
 
Quantitative urinalysis: includes RBC, protein, glucose, pH, ketones, bilirubin, leucocytes, 
nitrates and specific gravity. To be repeated if hematuria is observed or clinically indicated 
(local laboratory). 
 
Qualitative urinalysis (dipstick) (local laboratory). 
 
Any other examinations that are clinically indicated. 
12.4 
END OF TREATMENT  
The EOT visit will occur 30 (±7) days after the last IMP administration, or when the patient 
receives another anti-cancer therapy, whichever is earlier. 
The following procedures are to be performed at the EOT visit: 
 
Physical examination: includes examination of major body systems (neurological, 
digestive, respiratory [signs and symptoms, respiratory rate] and lymph node 
examination). 
 
Body weight. 
 
Vital signs including blood pressure, heart rate, temperature, and respiration rate. 
 
Performance status (ECOG). 
 
All AEs/SAEs, including AEs of new onset as well as worsening of baseline signs and 
symptoms. 
 
Concomitant medications. 
 
New anticancer therapy. 
 
Blood sample collection for PK and ADA evaluation (central laboratory, see Section 1.5). 
Laboratory assessments  
 
Serum or urine pregnancy test for WOCBP: a pregnancy test is to be done at the EOT visit 
(local laboratory). 
 
Blood chemistry: includes AST, ALT, bilirubin (total and direct), ALP, LDH, sodium, 
potassium, chloride, bicarbonate/carbon dioxide, calcium, magnesium, phosphate, uric 
acid, urea or BUN, serum creatinine, eGFR (MDRD formula; Appendix H), glucose 
(fasting), albumin, total protein, TSH, and free T4 if TSH is outside of the normal range. 
To be performed every 7 days in cases of Grade 3 or Grade 4 abnormalities (local 
laboratory). 
 
Hematology: includes hemoglobin, hematocrit, RBC, WBC with differential, and platelet 
counts. If Grade 4 neutropenia, assess ANC every 2 to 3 days until ANC ≥0.5 × 109/L and 
at least weekly thereafter until ANC ≥1.0 × 109/L (local laboratory). 
 
Quantitative or semi-quantitative urinalysis: includes RBC, protein, glucose, pH, ketones, 
bilirubin, leucocytes, nitrates and specific gravity (local laboratory). 
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Exploratory biomarkers (central laboratory, please refer to study flowchart in Section 1) 
 
Blood sample for tumor genetic markers. 
 
Blood sample for immunophenotyping. 
 
Blood sample for plasma or serum cytokines. 
Disease assessment (if not performed in the past 30 days) 
 
Tumor imaging: CT or MRI scan (the same method of assessment should be used 
throughout the study). 
 
Prostate-specific antigen assessment for patients with mCRPC (local laboratory). 
 
Bone scan for patients with mCRPC. In cases of PD based on bone scan only, the bone 
scan should be repeated after 6 weeks to confirm the progression. In case of doubtful 
lesions on bone scan, bone-centered X-ray or MRI scan should be performed to confirm 
the nature of those lesions (metastatic or not). 
If clinically indicated only 
 
12-lead ECG (single). 
 
Coagulation: includes prothrombin time or INR and activated PTT (local laboratory). 
 
Qualitative urinalysis (dipstick) (local laboratory). 
 
Any other examinations that are clinically indicated. 
12.5 
POST TREATMENT FOLLOW-UP  
The post treatment follow-up period includes an extended safety follow-up period of 90 days after 
the last dose of study treatment and further follow-up beyond 90 days after the last dose of study 
treatments until death or study cut-off date, whichever occurs first. 
12.5.1 Safety follow-up period  
There will be an extended safety follow-up period for 90 days after the last dose of IMP for ADA 
assessment and for safety assessment. If REGN2810 or isatuximab ADA testing is positive or 
inconclusive during post treatment follow-up, ADA testing will be repeated every 3 months until 
negative. 
Patients who discontinue the study treatment without PD will be followed every 90 days for 
disease assessment until confirmation of PD or start of treatment with another anti-cancer therapy, 
or until study cut-off date, whichever comes first. 
The following procedures are to be performed/assessed at 60 and 90 days after the last IMP 
administration: 
 
Physical examination: includes examination of major body systems (neurological, 
digestive, respiratory [signs and symptoms, respiratory rate] and lymph node 
examination). 
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 
Vital signs: includes blood pressure, heart rate, temperature, and respiration rate. 
 
Blood chemistry: includes AST, ALT, bilirubin (total and direct), ALP, LDH, sodium, 
potassium, chloride, bicarbonate/carbon dioxide, calcium, magnesium, phosphate, uric 
acid, urea or BUN, serum creatinine, eGFR (MDRD formula; Appendix H), glucose 
(fasting), albumin, total protein, TSH, and free T4 if TSH is outside of the normal range. 
To be performed every 7 days in cases of Grade 3 or Grade 4 abnormalities (local 
laboratory). 
 
Hematology: includes hemoglobin, hematocrit, RBC, WBC with differential, and platelet 
counts. If Grade 4 neutropenia, assess ANC every 2 to 3 days until ANC ≥0.5 × 109/L and 
at least weekly thereafter until ANC ≥1.0 × 109/L (local laboratory). 
 
Quantitative or semi-quantitative urinalysis: includes RBC, protein, glucose, pH, ketones, 
bilirubin, leucocytes, nitrates and specific gravity (local laboratory). 
 
Adverse events/SAEs: all ongoing related non-serious AEs, ongoing SAEs at the end of 
treatment visit (ie, 30 days after last IMP administration), and new related AEs/SAEs are 
to be followed to resolution or stabilization. Stabilization is defined as an event ongoing 
without any change for ≥3 months. 
 
Concomitant medications and relationship to AEs/SAEs. 
 
New anticancer therapy. 
 
Serum or urine pregnancy test for WOCBP: a pregnancy test is to be done at every 30  
(± 7) days until 6 months after the last dose of study treatment. 
Disease assessment (if discontinue IMP before PD, repeat every 90 days) 
 
Tumor imaging: CT or MRI scan (the same method of assessment should be used 
throughout the study). 
 
Prostate-specific antigen assessment for patients with mCRPC (local laboratory). 
 
Bone scan for patients with mCRPC. In cases of PD based on bone scan only, the bone 
scan should be repeated after 6 weeks to confirm the progression. In case of doubtful 
lesions on bone scan, bone-centered X-ray or MRI scan should be performed to confirm 
the nature of those lesions (metastatic or not). 
Exploratory biomarkers (central laboratory, please refer to study flowchart in Section 1) 
 
Blood sample for immunophenotyping (60 days after the last IMP administration only). 
 
Blood sample for plasma or serum cytokines (60 days after the last IMP administration 
only). 
12.5.2 Survival follow-up period  
The further follow-up schedule beyond 90 days after last treatment is according to the disease 
progression status: 
 
Patients who discontinue study treatment due to progression of disease: phone call 
follow-up will be done every 90 days from the date of last study treatment administration 
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until death or study cut-off date. Every effort will be made to follow all patients. If 
survival follow-up is missed and is not obtained at the time of the scheduled interval, it 
should be retrieved immediately. For subsequent survival follow-up, the patient follow-up 
visit should be scheduled at the original scheduled survival follow-up interval. If the 
patient is unable to visit the clinical center, the follow-up may be done via phone from the 
Investigator or designee to the patient or the patient’s caregiver or a family member, but 
this should be an exception and any effort should be done to schedule follow-up visit at 
clinical center. 
 
Patients who discontinue the study treatment without progression of disease: Will be 
followed every 90 days for disease assessment until confirmation of progression of disease 
or start treatment with another anti-cancer therapy. After progression of disease patients 
will be followed by phone call until death or study cut-off date. 
 
Patients who are still on study treatment after study cut-off date: will continue to 
receive study treatment and will undergo planned study procedures (except PK and ADA) 
until confirmation PD, or start with another anti-cancer therapy, or treatment period ended, 
whichever comes first. 
12.5.3 Post overall survival study cut-off date  
Patients still on study treatment after the study cut-off date (12 months after last patient initiates 
IMP) can continue study treatment until at least 1 treatment discontinuation criterion as defined in 
Section 6.7 is met. The following information will be collected during the study treatment 
administration: 
 
IMP administration. 
 
Disease assessment (for patients who are still on study treatment, until confirmation of PD, 
or start with another anti-cancer therapy, or treatment period ended, whichever comes 
first) 
 
All SAEs regardless of relationship to study treatment and AEs considered related to study 
treatment. 
 
End of treatment reason. 
One ADA sample should be drawn 90 days after last study treatment administration. If ADA is 
positive or inconclusive at 90 days, the repeat samples will be taken every 3 months days until the 
results become negative (see Section 1.5). 
No follow-up information will be collected after these patients discontinue study treatment except 
all SAEs still ongoing at the end of study treatment and all AEs considered as related to study 
treatment still ongoing or occurring after the end of study treatment, which will be followed until 
resolution/stabilization. 
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12.6 
CROSS-OVER PERIOD  
The patients in Cohort A-2 treated with isatuximab monotherapy who experience PD will be 
permitted to cross over to isatuximab in combination with REGN2810 for up to 2 years after 
progression on isatuximab monotherapy. 
All screening processes for the patients in the Phase 1 and Phase 2 parts are to be conducted 
before combination IMP initiation for the cross-over part, except informed consent, demography, 
medical/surgical and disease history, and weight/height. Tumor biopsy at cross-over screening is 
required unless clinically unfeasible and after discussion with the Sanofi Medical Monitor. On 
treatment biopsy at Cycle 2, Day 1 (≤7 days; after IMP administration on C1D15 wherever 
applicable, prior to IMP administration on Cycle 2 Day 1) of the cross-over part is optional (fine 
needle aspirate is not acceptable). Patients who are included in the cross over part should be 
evaluated as Cohort A-1 and Cohort B (except PK) in Section 12.3, Section 12.4, and  
Section 12.5. 
Patients who do not meet the cross-over part eligibility criteria should be followed up for safety 
and survival as detailed in Section 12.5. 
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13 
STATISTICAL CONSIDERATIONS  
The statistical considerations presented in this section forms the basis for the Statistical Analysis 
Plan (SAP), which will provide accurate definitions and more detailed specifications for the 
analyses to be performed on the data collected from this study. 
13.1 
DETERMINATION OF SAMPLE SIZE  
Phase 1 
In Phase 1, approximately 6 (assuming 6 patients for the starting dose) to 24 (assuming 
12 patients for the starting dose plus 12 patients for DL-1) DLT evaluable patients are expected to 
be enrolled. The actual sample size will vary depending on DLTs observed and the number of 
dose levels explored. Patients who are not evaluable for DLT assessment in the Phase 1 part may 
be replaced. 
Phase 2 
The Phase 2 part of the study is to evaluate initial anti-tumor activity based on tumor response 
using RECIST 1.1 criteria for NSCLC and PCWG3 for mCRPC. The efficacy evaluation is based 
on Simon’s 2 stage design with 90% power at 5% 1-sided alpha level for each of the patient 
cohorts of mCRPC and NSCLC patients, respectively. The assumption of RR, the required sample 
sizes and the number of responders at each stage are provided in Table 8. 
Table 8 - Sample size calculation  
Indication 
H0 
H1 
Sample size 
Number (%) of responses to 
reject H0 
 
 
 
Stage 1 
Final 
Stage 1 
Final 
mCRPC (Combo) 
10% 
26% 
23 
49 
≥3 (13.0%) 
≥9 (18.4%) 
mCRPC (Single) 
10% 
26% 
23 
49 
≥3 (13.0%) 
≥9 (18.4%) 
NSCLC (Combo) 
5% 
22% 
20 
36 
≥2 (10.0%) 
≥5 (13.9%) 
Abbreviations: H0=null hypothesis; H1=alternative hypothesis; mCRPC=metastatic, castration-resistant prostate cancer; NSCLC=non-small cell 
lung 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 Investigators. 
Patients who received the recommended dose regimen in Phase 1 will be also included in the 
Phase 2 Stage 1 (eg, if 6 NSCLC patients were enrolled in Phase 1, only 14 NSCLC patients will 
be needed to complete the Phase 2 Stage 1 NSCLC cohort). 
In Phase 2, approximately 134 patients are expected to be enrolled (assuming Cohort A-1, A-2 
and B complete 2 stages), including approximately 66 patients in Phase 2 Stage 1 and 
approximately 68 patients in Phase 2 Stage 2. The patients who are treated with RP2D in the 
Phase 1 part will be counted as Phase 2 part patients. If isatuximab 10 mg/kg Q3W in combination 
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with REGN2810 or monotherapy without the isatuximab 10 mg/kg QW for 3 weeks is to be tested 
in a mCRPC or NSCLC cohort, 49 or 36 additional patients will be needed, respectively. 
The isatuximab monotherapy cohort (Cohort A-2) will be initiated when the initial anti-tumor 
activity of isatuximab combination therapy is observed in the Phase 2 Stage 1 according to the 
study design. When an isatuximab monotherapy cohort (Cohort A-2) is initiated, patients with 
mCRPC will be randomly assigned in a 1:1 randomization to either the isatuximab in combination 
with REGN2810 (Cohort A-1) or the isatuximab monotherapy (Cohort A-2). The purpose of the 
randomization is to avoid the potential bias of patient assignment, and is not to compare between 
2 cohorts. Randomization will end when 1 of the 2 cohorts completes the enrollment. 
13.2 
PATIENT DESCRIPTION  
13.2.1 Disposition of patients  
Screened patients are defined as any patients who signed the study informed consent. The number 
of screened patients as well as the number and percentage of patients included in the analysis 
populations defined in Section 13.3 will be provided. 
Reasons for treatment discontinuation will be summarized using the all-treated population. 
13.2.2 Protocol deviations  
Major protocol deviations which compromise the evaluation of the safety and efficacy will be 
derived adequately and determination of deviations will be finalized based on data review 
conducted prior to database lock. Decisions made on a patient’s status will be documented. 
13.3 
ANALYSIS POPULATIONS  
13.3.1 All-treated/safety population  
For both Phase 1 and Phase 2 parts of the study, the all-treated/safety 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 REGN2810. 
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. 
13.3.2 Patients evaluable for dose-limiting toxicity assessment  
The DLT evaluable population is defined as patients in the Phase 1 part receiving the planned 
doses of isatuximab and REGN2810 during Cycle 1, and who completed the DLT observation 
period after the first IMP administration as per Section 9.1.1, unless they discontinue the study 
treatment(s) due to DLT. The dose recommended for Phase 2 will be determined on the DLT 
evaluable population. 
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13.3.3 Pharmacokinetic population  
The PK population will include patients from the all-treated population with at least 1 drug 
concentration after the first dose of study treatment. 
13.3.4 Pharmacodynamic population  
The pharmacodynamic population will include patients from the all-treated population with at 
least 1 pharmacodynamic marker result after the first dose of study treatment. 
13.3.5 Anti-drug antibody evaluable population  
ADA evaluable population will include all patients from the all-treated population with at least 
1 ADA non-missing result after the first dose of study treatment. 
13.3.6 Cross-over population  
The cross-over population is defined as patients in Cohort A-2 who progressed on isatuximab 
monotherapy and received isatuximab in combination with REGN2810. 
13.3.7 Response evaluable population  
The response evaluable population will include all patients in the all-treated population who fulfill 
all eligibility criteria with an evaluable baseline assessment and at least one evaluable  
post-baseline response assessment during the treatment period. 
13.4 
STATISTICAL METHODS  
A list of study endpoints and their definitions are provided in Section 9.6. 
Unless otherwise specified, analyses will be descriptive and performed based on the all-treated 
population. The baseline for a given parameter is defined as the last assessment for this parameter 
before first administration of study treatments unless otherwise noted. 
Data from mCRPC and NSCLC cohorts in the Phase 2 part will be analyzed and reported 
separately by cohort. Data from the cohort A-2 cross-over part will be summarized separately 
unless otherwise noted. 
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 in each dose level (if applicable). 
Summary tables will be presented by dose level and overall (if applicable), unless otherwise 
noted. 
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13.4.1 Demographics and baseline characteristics  
Demographic and baseline characteristics (including age, gender, race, ECOG performance 
status), medical or surgical history, and disease characteristics at diagnosis and at study entry will 
be summarized using descriptive statistics. 
13.4.2 Extent of investigational medicinal product exposure  
The following variables will be described to summarize the overall study treatment exposure (all 
study treatments together): 
 
Overall number of cycles started. 
 
Duration of overall exposure in weeks. 
In addition, the following variables will be summarized with descriptive statistics for each IMP 
(ie, isatuximab and REGN2810): 
 
Number of cycles started with each drug. 
 
Duration of exposure of each drug in weeks. 
 
Number of infusions. 
 
Cumulative dose. 
 
Actual dose intensity. 
 
Relative dose intensity. 
 
Dose reduction and reason for dose reduction. 
 
Cycle delays. 
 
Infusion delays within a cycle. 
 
Infusion interruption. 
 
Dose omission. 
13.4.3 Prior/concomitant medication/therapy  
Prior and concomitant medications will be summarized according to the World Health 
Organization Drug Dictionary, considering the first digit of the Anatomical Therapeutic Chemical 
(ATC) class (anatomic category) and the first 3 digits of the ATC class (therapeutic category). All 
ATC codes corresponding to a medication will be summarized. Patients will be counted once in 
each ATC categories (anatomic or therapeutic) linked to the medication. 
13.4.4 Analyses of efficacy variables  
All efficacy analyses will be performed using the all-treated/safety population unless otherwise 
specified. More details on efficacy analyses including the analyses for exploratory endpoints will 
be provided in the SAP. 
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13.4.4.1 Analysis of primary efficacy endpoint  
The RR will be summarized using descriptive statistics. A 90% 2-sided confidence interval will 
be computed using Clopper-Pearson method. The statistical inference will be based on the 
hypothesis defined in Section 13.1 using a 1-sided exact binomial test with a significance level of 
0.05 for each cohort. For each cohort, the analysis cut-off date for the primary analysis of RR will 
be 6 months after the last patient’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 will be updated. 
Same analysis will be performed for RR using the response evaluable population as a secondary 
analysis. Subgroup analyses for primary endpoint may be performed if relevant. 
13.4.4.2 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 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. 
 
Duration of response: Kaplan-Meier estimates such as median and Kaplan-Meier curves 
will be provided for patients who achieved a response. 
 
