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Clinical Trial Results:
A Phase 1/2 study to evaluate safety, pharmacokinetics and efficacy of isatuximab in combination with cemiplimab in patients with relapsed/refractory multiple myeloma

Summary
EudraCT number	2017-001431-39
Trial protocol	HU CZ ES GR IT
Global end of trial date	05 Apr 2023

Results information
Results version number	v1
This version publication date	19 Apr 2024
First version publication date	19 Apr 2024
Other versions	v2

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

TCD14906

ISRCTN number

US NCT number

NCT03194867

WHO universal trial number (UTN)

U1111-1189-4706

Sponsor organisation name

Sanofi aventis recherche & développement

Sponsor organisation address

1 avenue Pierre Brossolette, Chilly-Mazarin, France, 91380

Public contact

Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com

Scientific contact

Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

23 Apr 2023

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

05 Apr 2023

Was the trial ended prematurely?

Main objective of the trial

- To evaluate the safety and tolerability of the combination of isatuximab and cemiplimab. - Phase 2 only: To compare the overall response rate (ORR), defined as complete response (CR) + very good partial response (VGPR) + partial response (PR) of the combination of isatuximab and cemiplimab versus isatuximab alone in subjects with relapsed/refractory multiple myeloma (RRMM) based on International Myeloma Working Group (IMWG) criteria.

Protection of trial subjects

Subjects were fully informed of all pertinent aspects of clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject is participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.

Background therapy

Evidence for comparator

Actual start date of recruitment

21 Feb 2018

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 7

Country: Number of subjects enrolled

Brazil: 13

Country: Number of subjects enrolled

Canada: 17

Country: Number of subjects enrolled

Czechia: 12

Country: Number of subjects enrolled

France: 16

Country: Number of subjects enrolled

Greece: 5

Country: Number of subjects enrolled

Hungary: 2

Country: Number of subjects enrolled

Italy: 14

Country: Number of subjects enrolled

Spain: 9

Country: Number of subjects enrolled

United States: 14

Worldwide total number of subjects

109

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Subjects were screened at 30 sites. The study was conducted i.e. subjects were randomised at 29 sites in 10 countries. A total of 3 subjects in Phase 1 and 106 subjects in Phase 2 were enrolled (Phase 1)/randomised (Phase 2) from 21 Feb 2018 to 20 Mar 2019.

Screening details

The study consisted of 2 phases: Phase 1 confirmed the feasibility of isatuximab/cemiplimab combination and Phase 2 further evaluated safety, efficacy and pharmacokinetics (PK) of combination versus isatuximab monotherapy. Subjects in Phase 2 were randomised in a 1:1:1 ratio to receive either isatuximab monotherapy or combination therapy.

Period 1 title

Overall study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Phase 1: Isatuximab + Cemiplimab Once Every 2 Weeks (Q2W)

Arm description

Subjects received isatuximab 10 milligram/ kilogram (mg/kg) intravenous (IV) infusion once weekly for 4 weeks (QWx4) followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) and cemiplimab 250 mg IV infusion Q2W (on Days 1 and 15 every cycle of a 28-day cycle) until disease progression, unacceptable adverse events (AEs), consent withdrawal, or any other reason.

Arm type

Experimental

Investigational medicinal product name

Isatuximab

Investigational medicinal product code

SAR650984

Other name

Sarclisa

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Isatuximab 10 mg/kg IV infusion was administered QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) until protocol-defined discontinuation criteria were met.

Investigational medicinal product name

Cemiplimab

Investigational medicinal product code

REGN2810

Other name

Libtayo

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Cemiplimab 250 mg was administered as an IV infusion Q2W (on Days 1 and 15 every cycle of a 28-day cycle) until protocol-defined discontinuation criteria were met.

Phase 2: Isatuximab

Arm description

Subjects received isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.

Arm type

Experimental

Investigational medicinal product name

Isatuximab

Investigational medicinal product code

SAR650984

Other name

Sarclisa

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Phase 2: Isatuximab + CemiplimabQ2W

Arm description

Subjects received isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) and cemiplimab 250 mg IV infusion Q2W (on Days 1 and 15 every cycle of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.

Arm type

Experimental

Investigational medicinal product name

Isatuximab

Investigational medicinal product code

SAR650984

Other name

Sarclisa

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

Cemiplimab

Investigational medicinal product code

REGN2810

Other name

Libtayo

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Cemiplimab 250 mg was administered as an IV infusion Q2W (on Days 1 and 15 every cycle of a 28-day cycle) until protocol-defined discontinuation criteria were met.

Phase 2: Isatuximab + Cemiplimab Once Every 4 Weeks (Q4W)

Arm description

Subjects isatuximab 10 mg/kg IV infusion QWx4 followed by Q2W (on Days 1, 8, 15 and 22 in Cycle 1, and on Days 1 and 15 in Cycle 2 and beyond of a 28-day cycle) and cemiplimab 250 mg IV infusion Q4W (on Day 1 every cycle of a 28-day cycle) until disease progression, unacceptable AEs, consent withdrawal, or any other reason.

Arm type

Experimental

Investigational medicinal product name

Isatuximab

Investigational medicinal product code

SAR650984

Other name

Sarclisa

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

Cemiplimab

Investigational medicinal product code

REGN2810

Other name

Libtayo

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Cemiplimab 250 mg was administered as an IV infusion Q4W (on Days 1 and 15 every cycle of a 28-day cycle) until protocol-defined discontinuation criteria were met.

Number of subjects in period 1	Phase 1: Isatuximab + Cemiplimab Once Every 2 Weeks (Q2W)	Phase 2: Isatuximab	Phase 2: Isatuximab + CemiplimabQ2W	Phase 2: Isatuximab + Cemiplimab Once Every 4 Weeks (Q4W)
Started	3	34	36	36
Completed	3	34	35	36
Not completed	0	0	1	0
Incorrect completion of end of study form	-	-	1	-

Baseline characteristics

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Reporting group title

Phase 1: Isatuximab + Cemiplimab Once Every 2 Weeks (Q2W)

Reporting group description

Reporting group title

Phase 2: Isatuximab

Reporting group description

Reporting group title

Phase 2: Isatuximab + CemiplimabQ2W

Reporting group description

Reporting group title

Phase 2: Isatuximab + Cemiplimab Once Every 4 Weeks (Q4W)

Reporting group description

Reporting group values	Phase 1: Isatuximab + Cemiplimab Once Every 2 Weeks (Q2W)	Phase 2: Isatuximab	Phase 2: Isatuximab + CemiplimabQ2W	Phase 2: Isatuximab + Cemiplimab Once Every 4 Weeks (Q4W)	Total
Number of subjects	3	34	36	36	109
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	64.7 ( 2.9 )	66.1 ( 9.3 )	63.7 ( 10.0 )	66.4 ( 9.2 )	-
Gender categorical
Units: Subjects
Female	1	16	14	16	47
Male	2	18	22	20	62
Race
Units: Subjects
American Indian or Alaska Native	0	0	0	0	0
Asian	0	0	0	1	1
Native Hawaiian or Other Pacific Islander	0	0	0	0	0
Black or African American	0	2	3	3	8
White	3	29	30	29	91
More than one race	0	0	0	0	0
Unknown or Not Reported	0	3	3	3	9

End points

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Reporting group title

Phase 1: Isatuximab + Cemiplimab Once Every 2 Weeks (Q2W)

Reporting group description

Reporting group title

Phase 2: Isatuximab

Reporting group description

Reporting group title

Phase 2: Isatuximab + CemiplimabQ2W

Reporting group description

Reporting group title

Phase 2: Isatuximab + Cemiplimab Once Every 4 Weeks (Q4W)

Reporting group description

Subject analysis set title

Phase 2: Isatuximab: Safety

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis set title

Phase 2: Isatuximab + CemiplimabQ2W: Safety

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis set title

Phase 2: Isatuximab + CemiplimabQ4W: Safety

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis set title

Phase 2: Isatuximab: PK

Subject analysis set type

Per protocol

Subject analysis set description

Subject analysis set title

Phase 1 and 2: Combination Arm: Isatuximab + Cemiplimab: PK

Subject analysis set type

Per protocol

Subject analysis set description

All subjects who received isatuximab in combination with cemiplimab were included in this arm.

