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Clinical Trial Results:
A phase II open-label, randomized, three-arm, multicenter study of LAG525 given in combination with spartalizumab (PDR001), or with spartalizumab and carboplatin, or with carboplatin, as first or second line therapy in patients with advanced triple-negative breast cancer

Summary
EudraCT number	2017-004865-28
Trial protocol	GB BE FR DE HU ES IT
Global end of trial date	24 Nov 2021

Results information
Results version number	v1(current)
This version publication date	15 Dec 2022
First version publication date	15 Dec 2022
Other versions

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

CLAG525B2101

ISRCTN number

US NCT number

NCT03499899

WHO universal trial number (UTN)

Sponsor organisation name

Novartis Pharma AG

Sponsor organisation address

CH-4002, Basel, Switzerland,

Public contact

Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, novartis.email@novartis.com

Scientific contact

Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, novartis.email@novartis.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

24 Nov 2021

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

24 Nov 2021

Was the trial ended prematurely?

Main objective of the trial

The main objective of this trial is to assess the antitumor activity of the three treatment arms LAG525 + spartalizumab, LAG525 + spartalizumab + carboplatin and LAG525 + carboplatin, in patients with advanced triple-negative breast cancer (TNBC) in first or second line of therapy, as measured by the overall response rate (ORR) per investigator’s assessment according to RECIST v1.1.

Protection of trial subjects

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.

Background therapy

Evidence for comparator

Actual start date of recruitment

09 Mar 2018

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Argentina: 1

Country: Number of subjects enrolled

Australia: 14

Country: Number of subjects enrolled

Belgium: 7

Country: Number of subjects enrolled

Canada: 6

Country: Number of subjects enrolled

France: 4

Country: Number of subjects enrolled

Germany: 4

Country: Number of subjects enrolled

Hungary: 4

Country: Number of subjects enrolled

Israel: 1

Country: Number of subjects enrolled

Italy: 8

Country: Number of subjects enrolled

Japan: 7

Country: Number of subjects enrolled

Korea, Republic of: 7

Country: Number of subjects enrolled

Lebanon: 6

Country: Number of subjects enrolled

Singapore: 1

Country: Number of subjects enrolled

Spain: 6

Country: Number of subjects enrolled

Taiwan: 7

Country: Number of subjects enrolled

Thailand: 1

Country: Number of subjects enrolled

United States: 4

Worldwide total number of subjects

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

The study was conducted across 33 centers in 17 countries.

Screening details

A total of 132 participants were screened of which 88 participants were enrolled in the study and 87 participants received at least one dose of study treatment (1 participant was not treated due to physician decision)

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

LAG525 + PDR001

Arm description

Participants received LAG525 and PDR001 administered as infusion once every 3 weeks

Arm type

Experimental

Investigational medicinal product name

Spartalizumab

Investigational medicinal product code

PDR001

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Spartalizumab was a concentrate for solution for intravenous infusion, came in100mg vials as a liquid formulation for infusion and was dosed at 300mg every21 days. Spartalizumab was infused after LAG525

Investigational medicinal product name

LAG525

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

LAG525 was a concentrate for solution for intravenous infusion, came in100mg vials as a liquid formulation for infusion and was dosed at 400mg every21 days. For all arms, LAG525 was infused first

LAG525+ PDR001+ carboplatin

Arm description

Participants received LAG525, PDR001 and carboplatin administered as infusion once every 3 weeks.

Arm type

Experimental

Investigational medicinal product name

LAG525

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

LAG525 was a concentrate for solution for intravenous infusion, came in100mg vials as a liquid formulation for infusion and was dosed at 400mg every21 days. For all arms, LAG525 was infused first

Investigational medicinal product name

Carboplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Carboplatin was a concentrate for solution for intravenous infusion, came in100mg/mL and was dosed per area under the curve (AUC) 6 every 21 days. Carboplatin was infused once LAG525 infusion was completed

Investigational medicinal product name

Spartalizumab

Investigational medicinal product code

PDR001

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

LAG525 + carboplatin

Arm description

Participants received LAG525 and carboplatin administered as infusion once every 3 weeks

Arm type

Experimental

Investigational medicinal product name

Carboplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

LAG525

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

LAG525 was a concentrate for solution for intravenous infusion, came in100mg vials as a liquid formulation for infusion and was dosed at 400mg every21 days. For all arms, LAG525 was infused first

Number of subjects in period 1	LAG525 + PDR001	LAG525+ PDR001+ carboplatin	LAG525 + carboplatin
Started	20	34	34
Treated	19	34	34
Completed	0	0	0
Not completed	20	34	34
Adverse event, serious fatal	-	-	1
Physician decision	3	6	6
Patient decision	-	1	1
Adverse event, non-fatal	2	3	3
Progressive disease	15	23	23
Terminated by sponsor (end of study definition)	-	1	-

Baseline characteristics

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Reporting group title

LAG525 + PDR001

Reporting group description

Participants received LAG525 and PDR001 administered as infusion once every 3 weeks

Reporting group title

LAG525+ PDR001+ carboplatin

Reporting group description

Participants received LAG525, PDR001 and carboplatin administered as infusion once every 3 weeks.

Reporting group title

LAG525 + carboplatin

Reporting group description

Participants received LAG525 and carboplatin administered as infusion once every 3 weeks

Reporting group values	LAG525 + PDR001	LAG525+ PDR001+ carboplatin	LAG525 + carboplatin	Total
Number of subjects	20	34	34	88
Age categorical
Units: Subjects
In utero	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0
Newborns (0-27 days)	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0
Children (2-11 years)	0	0	0	0
Adolescents (12-17 years)	0	0	0	0
Adults (18-64 years)	18	30	28	76
From 65-84 years	2	4	6	12
85 years and over	0	0	0	0
Age Continuous
Units: Years
arithmetic mean (standard deviation)	53.8 ( 10.22 )	50.9 ( 10.88 )	53.3 ( 10.78 )	-
Sex: Female, Male
Units: Participants
Female	20	34	34	88
Male	0	0	0	0
Race/Ethnicity, Customized
Units: Subjects
Asian	8	8	7	23
Black or African American	0	0	1	1
Missing	0	3	1	4
White	12	23	25	60

End points

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Reporting group title

LAG525 + PDR001

Reporting group description

Participants received LAG525 and PDR001 administered as infusion once every 3 weeks

Reporting group title

LAG525+ PDR001+ carboplatin

Reporting group description

Participants received LAG525, PDR001 and carboplatin administered as infusion once every 3 weeks.

Reporting group title

LAG525 + carboplatin

Reporting group description

Participants received LAG525 and carboplatin administered as infusion once every 3 weeks

Primary: Overall response rate (ORR) per investigator’s assessment according to RECIST v1.1

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End point title

Overall response rate (ORR) per investigator’s assessment according to RECIST v1.1 ^[1]

End point description

Overall response rate (ORR) is defined as the percentage of participants with best overall response of complete response (CR) or partial response (PR) according to RECIST 1.1 based on investigator's assessment. The 95% CIs were computed using two-sided exact binomial method. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.