Progression-free survival: 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. 
 
Disease control rate: the DCR will be summarized using descriptive statistics. 
Subgroup analyses for secondary endpoints may be performed if relevant. 
13.4.5 Analyses of safety data  
13.4.5.1 Dose-limiting toxicities  
In the Phase 1 part, the DLTs will be listed by patient using the DLT evaluable population. 
13.4.5.2 Analyses of adverse events  
The observation period will be divided into 3 segments: pretreatment, TEAE and posttreatment: 
 
The pretreatment period is defined as the time informed consent is signed until the first 
dose of study treatments 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. 
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 
The posttreatment period is defined as the time starting 31 days after the last dose of study 
treatments to study closure or death, whichever comes first. 
Pretreatment AEs are defined as any AE during the pretreatment period. 
Treatment-emergent AEs are defined as AEs that develop, worsen (according to the Investigator 
opinion) or become serious during the TEAE period. 
Posttreatment AEs are defined as AEs that are reported during the posttreatment period. 
The grade will be taken into account in the summary. For patients with multiple occurrences of 
the same PT, the maximum grade will be used. 
The primary focus of AE reporting will be on TEAEs. Pretreatment and posttreatment AEs will be 
described separately. 
Treatment-emergent adverse events 
The TEAEs will be coded according to MedDRA. The AEs will be graded according to the 
NCI-CTCAE version 4.03. 
An overall summary of TEAEs will be provided. The number and percentage of patients who 
experience any of the following will be provided: 
 
TEAEs. 
 
TEAEs of ≥Grade 3. 
 
Grade 5 TEAE (any TEAE with a fatal outcome during the treatment period). 
 
Serious TEAEs. 
 
Serious treatment-related TEAEs. 
 
TEAE leading to permanent (full study treatment) discontinuation/premature (partial study 
treatment) discontinuation. 
 
AESIs. 
 
Treatment-related TEAEs. 
 
Treatment-related TEAEs of ≥Grade 3. 
The number and percentage of patients experiencing TEAEs by primary 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/premature discontinuation, 
TEAEs leading to dose modification, serious TEAEs, TEAEs with fatal outcome and AEs/SAEs 
occurring during the posttreatment dosing period. 
Sorting within tables should ensure the same presentation for the set of all AEs within the 
observation period (pretreatment, on-treatment and posttreatment). For that purpose, the table of 
all TEAEs will be presented by SOC and PT sorted by internationally agreed order unless 
otherwise specified. 
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13.4.5.3 Deaths  
The following deaths summaries will be generated: 
 
Number (%) of patients who died by study period (TEAE and posttreatment) and reasons 
for death summarized for the all-treated/safety population. 
 
TEAEs with fatal outcome (on the AE e-CRF page as reported by the Investigator), and 
related TEAEs with fatal outcome summarized by primary SOC and PT. 
A listing of deaths will be provided. 
13.4.5.4 Clinical laboratory evaluations  
Clinical laboratory values will be analyzed after conversion into standard international units. 
International units will be used in all listings and tables. Complete blood count and serum 
chemistry results will be graded according to NCI-CTCAE version 4.03, when applicable. For 
patients with multiple occurrences of the same laboratory variable during the TEAE 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. 
The number and proportion of patients with abnormal laboratory tests at baseline (ie, last 
assessment before the first dose of study treatments administration) will be presented for all 
grades together and each grade separately. Similar tables showing abnormalities during the TEAE 
period will be provided. 
When the NCI-CTCAE version 4.03 scale is not applicable, the number of patients with a 
laboratory abnormality out-of-normal laboratory range value will be displayed. 
13.4.5.5 Vital signs  
Potentially clinically significant abnormality (PCSA) values are defined as abnormal values 
considered medically important by the Sponsor according to predefined criteria/thresholds based 
on literature review. The incidence of PCSA during the TEAE period will be summarized. 
13.4.5.6 Immunogenicity  
The observation period for ADAs will be divided into 2 periods: 
 
The ADA pretreatment period will be defined as the time that informed consent is signed 
until the first study treatment administration. 
 
The ADA on-study observation period will be defined as the time from the first study 
treatment administration until the end of the study. 
Definitions: 
 
Pre-existing ADA, defined as ADA that are present in samples drawn during the 
pretreatment period. 
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 
Treatment-induced ADA, defined as ADA that developed at any time during the ADA 
on-study observation period in patients without pre-existing ADA (including patients 
without pretreatment samples). 
 
Treatment boosted ADA, defined as pre-existing ADA with a significant increase in the 
ADA titer during the study compared to the baseline titer. 
 
ADA positive patients, defined as patients with at least 1 treatment-induced or 
treatment-boosted ADA positive sample at any time following the first study treatment 
administration. 
 
ADA prevalence, defined as the sum of the number of patients with pre-existing ADA and 
the number of patients with treatment induced ADAs, divided by the number of evaluable 
patients. 
 
ADA incidence, defined as the number of ADA positive patients divided by the number of 
evaluable patients. 
The immunogenicity for isatuximab and REGN2810 will be assessed by summarizing the number 
and percentage of patients with pre-existing ADA and ADA negative at baseline, and by 
summarizing the number and percentage of ADA positive patients (including treatment-induced 
ADA and treatment boosted ADA) during the on-study observation period. 
ADA prevalence and ADA incidence will be also described. 
The impact of positive immune response will be evaluated on efficacy, PK and safety endpoints 
when relevant. 
13.4.6 Analyses of pharmacokinetic variables  
Individual concentrations and PK parameters of isatuximab and REGN2810 will be summarized 
by descriptive statistics (such as mean, geometric mean, median, standard deviation, standard 
error of the mean, coefficient of variation, minimum, and maximum). Individual and mean 
profiles will be presented graphically. 
13.4.7 Analyses of pharmacodynamic variables  
Findings from pharmacodynamics markers will be descriptively summarized and tabulated. 
13.5 
INTERIM ANALYSIS  
An interim analysis will be performed for each cohort after the first 23 patients for mCRPC 
cohorts or the first 20 patients for NSCLC cohorts in the Phase 2 part have completed 6 cycles. 
The interim analysis may be conducted earlier if the required number of responders proceeding to 
Phase 2 Stage 2 is achieved. 
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14 
ETHICAL AND REGULATORY CONSIDERATIONS  
14.1 
ETHICAL AND REGULATORY STANDARDS  
This clinical trial will be conducted by the Sponsor, the Investigator, delegated Investigator staff 
and Subinvestigator(s), in accordance, with consensus ethics principles derived from international 
ethics guidelines, including the Declaration of Helsinki, and the International Council for 
Harmonisation guidelines for good clinical practice (GCP), all applicable laws, rules, and 
regulations. 
Information regarding the clinical trial will be recorded in a free, publicly accessible,  
internet-based registry, no later than 21 days after the first patient enrollment, in compliance with 
applicable regulatory requirements and with Sanofi public disclosure commitments. 
14.2 
INFORMED CONSENT  
The Investigator (according to applicable regulatory requirements), or a person designated by the 
Investigator, and under the Investigator's responsibility, should fully inform the patient of all 
pertinent aspects of the study, including the written information giving approval/favorable opinion 
by the ethics committee (IRB/IEC). All participants should be informed to the fullest extent 
possible about the study, in language and terms they are able to understand. 
Prior to a patient’s participation in the clinical trial, the written informed consent form should be 
signed, with the name of the patient filled in and personally dated by the patient or by the patient’s 
legally acceptable representative, and by the person who conducted the informed consent 
discussion. A copy of the signed and dated written informed consent form will be provided to the 
patient. 
The informed consent form used by the Investigator for obtaining the patient’s informed consent 
must be reviewed and approved by the Sponsor prior to submission to the appropriate ethics 
committee (IRB/IEC) for approval/favorable opinion. 
14.3 
HEALTH AUTHORITIES AND INSTITUTIONAL REVIEW BOARD/INDEPENDENT 
ETHICS COMMITTEE (IRB/IEC)  
As required by local regulation, the Investigator or the Sponsor must submit this clinical trial 
protocol to the health authorities (competent regulatory authority) and the appropriate ethics 
committee (IRB/IEC), and is required to forward to the respective other party a copy of the 
written and dated approval/favorable opinion signed by the Chairman with IRB/IEC composition. 
The clinical trial (study number, clinical trial protocol title and version number), the documents 
reviewed (clinical trial protocol, informed consent form, Investigator’s Brochure with any 
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addenda, Investigator’s CV, etc) and the date of the review should be clearly stated on the written 
ethics committee (IRB/IEC) approval/favorable opinion. 
The IMP will not be released at the study site and the Investigator will not start the study before 
the written and dated approval/favorable opinion is received by the Investigator and the Sponsor. 
During the clinical trial, any amendment or modification to the clinical trial protocol should be 
submitted to the health authorities (competent regulatory authority), as required by local 
regulation, in addition to the IRB/IEC before implementation, unless the change is necessary to 
eliminate an immediate hazard to the patients, in which case the health authorities (competent 
regulatory authority) and the ethics committee (IRB/IEC) should be informed as soon as possible. 
They should also be informed of any event likely to affect the safety of patients or the continued 
conduct of the clinical trial, in particular any change in safety. All updates to the Investigator’s 
Brochure will be sent to the ethics committee (IRB/IEC) and to health authorities (competent 
regulatory authority), as required by local regulation. 
A progress report will be sent to the IRB/IEC at least annually and a summary of the clinical 
trial’s outcome at the end of the clinical trial. 
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15 
STUDY MONITORING  
15.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S)  
The Investigator is required to ensure compliance with all procedures required by the clinical trial 
protocol and with all study procedures provided by the Sponsor (including security rules). The 
Investigator agrees to provide reliable data and all information requested by the clinical trial 
protocol (with the help of the e-CRF, discrepancy resolution form [DRF], or other appropriate 
instrument) in an accurate manner according to the instructions provided and to ensure direct 
access to source documents by the Sponsor representatives. 
If any circuit includes transfer of data particular attention should be paid to the confidentiality of 
the patient's data to be transferred. 
The Investigator may appoint such other individuals as he/she may deem appropriate as 
Subinvestigators to assist in the conduct of the clinical trial in accordance with the clinical trial 
protocol. All Subinvestigators shall be appointed and listed in a timely manner. The 
Subinvestigators will be supervised by and work under the responsibility of the Investigator. The 
Investigator will provide them with a copy of the clinical trial protocol and all necessary 
information. 
15.2 
RESPONSIBILITIES OF SPONSOR  
The Sponsor of this clinical trial is responsible to regulatory authorities for taking all reasonable 
steps to ensure the proper conduct of the clinical trial as regards ethics, clinical trial protocol 
compliance, and integrity and validity of the data recorded in the e-CRFs. Thus, the main duty of 
the monitoring team is to help the Investigator and the Sponsor maintain a high level of ethical, 
scientific, technical and regulatory quality in all aspects of the clinical trial. 
At regular intervals during the clinical trial, the site will be contacted, through monitoring visits, 
letters or telephone calls, by a representative of the monitoring team to review study progress, 
Investigator and patient compliance with clinical trial protocol requirements and any emergent 
problems. These monitoring visits will include but not be limited to review of the following 
aspects: patient informed consent, patient recruitment and follow-up, SAE documentation and 
reporting, AESI documentation and reporting, AE documentation, IMP allocation, patient 
compliance with the IMP regimen, IMP accountability, concomitant therapy use and quality of 
data. 
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15.3 
SOURCE DOCUMENT REQUIREMENTS  
According to the ICH GCP, the Monitoring team must check the e-CRF entries against the source 
documents, except for the preidentified source data directly recorded in the e-CRF. 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 e-CRF (eg, patient's medical file, 
appointment books, 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). 
15.4 
USE AND COMPLETION OF CASE REPORT FORMS AND ADDITIONAL REQUESTS  
It is the responsibility of the Investigator to maintain adequate and accurate e-CRFs (according to 
the technology used) designed by the Sponsor to record (according to the Sponsor instructions) all 
observations and other data pertinent to the clinical investigation in a timely manner. All e-CRFs 
should be completed in their entirety to ensure accurate interpretation of data. 
Should a correction be made, the corrected information will be entered in the e-CRF overwriting 
the initial information. An audit trail allows identifying the modification. 
Data are available within the system to the Sponsor as soon as they are entered in the e-CRF. 
The computerized handling of the data by the Sponsor when available in the e-CRF may generate 
additional requests (DRF) to which the Investigator is obliged to respond by confirming or 
modifying the data questioned. The requests with their responses will be managed through the 
e-CRF. 
15.5 
USE OF COMPUTERIZED SYSTEMS  
The complete list of computerized systems used for the study is provided in a separate document 
which is maintained in the Sponsor trial master file. 
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16 
ADDITIONAL REQUIREMENTS  
16.1 
CURRICULUM VITAE  
A current copy of the curriculum vitae describing the experience, qualification and training of 
each Investigator and Subinvestigator will be signed, dated and provided to the Sponsor prior to 
the beginning of the clinical trial. 
16.2 
RECORD RETENTION IN STUDY SITES(S)  
The Investigator must maintain confidentiality of all study documentation, and take measures to 
prevent accidental or premature destruction of these documents. 
It is recommended that the Investigator retain the study documents at least 15 years after the 
completion or discontinuation of the clinical trial. 
However, applicable regulatory requirements should be taken into account in the event that a 
longer period is required. 
The Investigator must notify the Sponsor prior to destroying any study essential documents 
following the clinical trial completion or discontinuation. 
If the Investigator's personal situation is such that archiving can no longer be ensured by him/her, 
the Investigator shall inform the Sponsor and the relevant records shall be transferred to a 
mutually agreed upon designee. 
16.3 
CONFIDENTIALITY  
All information disclosed or provided by the Sponsor (or any company/institution acting on their 
behalf), or produced during the clinical trial, including, but not limited to, the clinical trial 
protocol, personal data in relation to the patients, the e-CRFs, the Investigator's Brochure and the 
results obtained during the course of the clinical trial, is confidential, prior to the publication of 
results. The Investigator and any person under his/her authority agree to undertake to keep 
confidential and not to disclose the information to any third party without the prior written 
approval of the Sponsor. 
However, the submission of this clinical trial protocol and other necessary documentation to the 
IRB/IEC is expressly permitted, the IRB/IEC members having the same obligation of 
confidentiality. 
The Subinvestigators shall be bound by the same obligation as the Investigator. The Investigator 
shall inform the Subinvestigators of the confidential nature of the clinical trial. 
The Investigator and the Subinvestigators shall use the information solely for the purposes of the 
clinical trial, to the exclusion of any use for their own or for a third party's account. 
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16.4 
PROPERTY RIGHTS  
All information, documents and IMP provided by the Sponsor or its designee are and remain the 
sole property of the Sponsor. 
The Investigator shall not and shall cause the delegated Investigator staff/Subinvestigator not to 
mention any information regarding the Product in any application for a patent or for any other 
intellectual property rights. 
All the results, data, documents, and inventions, which arise directly or indirectly from the clinical 
trial in any form, shall be the immediate and exclusive property of the Sponsor. 
The Sponsor may use or exploit all the results at its own discretion, without any limitation to its 
property right (territory, field, continuance). The Sponsor shall be under no obligation to patent, 
develop, market, or otherwise use the results of the clinical trial. 
As the case may be, the Investigator and/or the Subinvestigators shall provide all assistance 
required by the Sponsor, at the Sponsor's expense, for obtaining and defending any patent, 
including signature of legal documents. 
16.5 
DATA PROTECTION  
 
The patient's personal data, which may be included in the Sponsor database, shall be 
treated in compliance with all applicable laws and regulations. 
 
When archiving or processing personal data pertaining to the Investigator and/or to the 
patients, the Sponsor shall take all appropriate measures to safeguard and prevent access to 
this data by any unauthorized third party. 
 
The Sponsor also collects specific data regarding the Investigator as well as personal data 
from any person involved in the study which may be included in the Sponsor’s databases, 
shall be treated by both the Sponsor and the Investigator in compliance with all applicable 
laws and regulations. 
Patient race (American Indian or Alaska Native, Asian, Black or African American, Native 
Hawaiian or Other Pacific Islander, White, Japanese, Not Reported, or Unknown) will be 
collected in this study because these data are required by several regulatory authorities (eg, on 
Afro-American population for FDA, on Japanese population for the PMDA in Japan or on 
Chinese population for the CFDA in China). 
16.6 
INSURANCE COMPENSATION  
The Sponsor certifies that it has taken out a liability insurance policy covering all clinical trials 
under its sponsorship. This insurance policy is in accordance with local laws and requirements. 
The insurance of the Sponsor does not relieve the Investigator and the collaborators from any 
obligation to maintain their own liability insurance policy as required by applicable law. An 
insurance certificate will be provided to the IECs/IRBs or regulatory authorities in countries 
requiring this document. 
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16.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES  
For the purpose of ensuring compliance with the clinical trial protocol, GCP and applicable 
regulatory requirements, the Investigator should permit auditing by or on the behalf of the 
Sponsor and inspection by regulatory authorities. 
The Investigator agrees to allow the auditors/inspectors to have direct access to his/her study 
records for review, being understood that these personnel are bound by professional secrecy, and 
as such will not disclose any personal identity or personal medical information. 
The Investigator will make every effort to help with the performance of the audits and inspections, 
giving access to all necessary facilities, data, and documents. 
As soon as the Investigator is notified of a planned inspection by the authorities, he/she will 
inform the Sponsor and authorize the Sponsor to participate in this inspection. 
The confidentiality of the data verified and the protection of the patients should be respected 
during these inspections. 
Any result and information arising from the inspections by the regulatory authorities will be 
immediately communicated by the Investigator to the Sponsor. 
The Investigator shall take appropriate measures required by the Sponsor to take corrective 
actions for all problems found during the audit or inspections. 
16.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE  
16.8.1 By the Sponsor  
The Sponsor has the right to terminate the participation of either an individual site or the study at 
any time, for any reason, including but not limited to the following: 
 
The information on the IMP leads to doubt as to the benefit/risk ratio. 
 
Patient enrollment is unsatisfactory. 
 
The Investigator has received from the Sponsor all IMP, means and information necessary 
to perform the clinical trial and has not included any patient after a reasonable period of 
time mutually agreed upon. 
 
Noncompliance by the Investigator or Subinvestigator, or delegated staff with any 
provision of the clinical trial protocol, or breach of any applicable laws, regulations, or 
ICH GCP guidelines. 
 