Subject analysis set title

Phase 1 and 2: Isatuximab + CemiplimabQ2W: ADA

Subject analysis set type

Per protocol

Subject analysis set description

Primary: Phase 1: Number of Subjects With Dose-Limiting Toxicities (DLTs)

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End point title

Phase 1: Number of Subjects With Dose-Limiting Toxicities (DLTs) ^[1] ^[2]

End point description

Potential DLTs: Occurrence of any of following adverse reactions at first treatment cycle, unless due to disease progression or obviously unrelated cause: Hematological (hem) DLTs: Grade(G) 4 neutropenia (N) for more than 7 consecutive days,G3 to G4 N with fever (temperature >= 38.5 degree Celsius on more than 1 occasion) or microbiologically/radiographically documented infection,G3 to G4 thrombocytopenia with clinically significant bleeding requiring clinical intervention or Non-hem DLTs:G4 non-hem AE,G>=2 uveitis,G3 non-hem AE lasting >3 days despite optimal care support, delay in initiation of Cycle 2 >14 days due to Rx related laboratory abnormalities/AE or any other AE that investigator/study committee deemed to be DL. The DLT evaluable population: Phase 1 subjects who received planned doses of isatuximab and cemiplimab during Cycle 1 and completed DLT observation period of Cycle 1 after first study Rx administration, unless they discontinued study treatment (s) due to DLT.

End point type

Primary

End point timeframe

Cycle 1 Day 1 to Day 28

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: As the endpoint is descriptive in nature, no statistical analysis is provided.
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only Phase 1 subjects are included in this analysis.

End point values	Phase 1: Isatuximab + Cemiplimab Once Every 2 Weeks (Q2W)
Number of subjects analysed	3
Units: subjects
number (not applicable)	0

No statistical analyses for this end point

Primary: Phase 1 and Phase 2: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs)

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End point title

Phase 1 and Phase 2: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) ^[3] ^[4]

End point description

An AE: Any untoward medical occurrence in subject or clinical investigation subject administered with pharmaceutical product, did not necessarily have causal relationship with study treatment. SAEs: Any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalisation or prolongation of existing hospitalisation, resulted in persistent or significant disability/incapacity, was congenital anomaly/birth defect, was medically important event. TEAEs: An AE which occurred after first dose of study treatment administration up to 30 days after last dose of study treatment administration. DLT observation period was 1 cycle (28 days). However, all AEs during treatment, unless due to disease progression or an obviously unrelated cause,were taken into consideration by Study Committee for determination of maximum tolerated dose and recommended Phase 2 dose. Safety population tabulated according to treatment actually received [as treated].

End point type

Primary

End point timeframe

TEAEs were collected from the first dose up to 30 days after the last dose of study treatment, approximately 50 months

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: As the endpoint is descriptive in nature, no statistical analysis is provided.
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Safety population is tabulated according to treatment actually received [as treated]). 2 subjects randomised in isatuximab and isatuximab+cemiplimabQ4W respectively took another treatment.

End point values	Phase 1: Isatuximab + Cemiplimab Once Every 2 Weeks (Q2W)	Phase 2: Isatuximab: Safety	Phase 2: Isatuximab + CemiplimabQ2W: Safety	Phase 2: Isatuximab + CemiplimabQ4W: Safety
Number of subjects analysed	3	33 ^[5]	37	35 ^[6]
Units: subjects
number (not applicable)
TEAEs	3	33	36	33
TESAEs	1	17	17	21

Notes
[5] - 1 subject randomised in original arm took another treatment.
[6] - 1 subject randomised in original arm took another treatment.

No statistical analyses for this end point

Primary: Phase 2: Percentage of Subjects With ORR

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End point title

Phase 2: Percentage of Subjects With ORR ^[7] ^[8]

End point description

ORR by Investigator using IMWG response criteria: percentage of subjects with CR (including stringent CR [sCR], VGPR and PR). CR: negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas, less than (<)5% plasma cells in bone marrow (BM) aspirates and normal free light chain (FLC)ratio (0.26-1.65).sCR: CR plus no clonal cells in BM biopsy. VGPR: serum and urine M-protein detectable by immunofixation, not electrophoresis;>=90% reduction in serum M-protein plus urine M-protein level<100mg/24hour(h);FLC only:>=90% decrease in difference between involved and uninvolved FLC levels.PR:>=50% reduction of serum M-protein and reduction in 24h urine M-protein by >=90% or <200mg/24h.In addition to above, if present at baseline,>=50% reduction in size (sum of products of maximal perpendicular diameters of measured lesions [SPD]) of soft tissue plasmacytomas required. The Randomised population.

End point type

Primary

End point timeframe

From Cycle 1 Day 1 up to primary analysis completion date of 9 Oct 2019 i.e., up to approximately 17 months

Notes
[7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: As the endpoint is descriptive in nature, no statistical analysis is provided.
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only Phase 2 subjects are included in this analysis.

End point values	Phase 2: Isatuximab	Phase 2: Isatuximab + CemiplimabQ2W	Phase 2: Isatuximab + Cemiplimab Once Every 4 Weeks (Q4W)
Number of subjects analysed	34	36	36
Units: percentage of subjects
number (confidence interval 95%)	11.8 (3.30 to 27.45)	25.0 (12.12 to 42.20)	22.2 (10.12 to 39.15)

No statistical analyses for this end point

Secondary: Phase 2: Percentage of Subjects With Clinical Benefit Rate (CBR)

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End point title

Phase 2: Percentage of Subjects With Clinical Benefit Rate (CBR) ^[9]

End point description

CBR by Investigator using IMWG response criteria: percentage of subjects with CR (including sCR), VGPR, PR (all defined in previous endpoint) or MR. MR was defined as >= 25% but <= 49% reduction in serum M-protein and reduction in 24h urine M-protein by 50-89%, which still exceeded 200 mg/24h; if present at baseline, >=50% reduction in size (SPD) of soft tissue plasmacytomas was also required. The Randomised population consisted of all subjects from Phase 2 who gave their informed consent and were assigned a randomisation number by the interactive response technology (IRT), regardless of whether subjects received any study treatment or received a different study treatment from which they were randomised.

End point type

Secondary

End point timeframe

From Cycle 1 Day 1 up to primary analysis completion date of 9 Oct 2019 i.e., up to approximately 17 months

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only Phase 2 subjects are included in this analysis.

End point values	Phase 2: Isatuximab	Phase 2: Isatuximab + CemiplimabQ2W	Phase 2: Isatuximab + Cemiplimab Once Every 4 Weeks (Q4W)
Number of subjects analysed	34	36	36
Units: percentage of subjects
number (confidence interval 95%)	23.5 (10.75 to 41.17)	36.1 (20.82 to 53.78)	38.9 (23.14 to 56.54)

No statistical analyses for this end point

Secondary: Phase 2: Duration of Follow-up

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End point title

Phase 2: Duration of Follow-up ^[10]

End point description

Duration of follow-up was defined as the time from randomisation to last disease assessment before start of other therapy or cut-off date or death, whichever came first. Median duration of follow-up is reported. The Randomised population consisted of all subjects from Phase 2 who gave their informed consent and were assigned a randomisation number by the IRT, regardless of whether subjects received any study treatment or received a different study treatment from which they were randomised.

End point type

Secondary

End point timeframe

From Cycle 1 Day 1 up to primary analysis completion date of 9 Oct 2019 i.e., up to approximately 17 months

Notes
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only Phase 2 subjects are included in this analysis.