End point type

Primary

End point timeframe

Up to approximately 14 months

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: No statistical analyses planned for this endpoint

End point values	LAG525 + PDR001	LAG525+ PDR001+ carboplatin	LAG525 + carboplatin
Number of subjects analysed	20	34	34
Units: Percentage of participants
number (confidence interval 95%)	5.0 (0.1 to 24.9)	32.4 (17.4 to 50.5)	17.6 (6.8 to 34.5)

No statistical analyses for this end point

Secondary: Clinical Benefit Rate (CBR) per investigator’s assessment according to RECIST v1.1

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End point title

Clinical Benefit Rate (CBR) per investigator’s assessment according to RECIST v1.1

End point description

CBR is defined as the percentage of participants with a best overall response (BOR) of confirmed CR or PR, or stable disease (SD) lasting 24 weeks or longer, according to RECIST 1.1 criteria. The 95% CI were computed using two-sided exact binomial method. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. SD: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease.

End point type

Secondary

End point timeframe

Up to approximately 14 months

End point values	LAG525 + PDR001	LAG525+ PDR001+ carboplatin	LAG525 + carboplatin
Number of subjects analysed	20	34	34
Units: Percentage of Participants
number (confidence interval 95%)	5.0 (0.1 to 24.9)	35.3 (19.7 to 53.5)	20.6 (8.7 to 37.9)

No statistical analyses for this end point

Secondary: Duration of response (DOR) per investigator’s assessment according to RECIST v1.1

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End point title

Duration of response (DOR) per investigator’s assessment according to RECIST v1.1

End point description

DOR is the time between the first documented response (CR or PR) and the first documented progression or death due to underlying cancer based on RECIST1.1 and as per investigator’s assessment. The DOR distribution was estimated using the Kaplan-Meier method and the 95% confidence intervals using the method of Brookmeyer and Crowley. If progression or death did not occur, the participant was censored at the date of last adequate tumor assessment. CR: Disappearance of all non-nodal target lesions and any pathological lymph nodes assigned as target lesions must have a reduction in short axis to <10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. Progression: at least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. The sum must also demonstrate an absolute increase of at least 5 mm.

End point type

Secondary

End point timeframe

From first documented response up to disease progression or death due to underlying cancer, whichever occurs first, up to approximately 14 months

End point values	LAG525 + PDR001	LAG525+ PDR001+ carboplatin	LAG525 + carboplatin
Number of subjects analysed	1	11	6
Units: Months
median (confidence interval 95%)	4.9 (-9999 to 9999)	13.6 (2.8 to 9999)	12.6 (2.4 to 9999)

No statistical analyses for this end point

Secondary: Time to response (TTR) per investigator's assessment according to RECIST v1.1

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End point title

Time to response (TTR) per investigator's assessment according to RECIST v1.1

End point description

TTR is the time from date of randomization to first documented response of CR or PR based on investigators’ assessment and according to RECIST 1.1. Median TTR was summarized using descriptive statistics. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.

End point type

Secondary

End point timeframe

From date of randomization to first documented response (CR or PR), up to approximately 14 months

End point values	LAG525 + PDR001	LAG525+ PDR001+ carboplatin	LAG525 + carboplatin
Number of subjects analysed	1	11	6
Units: Months
median (full range (min-max))	1.5 (1.5 to 1.5)	1.7 (1.2 to 4.1)	1.4 (1.2 to 2.8)

No statistical analyses for this end point

Secondary: Progression free survival (PFS)

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End point title

Progression free survival (PFS)

End point description

PFS is defined as time from date of randomization to the date of first documented progression or death due to any cause. PFS was assessed via investigator's assessment according to RECIST 1.1. PFS was censored at the date of the last adequate tumor assessment if no PFS event was observed prior to the analysis cut-off date or before the start of the new anticancer therapy date, whichever is earlier. The PFS distribution was estimated using the Kaplan-Meier method. The 95% confidence intervals were calculated using the method of Brookmeyer and Crowley.

End point type

Secondary

End point timeframe

From date of randomization to disease progression or death due to any cause, whichever occurs first, up to approximately 14 months

End point values	LAG525 + PDR001	LAG525+ PDR001+ carboplatin	LAG525 + carboplatin
Number of subjects analysed	20	34	34
Units: Months
median (confidence interval 95%)	1.4 (1.2 to 1.5)	4.3 (2.8 to 5.6)	3.0 (2.2 to 5.5)

No statistical analyses for this end point

Secondary: Overall Survival (OS)

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End point title

Overall Survival (OS)

End point description

OS is defined as the time from date of randomization to date of death due to any cause. If a participant was not known to have died, then OS was censored at the latest date the participant was known to be alive (on or before the cut-off date). The OS distribution was estimated using the Kaplan-Meier method. The 95% confidence intervals were calculated using the method of Brookmeyer and Crowley

End point type

Secondary

End point timeframe

From date of randomization to date of death due to any cause, up to 18 months

End point values	LAG525 + PDR001	LAG525+ PDR001+ carboplatin	LAG525 + carboplatin
Number of subjects analysed	20	34	34
Units: Months
median (confidence interval 95%)	6.1 (4.6 to 9999)	11.6 (7.5 to 9999)	8.0 (6.2 to 9.3)

No statistical analyses for this end point

Secondary: Pharmacokinetics (PK) parameter, Area under the plasma concentration versus time curve from time 0 to 504 hours (AUC0-504h) of LAG525

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End point title

Pharmacokinetics (PK) parameter, Area under the plasma concentration versus time curve from time 0 to 504 hours (AUC0-504h) of LAG525

End point description

Blood samples were collected at the indicated time points for PK analysis. PK parameters were calculated by standard non-compartmental analysis. AUC0-504h was defined as the area under the plasma concentration-time curve from time zero to 504h.

End point type

Secondary

End point timeframe

Cycle 1 at pre-infusion, 1 hour (hr) post end of infusion, 168 hr, 336 hr and 504 hr post-infusion on Day 1 of Cycle 1. Cycle 3 at pre-infusion, 1 hr post end of infusion, 168 hr, 336 hr and 504 hr post-infusion on Day 1 of Cycle 3. Each cycle is 21 days

End point values	LAG525 + PDR001	LAG525+ PDR001+ carboplatin	LAG525 + carboplatin
Number of subjects analysed	11	24	33
Units: daymicrogram/miliLiter (dayug/mL)
geometric mean (geometric coefficient of variation)
Cycle 1 (n= 11/ 19 / 22)	1270 ( 25.8 )	1350 ( 22.4 )	1180 ( 23.4 )
Cycle 3 (n= 3 / 14 / 11)	2060 ( 60.1 )	2200 ( 34.4 )	1990 ( 31.3 )

No statistical analyses for this end point

Secondary: PK parameter, Cmax of LAG525

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End point title

PK parameter, Cmax of LAG525

End point description

Blood samples were collected at the indicated time points for PK analysis. PK parameters were calculated by standard non-compartmental analysis. Cmax is the maximum observed plasma LAG525 concentration

End point type

Secondary

End point timeframe

End point values	LAG525 + PDR001	LAG525+ PDR001+ carboplatin	LAG525 + carboplatin
Number of subjects analysed	16	34	30
Units: ug/mL
geometric mean (geometric coefficient of variation)
Cycle 1 (n= 16 / 31/ 28)	127 ( 26.5 )	136 ( 21.1 )	128 ( 17.9 )
Cycle 3 (n= 6 / 23 / 24)	144 ( 48.9 )	181 ( 29.5 )	168 ( 26.6 )