The total number of patients are included earlier than expected. 
In any case the Sponsor will notify the Investigator of its decision by written notice. 
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16.8.2 By the Investigator  
The Investigator may terminate his/her participation upon 30 days prior written notice if the study 
site or the Investigator for any reason becomes unable to perform or complete the clinical trial. 
In the event of premature discontinuation of the study or premature close-out of a site, for any 
reason whatsoever, the appropriate IRB/IEC and regulatory authorities should be informed 
according to applicable regulatory requirements. 
16.9 
CLINICAL TRIAL RESULTS  
The Sponsor will be responsible for preparing a clinical study report and to provide a summary of 
study results to Investigator. 
16.10 PUBLICATIONS AND COMMUNICATIONS  
The Investigator undertakes not to make any publication or release pertaining to the study and/or 
results of the study prior to the Sponsor’s written consent, being understood that the Sponsor will 
not unreasonably withhold his approval. 
As the study is being conducted at multiple sites, the Sponsor agrees that, consistent with 
scientific standards, a primary presentation or publication of the study results based on global 
study outcomes shall be sought. However, if no multicenter publication is submitted, underway, 
or planned within 12 months of the completion of this study at all sites, the Investigator shall have 
the right to publish or present independently the results of this study in agreement with other 
Investigators and stakeholders. The Investigator shall provide the Sponsor with a copy of any such 
presentation or publication for review and comment at least 30 days in advance of any 
presentation or submission for publication. In addition, if requested by the Sponsor, any 
presentation or submission for publication shall be delayed for a limited time, not to exceed 
90 days, to allow for filing of a patent application or such other justified measures as the Sponsor 
deems appropriate to establish and preserve its proprietary rights. 
The Investigator shall not use the name(s) of the Sponsor and/or of its employees in advertising or 
promotional material or publication without the prior written consent of the Sponsor. The Sponsor 
shall not use the name(s) of the Investigator and/or the Collaborators in advertising or promotional 
material or publication without having received his/her and/or their prior written consent(s). 
The Sponsor has the right at any time to publish the results of the study. 
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17 
CLINICAL TRIAL PROTOCOL AMENDMENTS  
All appendices attached hereto and referred to herein are made part of this clinical trial protocol. 
The Investigator should not implement any deviation from, or changes of the clinical trial protocol 
without agreement by the Sponsor and prior review and documented approval/favorable opinion 
from the IRB/IEC and/or notification/approval of health authorities (competent regulatory 
authority) of an amendment, as required by local regulation, except where necessary to eliminate 
an immediate hazard(s) to clinical trial patients, or when the change(s) involves only logistical or 
administrative aspects of the trial. Any change agreed upon will be recorded in writing, the 
written amendment will be signed by the Investigator and by the Sponsor and the signed 
amendment will be filed with this clinical trial protocol. 
Any amendment to the clinical trial protocol requires written approval/favorable opinion by the 
IRB/IEC prior to its implementation, unless there are overriding safety reasons. 
In case of substantial amendment to the clinical trial protocol, approval from the health authorities 
(competent regulatory authority) will be sought before implementation. 
In some instances, an amendment may require a change to the informed consent form. The 
Investigator must receive an IRB/IEC approval/favorable opinion concerning the revised informed 
consent form prior to implementation of the change and patient signature should be recollected if 
necessary. 
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19 
APPENDICES  
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Appendix A 
Prostate Cancer Clinical Trials Working Group 3 criteria for 
progression  
Details provided in bibliographic reference (48). 
Response evaluation definition for the primary efficacy endpoint (Table 9): 
 
In mCRPC: response will be defined per PCWG3 criteria on the basis of the following 
outcomes (if any of these occur, patients will be considered to have responded): 
- 
Radiographic objective response assessed and confirmed by the Investigators; 
- 
PSA decline of ≥50% (confirmed by a second PSA test). 
For analysis of DoR (secondary efficacy endpoint), disease progression includes radiographic 
disease progression or unequivocal clinical progression (Table 9). For patients with mCRPC, 
radiographic progression includes progression by PCWG3 modified RECIST 1.1 for soft tissue 
and/or PCWG3 defined progression by bone scan. 
Table 9 - Response evaluation definitions for ACT15319  
 
Primary endpoint (RR) 
in patients with 
mCRPC 
Primary endpoint (RR) 
in patients with 
mCRPC 
Disease progression in 
patients with mCRPC 
Assessment criteria 
PSA 
Radiographic objective 
response – soft tissue (bone 
lesions are not considered 
“non-measurable” lesions for 
RECIST; bone lesions will be 
assessed by bone scan only) 
Radiographic objective 
response – bone scan 
Timing of baseline 
assessment 
Cycle 1 Day 1 
Screening CT/MRI 
Screening bone scan 
Frequency of assessment 
Once every 9 weeks 
Once every 9 weeks 
Once every 9 weeks 
Response criteria 
Decline ≥50% 
RECIST 1.1 
NA 
Timing for confirmation of 
response 
4 weeks 
4 weeks 
NA 
Timing for confirmation of 
PD and stop treatment 
 
4 weeks 
6 weeks (2+2 rule) 
Abbreviations: CT=computed tomography; mCRPC=metastatic, castration resistant prostate cancer; MRI=magnetic resonance imaging; NA=not 
applicable; PD=progressive disease; PSA=prostate-specific antigen; RECIST=Response Evaluation Criteria in Solid Tumors; RR=response rate. 
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Table 10 - Prostate Cancer Clinical Trials Working Group 3 criteria for progression at trial entry by 
disease manifestation  
Variable 
Progression criterion 
Blood based 
 
PSA 
Obtain sequence of rising values at a minimum of 1-week intervals. 
 
1.0 ng/mL is the minimal starting value if confirmed rise is only indication of progression unless pure small-
cell carcinoma. 
 
Estimate pretherapy PSADT if at least 3 values available ≥4 weeks apart. 
Imaging 
 
Nodes 
Nodal progression sufficient for trial entry independent of PSA. 
 
Measurable lesions not required for entry. 
 
Modified RECIST 1.1 criteria, separate pelvic and extrapelvic disease, up to 5 nodal lesions total recorded. 
 
Previously normal (<1.0 cm) lymph nodes must have grown by ≥ 5 mm in the short axis from baseline or 
nadir and be ≥ 1.0 cm in the short axis to be considered to have progressed. 
 
If the node progresses to ≥1.5 cm in the short axis, it is measurable; nodes that have progressed to 1.0 to 
<1.5 cm are pathologic, subject to clinical discretion, and non-measurable. 
 
For existing pathologic adenopathy, progression is defined per RECIST 1.1. 
 
Record presence of nodal and/or visceral disease separately. Nodal sites: Locoregional: pelvic only; 
Extrapelvic: retroperitoneal, mediastinal, thoracic, or other. 
Viscera 
Visceral progression sufficient for trial entry independent of PSA and recorded separately by site of spread 
(lung, liver, adrenal, CNS); up to 5 lesions per site of spread. 
 
Measurable lesions not required for entry. 
 
Use RECIST to record visceral lesions as target or non-target. 
 
Record presence of nodal and/or visceral disease separately. Visceral sites: lung, liver, adrenal, CNS. 
Prostate/prostate 
bed (primary site) 
Record prior treatment of primary tumor. 
 
 
Perform directed pelvic imaging (CT, MRI, PET/CT, endorectal MRI, transrectal ultrasound) to document 
presence or absence of disease. 
Bone 
2 new lesions. 
 
Confirm ambiguous results by other imaging modalities (eg, CT or MRI). Only positivity on the bone scan 
defines metastatic disease to bone. 
 
Patients with treated epidural lesions and no other epidural progression are eligible. 
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Variable 
Progression criterion 
Type of progression at trial entry 
 
Report separately: 
PSA only; 
Bone only ±nodal disease; 
Nodal disease only (no bone disease present); 
Visceral (lung, liver, adrenal, CNS) disease (±other sites); 
Record new lesions and site of new lesions v growth of preexisting lesions, or both. 
Other markers 
 
Patient-reported 
outcomes 
For pain palliation analyses, presence of clinically meaningful pain at baseline (eg, ≥4 on a 10-point pain 
intensity scale) is a prerequisite; for pain progression analyses, patients may have any level of pain at 
baseline, including no pain. 
Abbreviations: CNS=central nervous system; CT=computed tomography; MRI=magnetic resonance imaging; PCWG3=Prostate Cancer Clinical 
Trials Working Group 3; PET=Positron emission tomography; PSA=Prostate-specific antigen; PSADT=PSA doubling time; RECIST=Response 
Evaluation Criteria in Solid Tumors. 
Table 11 - Prostate Cancer Clinical Trials Working Group 3 criteria for progression during study  
Variable 
Progression criterion 
Blood based 
 
PSA 
Recognize that a favorable effect on PSA may be delayed for ≥12 weeks, even for a cytotoxic drug. 
 
Monitor PSA by cycle but plan to continue through early rises for a minimum of 12 weeks unless other 
evidence of progression. 
 
Ignore early rises (before 12 weeks) in determining PSA response. 
 
Standards for reporting PSA progression date may not indicate a need to stop treatment. After decline from 
baseline: record time from start of therapy to first PSA increase that is ≥25% and ≥2 ng/mL above the nadir, 
and which is confirmed by a second value ≥3 weeks later (ie, a confirmed rising trend); the requirement for 
an increase of 5 ng/mL was decreased to 2 ng/mL, and the requirement for a 50% increase was reduced to 
25%. No decline from baseline: PSA progression ≥25% increase and ≥2 ng/mL increase from baseline 
beyond 12 weeks. 
Recording the duration of PSA decline of little value. 
Imaging 
 
Nodal and 
visceral 
General: 
Record changes in nodal and visceral (lung, liver, adrenal, and CNS) disease separately. 
Use RECIST 1.1 but clearly record type of progression (growth of existing lesions versus development of new 
lesions) separately by site. 
The recommendations apply to both nmCRPC and mCRPC 
Record up to 5 lesions per site of spread. 
Report the proportion who have not progressed at fixed time points (6 or 12 months). 
Nodal 
Note that for some treatments, a lesion may increase in size before it decreases 
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Variable 
Progression criterion 
 
Previously normal (<1.0 cm) lymph nodes must have grown by ≥5 mm in the short axis from baseline or nadir 
and be ≥1.0 cm in the short axis to be considered to have progressed. 
Nodes that have progressed to 1.0 to less than 1.5 cm are pathologic, subject to clinical discretion, and 
nonmeasurable. 
For existing pathologic adenopathy (≥1.5 cm), progression is defined per RECIST 1.1. 
 
Exclude pseudoprogression in the absence of symptoms or other signs of progression. 
Bone Scan 
At least 2 new lesions on first post-treatment scan, with at least 2 additional lesions on the next scan (2+2 
rule). 
If at least 2 additional new lesions are seen on the next (confirmatory) scan, the date of progression is the 
date of the first post-treatment scan, when the first 2 new lesions were documented. 
For scans after the first post-treatment scan, at least 2 new lesions relative to the first post-treatment scan 
confirmed on a subsequent scan. 
Date of progression is the date of the scan that first documents the second lesion. 
Changes in intensity of uptake alone do not constitute either progression or regression. 
Report the proportion of patients who have not progressed at fixed time intervals (6 and 12 months). 
Abbreviations: CNS=central nervous system; mCRPC=metastatic, castration resistant prostate cancer; nmCRPC=nonmetastatic, castration 
resistant prostate cancer; PSA=prostate-specific antigen; RECIST=Response Evaluation Criteria in Solid Tumors. 
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Appendix B  
Response Evaluation Criteria in Solid Tumors version 1.1  
Details provided in bibliographic reference (32). 
Measurability of tumor at baseline 
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as 
follows. 
Measurable lesions must be accurately measured in at least 1 dimension (longest diameter in the 
plane of the measurement to be recorded) with a minimum size of: 
 
10 mm by CT scan (CT scan slice thickness no greater than 5 mm). 
 
10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable). 
 
20 mm by chest X-ray. 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node 
must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended 
to be no greater than 5 mm). At baseline and in follow-up, only the short axis will be measured 
and followed. 
Non-measurable lesions are all other lesions, including small lesions (longest diameter <10 mm or 
pathological lymph nodes with ≥10 to <15 mm short axis), as well as non-measurable lesions. 
Lesions considered non-measurable include: leptomeningeal disease, ascites, pleural or pericardial 
effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses/abdominal organomegaly identified by physical exam that is not measurable by 
reproducible imaging techniques. 
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. 
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 
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 
loco-regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion. 
Method of assessment 
All measurements should be recorded in metric notation, using calipers if clinically assessed. All 
baseline evaluations should be performed as close as possible to the treatment start and never 
more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging based evaluation should 
always be performed rather than clinical examination unless the lesion(s) being followed cannot 
be imaged but are assessable by clinical examination. 
 
Clinical lesions: Clinical lesions will only be considered measurable when they are 
superficial and ≥10 mm diameter as assessed using calipers. For the case of skin lesions, 
documentation by color photography including a ruler to estimate the size of the lesion is 
suggested. As noted above, when lesions can be evaluated by both clinical exam and 
imaging, imaging evaluation should be undertaken since it is more objective and may be 
reviewed at the end of the study. 
 
Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new 
lesions. However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung. 
 
CT, MRI: CT is the best currently available and reproducible method to measure lesions 
selected for response assessment. Measurability of lesions on CT scan is based on the 
assumption that CT slice thickness is 5 mm or less. When CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion should be twice the slice 
thickness. 
 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement. If new lesions are identified by ultrasound in the course of 
the study, confirmation by CT or MRI is advised. 
 
Endoscopy, laparoscopy: The utilization of these techniques for objective tumor 
evaluation is not advised. 
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 
Tumor markers: Tumor markers alone cannot be used to assess objective tumor 
response. 
 
Cytology, histology: These techniques can be used to differentiate between PR and CR in 
rare cases if required by protocol. 
Baseline documentation of ‘target’ and ‘non-target’ lesions 
When more than 1 measurable lesion is present at baseline all lesions up to a maximum of 
5 lesions total (and a maximum of 2 lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline. 
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, and should lend themselves to reproducible repeated 
measurements. 
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
≥15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. All 
other pathological nodes (those with short axis ≥10 mm but <15 mm) should not be considered 
non-target lesions. Nodes that have a short axis <10 mm are considered non-pathological and 
should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. The baseline sum diameters 
will be used as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required and 
these lesions should be followed as ‘present’, ‘absent’, or ‘unequivocal progression’. In addition, 
it is possible to record multiple non-target lesions involving the same organ as a single item on the 
case (eg, ‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver metastases’). 
Response criteria 
Response criteria are described in Table 12. 
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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 CRF. If it is the opinion of the radiologist 
that the lesion has likely disappeared, the measurement should be recorded as 0 mm. If the lesion 
is believed to be present and is faintly seen but too small to measure, a default value of 5 mm 
should be assigned. 
When non-nodal lesions ‘fragment’, the longest diameters of the fragmented portions should be 
added together to calculate the target lesion sum. Similarly, as lesions coalesce, a plane between 
them may be maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion. If the lesions have truly coalesced such that they are no longer separable, the 
vector of the longest diameter in this instance should be the maximal longest diameter for the 
‘coalesced lesion’. 
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Evaluation of non-target lesions 
While some non-target lesions may actually be measurable, they need not be measured and 
instead should be assessed only qualitatively at the time points specified in the protocol. 
 
CR: Disappearance of all non-target lesions and normalization of tumor marker level. All 
lymph nodes must be non-pathological in size (<10 mm short axis). 
 
Non-CR/Non-PD: Persistence of 1 or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits. 
 
Progressive Disease: Unequivocal progression of existing non-target lesions. (Note: the 
appearance of 1 or more new lesions is also considered progression). 
The concept of progression of non-target disease requires additional explanation as follows: 
When the 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 be constitute PD even if 
he/she did not have brain imaging at baseline. 
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents new disease. If repeat scans confirm that there is a 
new lesion, then progression should be declared using the date of the initial scan. 
While fluorodeoxyglucose-positron emission tomography (FDG-PET) response assessments need 
additional study, it is sometimes reasonable to incorporate the use of FDG-PET scanning to 
complement CT scanning in assessment of progression (particularly possible ‘new’ disease). New 
lesions on the basis of FDG-PET imaging can be identified according to the following algorithm: 
A) Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
B) No FDG-PET at baseline and a positive FDG-PET at follow-up: 
- 
If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed 
by CT, this is PD. 
- 
If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan). If the positive FDG-PET at follow-up corresponds to a preexisting 
site of disease on CT that is not progressing on the basis of the anatomic images, this is 
not PD. 
Evaluation of best overall response 
Time point response: At each protocol specified time point, a response assessment should occur. 
Table 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 CRF. 
In trials where confirmation of response is required, repeated ‘NE’ time point assessments may 
complicate best response determination. The analysis plan for the trial must address how missing 
data/assessments will be addressed in determination of response and progression. For example, in 
most trials it is reasonable to consider a patient with time point responses of PR-NE-PR as a 
confirmed response. 
Patients with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be reported as ‘symptomatic 
deterioration’. Every effort should be made to document objective progression even after 
discontinuation of treatment. Symptomatic deterioration is not a descriptor of an objective 
response: it is a reason for stopping study therapy. 
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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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Appendix C 
Eastern Cooperative Oncology Group Performance Status Scale  
 
Performance 
Status 
Description 
0 
Fully active, able to carry on all predisease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary 
nature, eg, light house work, office work. 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities; up and about more than 
50% of waking hours. 
3 
Capable of only limited self-care; confined to bed or chair more than 50% of waking hours. 
4 
Completely disabled; cannot carry on any self-care; totally confined to bed or chair. 
5 
Dead. 
Developed by the Eastern Cooperative Oncology Group, Robert L. Comis, MD, Group Chair (55). 
 
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Appendix D  
Modified Response Evaluation Criteria in Solid Tumors for 
immune-based therapeutics  
Details provided in bibliographic reference (33). 
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 
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 
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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 
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. 
 