End point values	Phase 2: Isatuximab	Phase 2: Isatuximab + CemiplimabQ2W	Phase 2: Isatuximab + Cemiplimab Once Every 4 Weeks (Q4W)
Number of subjects analysed	34	36	36
Units: months
median (confidence interval 95%)	10.28 (8.739 to 11.368)	8.84 (8.016 to 11.072)	9.03 (8.016 to 10.875)

No statistical analyses for this end point

Secondary: Phase 2: Duration of Response (DOR)

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End point title

Phase 2: Duration of Response (DOR) ^[11]

End point description

DOR:Time from date of first response(>=PR) that was subsequently confirmed to date of first documented progressive disease (PD) or death.DOR was determined only for subjects who achieved a response of PR or better.If progression/death not observed, subject was censored at date of last valid disease assessment not showing disease progression performed prior to initiating further anticancer treatment and analysis cut-off date.PD(IMWG criteria):increase of >=25% from lowest confirmed value in any 1:serum M-protein(absolute increase>=0.5 gram/decilitre[g/dL]),serum M-protein increase>=1g/dL if lowest M component >=5g/dL;urine M-component(absolute increase >=200mg/24h),appearance of new lesion(s),>=50% increase from nadir in SPD of >1 lesion or >=50% increase in longest diameter of previous lesion >1cm in short axis,>=50% increase in circulating plasma cells(minimum 200 cells/microlitre[c/mcL]) if that was the only measure of disease.PR: as defined in endpoint 3.The Randomised population.

End point type

Secondary

End point timeframe

From Cycle 1 Day 1 up to primary analysis completion date of 9 Oct 2019 i.e., up to approximately 17 months

Notes
[11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only Phase 2 subjects are included in this analysis.

End point values	Phase 2: Isatuximab	Phase 2: Isatuximab + CemiplimabQ2W	Phase 2: Isatuximab + Cemiplimab Once Every 4 Weeks (Q4W)
Number of subjects analysed	4 ^[12]	9 ^[13]	8 ^[14]
Units: months
median (confidence interval 95%)	5.6 (4 to 7)	4.7 (3 to 12)	5.7 (2 to 12)

Notes
[12] - Only responders were included in the analysis.
[13] - Only responders were included in the analysis.
[14] - Only responders were included in the analysis.

No statistical analyses for this end point

Secondary: Phase 2: Time to Response (TTR)

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End point title

Phase 2: Time to Response (TTR) ^[15]

End point description

TTR was defined as the time from randomisation to first response (PR or better) that was subsequently confirmed. PR as per IMWG criteria was defined as >=50% reduction of serum M-protein and reduction in 24 hours urinary M-protein by >=90% or to <200 mg/24 hours. In addition to the above listed criteria, if present at baseline, a >=50% reduction in the size SPD of soft tissue plasmacytomas was also required. The Randomised population consisted of all subjects from Phase 2 who gave their informed consent and were assigned a randomisation number by the IRT, regardless of whether subjects received any study treatment or received a different study treatment from which they were randomised. Only responders were included in the analysis.

End point type

Secondary

End point timeframe

From Cycle 1 Day 1 up to primary analysis completion date of 9 Oct 2019 i.e., up to approximately 17 months

Notes
[15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only Phase 2 subjects are included in this analysis.

End point values	Phase 2: Isatuximab	Phase 2: Isatuximab + CemiplimabQ2W	Phase 2: Isatuximab + Cemiplimab Once Every 4 Weeks (Q4W)
Number of subjects analysed	4	9	8
Units: months
median (full range (min-max))	1.5 (1 to 2)	1.0 (1 to 3)	1.0 (1 to 4)

No statistical analyses for this end point

Secondary: Phase 2: Progression Free Survival (PFS)

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End point title

Phase 2: Progression Free Survival (PFS) ^[16]

End point description

PFS: Time interval from randomisation date to date of first documented disease progression that was subsequently confirmed or the date of death due to any cause, whichever came first. If progression or death was not observed, subject was censored at date of last valid disease assessment not showing disease progression performed prior to initiation of a further anticancer treatment or the analysis cut-off date. Analysis was performed by Kaplan-Meier method. PD (IMWG) criteria:increase of >=25% from lowest confirmed value in any 1:serum M-protein (absolute increase >=0.5g/dL), serum M-protein increase >=1g/dL if lowest M component was >=5g/dL; urine M-component (absolute increase >=200mg/24h), appearance of new lesion(s),>=50% increase from nadir in SPD of >1 lesion or >=50% increase in the longest diameter of a previous lesion >1 cm in short axis or >=50% increase in circulating plasma cells (minimum of 200 c/mcL) if that was the only measure of disease. The Randomised population.

End point type

Secondary

End point timeframe

From Cycle 1 Day 1 up to primary analysis completion date of 9 Oct 2019 i.e., up to approximately 17 months

Notes
[16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only Phase 2 subjects are included in this analysis.

End point values	Phase 2: Isatuximab	Phase 2: Isatuximab + CemiplimabQ2W	Phase 2: Isatuximab + Cemiplimab Once Every 4 Weeks (Q4W)
Number of subjects analysed	34	36	36
Units: months
median (confidence interval 95%)	2.89 (1.971 to 3.811)	3.75 (1.971 to 5.881)	3.02 (2.793 to 5.158)

No statistical analyses for this end point

Secondary: Phase 2: Overall Survival (OS)

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End point title

Phase 2: Overall Survival (OS) ^[17]

End point description

OS was defined as the time interval from the date of randomisation to death from any cause. Subjects without death prior to the analysis cut-off date were censored at the last date the subject was known to be alive or the cut-off date, whichever came first. The results provided below corresponds to descriptive OS information at the time of primary analysis completion date of 09 October 2019. The Randomised population consisted of all subjects from Phase 2 who gave their informed consent and were assigned a randomisation number by the IRT, regardless of whether subjects received any study treatment or received a different study treatment from which they were randomised. 99999 = Due to the limited follow-up time, most of subjects were still alive, so the parameter was not reached.

End point type

Secondary

End point timeframe

From Cycle 1 Day 1 up to primary analysis completion date of 9 Oct 2019 i.e., up to approximately 17 months

Notes
[17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only Phase 2 subjects are included in this analysis.

End point values	Phase 2: Isatuximab	Phase 2: Isatuximab + CemiplimabQ2W	Phase 2: Isatuximab + Cemiplimab Once Every 4 Weeks (Q4W)
Number of subjects analysed	34	36	36
Units: months
median (confidence interval 95%)	99999 (7.622 to 99999)	99999 (6.801 to 99999)	12.78 (7.392 to 99999)

No statistical analyses for this end point

Secondary: Phase 1 and 2: Plasma Concentration Observed at the End of IV Infusion (Ceoi) of Isatuximab Alone and in Combination With Cemiplimab

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End point title

Phase 1 and 2: Plasma Concentration Observed at the End of IV Infusion (Ceoi) of Isatuximab Alone and in Combination With Cemiplimab

End point description

Plasma samples were collected at specified timepoints and those non-impacted by the bioanalytical issue were used for evaluation of Ceoi. It was calculated using non-compartmental analysis (NCA) after the first administration in Cycle 1. The Pharmacokinetic (PK) population was defined independently for isatuximab and cemiplimab and consisted of all subjects from the all-treated (AT) population with at least 1 available concentration post-baseline (whatever the cycle and even if dosing was incomplete) with adequate documentation of dosing and sampling dates and times. "Isatuximab + Cemiplimab” arm includes 3 and 27 subjects from phase 1 and phase 2, respectively.

End point type

Secondary

End point timeframe

At end of infusion (EOI) on Cycle 1 Day 1

End point values	Phase 2: Isatuximab: PK	Phase 1 and 2: Combination Arm: Isatuximab + Cemiplimab: PK
Number of subjects analysed	10	30
Units: microgram (mcg)/mL
arithmetic mean (standard deviation)	255 ( 72.1 )	239 ( 67.7 )

No statistical analyses for this end point

Secondary: Phase 1 and 2: Maximum Observed Concentration (Cmax) of Isatuximab Alone and in Combination With Cemiplimab

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End point title

Phase 1 and 2: Maximum Observed Concentration (Cmax) of Isatuximab Alone and in Combination With Cemiplimab

End point description

Plasma samples were collected at specified timepoints and those non-impacted by the bioanalytical issue were used for evaluation of Cmax. It was calculated using NCA after the first administration in Cycle 1. The PK was defined independently for isatuximab and cemiplimab and consisted of all subjects from the AT population with at least 1 available concentration post-baseline (whatever the cycle and even if dosing was incomplete) with adequate documentation of dosing and sampling dates and times. “Isatuximab + Cemiplimab” arm includes 3 and 27 subjects from phase 1 and phase 2, respectively.