No statistical analyses for this end point

Secondary: PK parameter, AUClast of LAG525

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End point title

PK parameter, AUClast of LAG525

End point description

Blood samples were collected at the indicated time points for PK analysis. PK parameters were calculated by standard non-compartmental analysis. AUClast is the area under the curve (AUC) from time zero to the last measurable concentration sampling time (tlast) of LAG525

End point type

Secondary

End point timeframe

End point values	LAG525 + PDR001	LAG525+ PDR001+ carboplatin	LAG525 + carboplatin
Number of subjects analysed	16	34	29
Units: day*ug/mL
geometric mean (geometric coefficient of variation)
Cycle 1 (n= 16/ 31 / 28)	1170 ( 32.0 )	1310 ( 41.1 )	1010 ( 151.2 )
Cycle 3 (n= 6 / 23 / 24)	240 ( 9775.4 )	2040 ( 49.8 )	1490 ( 196.4 )

No statistical analyses for this end point

Secondary: PK parameter, Tmax of LAG525

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End point title

PK parameter, Tmax of LAG525

End point description

Blood samples were collected at the indicated time points for PK analysis. PK parameters were calculated by standard non-compartmental analysis. Tmax is the time to reach maximum LAG525 serum concentration. Actual time of sample collection was used (not the nominal time point as per scheduled assessment)

End point type

Secondary

End point timeframe

End point values	LAG525 + PDR001	LAG525+ PDR001+ carboplatin	LAG525 + carboplatin
Number of subjects analysed	16	34	30
Units: hr
geometric mean (geometric coefficient of variation)
Cycle 1 (n= 16 / 31 / 28)	1.51 ( 13.4 )	1.58 ( 15.0 )	1.77 ( 37.4 )
Cycle 3 (n= 6 / 23 / 24)	1.64 ( 13.4 )	1.58 ( 15.0 )	1.77 ( 37.4 )

No statistical analyses for this end point

Secondary: PK parameter, AUC0-504h of PDR001

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End point title

PK parameter, AUC0-504h of PDR001 ^[2]

End point description

End point type

Secondary

End point timeframe

Notes
[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: This endpoint is only applicable for arms with PDR001 administration

End point values	LAG525 + PDR001	LAG525+ PDR001+ carboplatin
Number of subjects analysed	11	24
Units: day*ug/mL
arithmetic mean (standard deviation)
Cycle 1 (n= 11 / 18)	819 ( 23.6 )	907 ( 29.1 )
Cycle 3 (n= 3 / 15)	1490 ( 41.0 )	1710 ( 29.5 )

No statistical analyses for this end point

Secondary: PK parameter, Cmax of PDR001

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End point title

PK parameter, Cmax of PDR001 ^[3]

End point description

Blood samples were collected at the indicated time points for PK analysis. PK parameters were calculated by standard non-compartmental analysis. Cmax is the maximum observed PDR001 serum concentration

End point type

Secondary

End point timeframe

Notes
[3] - 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: This endpoint is only applicable for arms with PDR001 administration

End point values	LAG525 + PDR001	LAG525+ PDR001+ carboplatin
Number of subjects analysed	16	33
Units: ug/mL
geometric mean (geometric coefficient of variation)
Cycle 1 (n= 16 / 28)	78.0 ( 18.9 )	82.4 ( 25.1 )
Cycle 3 (n= 6 / 21)	95.1 ( 41.4 )	117 ( 26.8 )

No statistical analyses for this end point

Secondary: PK parameter, AUClast of PDR001

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End point title

PK parameter, AUClast of PDR001 ^[4]

End point description

End point type

Secondary

End point timeframe

Notes
[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: This endpoint is only applicable for arms with PDR001 administration

End point values	LAG525 + PDR001	LAG525+ PDR001+ carboplatin
Number of subjects analysed	16	33
Units: day*ug/mL
geometric mean (geometric coefficient of variation)
Cycle 1 (n= 16 / 28)	780 ( 24.4 )	890 ( 44.6 )
Cycle 3 (n= 5 / 21)	374 ( 2703.2 )	1500 ( 55.7 )

No statistical analyses for this end point

Secondary: PK parameter, Tmax of PDR001

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End point title

PK parameter, Tmax of PDR001 ^[5]

End point description

Blood samples were collected at the indicated time points for PK analysis. PK parameters were calculated by standard non-compartmental analysis. Tmax is the time to reach maximum PDR001 serum concentration. Actual time of sample collection was used (not the nominal time point as per scheduled assessment)

End point type

Secondary

End point timeframe

Notes
[5] - 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: This endpoint is only applicable for arms with PDR001 administration

End point values	LAG525 + PDR001	LAG525+ PDR001+ carboplatin
Number of subjects analysed	16	33
Units: hr
geometric mean (geometric coefficient of variation)
Cycle 1 (n= 16 / 28)	1.43 ( 34.7 )	1.71 ( 29.7 )
Cycle 3 (n= 6 / 21)	1.67 ( 13.6 )	1.61 ( 13.9 )

No statistical analyses for this end point

Secondary: PK parameter, AUC0-4h of carboplatin (total platinium)

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End point title

PK parameter, AUC0-4h of carboplatin (total platinium) ^[6]

End point description

Blood samples were collected at the indicated time points for PK analysis. PK parameters were calculated by standard non-compartmental analysis. AUC0-4h was defined as the area under the plasma concentration-time curve from time zero to 4h (determined as total platinium).

End point type

Secondary

End point timeframe

Cycle 1 at pre-infusion, end of infusion, 1 hour, 2 hours and 3 hours post end of infusion. Cycle 3 at pre-infusion, end of infusion, 1 hour, 2 hours and 3 hours post end of infusion. Each cycle is 21 days

Notes
[6] - 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: This endpoint is only applicable for arms with carboplatin administration

End point values	LAG525+ PDR001+ carboplatin	LAG525 + carboplatin
Number of subjects analysed	24	20
Units: hournanogram/miliLiter (hrng/mL)
geometric mean (geometric coefficient of variation)
Cycle 1 (n= 20 / 16)	45000 ( 23.0 )	45200 ( 16.1 )
Cycle 3 (n= 14 / 14)	42700 ( 27.6 )	43500 ( 29.2 )

No statistical analyses for this end point

Secondary: PK parameter, Cmax of carboplatin (total platinium)

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End point title

PK parameter, Cmax of carboplatin (total platinium) ^[7]

End point description

Blood samples were collected at the indicated time points for PK analysis. PK parameters were calculated by standard non-compartmental analysis. Cmax is the maximum observed carboplatin plasma concentration (determined as total platinium)

End point type

Secondary

End point timeframe

Notes
[7] - 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: This endpoint is only applicable for arms with carboplatin administration

End point values	LAG525+ PDR001+ carboplatin	LAG525 + carboplatin
Number of subjects analysed	33	31
Units: ng/mL
geometric mean (geometric coefficient of variation)
Cycle 1 (n= 30 / 27)	22300 ( 32.0 )	21400 ( 32.2 )
Cycle 3 (n = 23 / 23)	20900 ( 33.4 )	20000 ( 199.2 )

No statistical analyses for this end point

Secondary: PK parameter, AUClast of carboplatin (total platinium)

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End point title

PK parameter, AUClast of carboplatin (total platinium) ^[8]