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Appendix F 
National Cancer Institute Common Terminology Criteria for Adverse 
Events  
Refer to NCI CTC AE version 4.03 (56) in the Study Reference Manual, or online at the 
following NCI website: http://ctep.cancer.gov/reporting/ctc.html. 
Toxicity grade should reflect the most severe degree occurring during the evaluated period, not an 
average. 
When 2 criteria are available for similar toxicities, the 1 resulting in the more severe grade should 
be used. 
The evaluator must attempt to discriminate between disease/treatment and related 
signs/symptoms. 
An accurate baseline prior to therapy is essential. 
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Appendix G 
Recommended dose modification or discontinuation and 
supportive care guidelines for specific REGN2810 drug-related 
adverse events  
Table 17 - Colitis adverse event management  
Colitis events 
CTCAE 
version 4.03 
Isatuximab 
Dose 
Management 
REGN2810 
Dose 
Management 
Actions and Guidelines 
Diagnostic 
considerations 
Grade 1 
Bowel obstruction 
Colitis 
Colitis 
microscopic 
No change in 
dose 
No change in 
dose 
For diarrhea, treat symptomatically 
(loperamide, oral hydration, electrolyte 
substitution and ADA colitis diet). Endoscopy is 
recommended if symptoms persist. 
 
Grade 1 diarrhea that persists for >1 week 
should be treated with the addition of oral 
diphenoxylate hydrochloride and atropine 
sulfate 4 times daily and budesonide 9 mg 
daily. 
All attempts should 
be made to rule out 
other causes such 
as metastatic 
disease, bacterial 
or parasitic 
infection, 
gastroenteritis or 
the first 
manifestation of an 
inflammatory bowel 
disease by 
examination for 
stool leukocytes, 
stool cultures, and 
a Clostridium 
difficile titer. 
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Colitis events 
CTCAE 
version 4.03 
Isatuximab 
Dose 
Management 
REGN2810 
Dose 
Management 
Actions and Guidelines 
Diagnostic 
considerations 
Grade 2 
Enterocolitis 
hemorrhagic 
GI perforation 
Necrotizing colitis 
Diarrhea: all 
patients who 
experience 
diarrhea should 
be advised to 
drink liberal 
quantities of clear 
fluids. If sufficient 
oral intake is not 
feasible, fluid and 
electrolytes 
should be 
substituted via IV 
infusion. 
Delay or omit 
dose until 
≤Grade 1 
(See 
Section 6.6.2) 
Delay or omit 
dose until 
≤Grade 1 
(See 
Section 6.6.2) 
GI consultation and endoscopy is 
recommended to confirm or rule out colitis for 
Grade 2 diarrhea that persists >1 week or 
Grade 1-2 diarrhea with rectal bleeding 
(additional guidelines for the treatment of 
persistent colitis are provided below). 
 
Grade 2 diarrhea should be treated with 
addition of oral diphenoxylate hydrochloride 
and atropine sulfate 4 times daily and 
budesonide 9 mg daily. 
 
Grade 2 diarrhea with diffuse ulceration and 
bleeding seen on endoscopy may require oral 
steroids with prolonged taper and represent an 
increased risk for the development of bowel 
perforation. 
 
When symptoms improve to Grade 1 or less, 
steroid taper should be started and continued 
over no less than 4 weeks. 
 
In patients with Grade 2 enterocolitis, 
REGN2810 should be withheld and 
anti-diarrheal treatment should be started. If 
symptoms are persistent for more than 1 week, 
systemic corticosteroids should be initiated 
(eg, 0.5 mg/kg/day of prednisone or 
equivalent). When symptoms improve to 
Grade 1 or less, corticosteroid taper should be 
started and continued over at least 1 month. 
 
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Colitis events 
CTCAE 
version 4.03 
Isatuximab 
Dose 
Management 
REGN2810 
Dose 
Management 
Actions and Guidelines 
Diagnostic 
considerations 
Grade 3 
Grade 4 
Grade 3: delay 
or omit dose 
until ≤Grade 1 
(See 
Section 6.6.2) 
Grade 4: 
discontinue 
treatment 
Delay or Omit 
dose until 
≤Grade 1 (See 
Section 6.6.2) 
Discontinue if 
unable to reduce 
corticosteroid 
dose to 
<10 mg/day 
prednisone 
equivalent within 
12 weeks of 
toxicity 
Patients with Grade 3 enterocolitis, drug will be 
permanently discontinued and treatment with 
systemic corticosteroids should be initiated at 
a dose of 1 to 2 mg/kg/day prednisone or 
equivalent. When symptoms improve to 
Grade 1 or less, corticosteroid taper should be 
started and continued over at least 1 month. 
 
For Grade 3-4 diarrhea (or Grade 2 diarrhea 
that persists after initial steroid treatment): 
Rule out bowel perforation. Imaging with plain 
films or CT can be useful. 
Consider consultation with gastroenterologist 
and confirmation biopsy with endoscopy. 
Treat with IV steroids (methylprednisolone 
125 mg) followed by high dose oral steroids 
(prednisone 1 to 2 mg/kg once per day or 
dexamethasone 4 mg every 4 hours). When 
symptoms improve to Grade 1 or less, 
corticosteroid taper should be started and 
continued over no less than 4 weeks. Taper 
over 6 to 8 weeks in patients with diffuse and 
severe ulceration and/or bleeding. 
If IV steroids followed by high-dose oral 
steroids does not reduce initial symptoms with 
48 to 72 hours, consider treatment with 
infliximab at 5 mg/kg once every 2 weeks. 
Discontinue infliximab upon symptom relief 
and initiate a prolonged steroid taper over 45 
to 60 days. If symptoms worsen during steroid 
reduction, initiate a re-tapering of steroids 
starting at a higher dose of 80 or 100 mg 
followed by a more prolonged taper and 
administer infliximab. CAUTION: Infliximab is 
contraindicated in patients with bowel 
perforation or sepsis. 
If symptoms persist despite the above 
treatment a surgical consult should be 
obtained. 
All attempts should 
be made to rule out 
other causes such 
as metastatic 
disease, bacterial 
or parasitic 
infection, 
gastroenteritis or 
the first 
manifestation of an 
inflammatory bowel 
disease by 
examination for 
stool leukocytes, 
stool cultures, and 
a Clostridium 
difficile titer. 
 
If symptoms are 
persistent and/or 
severe, endoscopic 
evaluation should 
be considered. 
Abbreviations: CT=computed tomography’ CTCAE=common terminology criteria for adverse events; GI=gastrointestinal; IV=intravenous. 
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Table 18 - Endocrine adverse event management  
Endocrine 
events 
CTCAE 
version 4.03 
Isatuximab 
Dose 
Management 
REGN2810 
Dose 
Management 
Actions and Guidelines 
Diagnostic 
considerations 
Grade 1-2 
Hyperthyroidism 
Hypothyroidism 
Thyroid disorder 
Thyroiditis 
No change in dose 
No change in 
REGN2810 dose 
Monitor thyroid function or other 
hormonal level tests and serum 
chemistries more frequently 
(every 3 to 6 weeks) until 
returned to baseline values. 
 
Replacement of thyroid hormone 
or thyroid suppression therapy as 
indicated. 
All attempts should be 
made to rule out other 
causes such as brain 
metastases, sepsis, 
and/or infection. An 
endocrinology 
consultation is 
recommended. 
Grade 3-4 
Hyperthyroidism 
Hypothyroidism 
Thyroid disorder 
Thyroiditis 
Delay or omit dose 
until resolves to 
Grade ≤2 (see 
Section 6.6.2) 
Delay or omit dose 
until on stable 
replacement dose 
as determined by 
resolution of 
symptoms and 
normalization of 
hormone levels (see 
Section 6.6.2) 
Consider endocrine consultation. 
 
Rule out infection and sepsis with 
appropriate cultures and imaging. 
 
Replacement of thyroid hormone 
or thyroid suppression therapy as 
indicated. 
Grade 1-4 
Adrenal 
insufficiency 
Hypophysitis 
Hypopituitarism 
Pan- 
hypopituitarism 
Grade 1, 2: no 
change in dose, 
Grade 3, 4: delay or 
omit dose until 
resolves to 
Grade ≤2 (see 
Section 6.6.2) 
Delay or omit dose 
until on stable 
replacement dose 
(see Section 6.6.2) 
Thyroid hormone and/or steroid 
replacement therapy to manage 
adrenal insufficiency. 
 
If Grade 1-2 hypophysitis is 
considered, pituitary gland 
imaging should be considered 
(MRI with gadolinium and 
selective cuts of the pituitary can 
show enlargement or 
heterogeneity and confirm the 
diagnosis). 
 
Grade 3-4 hypophysitis with 
clinically significant adrenal 
insufficiency and hypotension, 
dehydration, and electrolyte 
abnormalities (such as 
hyponatremia and hyperkalemia) 
constitutes adrenal crisis. 
Hospitalization and IV 
methylprednisolone should be 
initiated. 
All attempts should be 
made to rule out other 
causes such as brain 
metastases, sepsis, 
and/or infection. An 
endocrinology 
consultation is 
recommended 
Abbreviations: CTCAE=common terminology criteria for adverse events; IV=intravenous; MRI=magnetic resonance imaging. 
 
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Table 19 - Pneumonitis adverse event management  
Pneumonitis 
events 
CTCAE 
version 4.03 
Grade 
Isatuximab 
Dose 
Management 
REGN2810 
Dose 
Management 
Actions and Guidelines 
Diagnostic 
considerations 
Grade 1 
Pneumonitis 
Interstitial lung 
disease 
Acute interstitial 
pneumonitis 
No change in 
dose 
Consider delay or 
omit dose (see 
Section 6.6.2). 
REGN2810 may 
be continued with 
close monitoring. 
Radiological findings should be followed on 
serial imaging studies at least every 3 weeks. 
 
Monitor for symptoms every 2 to 3 days. 
 
Consider pulmonary consultation and/or 
bronchoscopy if clinically indicated. 
All attempts should be 
made to rule out other 
causes such as 
metastatic disease, 
bacterial or viral 
infection. 
Grade 2 
Pneumonitis 
Interstitial lung 
disease 
Acute interstitial 
pneumonitis 
Delay or omit 
dose until 
resolves to 
Grade ≤1 (see 
Section 6.6.2) 
Delay or omit 
dose until 
resolves to 
Grade ≤1 (see 
Section 6.6.2) 
To rule out other causes such as infection: 
Consider pulmonary consultation with 
bronchoscopy and biopsy/BAL. 
Consider pulmonary function tests 
Follow radiological findings on serial imaging 
studies every 1 to 3 days 
If the patient is determined to have study 
treatment-associated pneumonitis 
Monitor symptoms daily, consider 
hospitalization 
Treat with systemic corticosteroids at a dose 
of 1 to 2 mg/kg/day prednisone or equivalent. 
When symptoms improve to Grade 1 or less, 
steroid taper should be started and continued 
over no less than 4 weeks. 
Treatment with REGN2810 may be resumed 
if the event improves to ≤Grade 1 within 
12 weeks and corticosteroids have been 
reduced to the equivalent of 
methylprednisolone 10 mg by mouth daily or 
less. Repeat chest imaging monthly as 
clinically indicated. 
For Grade 2 pneumonitis that improves to 
≤Grade 1 within 12 weeks, the following 
rules should apply: 
First episode of pneumonitis: may decrease 
the dose to 1 mg/kg in subsequent cycles. 
Second episode of pneumonitis: Discontinue 
REGN2810 if upon re-challenge the patient 
develops a second episode of ≥Grade 2 
pneumonitis. 
All attempts should be 
made to rule out other 
causes such as 
metastatic disease, 
bacterial or viral 
infection 
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Pneumonitis 
events 
CTCAE 
version 4.03 
Grade 
Isatuximab 
Dose 
Management 
REGN2810 
Dose 
Management 
Actions and Guidelines 
Diagnostic 
considerations 
Grade 3-4 
Pneumonitis 
Interstitial lung 
disease 
Acute interstitial 
pneumonitis 
Grade 3: delay 
or omit dose 
until resolves to 
Grade ≤1 (see 
Section 6.6.2) 
Grade 4: 
discontinue 
treatment 
Discontinue 
REGN2810 
Consider pulmonary function tests with 
pulmonary consult. 
 
Bronchoscopy with biopsy and/or BAL is 
recommended. 
 
Treat with IV steroids (methylprednisolone 
125 mg). When symptoms improve to 
Grade 1 or less, a high dose oral steroid 
(prednisone 1 to 2 mg/kg once per day or 
dexamethasone 4 mg every 4 hours) taper 
should be started and continued over no less 
than 4 weeks. 
 
Add prophylactic antibiotics for opportunistic 
infections. 
 
If IV steroids followed by high-dose oral 
steroids does not reduce initial symptoms 
with 48 to 72 hours, consider treatment with 
infliximab at 5 mg/kg once every 2 weeks. 
Discontinue infliximab upon symptom relief 
and initiate a prolonged steroid taper over 45 
to 60 days. If symptoms worsen during 
steroid reduction, initiate a re-tapering of 
steroids starting at a higher dose of 80 or 
100 mg followed by a more prolonged taper 
and administer infliximab. 
All attempts should be 
made to rule out other 
causes such as 
metastatic disease, 
bacterial or viral 
infection 
Abbreviations: BAL= bronchoalveolar lavage; CTCAE=common terminology criteria for adverse events; IV=intravenous. 
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Table 20 - Renal adverse event management  
Renal events 
CTCAE 
version 4.03 
Grade 
Isatuximab 
Dose 
Management 
REGN2810 
Dose 
Management 
Actions and Guidelines 
Diagnostic 
considerations 
Grade 1 
Nephritis 
Nephritis 
autoimmune 
No change in 
Dose 
Consider delay or 
omit dose if event 
does not improve 
with symptomatic 
treatment (see 
Section 6.6.2) 
Provide symptomatic treatment. 
 
Monitor creatinine weekly: when it returns 
to baseline, resume routine creatinine 
monitoring per protocol. 
All attempts should be 
made to rule out other 
causes such as 
obstructive uropathy, 
progression of disease, 
or injury to other 
chemotherapy agents. 
A renal consultation is 
recommended. 
Grade 2 
Renal failure 
Delay or omit 
dose until 
resolves to 
Grade ≤1 (see 
Section 6.6.2) 
Consider delay or 
omit dose (see 
Section 6.6.2) 
Systemic corticosteroids at a dose of 1 to 
2 mg/kg/day of prednisone or equivalent 
may be indicated. When symptoms 
improve to Grade 1 or less, corticosteroid 
taper should be started and continued for 
at least 1 month. 
 
Consider prophylactic antibiotics for 
opportunistic infections. 
 
Consider renal biopsy. 
 
If elevations persist >7 days or worse, 
treat as Grade 4. 
All attempts should be 
made to rule out other 
causes such as 
obstructive uropathy, 
progression of disease, 
or injury to other 
chemotherapy agents. 
A renal consultation is 
recommended. 
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Renal events 
CTCAE 
version 4.03 
Grade 
Isatuximab 
Dose 
Management 
REGN2810 
Dose 
Management 
Actions and Guidelines 
Diagnostic 
considerations 
Grade 3-4 
Renal failure 
acute 
Grade 3: delay 
or omit dose 
until resolves to 
Grade ≤1 (see 
Section 6.6.2) 
Grade 4: 
discontinue 
treatment 
Discontinue 
REGN2810 
Renal consultation with consideration of 
ultrasound and/or biopsy as appropriate. 
 
Monitor creatinine daily. 
 
Treat with systemic corticosteroids at a 
dose of 1 to 2 mg/kg prednisone or 
equivalent once per day. 
 
When symptoms improve to Grade 1 or 
less, steroid taper should be started and 
continued over no less than 4 weeks. 
 
Discontinue REGN2810 if unable to 
reduce corticosteroid dose for irAEs to 
≤10 mg. 
 
REGN2810 treatment may be restated 
and the dose modified as specified in the 
protocol. 
All attempts should be 
made to rule out other 
causes such as 
obstructive uropathy, 
progression of disease, 
or injury to other 
chemotherapy agents. 
A renal consultation is 
recommended. 
Abbreviations: CTCAE=common terminology criteria for adverse events; irAEs=immune-related adverse events. 
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Table 21 - Dermatologic adverse event management  
Skin events 
CTCAE 
version 4.03 
Isatuximab 
Dosing 
managment 
REGN2810 
Dosing 
managemnt 
Action and Guidelines 
Diagnostic 
Considerations 
Grade 1, 2 
No change in 
dose 
No change in 
dose 
Symptomatic treatment should be given 
such as topical glucocorticosteroids (eg, 
betamethasone 0.1% cream or 
hydrocortisone 1%) or urea-containing 
creams in combination with oral antipruitics 
(eg, diphenhrdeamine HCl or hydroxyzine 
HCl) 
 
Treatment with oral steroids is at 
Investigator discretion for Grade 2 events. 
All attempts should be 
made to rule out other 
causes such as 
metastatic disease, 
infectious, or allergic 
dermatitis. 
Grade 3 
No change in 
dose 
Delay or omit 
dose until 
Grade ≤2 (see 
Section 6.6.2) 
Consider dermatology consultation and 
biopsy for confirmation of diagnosis. 
 
Treatment with oral steroids is 
recommended, starting with 1 mg/kg 
prednisone or equivalent once daily or 
dexamethasone 4 mg 4 times per day. 
When symptoms improve to Grade ≤1, 
steroids taper should be started and 
continue over no less than 4 weeks. 
 
Grade 4 
Delay or omit 
dose until 
Grade ≤3 (see 
Section 6.6.2) 
Discontinue 
treatment 
Dermatology consultation and 
consideration of biopsy and clinical 
dermatology photograph. Initiate with oral 
steroids with 1 mg/kg prednisone or 
equivalent. When symptoms improve to 
Grade ≤1, steroids taper should be started 
and continue over no less than 4 weeks. 
 
Abbreviations: CTCAE=common terminology criteria for adverse events. 
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Table 22 - Hepatitis adverse event management  
Hepatitis 
CTCAE 
version 4.03 
Isatuximab 
Dosing 
management 
REGN2810 
Dosing 
management 
Action and Guidelines 
Diagnostic 
Considerations 
Grade 1, 2 
No change in 
dose 
Delay or omit dose if 
there is a treatment-
emergent concurrent 
elevation of ALT and 
bilirubin that 
corresponds to an 
upward shift of 2 or 
more grades in both 
parameters (see 
Section 6.6.2) 
Monitor liver function tests more 
frequently until returned to baseline 
values 
All attempts should be 
made to rule out other 
causes such as 
metastatic disease, 
progressive liver 
disease, viral hepatitis, 
alternative drug 
toxicity, infectious 
causes and/or myositis 
Grade 3, 4 
Delay or omit 
dose until 
Grade ≤2 (see 
Section 6.6.2) 
Discontinue treatment 
if: AST or ALT 
≥5 x ULN 
Bilirubin ≥3 x ULN 
Consider appropriate consultation 
and liver biopsy to establish 
etiology of hepatic injury, if 
necessary. 
 