End point type

Secondary

End point timeframe

At start of infusion (SOI), EOI, EOI+4 hours, 72 hours and 168 hours on Day 1 of Cycle 1

End point values	Phase 2: Isatuximab: PK	Phase 1 and 2: Combination Arm: Isatuximab + Cemiplimab: PK
Number of subjects analysed	10	30
Units: mcg/mL
arithmetic mean (standard deviation)	264 ( 68.0 )	247 ( 65.9 )

No statistical analyses for this end point

Secondary: Phase 1 and 2: Time to Reach Cmax (Tmax) of Isatuximab Alone and in Combination With Cemiplimab

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End point title

Phase 1 and 2: Time to Reach Cmax (Tmax) of Isatuximab Alone and in Combination With Cemiplimab

End point description

Plasma samples were collected at specified timepoints and those non-impacted by the bioanalytical issue were used for evaluation of tmax. It was calculated using NCA after the first administration in Cycle 1. The PK population was defined independently for isatuximab and cemiplimab and consisted of all subjects from the AT population with at least 1 available concentration post-baseline (whatever the cycle and even if dosing was incomplete) with adequate documentation of dosing and sampling dates and times. “Isatuximab + Cemiplimab” arm includes 3 and 27 subjects from phase 1 and phase 2, respectively.

End point type

Secondary

End point timeframe

At SOI, EOI, EOI+4 hours, 72 hours and 168 hours on Day 1 of Cycle 1

End point values	Phase 2: Isatuximab: PK	Phase 1 and 2: Combination Arm: Isatuximab + Cemiplimab: PK
Number of subjects analysed	10	30
Units: hour
median (full range (min-max))	5.56 (3.25 to 10.50)	4.85 (2.58 to 13.70)

No statistical analyses for this end point

Secondary: Phase 1 and 2: Last Concentration Observed Above the Lower Limit of Quantitation (Clast) of Isatuximab Alone and in Combination With Cemiplimab

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End point title

Phase 1 and 2: Last Concentration Observed Above the Lower Limit of Quantitation (Clast) of Isatuximab Alone and in Combination With Cemiplimab

End point description

Plasma samples were collected at specified timepoints and those non-impacted by the bioanalytical issue were used for evaluation of Clast. It was calculated using NCA after the first administration in Cycle 1. The PK population was defined independently for isatuximab and cemiplimab and consisted of all subjects from the AT population with at least 1 available concentration post-baseline (whatever the cycle and even if dosing was incomplete) with adequate documentation of dosing and sampling dates and times. "Isatuximab + Cemiplimab” arm includes 3 and 27 subjects from phase 1 and phase 2, respectively.

End point type

Secondary

End point timeframe

At SOI, EOI, EOI+4 hours, 72 hours and 168 hours on Day 1 of Cycle 1

End point values	Phase 2: Isatuximab: PK	Phase 1 and 2: Combination Arm: Isatuximab + Cemiplimab: PK
Number of subjects analysed	10	30
Units: mcg/mL
arithmetic mean (standard deviation)	85.7 ( 44.9 )	64.1 ( 32.1 )

No statistical analyses for this end point

Secondary: Phase 1 and 2: Time of Clast (Tlast) of Isatuximab Alone and in Combination With Cemiplimab

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End point title

Phase 1 and 2: Time of Clast (Tlast) of Isatuximab Alone and in Combination With Cemiplimab

End point description

Plasma samples were collected at specified timepoints and those non-impacted by the bioanalytical issue were used for evaluation of tlast. It was calculated using NCA after the first administration in Cycle 1. The PK population was defined independently for isatuximab and cemiplimab and consisted of all subjects from the AT population with at least 1 available concentration post-baseline (whatever the cycle and even if dosing was incomplete) with adequate documentation of dosing and sampling dates and times. “Isatuximab + Cemiplimab” arm includes 3 and 27 subjects from phase 1 and phase 2, respectively.

End point type

Secondary

End point timeframe

At SOI, EOI, EOI+4 hours, 72 hours and 168 hours on Day 1 of Cycle 1

End point values	Phase 2: Isatuximab: PK	Phase 1 and 2: Combination Arm: Isatuximab + Cemiplimab: PK
Number of subjects analysed	10	30
Units: hour
median (full range (min-max))	155.00 (72.40 to 169.00)	165.00 (70.20 to 239.00)

No statistical analyses for this end point

Secondary: Phase 1 and 2: Area Under the Concentration Versus Time Curve (AUC) From Time Zero to Tlast (AUClast) of Isatuximab Alone and in Combination With Cemiplimab

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End point title

Phase 1 and 2: Area Under the Concentration Versus Time Curve (AUC) From Time Zero to Tlast (AUClast) of Isatuximab Alone and in Combination With Cemiplimab

End point description

AUClast was defined as the area under the plasma concentration versus time curve from time 0 to real time tlast calculated using the trapezoidal method over the dosing interval after the first administration in Cycle 1. The PK population was defined independently for isatuximab and cemiplimab and consisted of all subjects from the AT population with at least 1 available concentration post-baseline (whatever the cycle and even if dosing was incomplete) with adequate documentation of dosing and sampling dates and times. “Isatuximab + Cemiplimab” arm includes 3 and 27 subjects from phase 1 and phase 2, respectively.

End point type

Secondary

End point timeframe

At SOI, EOI, EOI+4 hours, 72 hours and 168 hours on Day 1 of Cycle 1

End point values	Phase 2: Isatuximab: PK	Phase 1 and 2: Combination Arm: Isatuximab + Cemiplimab: PK
Number of subjects analysed	10	30
Units: (mcg*h)/mL
arithmetic mean (standard deviation)	21000 ( 7220 )	20200 ( 6590 )

No statistical analyses for this end point

Secondary: Phase 1 and 2: AUC From Time 0 to Week 1 (AUC1week) of Isatuximab Alone and in Combination With Cemiplimab

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End point title

Phase 1 and 2: AUC From Time 0 to Week 1 (AUC1week) of Isatuximab Alone and in Combination With Cemiplimab

End point description

AUC1week was defined as the area under the plasma concentration versus time curve from time 0 to 1 week post dose calculated using the trapezoidal method over the dosing interval after the first administration in Cycle 1. The PK population was defined independently for isatuximab and cemiplimab and consisted of all subjects from the AT population with at least 1 available concentration post-baseline (whatever the cycle and even if dosing was incomplete) with adequate documentation of dosing and sampling dates and times. Only those subjects with data available were analysed. “Isatuximab + Cemiplimab” arm includes 3 and 27 subjects from phase 1 and phase 2, respectively. Only those subjects with data available were analysed.

End point type

Secondary

End point timeframe

At SOI, EOI, EOI+4 hours, 72 hours and 168 hours on Day 1 of Cycle 1

End point values	Phase 2: Isatuximab: PK	Phase 1 and 2: Combination Arm: Isatuximab + Cemiplimab: PK
Number of subjects analysed	10	29
Units: (mcg*h)/mL
arithmetic mean (standard deviation)	23000 ( 7250 )	21100 ( 6450 )

No statistical analyses for this end point

Secondary: Phase 1 and 2: Number of Subjects With Anti-Drug Antibodies (ADA) to Isatuximab

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End point title

Phase 1 and 2: Number of Subjects With Anti-Drug Antibodies (ADA) to Isatuximab ^[18]

End point description

ADA responses were categorised as treatment-induced ADA and treatment boosted ADA. Pre-existing ADA was defined as ADA that were present in samples drawn during the pre-treatment period. Treatment-induced ADA was defined as ADA that developed at any time during the ADA on-study observation period in subjects without pre-existing ADA. Treatment boosted ADA was defined as pre-existing ADAs with a significant increase in the ADA titer during the study compared to the Baseline titer. The ADA evaluable population was defined independently for isatuximab and cemiplimab and consisted of all subjects from the AT population with at least 1 ADA result (negative, positive, or inconclusive) post-baseline. “Isatuximab + CemiplimabQ2W” arm includes 3 and 36 subjects from phase 1 and phase 2, respectively.