End point description

End point type

Secondary

End point timeframe

Notes
[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: This endpoint is only applicable for arms with carboplatin administration

End point values	LAG525+ PDR001+ carboplatin	LAG525 + carboplatin
Number of subjects analysed	33	29
Units: ng/mL
geometric mean (geometric coefficient of variation)
Cycle 1 (n= 28 / 25)	42000 ( 30.8 )	38900 ( 56.3 )
Cycle 3 ( n= 23 / 22)	40800 ( 38.1 )	42600 ( 43.3 )

No statistical analyses for this end point

Secondary: PK parameter, Tmax of carboplatin (total platinium)

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End point title

PK parameter, Tmax of carboplatin (total platinium) ^[9]

End point description

Blood samples were collected at the indicated time points for PK analysis. PK parameters were calculated by standard non-compartmental analysis. Tmax is the time to reach maximum carboplatin plasma concentration (determined as total platinium). Actual time of sample collection was used (not the nominal time point as per scheduled assessment)

End point type

Secondary

End point timeframe

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: This endpoint is only applicable for arms with carboplatin administration

End point values	LAG525+ PDR001+ carboplatin	LAG525 + carboplatin
Number of subjects analysed	33	31
Units: hr
geometric mean (geometric coefficient of variation)
Cycle 1 (n= 30 / 27)	0.857 ( 35.5 )	0.720 ( 31.9 )
Cycle 3 ( n=23 / 23)	0.789 ( 33.0 )	0.720 ( 34.8 )

No statistical analyses for this end point

Secondary: PK parameter, AUC0-4h of carboplatin (ultrafilterable platinium)

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End point title

PK parameter, AUC0-4h of carboplatin (ultrafilterable platinium) ^[10]

End point description

End point type

Secondary

End point timeframe

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: This endpoint is only applicable for arms with carboplatin administration

End point values	LAG525+ PDR001+ carboplatin	LAG525 + carboplatin
Number of subjects analysed	12	7
Units: hournanogram/miliLiter (hrng/mL)
geometric mean (geometric coefficient of variation)
Cycle 1 (n= 8 / 5)	43600 ( 13.1 )	44700 ( 23.4 )
Cycle 3 (n= 9 / 5)	41100 ( 30.5 )	41000 ( 12.8 )

No statistical analyses for this end point

Secondary: PK parameter, Cmax of carboplatin (ultrafilterable platinium)

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End point title

PK parameter, Cmax of carboplatin (ultrafilterable platinium) ^[11]

End point description

End point type

Secondary

End point timeframe

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: This endpoint is only applicable for arms with carboplatin administration

End point values	LAG525+ PDR001+ carboplatin	LAG525 + carboplatin
Number of subjects analysed	15	19
Units: ng/mL
geometric mean (geometric coefficient of variation)
Cycle 1 (n= 12 / 13)	23200 ( 19.8 )	25700 ( 24.2 )
Cycle 3 (n= 12 / 12)	22300 ( 40.1 )	14700 ( 4159.6 )

No statistical analyses for this end point

Secondary: PK parameter, AUClast of carboplatin (ultrafilterable platinium)

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End point title

PK parameter, AUClast of carboplatin (ultrafilterable platinium) ^[12]

End point description

End point type

Secondary

End point timeframe

Notes
[12] - 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: This endpoint is only applicable for arms with carboplatin administration

End point values	LAG525+ PDR001+ carboplatin	LAG525 + carboplatin
Number of subjects analysed	15	17
Units: ng/mL
geometric mean (geometric coefficient of variation)
Cycle 1 (n= 10 / 11)	41400 ( 13.0 )	35600 ( 65.2 )
Cycle 3 (n= 12 / 11)	37400 ( 30.1 )	36300 ( 68.2 )

No statistical analyses for this end point

Secondary: PK parameter, Tmax of carboplatin (ultrafilterable platinium)

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End point title

PK parameter, Tmax of carboplatin (ultrafilterable platinium) ^[13]

End point description

Blood samples were collected at the indicated time points for PK analysis. PK parameters were calculated by standard non-compartmental analysis. Tmax is the time to reach maximum carboplatin plasma concentration (determined as ultrafilterable platinium). Actual time of sample collection was used (not the nominal time point as per scheduled assessment)

End point type

Secondary

End point timeframe

Notes
[13] - 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: This endpoint is only applicable for arms with carboplatin administration

End point values	LAG525+ PDR001+ carboplatin	LAG525 + carboplatin
Number of subjects analysed	15	19
Units: hr
geometric mean (geometric coefficient of variation)
Cycle 1 (n= 12 / 13)	0.802 ( 42.5 )	0.660 ( 34.4 )
Cycle 3 (n= 12 / 12)	0.828 ( 39.7 )	0.686 ( 34.6 )

No statistical analyses for this end point

Secondary: Number of participants with Anti-drug antibodies (ADA) at baseline for LAG525

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End point title

Number of participants with Anti-drug antibodies (ADA) at baseline for LAG525

End point description

Number of participants who had an ADA positive result at baseline for LAG525

End point type

Secondary

End point timeframe

Baseline

End point values	LAG525 + PDR001	LAG525+ PDR001+ carboplatin	LAG525 + carboplatin
Number of subjects analysed	18	34	33
Units: Participants	0	0	1

No statistical analyses for this end point

Secondary: Number of participants with Anti-drug antibodies (ADA) on treatment for LAG525

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End point title

Number of participants with Anti-drug antibodies (ADA) on treatment for LAG525

End point description

Number of participants who were treatment-induced ADA positive for LAG525 (post-baseline ADA positive with ADA-negative sample at baseline) and treatment-boosted ADA positive for LAG525 (post-baseline ADA positive with titer that was at least the fold titer change greater than the ADA-positive baseline titer)

End point type

Secondary

End point timeframe

From Cycle 1 to Cycle 7 (Day 1 pre-infusion) and end of treatment, assessed up to 3 years

End point values	LAG525 + PDR001	LAG525+ PDR001+ carboplatin	LAG525 + carboplatin
Number of subjects analysed	15	32	32
Units: Participants	0	0	1

No statistical analyses for this end point

Secondary: Number of participants with Anti-drug antibodies (ADA) at baseline for PDR001

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End point title

Number of participants with Anti-drug antibodies (ADA) at baseline for PDR001 ^[14]

End point description

ADA prevalence at baseline was calculated as the percentage of participants who had an ADA positive result at baseline for PDR001.

End point type

Secondary

End point timeframe

Baseline

Notes
[14] - 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: This endpoint is only applicable for arms with PDR001 administration

End point values	LAG525 + PDR001	LAG525+ PDR001+ carboplatin
Number of subjects analysed	18	34
Units: Participants	3	6

No statistical analyses for this end point

Secondary: Number of participants with Anti-drug antibodies (ADA) on treatment for PDR001

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End point title

Number of participants with Anti-drug antibodies (ADA) on treatment for PDR001 ^[15]

End point description

Number of participants who were treatment-induced ADA positive for PDR001 (post-baseline ADA positive with ADA-negative sample at baseline) and treatment-boosted ADA positive for PDR001 (post-baseline ADA positive with titer that was at least the fold titer change greater than the ADA-positive baseline titer)

End point type

Secondary

End point timeframe

From Cycle 1 to Cycle 7 (Day 1 pre-infusion) and end of treatment, assessed up to 2.8 years

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: This endpoint is only applicable for arms with PDR001 administration

End point values	LAG525 + PDR001	LAG525+ PDR001+ carboplatin
Number of subjects analysed	15	25
Units: Participants	1	0

No statistical analyses for this end point

Post-hoc: All collected deaths

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End point title

All collected deaths

End point description

On-treatment deaths were collected from first dose of study medication to 30 days after the last dose of study medication for a maximum duration of 2.9 years. Extended safety follow up deaths were collected from day 31 post treatment up to 150 days post-treatment, for a maximum duration of 3.2 years. Post-treatment deaths were collected after 150 days post-treatment, for a maximum duration of 3.2 years.