Treat with high-dose IV 
glucocorticosteroids for 24 to 
48 hours. When symptoms 
improves to Grade ≤1, a steroid 
taper with dexamethasone 4 mg 
every 4 hours or prednisone at 1 to 
2 mg/kg should be started and 
continued over no less than 
4 weeks. 
 
If AST/ALT levels bot not decease 
48 hours after initiation of systemic 
steroids, oral mycophenolate 
mofdtil 500 mg every 12 hours may 
be given. Infliximab is not 
recommended due to its potential 
for hepatotoxicity. 
 
Several courses of steroids taper 
may be necessary as symptoms 
may worsen when the steroids 
dose is decreased. 
All attempts should be 
made to rule out other 
causes such as 
metastatic disease, 
progressive liver 
disease, viral hepatitis, 
alternative drug 
toxicity, infectious 
causes and/or myositis 
Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=common terminology criteria for adverse events; 
ULN=upper limit of normal. 
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Table 23 - Ophthalmology (uveitis) adverse event management  
Uveitis 
CTCAE 
version 4.03 
Isatuximab 
Dosing 
management 
REGN2810 
Dosing 
management 
Action and Guidelines 
Diagnostic 
Considerations 
Grade 1 
No change in dose 
Discontinue treatment 
if symptoms persist 
despite treatment with 
topical 
immunosuppressive 
therapy 
Evaluation by an 
ophthalmologist is strongly 
recommended 
 
Treat with topical steroids such 
as 1% prednisolone acetate 
suspension and iridocyclitis 
All attempts should be 
made to rule out other 
causes such as 
metastatic disease, 
infection, or other 
ocular disease (eg, 
glaucoma or cataracts) 
Grade 2 
No change in dose 
Discontinue treatment 
if symptoms persist 
despite treatment with 
topical 
immunosuppressive 
therapy, and do not 
improve to Grade 1 
within the retreatment 
period or requires 
systemic treatment 
Grade ≥3 
Delay or omit dose 
until Grade ≤2 (see 
Section 6.6.2) 
Discontinue treatment 
Treatment with systemic 
corticosteroids such as 
prednisolone at a dose of 1 to 
2 mg/kg per day. When 
symptoms improve to Grade 
≤1, steroid taper should be 
started and continued over no 
less than 4 weeks 
Abbreviations: CTCAE=common terminology criteria for adverse events. 
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Table 24 - Nausea and vomiting adverse event management  
Nauea and 
Vomiting  
CTCAE 
version 4.03 
Isatuximab 
Dosing 
management 
REGN2810 Dosing 
management 
Action and 
Guidelines 
Diagnostic 
Considerations 
Grade 1 
No change in dose 
No change in dose 
Nausea and vomiting 
should be treated 
aggressively, and 
consideration should be 
given in subsequent cycles 
to the administration of 
prophylactic antiemetic 
therapy according to 
standard institution 
practice. Patients should 
be strongly encouraged to 
maintain liberal oral fluid 
intake. 
 
Grade 2 
Delay or omit dose 
until ≤Grade 1 (see 
Section 6.6.2) 
Restart treatment at 
same dose level 
Delay or omit dose until 
≤Grade 1 (see 
Section 6.6.2) 
May increase dosing interval 
by 1 week if it takes more 
than 4 weeks for toxicities 
for resolve. 
 
 
Grade 3 
Delay or omit dose 
until ≤Grade 1 (see 
Section 6.6.2) 
Restart at same dose 
level. 
Delay or omit until ≤Grade 1 
(see Section 6.6.2) 
May increase dosing interval 
by 1 week if it takes more 
than 4 weeks for toxicities 
for resolve. 
Discontinue if toxicity do not 
resolve within 12 weeks. 
 
 
Grade 4 
Discontinue treatment 
 
 
Abbreviations: CTCAE=common terminology criteria for adverse events. 
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Appendix H 
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) 
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Appendix I 
Multidisciplinary Collegial Meeting Requirement  
 
This appendix provides with country list where the eligibility of patient to take part in the study is 
to be validated at the multidisciplinary collegial meeting: 
France 
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Appendix J 
PROTOCOL AMENDMENT HISTORY  
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
Amendment 1 (05 October 2017) 
This amendment is not 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 a subsection with specific criteria for patients 
allocated to immunotherapy-based treatment arms to continue treatment through RECIST-defined 
radiological progression of disease. Other changes were implemented to clarify footnotes in 
flowcharts for height, weight, and dosing; correct links; add de-escalation text where missing; and 
delete tables of blood draw volumes because they are provided in the Laboratory Manual. 
 
Section # and Name 
Description of Change 
Brief Rationale 
Clinical Trial Summary, 
1.1 Design diagram 
1.5.2 For Phase 2 part of Cohort A-2, Stage 2 
Phase 2 part of Cohort A-1 and Cohort B (tests for 
REGN2810 are not applicable for 
Cohort A-2, tests for PK are not applicable for 
cross-over part) 
 1.5.3 For Cohort C and Cohort D (tests for 
REGN2810 are not applicable for Cohort C if 
isatuximab monotherapy is administered)  
 8.3.1 Study treatment 
 Appendix A Prostate cancer clinical trials working 
group 3 criteria for progression  
Administrative and typographical 
changes 
Correct typographical errors 
and note administrative 
changes 
1.3 Study Flowchart for Phase 1, Phase 2 Cohorts 
A-1, A-2, B and Cross-over part 
1.4 Study Flowchart for Cohort C and Cohort D 
6.5 Retreatment of patientss 
6.6.1 General rules 
6.7.1 Duration of study participation for each patient 
11.1 Permanent treatment discontinuation with IMP 
product(s) 
12.3 Treatment period 
Add specific criteria required for patients 
to continue study treatment after 
apparent radiographic progression 
Per FDA request, to include a 
subsection with specific criteria 
required for patients allocated 
to immunotherapy-based 
treatment arms to continue 
treatment through RECIST-
defined radiological progression 
of disease.  References to the 
subsection were also added in 
relevant sections. 
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Section # and Name 
Description of Change 
Brief Rationale 
1.3 Study flowchart for Phase 1, Phase 2 Cohorts 
A-1, A-2, B and crossover part 
Clarify weight/height data collection time 
point in study flowchart footnote 
Ambiguity in flowchart table and 
footnote may lead to confusion 
of when to collect height and 
weight data. 
1.4 Study flowchart for Cohort C and Cohort D 
1.5.3 For Cohort C and Cohort D (tests for 
REGN2810 are not applicable for Cohort C if 
isatuximab monotherapy is administered) 
Remove irrelevant/non-applicable text 
from study flowcharts 
Flowcharts in section 1.4 and 
1.5.3 are for cohorts without 
QW dosing, while the footnote 
included text regarding dose 
information for QW dosing. 
6.2.1 Starting dose and de-escalation design 
Add details on dose de-escalation 
design 
Certain description of the dose 
de-escalation design in Clinical 
Trial Summary and Design 
Diagram was not transcribed to 
Section 6.2.1. 
6.5 Retreatment of patients 
6.6.3 Dose modifications 
6.6.4 General guidelines for the management of 
immune-related adverse events  
Correct reference to Appendix F to 
Appendix G 
Incorrect hyperlinks in the 
document led to incorrect 
appendices referencing. 
9.1.5 Immunogenicity 
9.2.2 Pharmacokinetic sample handling procedure 
9.4 Samples blood volume 
Remove Tables 5, 7, 10, 11 
Details on blood draw volumes 
should be provided to study 
sites in Laboratory Manual 
instead of inclusion in the 
protocol. 
9.1.5 Immuogenicity 
9.2.3 Bioanalytical methods 
9.2.4.1 Noncompartmental analysis 
13.1 Determination of sample size 
Appendix A Prostate cancer clinical trials Working 
Group 3 criteria for progression 
Appendix B Response Evaluation Criteria in Solid 
Tumors version 1.1 
Appendix D Modified response evaluation criteria in 
solid tumors for immune-based therapeutics 
Appendix G Recommended dose modification or 
discontinuation and supportive care guidelines for 
specific REGN2810 drug-related adverse events. 
Renumbering of Tables 6-28 
Removal of Tables 5, 7, 10, and 
11 require renumbering Tables 
6-28. 
FDA=Food and Drug Administration; RECIST=Response evaluation criteria in solid tumors; QW=once weekly 
Amendment 2 (09 November 2017) 
This amendment applied to the UK only and 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 
The main reason for this amendment was to clarify that pregnancy testing would be performed on 
Day 1 of each cycle as required by MRHA regulations. 
Section # and 
Name 
Description of Change 
Brief Rationale 
1.3 Study flowchart for 
Phase 1, Phase 2 
Cohorts Q-1, A-2, B and 
cross-over part 
1.4 Study flowchart for 
Cohort C and Cohort D 
12.3.1 Cycle 1 (Day 1, 
Day 8 and Day 15) 
12.3.2 Subsequent 
cycles (Day 1) 
12.4 End of treatment 
Clarify that pregnancy testing must be 
performed on Day 1 of each cycle prior 
to the study treatment and at the EOT 
visit 
Per MHRA request, the current protocol is unclear to 
investigators whether the more frequency tests are a legal 
requirement or not in the UK according to the phrase “in 
countries where required by local regulations”.  In order to 
meet the legal requirement, MHRA is requesting to 
indicate that pregnancy testing must be performed on  
Day 1 of each cycle prior to the study treatment and at the 
EOT visit. 
EOT=end of treatment; MHRA= Medicines and Healthcare Products Regulatory Agency 
 
Amendment 3 (02 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. 
OVERALL RATIONALE FOR THE AMENDMENT 
The main reason for this amendment is to implement changes to the protocol in response to 
feedback provided by ANSM dated 07 December  2017. This amendment also includes extension 
of the analysis and study cut-off dates to 12 months instead of 6 months after last ongoing patient 
initiates study treatment, with rationale provided below. Administrative changes such as 
clarifications, corrections of inconsistencies and of typographic errors are also included in this 
amendment. 
Local amendment for United Kingdom (amendment #2), relating to feedback provided by MHRA 
dated October 30th, 2017, is also included in this global amendment (amendment #3), to revert 
back to a unique protocol version for all participating countries. 
Section # and Name 
Description of Change 
Brief Rationale 
Clinical Summary 
7.2 Inclusion criteria 
Modify inclusion criterion I09 
to allow mCRPC patients to 
receive up to 2 previous 
taxane-based chemotherapy 
regimens 
In France, mCRPC patients typically receive 
docetaxel and cabazitaxel as standard treatment. 
ANSM requested the protocol to be amended to 
accommodate patients enrolling into this study 
should have received docetaxel and cabazitaxel as 
per local standard of care, unless an investigator 
believes that a chemotherapy regimen is not 
appropriate for a specific patient. 
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Section # and Name 
Description of Change 
Brief Rationale 
Clinical Trial Summary 
7.2 Inclusion criteria 
7.3 Exclusion criteria 
Exclude NSCLC patients with 
ROS translocation and BRAF 
mutation 
In France, standard treatments are available for 
NSCLC patients with ROS translocation and BRAF 
mutation; therefore, ANSM requested the protocol to 
be amended to exclude patients with these genetic 
alterations. As molecular screening is not performed 
routinely in countries where ROS/BRAF targeted 
therapies are not available as standard treatment 
options, this eligibility criterion is now reflected in a 
new exclusion criterion E26, along with the other 
genetic alterations already specified in inclusion 
criterion I17, to exclude patients with known 
EGFR/ALK/ROS1/BRAF alterations. 
Clinical Trial Summary 
7.3 Exclusion criteria 
Clarify exclusion criterion E18 
regarding criteria that may 
interfere with the immune-
modulation mechanism of 
study treatment 
ANSM suggested adding “active tuberculosis” and 
“severe infection requiring parenteral antibiotic 
treatment” to E18. In addition, hepatitis definitions in 
E18 were modified to improve clarity following 
multiple inquiries from study sites. 
Clinical Trial Summary 
7.2 Inclusion criteria 
Appendix I Multidisciplinary collegial 
meeting requirement 
Specify that patient eligibility 
is to be discussed at a 
multidisciplinary collegial 
meeting per local practice 
ANSM requested to specify in inclusion criterion I04 
that eligibility of patients to take part in the study will 
be validated at the multidisciplinary collegial meeting, 
as per local practice in France.  The rationale is that 
NSCLC patients who are eligible for this study would 
have second line chemotherapies as standard 
treatment option, ANSM wanted assurance from a 
multidisciplinary collegial committee to decide that 
chemotherapy is not the best treatment option for 
this specific patient (I04). 
6.9 Study Committees 
Implement an independent 
data safety monitoring board 
for the Phase 2 part 
ANSM requested to implement an independent 
review committee because this study includes a 
Phase 2 part which enrolls more than 100 patients. 
Clinical Trial Summary 
7.3 Exclusion criteria 
8.9.2 Contraceptive measures and 
pregnancy counseling 
Extend effective contraceptive 
requirement to 2 weeks 
before IMP initiation 
ANSM requested effective contraceptive measures 
to be implemented starting 2 weeks prior to IMP 
initiation, in accordance with isatuximab IB. 
 
1.3 Study flowchart for Phase 1, Phase 
2 Cohorts A-1, A-2, B and cross-over 
part 
1.4 Study flowchart for Cohort C and 
Cohort D 
12.3.1 Cycle 1 (Day 1, Day 8 and Day 
15) 
12.3.2 Subsequent cycles (Day 1) 
12.4 End of treatment 
Clarify that pregnancy testing 
must be performed on Day 1 
of each cycle prior to the 
study treatment and at the 
EOT visit (implemented in 
local amendment for United 
Kingdom – amendment #2) 
Per MHRA request, the current protocol is unclear to 
investigators whether the more frequent tests are a 
legal requirement in the UK according to the phrase 
“in countries where required by local regulations”.  In 
order to meet the legal requirement, MHRA is 
requesting to indicate that pregnancy testing (urine 
or serum) must be performed on Day 1 of each cycle 
prior to the study treatment and at the EOT visit. 
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Section # and Name 
Description of Change 
Brief Rationale 
Clinical Trial Summary 
1.3 Study flowchart for Phase 1, Phase 
2 Cohorts A-1, A-2, B and cross-over 
part 
1.4 Study flowchart for Cohort C and 
Cohort D 
7.2 Inclusion criteria 
9.3 Biomarkers 
Clarify that archival pre-
treatment tissue sample can 
be provided in place of 
mandatory baseline biopsy 
Footnote in the original protocol specified that tumor 
tissue sample performed after progression to prior 
therapy may be considered as baseline biopsy.  To 
avoid confusion, this is now incorporated into 
inclusion criterion I03. 
Clinical Trial Summary 
7.3 Exclusion criteria 
Unify prior anti-cancer 
therapies washout period to 
within 14 days from IMP 
initiation 
There is no rationale to support the use of two 
different washout periods for intravenous (21 days) 
and oral (14 days) anti-cancer therapies. 
Clinical Trial summary 
5.2 Secondary objectives 
9.6.2 Secondary endpoints 
13.4.4.1 Analysis of secondary efficacy 
endpoints 
Add DCR as secondary 
endpoint 
DCR, a typical endpoint for advanced malignancies, 
was intended to be included as a secondary endpoint 
in the original protocol. 
Clinical Trial summary  
6.7.1 Duration of study participation for 
each patient 
6.7.2 Determination of end of clinical 
trial (all patients) 
12.1 Visit schedule 
12.5.2 Survival follow-up period 
12.5.3 Post overall survival study cutoff 
date 
13.4.4.1 Analysis of primary efficacy 
endpoint 
Extend analysis and study 
cut-off dates from 6 months to 
12 months after last ongoing 
patient initiates IMP 
The rationale for this change is that time-to-event 
endpoints such as DoR and PFS for checkpoint 
inhibitors are often >12 months and cutting off tumor 
assessment data early will comprise the maturity of 
these secondary endpoints. In addition, patients who 
are still on study treatment after study-cutoff date will 
continue disease assessment until confirmation of 
PD or end of treatment period, whichever comes 
first, to ensure patients are not progressing while 
continuing to be treated with study drugs. 
1.3 Study flowchart for Phase 1, Phase 
2 Cohorts A-1, A-2, B and cross-over 
part 
1.4 Study flowchart for Cohort C and 
Cohort D 
6.4 Cross-over part (A subpart of cohor 
A-2) 
12.3.2 Subsequent cycles (Day 1) 
12.6 Cross-over period 
Change in time window for 
biomarker sample collection 
(tumor biopsy and blood 
samples for cytokines 
analysis) 
C2D1 tumor biopsy window is changed from ±7 days 
to -7 days (after C1D15 IMP administration).  The 
rationale is that it would be a more robust analysis to 
collect samples from patients who have consistently 
received 1 cycle of study treatment. Blood draw for 
cytokine analysis between baseline and C1D1 is also 
specified to be at least 15 days apart. 
1.3 Study flowchart for Phase 1, Phase 
2 Cohorts A-1, A-2, B and cross-over 
part 
1.4 Study flowchart for Cohort C and 
Cohort D 
Appendix A 
9.6.1 Primary assessment 
Clarify disease assessment 
should follow calendar days 
and not be adjusted for delays 
in cycle start 
Disease assessment should be performed at regular 
frequency despite cycle delays.  Currently protocol 
uses “at the end of every 3 cycles” in most sections, 
and in one section it specified “tumor imaging timing 
should follow calendars and should not be adjusted 
for delays in cycle starts”.  For consistency, calendar 
days will be used to describe disease assessment 
schedule. 
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Section # and Name 
Description of Change 
Brief Rationale 
Clinical Trial Summary 
7.3 Exclusion criteria 
8.9.1 Prohibited concomitant treatments 
Add denosumab and 
interferon as prohibited 
concomitant medications, and 
clarify use of corticosteroids 
throughout study 
Interferon is immunosuppressive and may affect the 
mechanism of study treatment. Denosumab, for 
treatment of osteoporosis and prevention of bone 
metastases, will be added as a prohibited 
concomitant medication (as for bisphosphonate 
therapy). Use of corticosteroids is also further 
elaborated to improve clarity. 
10.5.5 Adverse event  of special interest 
Correct definition for 
REGN2810 symptomatic 
overdose 
REGN2810 symptomatic overdose definition is 
incorrectly indicated on a body weight basis (note:  
REGN2810 is administered as a flat dose). The 
definition is corrected in accordance with REGN2810 
IB edition No. 5, dated May 12, 2017. 
1.3 Study flowchart for Phase 1, Phase 
2 Cohorts A-1, A-2, B and cross-over 
part 
1.4 Study flowchart for Cohort C and 
Cohort D 
12.2 Baseline evaluation 
12.3.1 Cycle 1 (Day 1, Day 8 and Day 
15) 
12.3.2 Subsequent cycles (Day 1) 
12.4 End of treatment 
12.5.1 Safety follow-up period 
Add time window for clinical 
blood tests, urinalysis, and 
biomarker blood draw 
Allow blood chemistry, hematology, urinalysis, PSA 
assessment (time window for C1D1 only), and 
biomarker blood draw to be performed within 24h 
prior to IMP administration, wherever applicable. 
1.3 Study flowchart for Phase 1, Phase 
2 Cohorts A-1, A-2, B and cross-over 
part 
1.4 Study flowchart for Cohort C and 
Cohort D 
To allow semi-quantitative 
urinalysis 
Allow semi-quantitative urinalysis if semi-quantitative 
method used at site level can provide an absolute 
numeric value of the parameters. 
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Section # and Name 
Description of Change 
Brief Rationale 
Throughout 
Miscellaneous clarifications, 
correction of inconsistencies 
and typographic errors 
 