End point type

Secondary

End point timeframe

From Cycle 1 Day 1 up to primary analysis completion date of 9 Oct 2019 i.e., up to approximately 20 months

Notes
[18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: “Isatuximab + CemiplimabQ2W” arm in ADA includes 3 and 36 subjects from phase 1 and phase 2, respectively.

End point values	Phase 2: Isatuximab	Phase 2: Isatuximab + Cemiplimab Once Every 4 Weeks (Q4W)	Phase 1 and 2: Isatuximab + CemiplimabQ2W: ADA
Number of subjects analysed	32	34	39
Units: subjects
number (not applicable)
Pre-existing ADA	0	0	1
Treatment-induced	0	0	0
Treatment boosted	0	0	0

No statistical analyses for this end point

Secondary: Phase 1 and 2: Number of Subjects With ADA to Cemiplimab

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End point title

Phase 1 and 2: Number of Subjects With ADA to Cemiplimab ^[19]

End point description

End point type

Secondary

End point timeframe

From Cycle 1 Day 1 up to primary analysis completion date of 9 Oct 2019 i.e., up to approximately 20 months

Notes
[19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: “Isatuximab + CemiplimabQ2W” arm in ADA includes 3 and 36 subjects from phase 1 and phase 2, respectively.

End point values	Phase 2: Isatuximab + Cemiplimab Once Every 4 Weeks (Q4W)	Phase 1 and 2: Isatuximab + CemiplimabQ2W: ADA
Number of subjects analysed	34	39
Units: subjects
number (not applicable)
Pre-existing ADA	0	1
Treatment-induced	0	2
Treatment boosted	0	0

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

TEAEs were collected from the first dose up to 30 days after the last dose of study treatment, approximately 50 months. Number of deaths (all causes) was reported for the whole study duration, approximately 62 months

Adverse event reporting additional description

Analysis was performed on the Safety population (tabulated according to treatment actually received [as treated]). There were 2 subjects randomised in group isatuximab and isatuximab + cemiplimabQ4W respectively and who took another treatment/schedule.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