End point type

Post-hoc

End point timeframe

Up to 2.9 years (on-treatment), up to 3.2 years (extended safety follow-up and post-treatment)

End point values	LAG525 + PDR001	LAG525+ PDR001+ carboplatin	LAG525 + carboplatin
Number of subjects analysed	19	34	34
Units: Participants
On-treatment	0	2	1
Extended safety follow-up deaths	7	7	16
Post-treatment deaths	8	15	11
All deaths	15	24	28

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

On-treatment: from first dose of study treatment until last dose of study treatment plus 30 days post treatment, up to 2.9 years. Extended safety follow-up: from day 31 to day 150 after last administration of study treatment, up to 3.2 years

Adverse event reporting additional description

Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

24.1

Reporting group title

LAG525 + PDR001 (On-treatment)

Reporting group description

Participants received LAG525 and PDR001 administered as infusion once every 3 weeks

Reporting group title

LAG525 + PDR001 (Extended safety follow-up)

Reporting group description

Participants received LAG525 and PDR001 administered as infusion once every 3 weeks

Reporting group title

LAG525 + PDR001 +Carboplatin (On-treatment)

Reporting group description

Participants received LAG525, PDR001 and carboplatin administered as infusion once every 3 weeks

Reporting group title

LAG525 + PDR001 + Carboplatin (Extended safety follow-up)

Reporting group description

Participants received LAG525, PDR001 and carboplatin administered as infusion once every 3 weeks.

Reporting group title

LAG525 + Carboplatin (On-treatment)

Reporting group description

Participants received LAG525 and carboplatin administered as infusion once every 3 weeks

Reporting group title

LAG525 + Carboplatin (Extended safety follow-up)

Reporting group description

Participants received LAG525 and carboplatin administered as infusion once every 3 weeks