Includes but not limited to: 
Correct typo in E14 and E20 
Correct indicative clocks and clarify sampling 
timing in PK flow chart 
Biomarker exploratory endpoints stated in the 
Clinical Trial Summary is now also inserted under 
Section 9.6.3 Exploratory endpoints 
Remove biomarker sample preservation methods 
(keep details in laboratory manual) 
Correct units and typos of absolute neutrophil 
count under E20 
Clarify isatuximab monotherapy dose is to be 
determined depending on the recommended 
Phase 2 dose 
Clarify inform consent form can be signed more 
than 28 days prior to enrollment/randomization and 
define screening period time frame, and redefine 
“pretreatment AEs” as AEs during “pretreatment 
period” instead of “screening period” 
Introduce INN (cemiplimab) when REGN2810 was 
first mentioned and in Introduction 
Remind study sites must retain disease 
assessment images as Sponsor may decide to 
collect images in the future for possible 
Independent Central Review 
Inconsistencies in visit schedule 
AESI specified in Section 6.6.4 was not mentioned 
in Section 10.5.5 
ANSM= Agence Nationale de Sécurité du Médicament et des Produits de Santé; DCR=disease control rate; DoR=duration of response; 
EOT=end of treatment;  IMP=investigational medicinal product; mCRPC=metastatic castration-resistant prostate cancer; MHRA= Medicines and 
Healthcare Products Regulatory Authority; PD=disease progression; PFS=progression-free survival 
Amendment 4 (23 July 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 reduce the number of radiographic scans showing SD 
required for patients with NSCLC from 2 to 1, specify the frequency of DMC meetings. In 
addition, there were changes to the time window for PK and ADA sample collection and 
administrative changes such as clarifications and corrections. 
   
 
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Section # and Name 
Description of Change 
Brief Rationale 
Clinical Trial Summary 
7.2 Inclusion criteria 
Modify inclusion criterion I16 for 
NSCLC patients to reduce 
requirement of at least 2 
radiographic imaging scans to 
confirm SD to at least 1 
radiographic imaging scan 
In certain countries the standard of care for disease 
assessment using radiographic scan is every 3 months, 
this would in turn lead to documented benefits 
requirement of SD ≥ 6 months, which is inconsistent with 
that listed in I16 where documented benefit is defined as 
SD ≥ 4 months. 
6.9 Study committees 
Added frequency of DMC meeting 
To specify DMC data review meeting will occur at 
intervals planned to be no longer than 3 months (starting 
from the first data review meeting). 
1.5.1 For Phase 1 part, Stage 
1 Phase 2 part of Cohort A-1 
and Cohort B 
1.5.2 For Phase 2 part of 
Cohort A-2, Stage 2 Phase 2 
part of Cohort A-1 and Cohort 
B (tests for REGN2810 are 
not applicable for Cohort A-2, 
tests for PK are not applicable 
for cross-over part) 
1.5.3 For Cohort C and Cohort 
D (tests for REGN2810 are 
not applicable for Cohort C if 
isatuximab monotherapy is 
administered) 
9.1.5 Immunogenicity 
9.2.1 Sampling time 
9.2.3 Bioanalytical methods 
9.2.4.1 Noncompartmental 
analysis 
Clarifications, minor corrections, 
and change in time windows for PK 
and ADA samples collection 
 
Clarified sample collection details and updated sample 
collection time windows within flow chart in consistent 
with footnote descriptions 
Extended follow-up period time window from 90 ± 5 days 
to 90 ± 7 days to improve sample collection feasibility 
Removed indicative clock time from flowchart to avoid 
confusion and inconsistencies 
Updated “Site of bioanalysis” to “Covance Harrogate 
(UK)” from “Refer to laboratory manual” 
Updated “Analytical technique” to “Immunoassay” from 
“ELISA” 
Clarified PK parameters definitions and added AUC0-21d 
as an additional PK parameter 
Updated lower limit of quantification for isatuximab PK 
analysis due to assay transfer to Covance Harrogate 
(UK) 
ADA=anti-drug antibody; DMC=Data Monitoring Committee; ELISA=enzyme-linked immunosorbent assay; NSCLC=nonsmall cell lung cancer; 
PK=pharmacokinetic; SD=stable disease 
 
 
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Amended Protocol 04 [Amendment 05] (21 November 2018) 
This amended protocol (amendment 05) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
OVERALL RATIONALE FOR THE AMENDMENT 
The main reason for this amendment was to modify the inclusion criteria for patients with 
nonsmall cell lung cancer (NSCLC) by allowing patients with NSCLC with best response as 
complete response (CR), partial response (PR) or stable disease (SD) at ≥1 radiographic imaging 
scan who had progressed radiographically to participate.  Additional changes for patients with 
NSCLC include not requiring a tumor biopsy to qualify for enrollment if the procedure could put 
the patient at excessive risk and minimizing the number of pharmacokinetic (PK) and anti-drug 
antibody (ADA) samples to be collected.  For all patients, premedication requirements were 
modified to allow patients with no or Grade ≤2 infusion associated reactions to omit 
premedications at Investigators’ discretion. The window for collection of follow-up samples was 
also extended and text clarified that the follow-up period could extend beyond 6 cycles.  
 
Section # and Name 
Description of Change 
Brief Rationale 
Clinical Trial Summary 
Section 6.3 Phase 2 part 
(efficacy Signal) 
In Part 2, the observation period after last dose of IMP 
was changed from up to 6 cycles to at least 6 cycles. 
Clarified that due to the time needed 
to analyze biomarker and PK 
samples, the totality of data could be 
generated after the last ongoing 
patients in individual cohort received 
6 cycles. 
Clinical Trial Summary 
Section 1.3  Study flowchart 
for Phase 1, Phase 2 cohorts 
A-1, A-2, B and  cross-over 
part 
Section 1.4 Study Flowchart 
for cohort C and cohort D  
Section 7.2 Inclusion criteria 
Section 9.3 Biomarkers 
I 03: For NSCLC patients, the mandatory tumor biopsy 
requirement was modified to allow a patient to enter the 
study without a tumor biopsy at baseline if, in the written 
opinion of the investigator, performing a biopsy would put 
the wellbeing of the patient at an excessive risk due to 
the location of the lesion. Written agreement from the 
Sponsor was required. 
To decrease risk for patients with 
NSCLC whose lesion is located in a 
site where performing a biopsy 
would but the wellbeing of the patient 
at an excessive risk. 
Clinical Trial Summary 
Section 7.2 Inclusion criteria 
I 12 Added that patients with NSCLC could enter the 
study with inoperable recurrent NSCLC rather than only 
Stage IIIB/IV NSCLC. 
To clarify that patients with 
inoperable recurrent NSCLC could 
be enrolled. 
Clinical Trial Summary 
Section 7.2 Inclusion criteria 
I 14 Clarified that prior regimen containing anti-PD-1/PD-
L1 therapy applied to all patients who entered with 
NSCLC (Stage IIIB/IV or inoperable recurrent). 
Clarification 
Clinical Trial Summary 
Section 7.2 Inclusion criteria 
I 15 Clarified that having received no more than 1 
previous chemotherapy applied to all patients who 
entered with NSCLC (Stage IIIB/IV or inoperable 
recurrent). 
Clarification 
Clinical Trial Summary, 
I 16 For patients with NSCLC, removed time and scan 
To allow sites with different scan 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 7.2 Inclusion criteria 
number requirements for prior documentation of clinical 
benefit by radiographic scan. 
frequencies to recruit patients 
Clinical Trial Summary 
Section 7.3 Exclusion criteria 
E 10 Changed time limit from 14 to 21 days before 
initiation of IMP for patients who had received prior 
intravenous cytotoxic chemotherapy, antineoplastic 
biological therapy, major surgery, or local prostatic 
intervention. 
To give patients an extra week to 
recover from intravenous cytotoxic 
chemotherapy, antineoplastic 
biological therapy, major surgery, or 
local prostatic intervention. 
Clinical Trial Summary 
4.4.2.1 Isatuximab 
Section 4.4.4 Preventive 
measures to minimize the 
risk of the combination 
Section 8.2 Noninvesti-
gational medicinal product(s) 
Premedication requirements were modified. 
Timing of premedication dosing modified to match 
Clinical Trial Summary. 
Change based on data from 
completed and ongoing studies.  
This is also to allow patients with no 
or Grade ≤2 infusion associated 
reactions to omit premedications at 
Investigators’ discretion. 
Section 1.3 Study flowchart 
for Phase 1, Phase 2 
Cohorts A-1, A-2, B and  
cross-over part  
Section 1.4 Study Flowchart 
for Cohort C and Cohort D  
Section 12.2 Baseline 
evaluation 
Delete unused abbreviation for IAR. 
Correction 
Section 1.3  Study flowchart 
for Phase 1, Phase 2 cohorts 
A-1, A-2, B and  cross-over 
part 
Section 1.4 Study Flowchart 
for cohort C and cohort D 
4.4.4 Preventative measures 
to minimize the risk of the 
combination 
12.3.1 Cycle 1 (Day 1, Day 8 
and Day 15) 
12.3.2 Subsequent cycles 
(Day 1) 
Vital signs monitoring during isatuximab infusion was 
modified.  
To add monitoring of vital signs 
during the isatuximab infusion, when 
clinically indicated. 
Clinical Trial Summary 
Section 8.2 Noninvesti-
gational medicinal product(s) 
8.2.5 Montelukast 
Montelukast 10 mg orally or equivalent was added as a 
premedication. 
Change made based on data from 
recent references that adding 
montelukast could decrease 
incidence of infusion associated 
reaction. 
Clinical Trial Summary, 
Section 13.3.7 Response 
evaluable population 
Response evaluable population: Added that patients 
must fulfill all eligibility criteria. 
Clarification 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 1.3 Study flowchart 
for Phase 1, Phase 2 
Cohorts A-1, A-2, B and  
cross-over part  
Section 1.4 Study Flowchart 
for Cohort C and Cohort D  
Section 12.2 Baseline 
evaluation 
Section 12.3.1 Cycle 1 (Day 
1, Day 8 and Day 15) 
Section 12.3.2 Subsequent 
cycles (Day 1) 
Section 12.4 End of 
treatment 
Section 12.5.1 Safety follow-
up period 
Urinalysis: sodium, potassium, calcium, and chloride will 
no longer be analyzed. 
Change based on data from 
completed and ongoing studies and 
to align with other isatuximab 
protocols. 
Section 1.5.1  For Phase 1 
part, Stage 1 Phase 2 part of 
Cohort A-1 and Cohort B  
For the patients with NSCLC who are enrolled for Phase 
2 Stage 1 after implementation of Amendment #5 at 
individual sites, PK/ADA will not be collected for 
REGN2810 and isatuximab.  Section title modified to 
reflect changes. 
To decrease burden for patients with 
NSCLC without increasing risk 
Section 1.5.1 For Phase 1 
part, Stage 1 Phase 2 part of 
Cohort A-1 and Cohort B 
Section 1.5.2 For Phase 2 
part of Cohort A-2, Stage 2 
Phase 2 part of Cohort A-1 
and Cohort B (tests for 
REGN2810 are not 
applicable for Cohort A-2, 
tests for PK are not 
applicable for cross-over 
part)  
Section 1.5.3 For Cohort C 
and Cohort D (tests for 
REGN2810 are not 
applicable for Cohort C if 
isatuximab monotherapy is 
administered) 
REGN2810 PK sample to be collected at EOI+ 4h rather 
than EOI+ 4.5h and EOI+ 1h rather than 1h post EOI. 
Clarified that S06 and S06 samples must be collected 
even if second REGN 2810 infusion is not done or is 
delayed. 
Added that PK and ADA collection could be reduced 
upon notification from the Sponsor based on the updated 
knowledge of isatuximab immunogenicity and PK. 
After start of study treatment, if 1 drug is prematurely 
discontinued, ADA samples for this drug will be collected 
on Day 1 of the 2 next cycles. If ADA test at the second 
cycle is positive or inconclusive, ADA testing will be 
repeated every 3 months until negative. 
The window for posttreatment follow-up samples was 
extended from 90±5 days to 90±7 days. 
Typographical correction and to align 
with other protocols 
Section 9.1.5 
Immunogenicity 
Shortened instructions for collection of immunogenicity 
samples and referred to the laboratory manual and 
flowchart for additional information. 
Deleted LLQ row in Table 5 
The laboratory manual and flowchart 
information was more concise. 
 
Row not applicable 
Section 9.2.1 Sampling time 
Deleted information that could be found in PK flowchart 
The information in the PK flowchart 
was more concise. 
Section 9.2.3 Bioanalytical 
methods 
Deleted LLQ row in Table 6 
 
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Section # and Name 
Description of Change 
Brief Rationale 
Appendix G Recommended 
dose modification or 
discontinuation and 
supportive care guidelines 
for specific REGN2810 drug 
related adverse events 
Table 23 Ophthalmology 
(uveitis) adverse event 
management 
Corrected to include steroid dose for Grade ≥3 
ophthalmology AEs (ie, mg/kg) 
Dosing information was incomplete 
Clinical Trial Summary 
13.5 Interim analysis 
Minor wording changes  
Clarification 
Appendix G Recommended 
dose modification or 
discontinuation and 
supportive care guidelines 
for specific REGN2810 drug 
related adverse events 
Table 20 Renal adverse 
event management 
For patients with Grade 3-4 renal events, under 
Isatuximab Dose Management, “Grade 3:  discontinue 
treatment” is corrected to “Grade 4:  discontinue 
treatment” (as Grade 3 is already noted as “delay or omit 
dose until resolves to Grade ≤1”)  
Correction of typographical error 
ADA=anti-drug antibody; AE=adverse event; EOI=end of infusion; LLQ=lower limit of quantitation; NSCLC=nonsmall cell lung cancer; 
PK=pharmacokinetic(s) 
 