25.1

Reporting group title

Phase 1 Isa+CemQ2W

Reporting group description

Reporting group title

Phase 2 Isa+CemQ4W

Reporting group description

Reporting group title

Phase 2 Isa+CemQ2W

Reporting group description

Reporting group title

Phase 2 Isa

Reporting group description

Serious adverse events	Phase 1 Isa+CemQ2W	Phase 2 Isa+CemQ4W	Phase 2 Isa+CemQ2W	Phase 2 Isa
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 3 (33.33%)	21 / 35 (60.00%)	17 / 37 (45.95%)	17 / 33 (51.52%)
number of deaths (all causes)	1	22	23	20
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neuroendocrine Carcinoma Of The Skin
subjects affected / exposed	0 / 3 (0.00%)	0 / 35 (0.00%)	0 / 37 (0.00%)	1 / 33 (3.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Colon Neoplasm
subjects affected / exposed	0 / 3 (0.00%)	1 / 35 (2.86%)	0 / 37 (0.00%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cancer Pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 35 (0.00%)	0 / 37 (0.00%)	1 / 33 (3.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
Euthanasia
subjects affected / exposed	0 / 3 (0.00%)	1 / 35 (2.86%)	0 / 37 (0.00%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
General disorders and administration site conditions
Disease Progression
subjects affected / exposed	0 / 3 (0.00%)	2 / 35 (5.71%)	1 / 37 (2.70%)	1 / 33 (3.03%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 2	0 / 1	0 / 1
Multiple Organ Dysfunction Syndrome
subjects affected / exposed	0 / 3 (0.00%)	0 / 35 (0.00%)	1 / 37 (2.70%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Pyrexia
subjects affected / exposed	0 / 3 (0.00%)	0 / 35 (0.00%)	3 / 37 (8.11%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Non-Cardiac Chest Pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 35 (0.00%)	0 / 37 (0.00%)	1 / 33 (3.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Respiratory, thoracic and mediastinal disorders
Epistaxis
subjects affected / exposed	0 / 3 (0.00%)	0 / 35 (0.00%)	1 / 37 (2.70%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pleural Effusion
subjects affected / exposed	0 / 3 (0.00%)	1 / 35 (2.86%)	0 / 37 (0.00%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary Embolism
subjects affected / exposed	0 / 3 (0.00%)	0 / 35 (0.00%)	1 / 37 (2.70%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Delirium
subjects affected / exposed	0 / 3 (0.00%)	0 / 35 (0.00%)	1 / 37 (2.70%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Platelet Count Decreased
subjects affected / exposed	0 / 3 (0.00%)	1 / 35 (2.86%)	0 / 37 (0.00%)	1 / 33 (3.03%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Infusion Related Reaction
subjects affected / exposed	0 / 3 (0.00%)	2 / 35 (5.71%)	0 / 37 (0.00%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Cardiac Failure Congestive
subjects affected / exposed	0 / 3 (0.00%)	1 / 35 (2.86%)	0 / 37 (0.00%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Psychomotor Hyperactivity
subjects affected / exposed	0 / 3 (0.00%)	1 / 35 (2.86%)	0 / 37 (0.00%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Spinal Cord Compression
subjects affected / exposed	0 / 3 (0.00%)	1 / 35 (2.86%)	0 / 37 (0.00%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Radicular Pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 35 (0.00%)	0 / 37 (0.00%)	1 / 33 (3.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Hyperviscosity Syndrome
subjects affected / exposed	0 / 3 (0.00%)	1 / 35 (2.86%)	0 / 37 (0.00%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Anaemia
subjects affected / exposed	0 / 3 (0.00%)	1 / 35 (2.86%)	0 / 37 (0.00%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	0 / 3 (0.00%)	0 / 35 (0.00%)	1 / 37 (2.70%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	0 / 3 (0.00%)	0 / 35 (0.00%)	2 / 37 (5.41%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	0 / 3 (0.00%)	1 / 35 (2.86%)	0 / 37 (0.00%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Anal Haemorrhage
subjects affected / exposed	0 / 3 (0.00%)	0 / 35 (0.00%)	0 / 37 (0.00%)	1 / 33 (3.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Acute Abdomen
subjects affected / exposed	0 / 3 (0.00%)	1 / 35 (2.86%)	0 / 37 (0.00%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 3 (0.00%)	0 / 35 (0.00%)	1 / 37 (2.70%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Obstruction Gastric
subjects affected / exposed	0 / 3 (0.00%)	0 / 35 (0.00%)	1 / 37 (2.70%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Small Intestinal Obstruction
subjects affected / exposed	0 / 3 (0.00%)	0 / 35 (0.00%)	1 / 37 (2.70%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 3 (0.00%)	0 / 35 (0.00%)	1 / 37 (2.70%)	1 / 33 (3.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute Kidney Injury
subjects affected / exposed	0 / 3 (0.00%)	2 / 35 (5.71%)	2 / 37 (5.41%)	3 / 33 (9.09%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Fanconi Syndrome Acquired
subjects affected / exposed	0 / 3 (0.00%)	1 / 35 (2.86%)	0 / 37 (0.00%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haematuria
subjects affected / exposed	0 / 3 (0.00%)	0 / 35 (0.00%)	0 / 37 (0.00%)	1 / 33 (3.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Proteinuria
subjects affected / exposed	0 / 3 (0.00%)	0 / 35 (0.00%)	0 / 37 (0.00%)	1 / 33 (3.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal Failure
subjects affected / exposed	0 / 3 (0.00%)	0 / 35 (0.00%)	0 / 37 (0.00%)	1 / 33 (3.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary Tract Obstruction
subjects affected / exposed	0 / 3 (0.00%)	1 / 35 (2.86%)	0 / 37 (0.00%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back Pain
subjects affected / exposed	1 / 3 (33.33%)	1 / 35 (2.86%)	0 / 37 (0.00%)	1 / 33 (3.03%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bone Lesion
subjects affected / exposed	0 / 3 (0.00%)	1 / 35 (2.86%)	0 / 37 (0.00%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bone Pain
subjects affected / exposed	0 / 3 (0.00%)	1 / 35 (2.86%)	0 / 37 (0.00%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal Pain
subjects affected / exposed	0 / 3 (0.00%)	1 / 35 (2.86%)	0 / 37 (0.00%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pathological Fracture
subjects affected / exposed	0 / 3 (0.00%)	1 / 35 (2.86%)	0 / 37 (0.00%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Covid-19 Pneumonia
subjects affected / exposed	0 / 3 (0.00%)	0 / 35 (0.00%)	1 / 37 (2.70%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Encephalomyelitis
subjects affected / exposed	0 / 3 (0.00%)	1 / 35 (2.86%)	0 / 37 (0.00%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Encephalitis
subjects affected / exposed	0 / 3 (0.00%)	1 / 35 (2.86%)	0 / 37 (0.00%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Catheter Site Infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 35 (0.00%)	1 / 37 (2.70%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Parainfluenzae Virus Infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 35 (0.00%)	0 / 37 (0.00%)	1 / 33 (3.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Osteomyelitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 35 (0.00%)	1 / 37 (2.70%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lower Respiratory Tract Infection
subjects affected / exposed	0 / 3 (0.00%)	1 / 35 (2.86%)	0 / 37 (0.00%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	0 / 3 (0.00%)	0 / 35 (0.00%)	0 / 37 (0.00%)	3 / 33 (9.09%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Herpes Zoster Disseminated
subjects affected / exposed	0 / 3 (0.00%)	0 / 35 (0.00%)	0 / 37 (0.00%)	1 / 33 (3.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Escherichia Bacteraemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 35 (0.00%)	1 / 37 (2.70%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Salmonellosis
subjects affected / exposed	0 / 3 (0.00%)	0 / 35 (0.00%)	0 / 37 (0.00%)	1 / 33 (3.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory Tract Infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 35 (0.00%)	0 / 37 (0.00%)	1 / 33 (3.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	0 / 3 (0.00%)	0 / 35 (0.00%)	1 / 37 (2.70%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary Sepsis
subjects affected / exposed	0 / 3 (0.00%)	2 / 35 (5.71%)	0 / 37 (0.00%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
Pneumonia Staphylococcal
subjects affected / exposed	0 / 3 (0.00%)	0 / 35 (0.00%)	1 / 37 (2.70%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 3 (0.00%)	1 / 35 (2.86%)	1 / 37 (2.70%)	1 / 33 (3.03%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 3 (0.00%)	5 / 35 (14.29%)	1 / 37 (2.70%)	2 / 33 (6.06%)
occurrences causally related to treatment / all	0 / 0	1 / 5	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Septic Shock
subjects affected / exposed	0 / 3 (0.00%)	1 / 35 (2.86%)	2 / 37 (5.41%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Upper Respiratory Tract Infection
subjects affected / exposed	0 / 3 (0.00%)	2 / 35 (5.71%)	0 / 37 (0.00%)	1 / 33 (3.03%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Metabolism and nutrition disorders
Tumour Lysis Syndrome
subjects affected / exposed	0 / 3 (0.00%)	0 / 35 (0.00%)	0 / 37 (0.00%)	1 / 33 (3.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypercalcaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 35 (0.00%)	2 / 37 (5.41%)	1 / 33 (3.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Phase 1 Isa+CemQ2W	Phase 2 Isa+CemQ4W	Phase 2 Isa+CemQ2W	Phase 2 Isa
Total subjects affected by non serious adverse events
subjects affected / exposed	3 / 3 (100.00%)	27 / 35 (77.14%)	34 / 37 (91.89%)	31 / 33 (93.94%)