Serious adverse events	LAG525 + PDR001 (On-treatment)	LAG525 + PDR001 (Extended safety follow-up)	LAG525 + PDR001 +Carboplatin (On-treatment)	LAG525 + PDR001 + Carboplatin (Extended safety follow-up)	LAG525 + Carboplatin (On-treatment)	LAG525 + Carboplatin (Extended safety follow-up)
Total subjects affected by serious adverse events
subjects affected / exposed	6 / 19 (31.58%)	0 / 19 (0.00%)	12 / 34 (35.29%)	6 / 34 (17.65%)	14 / 34 (41.18%)	2 / 34 (5.88%)
number of deaths (all causes)	0	7	2	7	1	16
number of deaths resulting from adverse events	0	0	0	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Metastases to meninges
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	1 / 34 (2.94%)	0 / 34 (0.00%)	1 / 34 (2.94%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
General disorders and administration site conditions
Disease progression
subjects affected / exposed	1 / 19 (5.26%)	0 / 19 (0.00%)	0 / 34 (0.00%)	1 / 34 (2.94%)	0 / 34 (0.00%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)	1 / 34 (2.94%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pain
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)	1 / 34 (2.94%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Malaise
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)	1 / 34 (2.94%)	0 / 34 (0.00%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	1 / 19 (5.26%)	0 / 19 (0.00%)	2 / 34 (5.88%)	0 / 34 (0.00%)	3 / 34 (8.82%)	1 / 34 (2.94%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2	0 / 0	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea exertional
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	1 / 34 (2.94%)	0 / 34 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	1 / 34 (2.94%)	0 / 34 (0.00%)	2 / 34 (5.88%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pleuritic pain
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)	1 / 34 (2.94%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Interstitial lung disease
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)	1 / 34 (2.94%)	0 / 34 (0.00%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Confusional state
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)	1 / 34 (2.94%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Platelet count decreased
subjects affected / exposed	1 / 19 (5.26%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Troponin increased
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)	1 / 34 (2.94%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Thoracic vertebral fracture
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	1 / 34 (2.94%)	0 / 34 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Congenital, familial and genetic disorders
Fanconi syndrome
subjects affected / exposed	1 / 19 (5.26%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Myocardial infarction
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)	1 / 34 (2.94%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myocarditis
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)	1 / 34 (2.94%)	1 / 34 (2.94%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pericardial effusion
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)	1 / 34 (2.94%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Wolff-Parkinson-White syndrome
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	1 / 34 (2.94%)	0 / 34 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atrial thrombosis
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)	1 / 34 (2.94%)	0 / 34 (0.00%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Brain oedema
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)	1 / 34 (2.94%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Headache
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)	1 / 34 (2.94%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)	2 / 34 (5.88%)	1 / 34 (2.94%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	1 / 34 (2.94%)	0 / 34 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)	1 / 34 (2.94%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Erosive duodenitis
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	1 / 34 (2.94%)	0 / 34 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Faeces discoloured
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)	1 / 34 (2.94%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal ischaemia
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	1 / 34 (2.94%)	0 / 34 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)	1 / 34 (2.94%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)	1 / 34 (2.94%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Biliary colic
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	1 / 34 (2.94%)	0 / 34 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Renal tubular acidosis
subjects affected / exposed	1 / 19 (5.26%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	1 / 34 (2.94%)	0 / 34 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Pneumocystis jirovecii pneumonia
subjects affected / exposed	1 / 19 (5.26%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	1 / 19 (5.26%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)	1 / 34 (2.94%)	1 / 34 (2.94%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Septic shock
subjects affected / exposed	1 / 19 (5.26%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin infection
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	1 / 34 (2.94%)	0 / 34 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Subcutaneous abscess
subjects affected / exposed	1 / 19 (5.26%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Hypercalcaemia
subjects affected / exposed	1 / 19 (5.26%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	LAG525 + PDR001 (On-treatment)	LAG525 + PDR001 (Extended safety follow-up)	LAG525 + PDR001 +Carboplatin (On-treatment)	LAG525 + PDR001 + Carboplatin (Extended safety follow-up)	LAG525 + Carboplatin (On-treatment)	LAG525 + Carboplatin (Extended safety follow-up)
Total subjects affected by non serious adverse events
subjects affected / exposed	17 / 19 (89.47%)	0 / 19 (0.00%)	34 / 34 (100.00%)	11 / 34 (32.35%)	33 / 34 (97.06%)	3 / 34 (8.82%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Metastases to skin
subjects affected / exposed	2 / 19 (10.53%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)
occurrences all number	2	0	0	0	0	0
Vascular disorders
Hot flush
subjects affected / exposed	1 / 19 (5.26%)	0 / 19 (0.00%)	2 / 34 (5.88%)	0 / 34 (0.00%)	1 / 34 (2.94%)	0 / 34 (0.00%)
occurrences all number	1	0	2	0	1	0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	11 / 34 (32.35%)	0 / 34 (0.00%)	5 / 34 (14.71%)	0 / 34 (0.00%)
occurrences all number	0	0	13	0	5	0
Chest pain
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	2 / 34 (5.88%)	0 / 34 (0.00%)	2 / 34 (5.88%)	0 / 34 (0.00%)
occurrences all number	0	0	2	0	2	0
Gait disturbance
subjects affected / exposed	1 / 19 (5.26%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)
occurrences all number	1	0	0	0	0	0
Fatigue
subjects affected / exposed	2 / 19 (10.53%)	0 / 19 (0.00%)	11 / 34 (32.35%)	1 / 34 (2.94%)	12 / 34 (35.29%)	0 / 34 (0.00%)
occurrences all number	3	0	13	1	12	0
Chills
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	2 / 34 (5.88%)	0 / 34 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	2	0	0	0
Malaise
subjects affected / exposed	1 / 19 (5.26%)	0 / 19 (0.00%)	3 / 34 (8.82%)	0 / 34 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)
occurrences all number	1	0	3	0	0	0
Influenza like illness
subjects affected / exposed	1 / 19 (5.26%)	0 / 19 (0.00%)	2 / 34 (5.88%)	0 / 34 (0.00%)	2 / 34 (5.88%)	0 / 34 (0.00%)
occurrences all number	1	0	2	0	2	0
Induration
subjects affected / exposed	1 / 19 (5.26%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)
occurrences all number	1	0	0	0	0	0
Non-cardiac chest pain
subjects affected / exposed	1 / 19 (5.26%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)	1 / 34 (2.94%)	0 / 34 (0.00%)
occurrences all number	1	0	0	0	1	0
Oedema peripheral
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)	2 / 34 (5.88%)	2 / 34 (5.88%)	0 / 34 (0.00%)
occurrences all number	0	0	0	2	3	0
Pain
subjects affected / exposed	2 / 19 (10.53%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)	2 / 34 (5.88%)	0 / 34 (0.00%)
occurrences all number	2	0	0	0	2	0
Pyrexia
subjects affected / exposed	1 / 19 (5.26%)	0 / 19 (0.00%)	4 / 34 (11.76%)	0 / 34 (0.00%)	3 / 34 (8.82%)	1 / 34 (2.94%)
occurrences all number	1	0	4	0	3	1
Reproductive system and breast disorders
Breast pain
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)	2 / 34 (5.88%)	0 / 34 (0.00%)
occurrences all number	0	0	0	0	2	0
Vaginal discharge
subjects affected / exposed	1 / 19 (5.26%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)
occurrences all number	1	0	0	0	0	0
Pelvic pain
subjects affected / exposed	1 / 19 (5.26%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)
occurrences all number	1	0	0	0	0	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	2 / 19 (10.53%)	0 / 19 (0.00%)	7 / 34 (20.59%)	0 / 34 (0.00%)	4 / 34 (11.76%)	0 / 34 (0.00%)
occurrences all number	2	0	8	0	6	0
Dyspnoea
subjects affected / exposed	1 / 19 (5.26%)	0 / 19 (0.00%)	4 / 34 (11.76%)	0 / 34 (0.00%)	6 / 34 (17.65%)	0 / 34 (0.00%)
occurrences all number	1	0	5	0	6	0
Oropharyngeal pain
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	4 / 34 (11.76%)	0 / 34 (0.00%)	1 / 34 (2.94%)	0 / 34 (0.00%)
occurrences all number	0	0	4	0	1	0
Haemoptysis
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	2 / 34 (5.88%)	0 / 34 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	2	0	0	0
Pleural effusion
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	1 / 34 (2.94%)	0 / 34 (0.00%)	3 / 34 (8.82%)	0 / 34 (0.00%)
occurrences all number	0	0	1	0	3	0
Psychiatric disorders
Anxiety
subjects affected / exposed	1 / 19 (5.26%)	0 / 19 (0.00%)	1 / 34 (2.94%)	0 / 34 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)
occurrences all number	1	0	1	0	0	0
Insomnia
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	1 / 34 (2.94%)	1 / 34 (2.94%)	6 / 34 (17.65%)	0 / 34 (0.00%)
occurrences all number	0	0	1	1	6	0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	1 / 19 (5.26%)	0 / 19 (0.00%)	6 / 34 (17.65%)	0 / 34 (0.00%)	1 / 34 (2.94%)	0 / 34 (0.00%)
occurrences all number	1	0	6	0	1	0
Aspartate aminotransferase increased
subjects affected / exposed	2 / 19 (10.53%)	0 / 19 (0.00%)	4 / 34 (11.76%)	1 / 34 (2.94%)	2 / 34 (5.88%)	0 / 34 (0.00%)
occurrences all number	2	0	4	1	2	0
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	4 / 34 (11.76%)	0 / 34 (0.00%)	1 / 34 (2.94%)	0 / 34 (0.00%)
occurrences all number	0	0	4	0	1	0
Blood creatine phosphokinase increased
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)	2 / 34 (5.88%)	0 / 34 (0.00%)
occurrences all number	0	0	0	0	2	0
Blood thyroid stimulating hormone increased
subjects affected / exposed	1 / 19 (5.26%)	0 / 19 (0.00%)	1 / 34 (2.94%)	0 / 34 (0.00%)	1 / 34 (2.94%)	0 / 34 (0.00%)