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Statistical Analysis Plan  
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Page 2 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ...................................................................................................................1 
TABLE OF CONTENTS..................................................................................................................................2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS..........................................................................5 
1 
OVERVIEW AND INVESTIGATIONAL PLAN ................................................................................7 
1.1 
STUDY DESIGN ..............................................................................................................................7 
1.1.1 
Phase 1 part (safety run-in) .............................................................................................................7 
1.1.1.1 
Starting dose and de-escalation design...........................................................................................7 
1.1.1.2 
Maximum tolerated dose..................................................................................................................8 
1.1.2 
Phase 2 part (efficacy signal)...........................................................................................................8 
1.1.3 
Cross-over part (a subpart of cohort A-2) ........................................................................................9 
1.2 
OBJECTIVES.................................................................................................................................10 
1.2.1 
Primary objectives..........................................................................................................................10 
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) .............................................13 
2.1.3 
Efficacy endpoints..........................................................................................................................14 
2.1.3.1 
Primary efficacy endpoint(s) ..........................................................................................................14 
2.1.3.2 
Secondary efficacy endpoint(s)......................................................................................................14 
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 
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2.1.4.6 
Vital signs variables .......................................................................................................................20 
2.1.4.7 
Electrocardiogram variables ..........................................................................................................20 
2.1.4.8 
Immunogenicity variables ..............................................................................................................20 
2.1.5 
Pharmacokinetic variables .............................................................................................................22 
2.1.6 
Biomarker endpoints ......................................................................................................................23 
2.1.6.1 
Immune Genetic Determinants ......................................................................................................23 
2.1.6.2 
Immune phenotyping......................................................................................................................23 
2.1.6.3 
PD-L1 expression singleplex IHC ..................................................................................................23 
2.1.6.4 
Cluster of differentiation 38 (CD38) expression singleplex IHC ....................................................23 
2.1.6.5 
Immune cell subpopulation tumor infiltration and markers co-expression multiplex 
immunofluorescence......................................................................................................................23 
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 
Pharmacodynamic population........................................................................................................25 
2.3.5 
Anti-drug antibody (ADA) evaluable population.............................................................................25 
2.3.6 
Cross-over population....................................................................................................................26 
2.3.7 
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 
REGN2810 exposure.....................................................................................................................29 
2.4.5 
Analyses of efficacy endpoints.......................................................................................................30 
2.4.5.1 
Analysis of primary efficacy endpoint(s) ........................................................................................30 
2.4.5.2 
Analyses of secondary efficacy endpoints.....................................................................................31 
2.4.5.3 
Multiplicity issues ...........................................................................................................................31 
2.4.6 
Analyses of safety data..................................................................................................................31 
2.4.6.1 
Analyses of DLTs (Phase 1 only)...................................................................................................31 
2.4.6.2 
Analyses of adverse events ...........................................................................................................31 
2.4.6.3 
Deaths............................................................................................................................................33 
2.4.6.4 
Analyses of laboratory variables....................................................................................................34 
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2.4.6.5 
Analyses of vital sign variables ......................................................................................................34 
2.4.6.6 
Analyses of electrocardiogram variables .......................................................................................35 
2.4.6.7 
Analysis of Immunogenicity ...........................................................................................................35 
2.4.7 
Analyses of pharmacokinetic variables..........................................................................................35 
2.4.7.1 
PK parameters ...............................................................................................................................35 
2.4.7.2 
Immunogenicity impact on PK .......................................................................................................36 
2.4.8 
Analyses of biomarker variables....................................................................................................36 
2.4.9 
Analyses of quality of life/health economics variables...................................................................37 
2.4.10 
Further therapy after discontinuation of investigational medicinal product administration 
during the study..............................................................................................................................37 
2.5 
DATA HANDLING CONVENTIONS ..............................................................................................37 
2.5.1 
General conventions ......................................................................................................................37 
2.5.2 
Data handling conventions for secondary efficacy variables.........................................................37 
2.5.3 
Missing data...................................................................................................................................37 
2.5.4 
Windows for time points.................................................................................................................41 
2.5.5 
Unscheduled visits .........................................................................................................................41 
2.5.6 
Pooling of centers for statistical analyses......................................................................................41 
2.5.7 
Statistical technical issues .............................................................................................................41 
3 
INTERIM ANALYSIS (IA) ..............................................................................................................42 
4 
DATABASE LOCK........................................................................................................................43 
5 
SOFTWARE DOCUMENTATION .................................................................................................44 
6 
REFERENCES...............................................................................................................................45 
7 
LIST OF APPENDICES.................................................................................................................46 
APPENDIX A 
GENERIC RANGES FOR HEMATOLOGICAL AND BIOCHEMISTRY 
PARAMETERS ..............................................................................................................................47 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
ADA: 
anti-drug antibodies 
AE: 
adverse event 
AESI: 
adverse event of special interest 
ALT: 
alanine aminotransferase 
ANC: 
absolute neutrophils count 
aPTT: 
activated partial thromboplastin time 
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 
CTCAE: 
common terminology criteria for adverse events 
DCR: 
disease control rate 
DL-1: 
dose level minus 1 
DLT: 
dose limiting toxicity 
DOR: 
duration of response 
ECG: 
electorcardiogram 
ECOG: 
Eastern Cooperative Oncology Group 
eCRF: 
electronic case report form 
EOT: 
end of treatment 
FCGR: 
fc gamma receptor 
IAR: 
infusion associated reaction 
IMP: 
investigational medicinal product 
INR: 
international normalized ratio 
iRECIST: 
modified response evaluation criteria in solid tumors for immune based 
therapies 
IV: 
intravenous 
LDH: 
lactate dehydrogenase 
mCRPC: 
metastatic, castration resistant prostate cancer 
MDRD: 
modified diet in renal disease 
MedDRA: 
medical dictionary for regulatory activities 
MTD: 
maximum tolerated dose 
NCI: 
National Cancer Institute, National Cancer Institute 
NIMP: 
non-investigational medicinal product 
NSCLC: 
non-small cell lung cancer 
OS: 
overall survival 
PCSA: 
potentially clinically significant abnormality 
PCWG3: 
prostate cancer clinical trials working group 3 
PD: 
progressive disease 
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PD-1: 
programmed cell death 1 
PD-L1: 
programmed cell death-ligand 
PFS: 
progression-free survival 
PK/PD: 
pharmacokinetics/pharmacodynamics 
PR: 
partial response 
PSA: 
prostate-specific antigen 
PT: 
preferred term 
PTT: 
partial thromboplastin time 
RBC: 
red blood cell 
RECIST: 
response evaluation criteria in solid tumors 
ROI: 
region of interest 
RP2D: 
recommended phase 2 dose 
rPFS: 
radiographic progression-free survival 
SAE: 
serious adverse event 
SAP: 
statistical analysis plan 
SD: 
stable disease 
SOC: 
system organ class 
TEAE: 
treatment-emergent adverse event 
TSH: 
thyroid stimulating hormone 
WBC: 
white blood cells 
WHO-DD: 
World Health Organization-Drug Dictionnary 
 
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1 
OVERVIEW AND INVESTIGATIONAL PLAN   
1.1 
STUDY DESIGN  
This is an open-label, multi-center, non-comparative, Phase 1/2 study to evaluate the safety, 
preliminary efficacy and PK of isatuximab in combination with REGN2810 (cemiplimab) or 
isatuximab alone in patients with advanced malignancies. 
 
The study will be conducted in up to 3 parts: 
• 
The Phase 1 part (safety run-in) is to characterize the safety and tolerability of isatuximab 
in combination with REGN2810 and to confirm the recommended phase 2 dose (RP2D) 
• 
The Phase 2 part (efficacy signal search with Simon’s 2-stage design) is to assess the 
preliminary efficacy of isatuximab in combination with REGN2810 or isatuximab alone 
• 
Cross-over part (a subpart of Cohort A-2) in which patients who progress on isatuximab 
monotherapy may receive isatuximab plus REGN2810 if they still fulfill the eligibility 
criteria (except exclusion criteria #3 and #8) 
Isatuximab and REGN2810 are defined in this protocol as “study treatments”. 
1.1.1 Phase 1 part (safety run-in) 
Patients with either metastatic, castration resistant prostate cancer (mCRPC) or non-small cell 
lung cancer (NSCLC) will be enrolled in the Phase 1 part. There is no minimum patient number 
requirement for either tumor type. 
1.1.1.1 Starting dose and de-escalation design 
 
The starting dose is selected based on past and ongoing clinical trials. Starting dose is 350 mg 
Q3W for REGN2810 with isatuximab given 10 mg/kg QW for 3 weeks followed by Q3W. Dose 
de-escalation will be performed if necessary as defined in Table 1 below: 
Table 1 - Dose modification for Phase 1 
Dose level 
Isatuximab 
REGN2810 
 
Starting dose 
10 mg/kg 
QW × 3->Q3W 
350 mg 
Q3W 
Minus 1 (DL-1) 
5 mg/kg 
QW × 3->Q3W 
350 mg 
Q3W 
Abbreviations: DL=dose level; QW=once weekly; Q3W=once every 3 weeks. 
 
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At the starting dose, dose limiting toxicity (DLT) will be assessed in the first 6 patients  
(1 cycle; 21 days): 
• 
If ≤1/6 patient has DLT, the starting dose will be the RP2D 
• 
If 2/6 patients have DLT, 6 additional patients will be enrolled at starting dose level: 
- 
If a total of 2/12 patients treated at starting dose have DLT, starting dose will be the 
RP2D 
- 
If a total of ≥3/12 patients have DLT, dose will be de-escalated to dose level minus 1 
(DL-1) 
• 
If ≥3/6 patients have DLT, dose will be de-escalated to DL-1 
An additional 6 patients may be enrolled at DL-1; if ≤1/6 patient has DLT, DL-1 will be the 
RP2D. At DL-1, if ≥2/6 patients have DLT, an alternative dose/schedule might be considered 
from a safety viewpoint by the Sponsor after consulting with the Investigators who recruit patients 
for the Phase 1 part.  
The DLT observation period is 1 cycle (21 days). The duration of the DLT observation period will 
be longer for patients who delay initiation of Cycle 2 due to treatment-related adverse event (AE) 
for which the duration must be assessed in order to determine if the event is a DLT. All AEs 
during treatment, unless due to disease progression or an obviously unrelated cause, will be taken 
into consideration by the Sponsor and recruiting Investigators for the determination of the 
maximum tolerated dose (MTD) and RP2D.  
Investigational medicinal product (IMP) initiation of patients in the Phase 1 part is to be staggered 
by ≥3 days. The National Cancer Institute (NCI) common terminology criteria for adverse events 
(CTCAE) version 4.03 will be used to assess the severity of AEs. Causal relationship is to be 
determined by the Investigator. The DLTs will be confirmed by the Sponsor and recruiting 
Investigators. 
1.1.1.2 Maximum tolerated dose 
The MTD is defined as the highest dose level at which no more than 1 out of 6 patients (starting 
dose or DL-1) or 2 out of 12 patients (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 part (efficacy signal) 
The Phase 2 part may include up to 5 cohorts: 
• 
Cohort A-1: mCRPC, isatuximab and REGN2810 combination therapy 
• 
Cohort A-2: mCRPC, isatuximab monotherapy 
• 
Cohort B: NSCLC, isatuximab and REGN2810 combination therapy 
• 
Possibly Cohort C: mCRPC, isatuximab and REGN2810 combination therapy, or 
isatuximab monotherapy without initial isatuximab weekly dosing 
• 
Possibly Cohort D: NSCLC, isatuximab and REGN2810 combination therapy without 
initial isatuximab weekly dosing 
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Enrollment in Cohort A-2 will start only if the decision to proceed to Phase 2 Stage 2 in Cohort 
A-1 is made. 
The patients treated at the RP2D of isatuximab and REGN2810 in combination during Phase 1 
will be included in the efficacy analysis together with patients of the same tumor type in Stage 1 
of Phase 2. Based on the number of objective responses (observed up to 6 cycles after the last 
ongoing patient receives first dose of IMP) 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 Investigators. After enrollment completion of Phase 2 Stage 1, if 
efficacy results do not warrant initiation of Stage 2, enrolment will be paused until sufficient 
results or analyses warrant initiation of Phase 2 Stage 2. 
For patients with mCRPC, if it is decided to run Phase 2 Stage 2, an isatuximab monotherapy 
cohort will be initiated for this population (Cohort A-2); patients with mCRPC will be randomly 
assigned in a 1:1 randomization ratio to enter Cohort A-1, isatuximab and REGN2810 
combination (Phase 2 Stage 2) or Cohort A-2, isatuximab monotherapy (Phase 2 Stage 1). The 
isatuximab single agent dose and schedule for cohort A-2 is 10 mg/kg QW for 3 weeks followed 
by Q3W. 
Based on the efficacy signal and the totality of data observed within a tumor type at end of Phase 
2 Stage 2, the Sponsor may decide to further study isatuximab 10 mg/kg Q3W in combination 
with REGN2810 or isatuximab 10 mg/kg Q3W as a monotherapy in patients with mCRPC 
(Cohort C) or isatuximab 10 mg/kg Q3W in combination with REGN2810 in patients with 
NSCLC (Cohort D), without the isatuximab doses of 10 mg/kg QW for 3 weeks. The schedule 
without the initial weekly dosing may be more practical for patients and health care providers. 
Objectives and study design considerations for Cohort C and Cohort D are the same as those for 
other cohorts in the same tumor type. The Sponsor may decide to test an isatuximab dose of  
20 mg/kg in case of inadequate efficacy and PK results. 
1.1.3 Cross-over part (a subpart of cohort A-2) 
Patients from Cohort A-2 who progress on isatuximab monotherapy may receive isatuximab plus 
REGN2810 at the discretion of the Investigators and if they still fulfill the eligibility criteria 
(except exclusion criteria #3 and #8). The screening period for the cross-over part is 28 days from 
progressive disease (PD) confirmation. 
All screening processes for the patients in the Phase 1 and Phase 2 parts are to be conducted 
before combination IMP initiation for the cross-over part, except informed consent, demography, 
medical/surgical and disease history, and weight/height. Tumor biopsy at cross-over screening is 
required unless clinically unfeasible and after discussion with the Sanofi Medical Monitor. On 
treatment biopsy at Cycle 2, Day 1 (±7 days) of the cross-over part is optional (fine needle 
aspirate is not acceptable). Patients who are included in the cross-over part should be evaluated as 
Cohort A-1 and Cohort B (except PK). 
Patients who do not meet the cross-over part eligibility criteria should be followed up for safety 
and survival. 
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1.2 
OBJECTIVES 
1.2.1 Primary objectives 
 
Phase 1: 
• 
To characterize the safety and tolerability of isatuximab in combination with REGN2810 
in patients with mCRPC who are naïve to anti-programmed cell death 1  
(PD-1)/programmed cell death-ligand (PD-L1)-containing therapy naive, or NSCLC who 
progressed on anti-PD-1/PD-L1-containing therapy, and to confirm the RP2D 
Phase 2 (applicable to Cohorts A-1, A-2, B, C, and D): 
• 
To assess the RR of isatuximab in combination with REGN2810 in patients with either 
mCRPC who are anti-PD-1/PD-L1 therapy naive, or NSCLC who progressed on  
anti-PD-1/PD-L1 therapy, or of isatuximab as single agent in patients with mCRPC 
1.2.2 Secondary objectives 
• 
To evaluate the safety of the combination of isatuximab with REGN2810 or isatuximab 
monotherapy  
• 
To evaluate the immunogenicity of isatuximab and REGN2810 
• 
To characterize the PK profile of isatuximab single agent or in combination with 
REGN2810, and to characterize the PK of REGN2810 in combination with isatuximab 
• 
To assess overall efficacy of isatuximab in combination with REGN2810 or single agent 
(tumor burden change, duration of response [DOR], and progression-free survival [PFS]) 
1.3 
DETERMINATION OF SAMPLE SIZE 
 
Phase 1 
In Phase 1, approximately 6 (assuming 6 patients for the starting dose) to 24 (assuming 12 
patients for the starting dose plus 12 patients for DL-1) DLT evaluable patients are expected to be 
enrolled. The actual sample size will vary depending on DLTs observed and the number of dose 
levels explored. Patients who are not evaluable for DLT assessment in the Phase 1 part may be 
replaced. 
 
Phase 2 
The Phase 2 part 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 NSCLC and 
prostate cancer clinical trials working group 3 (PCWG3) criteria (2) for mCRPC. The efficacy 
evaluation is based on Simon’s 2 stage designs with 90% power at 5% 1-sided alpha level for 
each of the patient cohorts of mCRPC and NSCLC patients, respectively. The assumption of RR, 
the required sample sizes and the number of responders at each stage are provided in Table 2. 
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Table 2 - Sample size calculation 
Indication 
H0 
H1 
Sample size 
Number (%) of required 
responses  
 
 
 
 
Stage 1 
Final 
Stage 1 
Final 
mCRPC (Combo) 
10% 
26% 
23 
49 
≥3 (13.0%) 
≥9 (18.4%) 
mCRPC (Single) 
10% 
26% 
20 
36 
≥2 (10.0%)  
≥5 (13.9%) 
NSCLC (Combo) 
5% 
22% 
20 
36 
≥2 (10.0%)  
≥5 (13.9%) 
Abbreviations: H0=null hypothesis; H1=alternative hypothesis; mCRPC=metastatic, castration-resistant prostate cancer; NSCLC=non-
small cell lung 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 Investigators. 
 