Vascular disorders
Hypertension
subjects affected / exposed	0 / 3 (0.00%)	2 / 35 (5.71%)	3 / 37 (8.11%)	3 / 33 (9.09%)
occurrences all number	0	2	3	4
General disorders and administration site conditions
Influenza Like Illness
subjects affected / exposed	0 / 3 (0.00%)	0 / 35 (0.00%)	1 / 37 (2.70%)	2 / 33 (6.06%)
occurrences all number	0	0	2	2
Fatigue
subjects affected / exposed	0 / 3 (0.00%)	5 / 35 (14.29%)	8 / 37 (21.62%)	3 / 33 (9.09%)
occurrences all number	0	5	12	3
Disease Progression
subjects affected / exposed	0 / 3 (0.00%)	0 / 35 (0.00%)	2 / 37 (5.41%)	0 / 33 (0.00%)
occurrences all number	0	0	2	0
Chills
subjects affected / exposed	1 / 3 (33.33%)	0 / 35 (0.00%)	0 / 37 (0.00%)	0 / 33 (0.00%)
occurrences all number	1	0	0	0
Asthenia
subjects affected / exposed	0 / 3 (0.00%)	2 / 35 (5.71%)	5 / 37 (13.51%)	3 / 33 (9.09%)
occurrences all number	0	2	5	6
Oedema Peripheral
subjects affected / exposed	1 / 3 (33.33%)	3 / 35 (8.57%)	1 / 37 (2.70%)	2 / 33 (6.06%)
occurrences all number	1	4	1	2
Pyrexia
subjects affected / exposed	0 / 3 (0.00%)	2 / 35 (5.71%)	6 / 37 (16.22%)	4 / 33 (12.12%)
occurrences all number	0	3	10	7
Pain
subjects affected / exposed	1 / 3 (33.33%)	0 / 35 (0.00%)	0 / 37 (0.00%)	0 / 33 (0.00%)
occurrences all number	1	0	0	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	1 / 3 (33.33%)	2 / 35 (5.71%)	5 / 37 (13.51%)	5 / 33 (15.15%)
occurrences all number	1	2	7	6
Dysphonia
subjects affected / exposed	1 / 3 (33.33%)	1 / 35 (2.86%)	0 / 37 (0.00%)	0 / 33 (0.00%)
occurrences all number	1	1	0	0
Epistaxis
subjects affected / exposed	1 / 3 (33.33%)	0 / 35 (0.00%)	0 / 37 (0.00%)	1 / 33 (3.03%)
occurrences all number	1	0	0	1
Dyspnoea
subjects affected / exposed	0 / 3 (0.00%)	2 / 35 (5.71%)	1 / 37 (2.70%)	1 / 33 (3.03%)
occurrences all number	0	2	1	1
Dyspnoea Exertional
subjects affected / exposed	1 / 3 (33.33%)	0 / 35 (0.00%)	1 / 37 (2.70%)	1 / 33 (3.03%)
occurrences all number	2	0	1	1
Oropharyngeal Pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 35 (0.00%)	0 / 37 (0.00%)	2 / 33 (6.06%)
occurrences all number	0	0	0	2
Productive Cough
subjects affected / exposed	0 / 3 (0.00%)	3 / 35 (8.57%)	0 / 37 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	3	0	0
Psychiatric disorders
Agitation
subjects affected / exposed	0 / 3 (0.00%)	0 / 35 (0.00%)	2 / 37 (5.41%)	0 / 33 (0.00%)
occurrences all number	0	0	2	0
Anxiety
subjects affected / exposed	0 / 3 (0.00%)	0 / 35 (0.00%)	3 / 37 (8.11%)	0 / 33 (0.00%)
occurrences all number	0	0	4	0
Confusional State
subjects affected / exposed	0 / 3 (0.00%)	0 / 35 (0.00%)	2 / 37 (5.41%)	0 / 33 (0.00%)
occurrences all number	0	0	2	0
Insomnia
subjects affected / exposed	0 / 3 (0.00%)	1 / 35 (2.86%)	2 / 37 (5.41%)	3 / 33 (9.09%)
occurrences all number	0	1	2	3
Investigations
Weight Decreased
subjects affected / exposed	0 / 3 (0.00%)	4 / 35 (11.43%)	1 / 37 (2.70%)	0 / 33 (0.00%)
occurrences all number	0	4	1	0
Injury, poisoning and procedural complications
Infusion Related Reaction
subjects affected / exposed	2 / 3 (66.67%)	15 / 35 (42.86%)	15 / 37 (40.54%)	18 / 33 (54.55%)
occurrences all number	2	15	15	22
Fall
subjects affected / exposed	0 / 3 (0.00%)	2 / 35 (5.71%)	1 / 37 (2.70%)	3 / 33 (9.09%)
occurrences all number	0	2	1	3
Nervous system disorders
Dizziness
subjects affected / exposed	0 / 3 (0.00%)	2 / 35 (5.71%)	0 / 37 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	2	0	0
Peripheral Sensory Neuropathy
subjects affected / exposed	0 / 3 (0.00%)	2 / 35 (5.71%)	1 / 37 (2.70%)	0 / 33 (0.00%)
occurrences all number	0	2	1	0
Paraesthesia
subjects affected / exposed	0 / 3 (0.00%)	0 / 35 (0.00%)	1 / 37 (2.70%)	2 / 33 (6.06%)
occurrences all number	0	0	1	2
Neuralgia
subjects affected / exposed	1 / 3 (33.33%)	0 / 35 (0.00%)	1 / 37 (2.70%)	0 / 33 (0.00%)
occurrences all number	1	0	1	0
Lethargy
subjects affected / exposed	1 / 3 (33.33%)	0 / 35 (0.00%)	0 / 37 (0.00%)	0 / 33 (0.00%)
occurrences all number	1	0	0	0
Headache
subjects affected / exposed	0 / 3 (0.00%)	4 / 35 (11.43%)	3 / 37 (8.11%)	3 / 33 (9.09%)
occurrences all number	0	4	5	3
Blood and lymphatic system disorders
Thrombocytopenia
subjects affected / exposed	0 / 3 (0.00%)	3 / 35 (8.57%)	4 / 37 (10.81%)	1 / 33 (3.03%)
occurrences all number	0	3	6	1
Neutropenia
subjects affected / exposed	0 / 3 (0.00%)	1 / 35 (2.86%)	2 / 37 (5.41%)	2 / 33 (6.06%)
occurrences all number	0	1	2	2
Anaemia
subjects affected / exposed	0 / 3 (0.00%)	3 / 35 (8.57%)	1 / 37 (2.70%)	1 / 33 (3.03%)
occurrences all number	0	8	1	1
Gastrointestinal disorders
Abdominal Pain Upper
subjects affected / exposed	0 / 3 (0.00%)	1 / 35 (2.86%)	2 / 37 (5.41%)	0 / 33 (0.00%)
occurrences all number	0	1	2	0
Abdominal Pain
subjects affected / exposed	0 / 3 (0.00%)	2 / 35 (5.71%)	1 / 37 (2.70%)	2 / 33 (6.06%)
occurrences all number	0	4	1	2
Constipation
subjects affected / exposed	0 / 3 (0.00%)	1 / 35 (2.86%)	2 / 37 (5.41%)	0 / 33 (0.00%)
occurrences all number	0	1	2	0
Diarrhoea
subjects affected / exposed	1 / 3 (33.33%)	7 / 35 (20.00%)	7 / 37 (18.92%)	6 / 33 (18.18%)
occurrences all number	1	10	10	8
Dyspepsia
subjects affected / exposed	1 / 3 (33.33%)	0 / 35 (0.00%)	0 / 37 (0.00%)	0 / 33 (0.00%)
occurrences all number	1	0	0	0
Vomiting
subjects affected / exposed	1 / 3 (33.33%)	6 / 35 (17.14%)	1 / 37 (2.70%)	2 / 33 (6.06%)
occurrences all number	1	6	1	4
Stomatitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 35 (0.00%)	3 / 37 (8.11%)	1 / 33 (3.03%)
occurrences all number	0	0	3	1
Oral Papule
subjects affected / exposed	1 / 3 (33.33%)	0 / 35 (0.00%)	0 / 37 (0.00%)	0 / 33 (0.00%)
occurrences all number	1	0	0	0
Nausea
subjects affected / exposed	1 / 3 (33.33%)	5 / 35 (14.29%)	5 / 37 (13.51%)	5 / 33 (15.15%)
occurrences all number	1	6	7	5
Lip Oedema
subjects affected / exposed	1 / 3 (33.33%)	0 / 35 (0.00%)	0 / 37 (0.00%)	0 / 33 (0.00%)
occurrences all number	1	0	0	0
Gingival Pain
subjects affected / exposed	1 / 3 (33.33%)	0 / 35 (0.00%)	0 / 37 (0.00%)	0 / 33 (0.00%)
occurrences all number	1	0	0	0
Skin and subcutaneous tissue disorders
Eczema
subjects affected / exposed	0 / 3 (0.00%)	0 / 35 (0.00%)	2 / 37 (5.41%)	0 / 33 (0.00%)
occurrences all number	0	0	2	0
Pruritus
subjects affected / exposed	0 / 3 (0.00%)	0 / 35 (0.00%)	0 / 37 (0.00%)	2 / 33 (6.06%)
occurrences all number	0	0	0	2
Erythema
subjects affected / exposed	0 / 3 (0.00%)	0 / 35 (0.00%)	2 / 37 (5.41%)	2 / 33 (6.06%)
occurrences all number	0	0	2	2
Renal and urinary disorders
Pollakiuria
subjects affected / exposed	0 / 3 (0.00%)	2 / 35 (5.71%)	0 / 37 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	2	0	0
Musculoskeletal and connective tissue disorders
Muscular Weakness
subjects affected / exposed	0 / 3 (0.00%)	0 / 35 (0.00%)	1 / 37 (2.70%)	2 / 33 (6.06%)
occurrences all number	0	0	1	2
Muscle Spasms
subjects affected / exposed	0 / 3 (0.00%)	2 / 35 (5.71%)	1 / 37 (2.70%)	1 / 33 (3.03%)
occurrences all number	0	2	3	1
Groin Pain
subjects affected / exposed	1 / 3 (33.33%)	0 / 35 (0.00%)	2 / 37 (5.41%)	1 / 33 (3.03%)
occurrences all number	1	0	2	1
Bone Pain
subjects affected / exposed	0 / 3 (0.00%)	3 / 35 (8.57%)	3 / 37 (8.11%)	4 / 33 (12.12%)
occurrences all number	0	3	3	4
Musculoskeletal Chest Pain
subjects affected / exposed	0 / 3 (0.00%)	1 / 35 (2.86%)	3 / 37 (8.11%)	1 / 33 (3.03%)
occurrences all number	0	1	5	1
Arthralgia
subjects affected / exposed	0 / 3 (0.00%)	2 / 35 (5.71%)	4 / 37 (10.81%)	5 / 33 (15.15%)
occurrences all number	0	3	6	5
Back Pain
subjects affected / exposed	1 / 3 (33.33%)	3 / 35 (8.57%)	7 / 37 (18.92%)	3 / 33 (9.09%)
occurrences all number	1	3	9	3
Myalgia
subjects affected / exposed	0 / 3 (0.00%)	1 / 35 (2.86%)	4 / 37 (10.81%)	1 / 33 (3.03%)
occurrences all number	0	1	4	1
Neck Pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 35 (0.00%)	1 / 37 (2.70%)	2 / 33 (6.06%)
occurrences all number	0	0	1	2
Pain In Extremity
subjects affected / exposed	0 / 3 (0.00%)	0 / 35 (0.00%)	2 / 37 (5.41%)	4 / 33 (12.12%)
occurrences all number	0	0	2	4
Infections and infestations
Bronchitis
subjects affected / exposed	0 / 3 (0.00%)	5 / 35 (14.29%)	3 / 37 (8.11%)	0 / 33 (0.00%)
occurrences all number	0	5	3	0
Labyrinthitis
subjects affected / exposed	0 / 3 (0.00%)	2 / 35 (5.71%)	0 / 37 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	2	0	0
Nasopharyngitis
subjects affected / exposed	0 / 3 (0.00%)	2 / 35 (5.71%)	1 / 37 (2.70%)	0 / 33 (0.00%)
occurrences all number	0	4	1	0
Upper Respiratory Tract Infection
subjects affected / exposed	1 / 3 (33.33%)	7 / 35 (20.00%)	4 / 37 (10.81%)	4 / 33 (12.12%)
occurrences all number	2	13	9	4
Sinusitis
subjects affected / exposed	1 / 3 (33.33%)	0 / 35 (0.00%)	3 / 37 (8.11%)	0 / 33 (0.00%)
occurrences all number	1	0	3	0
Respiratory Tract Infection
subjects affected / exposed	0 / 3 (0.00%)	1 / 35 (2.86%)	0 / 37 (0.00%)	3 / 33 (9.09%)
occurrences all number	0	1	0	4
Pneumonia
subjects affected / exposed	1 / 3 (33.33%)	2 / 35 (5.71%)	2 / 37 (5.41%)	1 / 33 (3.03%)
occurrences all number	1	2	2	1
Oral Candidiasis
subjects affected / exposed	0 / 3 (0.00%)	2 / 35 (5.71%)	0 / 37 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	2	0	0
Urinary Tract Infection
subjects affected / exposed	0 / 3 (0.00%)	3 / 35 (8.57%)	2 / 37 (5.41%)	3 / 33 (9.09%)
occurrences all number	0	3	3	4
Viral Upper Respiratory Tract Infection
subjects affected / exposed	0 / 3 (0.00%)	1 / 35 (2.86%)	2 / 37 (5.41%)	0 / 33 (0.00%)
occurrences all number	0	1	2	0
Metabolism and nutrition disorders
Decreased Appetite
subjects affected / exposed	1 / 3 (33.33%)	2 / 35 (5.71%)	4 / 37 (10.81%)	3 / 33 (9.09%)
occurrences all number	1	3	4	3