occurrences all number	1	0	2	0	1	0
Gamma-glutamyltransferase increased
subjects affected / exposed	1 / 19 (5.26%)	0 / 19 (0.00%)	4 / 34 (11.76%)	0 / 34 (0.00%)	1 / 34 (2.94%)	0 / 34 (0.00%)
occurrences all number	1	0	5	0	1	0
Platelet count decreased
subjects affected / exposed	1 / 19 (5.26%)	0 / 19 (0.00%)	14 / 34 (41.18%)	2 / 34 (5.88%)	9 / 34 (26.47%)	0 / 34 (0.00%)
occurrences all number	1	0	41	2	26	0
Neutrophil count decreased
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	11 / 34 (32.35%)	2 / 34 (5.88%)	6 / 34 (17.65%)	0 / 34 (0.00%)
occurrences all number	0	0	24	2	13	0
Weight decreased
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)	3 / 34 (8.82%)	2 / 34 (5.88%)	0 / 34 (0.00%)
occurrences all number	0	0	0	3	2	0
SARS-CoV-2 test negative
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	2 / 34 (5.88%)	1 / 34 (2.94%)	1 / 34 (2.94%)	0 / 34 (0.00%)
occurrences all number	0	0	2	1	1	0
White blood cell count decreased
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	5 / 34 (14.71%)	1 / 34 (2.94%)	1 / 34 (2.94%)	0 / 34 (0.00%)
occurrences all number	0	0	8	1	1	0
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	2 / 34 (5.88%)	0 / 34 (0.00%)	1 / 34 (2.94%)	0 / 34 (0.00%)
occurrences all number	0	0	2	0	1	0
Fall
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	2 / 34 (5.88%)	0 / 34 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	2	0	0	0
Nervous system disorders
Dizziness
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	1 / 34 (2.94%)	1 / 34 (2.94%)	6 / 34 (17.65%)	0 / 34 (0.00%)
occurrences all number	0	0	2	1	8	0
Dysgeusia
subjects affected / exposed	1 / 19 (5.26%)	0 / 19 (0.00%)	2 / 34 (5.88%)	0 / 34 (0.00%)	1 / 34 (2.94%)	0 / 34 (0.00%)
occurrences all number	1	0	3	0	1	0
Intercostal neuralgia
subjects affected / exposed	1 / 19 (5.26%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)
occurrences all number	1	0	0	0	0	0
Headache
subjects affected / exposed	2 / 19 (10.53%)	0 / 19 (0.00%)	8 / 34 (23.53%)	0 / 34 (0.00%)	4 / 34 (11.76%)	1 / 34 (2.94%)
occurrences all number	2	0	10	0	5	1
Paraesthesia
subjects affected / exposed	1 / 19 (5.26%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)	1 / 34 (2.94%)	1 / 34 (2.94%)
occurrences all number	1	0	0	0	1	1
Peripheral sensory neuropathy
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	1 / 34 (2.94%)	0 / 34 (0.00%)	3 / 34 (8.82%)	0 / 34 (0.00%)
occurrences all number	0	0	1	0	3	0
Somnolence
subjects affected / exposed	1 / 19 (5.26%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)
occurrences all number	1	0	0	0	0	0
Blood and lymphatic system disorders
Leukopenia
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	3 / 34 (8.82%)	0 / 34 (0.00%)	5 / 34 (14.71%)	0 / 34 (0.00%)
occurrences all number	0	0	6	0	11	0
Anaemia
subjects affected / exposed	1 / 19 (5.26%)	0 / 19 (0.00%)	20 / 34 (58.82%)	5 / 34 (14.71%)	19 / 34 (55.88%)	1 / 34 (2.94%)
occurrences all number	1	0	28	7	26	1
Neutropenia
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	9 / 34 (26.47%)	1 / 34 (2.94%)	7 / 34 (20.59%)	0 / 34 (0.00%)
occurrences all number	0	0	16	1	10	0
Thrombocytopenia
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	15 / 34 (44.12%)	0 / 34 (0.00%)	14 / 34 (41.18%)	1 / 34 (2.94%)
occurrences all number	0	0	34	0	28	1
Eye disorders
Dry eye
subjects affected / exposed	1 / 19 (5.26%)	0 / 19 (0.00%)	1 / 34 (2.94%)	0 / 34 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)
occurrences all number	1	0	1	0	0	0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	1 / 19 (5.26%)	0 / 19 (0.00%)	5 / 34 (14.71%)	2 / 34 (5.88%)	2 / 34 (5.88%)	0 / 34 (0.00%)
occurrences all number	1	0	5	2	3	0
Abdominal distension
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	2 / 34 (5.88%)	0 / 34 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	2	0	0	0
Abdominal pain upper
subjects affected / exposed	1 / 19 (5.26%)	0 / 19 (0.00%)	5 / 34 (14.71%)	0 / 34 (0.00%)	3 / 34 (8.82%)	0 / 34 (0.00%)
occurrences all number	1	0	6	0	3	0
Constipation
subjects affected / exposed	3 / 19 (15.79%)	0 / 19 (0.00%)	7 / 34 (20.59%)	1 / 34 (2.94%)	16 / 34 (47.06%)	0 / 34 (0.00%)
occurrences all number	3	0	11	1	19	0
Diarrhoea
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	5 / 34 (14.71%)	2 / 34 (5.88%)	7 / 34 (20.59%)	0 / 34 (0.00%)
occurrences all number	0	0	10	2	8	0
Dry mouth
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	5 / 34 (14.71%)	0 / 34 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	5	0	0	0
Dyspepsia
subjects affected / exposed	1 / 19 (5.26%)	0 / 19 (0.00%)	2 / 34 (5.88%)	0 / 34 (0.00%)	3 / 34 (8.82%)	0 / 34 (0.00%)
occurrences all number	1	0	2	0	3	0
Dysphagia
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	1 / 34 (2.94%)	0 / 34 (0.00%)	2 / 34 (5.88%)	0 / 34 (0.00%)
occurrences all number	0	0	1	0	2	0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	3 / 34 (8.82%)	0 / 34 (0.00%)	1 / 34 (2.94%)	0 / 34 (0.00%)
occurrences all number	0	0	3	0	1	0
Nausea
subjects affected / exposed	3 / 19 (15.79%)	0 / 19 (0.00%)	18 / 34 (52.94%)	2 / 34 (5.88%)	13 / 34 (38.24%)	1 / 34 (2.94%)
occurrences all number	3	0	42	2	17	1
Toothache
subjects affected / exposed	1 / 19 (5.26%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)	1 / 34 (2.94%)	0 / 34 (0.00%)
occurrences all number	1	0	0	0	1	0
Vomiting
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	7 / 34 (20.59%)	1 / 34 (2.94%)	7 / 34 (20.59%)	0 / 34 (0.00%)
occurrences all number	0	0	12	4	8	0
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	3 / 34 (8.82%)	0 / 34 (0.00%)	3 / 34 (8.82%)	0 / 34 (0.00%)
occurrences all number	0	0	3	0	3	0
Dry skin
subjects affected / exposed	3 / 19 (15.79%)	0 / 19 (0.00%)	3 / 34 (8.82%)	0 / 34 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)
occurrences all number	3	0	3	0	0	0
Eczema
subjects affected / exposed	1 / 19 (5.26%)	0 / 19 (0.00%)	2 / 34 (5.88%)	0 / 34 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)
occurrences all number	1	0	2	0	0	0
Pruritus
subjects affected / exposed	2 / 19 (10.53%)	0 / 19 (0.00%)	4 / 34 (11.76%)	0 / 34 (0.00%)	1 / 34 (2.94%)	0 / 34 (0.00%)
occurrences all number	2	0	6	0	1	0
Rash
subjects affected / exposed	2 / 19 (10.53%)	0 / 19 (0.00%)	6 / 34 (17.65%)	1 / 34 (2.94%)	1 / 34 (2.94%)	0 / 34 (0.00%)
occurrences all number	2	0	7	2	1	0
Skin lesion
subjects affected / exposed	1 / 19 (5.26%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)
occurrences all number	1	0	0	0	0	0
Renal and urinary disorders
Polyuria
subjects affected / exposed	1 / 19 (5.26%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)
occurrences all number	1	0	0	0	0	0
Endocrine disorders
Goitre
subjects affected / exposed	1 / 19 (5.26%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)
occurrences all number	1	0	0	0	0	0
Hypothyroidism
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	5 / 34 (14.71%)	0 / 34 (0.00%)	1 / 34 (2.94%)	0 / 34 (0.00%)
occurrences all number	0	0	5	0	1	0
Thyroiditis
subjects affected / exposed	1 / 19 (5.26%)	0 / 19 (0.00%)	1 / 34 (2.94%)	1 / 34 (2.94%)	0 / 34 (0.00%)	0 / 34 (0.00%)
occurrences all number	1	0	1	1	0	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	1 / 19 (5.26%)	0 / 19 (0.00%)	3 / 34 (8.82%)	1 / 34 (2.94%)	4 / 34 (11.76%)	0 / 34 (0.00%)
occurrences all number	1	0	5	1	5	0
Back pain
subjects affected / exposed	1 / 19 (5.26%)	0 / 19 (0.00%)	7 / 34 (20.59%)	2 / 34 (5.88%)	3 / 34 (8.82%)	0 / 34 (0.00%)
occurrences all number	1	0	8	3	3	0
Bone pain
subjects affected / exposed	1 / 19 (5.26%)	0 / 19 (0.00%)	1 / 34 (2.94%)	0 / 34 (0.00%)	1 / 34 (2.94%)	0 / 34 (0.00%)
occurrences all number	1	0	1	0	1	0
Musculoskeletal chest pain
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	2 / 34 (5.88%)	2 / 34 (5.88%)	1 / 34 (2.94%)	0 / 34 (0.00%)
occurrences all number	0	0	2	2	1	0
Musculoskeletal pain
subjects affected / exposed	1 / 19 (5.26%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)
occurrences all number	1	0	0	0	0	0
Neck pain
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)	2 / 34 (5.88%)	0 / 34 (0.00%)
occurrences all number	0	0	0	0	2	0
Myalgia
subjects affected / exposed	2 / 19 (10.53%)	0 / 19 (0.00%)	2 / 34 (5.88%)	0 / 34 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)
occurrences all number	2	0	2	0	0	0
Pain in extremity
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	5 / 34 (14.71%)	0 / 34 (0.00%)	2 / 34 (5.88%)	0 / 34 (0.00%)
occurrences all number	0	0	8	0	2	0
Infections and infestations
Herpes zoster
subjects affected / exposed	1 / 19 (5.26%)	0 / 19 (0.00%)	1 / 34 (2.94%)	1 / 34 (2.94%)	1 / 34 (2.94%)	0 / 34 (0.00%)
occurrences all number	1	0	1	1	1	0
Conjunctivitis
subjects affected / exposed	1 / 19 (5.26%)	0 / 19 (0.00%)	1 / 34 (2.94%)	0 / 34 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)
occurrences all number	1	0	1	0	0	0
Lymphangitis
subjects affected / exposed	1 / 19 (5.26%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)
occurrences all number	1	0	0	0	0	0
Nasopharyngitis
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	2 / 34 (5.88%)	1 / 34 (2.94%)	0 / 34 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	2	1	0	0
Rhinitis
subjects affected / exposed	1 / 19 (5.26%)	0 / 19 (0.00%)	2 / 34 (5.88%)	0 / 34 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)
occurrences all number	1	0	3	0	0	0
Skin infection
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	2 / 34 (5.88%)	1 / 34 (2.94%)	0 / 34 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	2	1	0	0
Upper respiratory tract infection
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	2 / 34 (5.88%)	0 / 34 (0.00%)	1 / 34 (2.94%)	0 / 34 (0.00%)
occurrences all number	0	0	3	0	1	0
Urinary tract infection
subjects affected / exposed	1 / 19 (5.26%)	0 / 19 (0.00%)	1 / 34 (2.94%)	1 / 34 (2.94%)	2 / 34 (5.88%)	0 / 34 (0.00%)
occurrences all number	1	0	1	1	2	0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	2 / 19 (10.53%)	0 / 19 (0.00%)	4 / 34 (11.76%)	0 / 34 (0.00%)	4 / 34 (11.76%)	0 / 34 (0.00%)
occurrences all number	2	0	5	0	4	0
Hyperglycaemia
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	2 / 34 (5.88%)	0 / 34 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	2	0	0	0
Hypocalcaemia
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	2 / 34 (5.88%)	0 / 34 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	2	0	0	0
Hypokalaemia
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	4 / 34 (11.76%)	2 / 34 (5.88%)	2 / 34 (5.88%)	0 / 34 (0.00%)
occurrences all number	0	0	7	3	2	0
Hypomagnesaemia
subjects affected / exposed	0 / 19 (0.00%)	0 / 19 (0.00%)	4 / 34 (11.76%)	1 / 34 (2.94%)	3 / 34 (8.82%)	0 / 34 (0.00%)
occurrences all number	0	0	5	1	4	0
Hyponatraemia
subjects affected / exposed	1 / 19 (5.26%)	0 / 19 (0.00%)	1 / 34 (2.94%)	0 / 34 (0.00%)	1 / 34 (2.94%)	0 / 34 (0.00%)
occurrences all number	1	0	1	0	1	0
Hypophagia
subjects affected / exposed	1 / 19 (5.26%)	0 / 19 (0.00%)	0 / 34 (0.00%)	0 / 34 (0.00%)	1 / 34 (2.94%)	0 / 34 (0.00%)
occurrences all number	1	0	0	0	1	0