Patients who received the recommended dose regimen in Phase 1 will be also included in the 
Phase 2 Stage 1 (eg, if 6 NSCLC patients were enrolled in Phase 1, only 14 NSCLC patients will 
be needed to complete the Phase 2 Stage 1 NSCLC cohort).  
In Phase 2, approximately 134 patients are expected to be enrolled (assuming Cohort A-1, A-2 
and B complete 2 stages), including approximately 66 patients in Phase 2 Stage 1 and 
approximately 68 patients in Phase 2 Stage 2. The patients who are treated with RP2D in the 
Phase 1 part will be counted as Phase 2 part patients. If isatuximab 10 mg/kg Q3W in combination 
with REGN2810 or monotherapy without the isatuximab 10 mg/kg QW for 3 weeks is to be tested 
in a mCRPC or NSCLC cohort, 49 or 36 additional patients will be needed, respectively. 
The isatuximab monotherapy cohort (Cohort A-2) will be initiated when the initial anti-tumor 
activity of isatuximab combination therapy is observed in the Phase 2 Stage 1 according to the 
study design. When an isatuximab monotherapy cohort (Cohort A-2) is initiated, patients with 
mCRPC will be randomly assigned in a 1:1 randomization to either the isatuximab in combination 
with REGN2810 (Cohort A-1) or the isatuximab monotherapy (Cohort A-2). The purpose of the 
randomization is to avoid the potential bias of patient assignment, and is not to compare between 
2 cohorts. Randomization will end when 1 of the 2 cohorts completes the enrollment. 
1.4 
STUDY PLAN 
The complete study plan is presented in section 1.1 of the protocol. 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL  
Not applicable. 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN 
Not applicable. This is not an amended statistical analysis plan (SAP). 
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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 mCRPC and NSCLC cohorts in the Phase 2 part will be analyzed and reported 
separately by cohort. Data from the cohort A-2 cross-over part 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) and eastern cooperative oncology group (ECOG) performance status 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 
• 
Histopathology type (as collected in eCRF) 
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• 
Stage of the disease (as collected in eCRF) 
• 
Gleason Score (for patients with mCRPC) 
Disease characteristics at study entry - mCRPC 
The following disease characteristics at study entry will be described: 
• 
Disease extent (metastatic, Loco Regional Recurrence, Primary, locally advanced) 
• 
Criteria for progression (prostate-specific antigen (PSA),  soft tissue, bone metastasis) 
• 
Baseline PSA 
Disease characteristics at study entry - NSCLC 
Disease extent (metastatic, Loco Regional Recurrence, Primary, locally advanced) will be 
summarized. 
Prior anticancer therapies 
Prior anti-cancer treatments are collected by regimen in the eCRF. The following variables will be 
summarized: 
• 
Prior chemotherapy (by category: 0, 1, 2, 3 or more regimens): Number (%) of patients 
who received Taxane chemotherapy will be summarized for mCRPC cohorts 
• 
Number of prior regimens (by category: 1, 2, 3, >3) 
• 
Prior radiation therapy: number (%) of patients with any prior radiotherapy related to 
mCRPC or NSCLC by intent 
• 
Prior surgery: number (%) of patients with any prior surgery related to mCRPC or NSCLC 
by type of procedure (Preferred Term) 
In addition, for mCRPC cohorts, prior hormonal therapy will be summarized by category (1, 2, 3 
or more regimens).  Number (%) of patients who received enzalutamide only, abiraterone only 
and enzalutamide + abiraterone will be summarized. 
For NSLCL cohort, number (%) of patients who received anti-PD1/PDL-1 containing regimen 
will be summarized by category (1, 2 or more regimens). 
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   
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• 
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 8.2 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 NSCLC, the RR is defined as the proportion of patients achieving complete 
response (CR) or partial response (PR) as best overall response (BOR), assessed by the 
investigator 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 cutoff date or 
following the initiation of a further anticancer treatment.  Clinical deterioration will not be 
considered as progression in the primary analysis of RR. 
For patients with mCRPC, response will be defined by radiographic objective response (achieving 
CR or PR as BOR for soft tissue) assessed and confirmed by the Investigators and/or a PSA 
decline of ≥50% from baseline that is subsequently confirmed per PCWG3 criteria (protocol 
Appendix A). The PSA decline must be confirmed to be sustained by a second PSA value 
obtained 4 or more weeks later.  BOR for soft tissue will be Non-CR/Non-PD for patients with no 
baseline target and non-target lesions identified at baseline and no new lesions reported in post-
baseline tumor assessments. 
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  
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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 
• 
Duration of response: Duration of response is defined as the time from the date of first 
response (PR or CR in radiographic objective response, or PSA decline ≥50% for patients 
with mCRPC) that is subsequently confirmed to the date of first disease progression or 
death, whichever occurs first. Disease progression includes radiographic disease 
progression or unequivocal clinical progression. The RECIST 1.1 criteria will be followed 
for assessment of radiographic disease progression in patients with NSCLC and the 
PCWG3 criteria will be followed in patients with mCRPC. For patients with mCRPC, 
radiographic progression includes progression by PCWG3 modified RECIST 1.1 for soft 
tissue and/or PCWG3 defined progression by bone scan. 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 and the analysis cut-off date, whichever is earlier. DOR will not be 
calculated for patients who do not achieve a response 
• 
Progression-free survival: For mCRPC patients, PFS is defined as the time from first study 
treatment administration to the date of first documented disease progression or the date of 
death from any cause, whichever occurs first. Disease progression includes radiographic 
disease progression (per PCWG3 criteria) or unequivocal clinical progression. For NSCLC 
patients, PFS is defined as the time from first study treatment administration to the date of 
first documented radiographic progression (per RECIST 1.1) or the date of death from any 
cause, whichever occurs first 
For patients who did not experience documented disease/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/radiographic 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 PFS event (death 
or documented disease/radiographic progression) and without any valid post-baseline 
disease assessments will be censored at the day of first treatment (Day 1)  
• 
Disease control rate (DCR): DCR is defined as the proportion of patients with confirmed 
complete response (CR) or partial response (PR) or stable disease (SD), as assessed by 
Investigator (per PCWG3 criteria for mCRPC patients and per RECIST 1.1 criteria for 
NSCLC patients) relative to the total number of patients in the analysis population 
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2.1.3.3 Exploratory efficacy endpoint(s) 
For patients with mCRPC and patients with NSCLC, the following endpoints will be summarized: 
• 
Overall survival (OS): defined as the time from first study treatment administration to 
death for 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 
• 
Time to response: defined as the time from first study treatment administration to the first 
response (PR or CR in radiographic objective response, or PSA decline ≥50% for patients 
with mCRPC) that is subsequently confirmed (RECIST 1.1 for patient with NSCLC and 
PCWG3 criteria for patients with mCRPC) 
• 
PFS by modified response evaluation criteria in solid tumors for immune based therapies 
(iRECIST) (3): is defined as the time from first study treatment administration to the date 
of first documented disease progression that is subsequently confirmed or the date of death 
from any cause, whichever occurs first. The same censoring rule as PFS will be used 
In addition, the following endpoints will be summarized for patients with mCRPC:  
• 
Disease control rate (DCR) ≥6 months: DCR ≥6 months includes patients with BOR of CR 
or PR of any duration or SD of ≥6 months duration.  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. Disease progression includes radiographic disease 
progression (per PCWG3 criteria) or unequivocal clinical progression. 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 duration of SD 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 and the analysis cut-off date, whichever is earlier 
DCR ≥6 months rate is defined as the proportion of patients with DCR ≥6 months relative 
to the total number of patients in the analysis population 
Similarly, DCR ≥6 months rate requiring PD confirmation will also be summarized 
• 
Radiographic PFS (rPFS): For mCRPC patients, rPFS is defined as the time from first 
study treatment administration to the date of first documented radiographic progression or 
the date of death from any cause, whichever occurs first.  The same censoring rule as PFS 
will be used 
• 
rPFS by iRECIST: For mCRPC patients, rPFS is defined as the time from first study 
treatment administration to the date of first documented radiographic progression that is 
subsequently confirmed or the date of death from any cause, whichever occurs first.  The 
same censoring rule as PFS will be used 
• 
PSA response rate: defined as a PSA decline of ≥50% from baseline that is subsequently 
confirmed 
• 
Radiographic RR: defined as radiographic objective response assessed and confirmed by 
investigator 
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• 
Duration of PSA response: defined as the time from the date of the PSA first decline of 
≥50% from baseline that is subsequently confirmed to the date of first confirmed PSA 
progression or death, whichever occurs first. PSA progression for patients who have 
achieved a ≥50% decrease from baseline is defined as at least a 25% increase and an 
absolute increase of ≥2 ng/mL above the nadir (the lowest PSA value on study). The same 
censoring rules as for DOR will be used 
• 
Duration of radiographic response: defined as the time from the date of the first 
radiographic response (PR or CR) that is subsequently confirmed to the date of first 
radiographic progression or death, whichever occurs first. The same censoring rules as for 
DOR will be used 
• 
Time to PSA response: defined as the time from first study treatment administration to the 
first PSA response that is subsequently confirmed 
• 
Time to radiographic response: defined as the time from first study treatment 
administration to the first radiograph response that is subsequently confirmed 
• 
Time to PSA progression: defined as the time from first study treatment administration to 
the date of first confirmed PSA progression. For patients who have achieved a ≥50% 
decrease from baseline, PSA progression is defined as at least a 25% increase and an 
absolute increase of ≥2 ng/mL above the nadir (the lowest PSA value on study). For 
patients without a PSA decrease of this magnitude or no decrease at all, PSA progression 
is defined as at least a 25% increase and an absolute increase of ≥2 ng/mL above the 
baseline. Death from prostate cancer or any other cause without prior evidence of PSA 
progression will not count as an event. If no event exists, then time to PSA progression 
will be censored at the last scheduled PSA assessment on study or date of death, 
whichever occurs first 
For patients with NSCLC, the following endpoint will also be summarized: 
• 
ORR by iRECIST (NSCLC patients): defined as the proportion of patients achieving 
complete response (CR) or partial response (PR) as best overall response (BOR) as 
assessed by the investigator per iRECIST criteria relative to the total number of patients in 
the analysis population 
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) and 
Eastern Cooperative Oncology Group (ECOG) performance status. 
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 
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• 
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) 
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 IARs. An IAR occurs typically within 24 hours from the start of the infusion  
• 
Grade ≥3 immune-related TEAEs 
• 
Immune-related AEs of any grade in a patient previously treated with a PI3K 
inhibitor (only applicable for patients who receive REGN2810) 
• 
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 IMP/NIMP 
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2.1.4.3 Infusion associated reactions 
IARs typically occur within 24 hours from the start of each isatuximab/REGN2810 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) platelet 
counts, prothrombin time or international normalized ratio (INR) and activated partial 
thromboplastin time (PTT) 
- 
White blood cells (WBCs): WBC count, leukocytes, neutrophils, lymphocytes, 
monocytes, basophils, eosinophils 
• 
Biochemistry 
- 
Metabolism: fasting glucose, total protein 
- 
Electrolytes: sodium, potassium, chloride, calcium, albumin, magnesium, phosphate, 
bicarbonate/carbon dioxide 
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- 
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, ketone, 
bilirubin, leukocytes, nitrates and specific gravity 
2.1.4.6 Vital signs variables 
Vital signs include: heart rate, systolic and diastolic blood pressure, respiratory rate, weight and 
temperature.  
For vital signs, each assessment performed at cycle 1 Day 1, Day 8 and Day 15 prior to study 
treatment administration unless specified otherwise and at cycle N, Day 1. 
Thus, parameters measured on the day of the first study treatment infusion will be considered as 
part of the baseline measurements. 
For vital signs, the treatment period will start at first study treatment infusion + 1 day. 
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 Immunogenicity variables 
Anti-drug antibodies (ADA) against isatuximab and REGN2810 will be collected according to the 
pharmacokinetics/pharmacodynamics (PK/PD) flowcharts in Section 1.5 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. 
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Treatment-induced ADA is defined as ADAs developed de novo (seroconversion) following 
administration of the biotherapeutic (i.e., 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 
• 
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 
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- 
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  
The PK sampling times for isatuximab and REGN2810 were provided in the PK/PD flowchart in 
Section 1.5 of the protocol. 
The following PK parameters (listed in Table 3) will be calculated with PKDMS software 
(Pharsight) V3.0, using non-compartmental method from isatuximab and REGN2810 
concentrations after the first administration on Cycle 1.  The parameters will include, but may not 
be limited to the following: 
Table 3 - List of pharmacokinetic parameters and definitions 
Parameters 
Analyte 
Definition 
 
REGN2810 
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 
AUC0-21d 
X 
 
Area under the concentration versus time curve calculated using the 
trapezoidal method over the dosing interval (21 days)  
AUC0-7d or 
AUC0-21d 
 
X 
Area under the plasma concentration versus time curve calculated using 
the trapezoidal method over the dosing interval (7 days, and for cohorts C 
and D: 21 days)  
 
 
 
 
Ctrough are defined as sample collected just before treatment administration during repeated dosing.   
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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 Immune Genetic Determinants 
Germline genetic data of Fc gamma receptor (FCGR) genes will be analyzed on blood samples 
collected on Day 1 of Cycle 1: 
• 
FCGR polymorphisms (FCGR3A): For each gene, the results will be of the form AA, Aa 
or aa with A and a-alleles, the major and minor allele, respectively 
2.1.6.2 Immune phenotyping 
Immune phenotyping in peripheral blood (baseline, D1 of Cycle 1, 2, 3, 5, 7, 9, end of treatment 
(EOT) and FUP60) will be assessed. Immune cell sub-populations will be determined by 
multiparametric flow cytometry based on the expression of different cell surface markers. 
Percentages of a given immune cell sub-populations and absolute counts as well as expression 
intensity of certain markers will be provided. 
2.1.6.3 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. 
2.1.6.4 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. 
2.1.6.5 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. 
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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.  
Randomized patients include all patients in cohort A-1 stage 2 and cohort A-2 who signed the 
study informed consent and were randomized regardless of whether the patient was treated or not. 
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/randomized patients 
• 
Enrolled/randomized and not treated patients 
• 
Enrolled/randomized and treated patients 
• 
Patients still on treatment 
• 
Patients completed treatment 
• 
Patients who discontinued the study treatments period and reasons for permanent 
discontinuation 
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. 
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2.2.1 Randomization and drug dispensing irregularities 
For patients with mCRPC, if an isatuximab monotherapy cohort is initiated, patients with mCRPC 
will be randomly assigned in a 1:1 randomization ratio to enter Cohort A-1, isatuximab and 
REGN2810 combination (Phase 2 Stage 2) or Cohort A-2, isatuximab monotherapy (Phase 2 
Stage 1).  
All randomization and drug-dispensing irregularities will be documented in the clinical study 
report.  The irregularities will be categorized and summarized among randomized patients 
(number and percentages).   
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 REGN2810. 
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 REGN2810 during Cycle 1, and who completed the DLT observation 
period after the first IMP administration as per Section 9.1.1 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 REGN2810, and include 
patients from the all treated population with at least one reportable concentration after the study 
drug administration (whatever the cycle and even if dosing is incomplete).   
2.3.4 Pharmacodynamic population 
The pharmacodynamic population will include patients from the all-treated population with at 
least 1 pharmacodynamic marker result after the first dose of study treatment. 
2.3.5 Anti-drug antibody (ADA) evaluable population 
The ADA evaluable population will be defined independently for isatuximab and REGN2810, and 
include subjects with at least one sample, taken post-baseline after drug administration during the 
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treatment or follow-up observation period, that is appropriate for ADA testing with a reportable 
result (positive, negative or inconclusive).  
2.3.6 Cross-over population 
The cross-over population is defined as patients in Cohort A-2 who progressed on isatuximab 
monotherapy and received isatuximab in combination with REGN2810. 
2.3.7 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 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. 
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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. In 
addition, prior anti-cancer treatments after disease became mCRPC for prostate patients or after 
disease became advanced for NSCLC patients 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 REGN2810 + 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. They 
cycle start date is defined as the earlier date of isatuximab or REGN2810 administration within a 
cycle. Cycle delay is not defined for the first cycle. 
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 
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• 
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. 
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 
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• 
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 REGN2810 exposure 
The REGN2810 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 REGN2810 exposure (weeks) is defined as (Date of the last dose of 
REGN2810 + 21 days – Date of the first dose of REGN2810)/7 
• 
Actual dose (mg): is defined as actual dose administered 
• 
Cumulative dose (mg): the cumulative dose is the sum of all actual REGN2810 doses 
• 
ADI (mg/week): is defined the cumulative dose (mg) divided by the duration of 
REGN2810 exposure (weeks) 
• 
RDI (%): 
(mg/week)
Intensity 
 
Dose
 
Planned
 
(mg/week)
 
ADI
100×
, where the planned dose intensity 
(mg/week) is 116.7 mg/week for Q3W schedule 
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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 REGN2810 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 REGN2810 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 REGN2810 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.) 
2.4.5 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 of RR will be 6 months after the 
last patient’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 patient’s first treatment in the 
cohort.  The primary analysis of RR will be updated. 
2.4.5.1 Analysis of primary efficacy endpoint(s) 
 
The RR will be summarized using descriptive statistics. A 90% 2-sided confidence interval will be 
computed using Clopper-Pearson method. BOR will be summarized descriptively. For mCRPC 
cohorts, PSA response will also be summarized using descriptive statistics. 
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2.4.5.2 Analyses of secondary efficacy endpoints 
The secondary efficacy endpoints are: 
• 
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  
• 
DoR: Kaplan-Meier estimates such as median and Kaplan-Meier curves will be provided 
for patients who achieved a response (PR or CR, or PSA response for mCRPC patients) 
• 
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 
DCR ≥6 months, PSA response rate, radiographic RR for mCRPC patients and ORR by iRECIST 
for NSCLC patients will be summarized with descriptive statistics.  OS, time to response, and PFS 
by iRECIST will be analyzed using the Kaplan-Meier method.  In addition, for mCRPC patients, 
rPFS, rPFS by iRECIST, duration of PSA response, duration of radiographic response, time to 
PSA response, time to radiographic response, and time to PSA progression will be also be 
analyzed using the Kaplan-Meier method. 
2.4.5.3 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.  
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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  
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 REGN2810 
• 
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, cemiplimab 
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 IRs (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), 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 6 
and Table 7). 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 4) 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 4 - 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 REGN2810.  
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 
PK analysis will be done separately for isatuximab and REGN2810.  
2.4.7.1 PK parameters  
2.4.7.1.1 Cycle 1 
 
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 possibly 
overall. 
Individual and mean concentration profiles over time will be plotted by cohort and possibly 
overall under the responsibility of Sanofi, Pharmacokinetic, Dynamic and Metabolism (PKDM), 
Translational Medicine and Early Development (TMED) department.  
2.4.7.1.2 Overall treatment: Ctrough and Ceoi 
 
Ctrough defined as a sample collected before dosing, and in a time window of 12 to 16 days after 
the previous infusion for the Q2W administration, or in a time window of 6 to 8 days after the 
previous infusion for the QW administration will be included in the descriptive analysis 
irrespectively of interruption of infusion. However Ctrough drawn outside collection of time window 
described in the protocol PKPD flowchart or collected after dose deviation higher than ±50% from 
intended dose will be excluded from the analyses. 
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Ceoi collected after significant infusion interruption, drawn outside collection of time window 
described in the protocol PKPD flowchart or collected after dose deviation higher than ±50% from 
intended dose will be excluded from the analyses. 
Individual Ctrough and Ceoi will be listed and summarized with same descriptive statistics as above 
by cohort and possibly overall.  
Mean (±SE) of Ctrough will be plotted over treatment phase by cohort and possibly overall for 
isatuximab and for REGN2810. 
Individual Ctrough ratio and Ceoi ratio (described in Table 5) will be listed and summarized by 
descriptive statistics by cohort and possibly overall as described above.  
Table 5 - Ctrough and Ceoi ratio 
Analyte 
Ctrough 
Ceoi 
C2D1 vs C1D8 
C2D1 vs C1D1 
Isatuximab 
C4D1 vs C1D8 
C4D1 vs C1D1 
REGN2810 
C4D1 vs C1D22  
C4D1 vs C1D1 
 
2.4.7.2 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 possibly 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 REGN2810 at the same time as ADA positive result will be notified.  
2.4.8 Analyses of biomarker variables 
The biomarker variables will be summarized by clinical group (eg, DCR≥6 months for mCRPC 
patients vs. others) and overall. Graphics will be provided as appropriate. The biomarker variables 
include, but not limited to, the following variables: 
• 
FCGR3A types: F/F, F/V, V/V and missing, 
• 
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/REGN2810, 
may be conducted on remaining samples pending evolving literature. 
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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. 
Creatinine clearance (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. 
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 
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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 
• 
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 
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• 
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. 
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. 
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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 REGN2810 and isatuximab are given to a patient on the same visit: 
• 
Missing REGN2810 end date/time will be imputed by isatuximab start date/time (if 
available) 
• 
Missing isatuximab start date/time will be imputed by REGN2810 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 
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. 
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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 (IA) 
An IA will be performed for each cohort after the first 23 patients for mCRPC cohorts or the first 
20 patients for NSCLC cohorts in the Phase 2 part have completed 6 cycles. The interim analysis 
may be conducted earlier if the required number of responders proceeding to Phase 2 Stage 2 is 
achieved. 
The analysis will include the following parameters/analyses (defined in Section 2.1): response 
rate, 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. 
Scher HI, Morris MJ, Stadler WM, Higano C, Basch E, Fizazi K, Antonarakis ES, et al. 
Trial design and objectives for castration-resistant prostate cancer: updated recommendations 
from the Prostate Cancer Clinical Trials Working Group 3. J Clin Oncol. 2016;34:1402-18. 
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. 
Alexander Kratz, Maryjane Ferraro, Patrick M. Sluss and Kent B. Lewandrowski, MD. 
Laboratory reference values.  
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7 
LIST OF APPENDICES 
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Appendix A 
Generic ranges for hematological and biochemistry parameters 
Table 6 - 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.((4) 
Table 7 - 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 
 
 
(electronic 
 
 
 
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