More information

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Were there any global substantial amendments to the protocol? Yes

30 May 2017

Changed DLT definition. Added physical examinations, haematology, biochemistry and urinalysis lab tests at visits 60 and 90 days after last dose of study treatment.

17 Nov 2017

Revised Phase 1 and Phase 2 study design. Body weight-based dose was changed to flat dose. Added a data monitoring committee (DMC). Added an exclusion criterion: Subjects who have previously been treated with idelalisib (a PI3K inhibitor). Added additional safety guidance language added for the management of subjects developing stomatitis or mucositis. An adverse event of special interest (AESI) was added to the list of AESIs: an immune related AE of any grade in a subject previously treated with a PI3K inhibitor and additional safety guidance language added for the management of subjects developing stomatitis or mucositis. Clarify plasmacytoma assessment at screening: in subjects with known or suspected extramedullary disease. Changed REGN2810 to cemiplimab.

06 Aug 2018

Added an anti-CD38 refractory cohort in Phase 2. Added assessment of humoral and cellular immune responses to myeloma-related tumor antigens in blood and their correlation with clinical response. Updated PK/Pharmacodynamic flowcharts. Added an appendix of contraceptive guidance and collection of pregnancy information and provided reference in exclusion criteria No.18. Extended OS follow-up period to 24 months after last subject first dose, best of response for post anticancer therapy was collected during this study follow-up period. Changed DMC review for every 4 months to every 3 months. Updated cemiplimab clinical information. Added an instruction for prophylaxis of opportunistic infections. Added additional exclusion criterion.

11 Jun 2019

Updated contraceptive measures and pregnancy counseling.

14 Aug 2020

Based on updated analysis of primary endpoint (overall response rate [ORR]) planned six months after last subject in (LSI) and other secondary endpoints (including overall survival [OS]) performed at the planned cutoff date 1 year after LPI, the addition to cemiplimab to SAR650984 only resulted in marginal additive efficacy. No safety concerns were observed during periodic Data Monitoring Committee (DMC) review. No further efficacy data collection at longer follow-up was performed. Per DMC recommendation, the final OS analysis planned at 24 months after LPI was not performed and the follow-up stopped after the extended safety period of 90 days after last study treatment dose. Subjects under treatment continued to be treated as long as they benefited from it. A risk of hepatitis reactivation had been identified in the SAR650984 Investigator’s Brochure Edition 11 (30-Apr-2020).

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: A Phase 1/2 study to evaluate safety, pharmacokinetics and efficacy of isatuximab in combination with cemiplimab in patients with relapsed/refractory multiple myeloma

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Phase 1: Number of Subjects With Dose-Limiting Toxicities (DLTs)

Primary: Phase 1: Number of Subjects With Dose-Limiting Toxicities (DLTs)

Primary: Phase 1 and Phase 2: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs)

Primary: Phase 1 and Phase 2: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs)

Primary: Phase 2: Percentage of Subjects With ORR

Primary: Phase 2: Percentage of Subjects With ORR

Secondary: Phase 2: Percentage of Subjects With Clinical Benefit Rate (CBR)

Secondary: Phase 2: Percentage of Subjects With Clinical Benefit Rate (CBR)

Secondary: Phase 2: Duration of Follow-up

Secondary: Phase 2: Duration of Follow-up

Secondary: Phase 2: Duration of Response (DOR)

Secondary: Phase 2: Duration of Response (DOR)

Secondary: Phase 2: Time to Response (TTR)

Secondary: Phase 2: Time to Response (TTR)

Secondary: Phase 2: Progression Free Survival (PFS)

Secondary: Phase 2: Progression Free Survival (PFS)

Secondary: Phase 2: Overall Survival (OS)

Secondary: Phase 2: Overall Survival (OS)

Secondary: Phase 1 and 2: Plasma Concentration Observed at the End of IV Infusion (Ceoi) of Isatuximab Alone and in Combination With Cemiplimab

Secondary: Phase 1 and 2: Plasma Concentration Observed at the End of IV Infusion (Ceoi) of Isatuximab Alone and in Combination With Cemiplimab

Secondary: Phase 1 and 2: Maximum Observed Concentration (Cmax) of Isatuximab Alone and in Combination With Cemiplimab

Secondary: Phase 1 and 2: Maximum Observed Concentration (Cmax) of Isatuximab Alone and in Combination With Cemiplimab

Secondary: Phase 1 and 2: Time to Reach Cmax (Tmax) of Isatuximab Alone and in Combination With Cemiplimab

Secondary: Phase 1 and 2: Time to Reach Cmax (Tmax) of Isatuximab Alone and in Combination With Cemiplimab

Secondary: Phase 1 and 2: Last Concentration Observed Above the Lower Limit of Quantitation (Clast) of Isatuximab Alone and in Combination With Cemiplimab

Secondary: Phase 1 and 2: Last Concentration Observed Above the Lower Limit of Quantitation (Clast) of Isatuximab Alone and in Combination With Cemiplimab

Secondary: Phase 1 and 2: Time of Clast (Tlast) of Isatuximab Alone and in Combination With Cemiplimab

Secondary: Phase 1 and 2: Time of Clast (Tlast) of Isatuximab Alone and in Combination With Cemiplimab

Secondary: Phase 1 and 2: Area Under the Concentration Versus Time Curve (AUC) From Time Zero to Tlast (AUClast) of Isatuximab Alone and in Combination With Cemiplimab

Secondary: Phase 1 and 2: Area Under the Concentration Versus Time Curve (AUC) From Time Zero to Tlast (AUClast) of Isatuximab Alone and in Combination With Cemiplimab

Secondary: Phase 1 and 2: AUC From Time 0 to Week 1 (AUC1week) of Isatuximab Alone and in Combination With Cemiplimab

Secondary: Phase 1 and 2: AUC From Time 0 to Week 1 (AUC1week) of Isatuximab Alone and in Combination With Cemiplimab

Secondary: Phase 1 and 2: Number of Subjects With Anti-Drug Antibodies (ADA) to Isatuximab

Secondary: Phase 1 and 2: Number of Subjects With Anti-Drug Antibodies (ADA) to Isatuximab

Secondary: Phase 1 and 2: Number of Subjects With ADA to Cemiplimab

Secondary: Phase 1 and 2: Number of Subjects With ADA to Cemiplimab

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Phase 1/2 study to evaluate safety, pharmacokinetics and efficacy of isatuximab in combination with cemiplimab in patients with relapsed/refractory multiple myeloma