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Were there any global substantial amendments to the protocol? Yes

18 Jun 2018

The key purpose of this amendment was to update the protocol with the iRECIST guideline in Appendix 4, to align withdrawal of consent (WoC) language with the European Economic Area (EEA) General Data Protection Regulation (GDPR), to specify and clarify various Inclusion/Exclusion criteria, to clarify study assessments parameters related to blood samples, pregnancy, sample collections, and ECG, to clarify that patient receiving study treatment beyond progressive disease should be re-consented in a separate ICF, to extend the period to 9 months until when efficacy assessments were performed every 6 weeks, to specify an early safety review will be done after the first 8 patients enrolled in each arm have completed their first 3-week treatment cycle, etc.

05 Oct 2018

The purpose of this amendment was to implement Health Authority feedback as well as updates to the Novartis standard protocol language for PDR001-related protocols. An increased risk of potentially fatal autoimmune myocarditis was observed in non-Novartis clinical trials with the combination of anti-LAG-3 and PD-1 inhibitors. Therefore, measures to optimize detection of possible autoimmune myocarditis have been included. The implementation of version 5.0 of the NCI-CTCAE grading system throughout the protocol also occurred.

28 Mar 2019

The main purpose of this amendment was to stop enrollment to treatment Arm 1 (LAG525 + spartalizumab combination). Novartis and the study SC decided to prematurely stop enrollment of patients to Arm 1 after data review showed an increased treatment discontinuation rate due to progressive disease in Arm 1 as compared to the other two arms (both containing carboplatin).

15 Feb 2021

The key changes of protocol amendment 4 were to define the duration of the follow-up period and to clarify the trial discontinuation rules for participants who are still ongoing in the trial as to whether they are eligible for a Post Trial Access (PTA) program i.e. rollover protocol or a post study drug supply (PSDS).

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.

Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use: https://www.novctrd.com complete trial results.

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Clinical trials

Clinical Trial Results: A phase II open-label, randomized, three-arm, multicenter study of LAG525 given in combination with spartalizumab (PDR001), or with spartalizumab and carboplatin, or with carboplatin, as first or second line therapy in patients with advanced triple-negative breast cancer

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Overall response rate (ORR) per investigator’s assessment according to RECIST v1.1

Primary: Overall response rate (ORR) per investigator’s assessment according to RECIST v1.1

Secondary: Clinical Benefit Rate (CBR) per investigator’s assessment according to RECIST v1.1

Secondary: Clinical Benefit Rate (CBR) per investigator’s assessment according to RECIST v1.1

Secondary: Duration of response (DOR) per investigator’s assessment according to RECIST v1.1

Secondary: Duration of response (DOR) per investigator’s assessment according to RECIST v1.1

Secondary: Time to response (TTR) per investigator's assessment according to RECIST v1.1

Secondary: Time to response (TTR) per investigator's assessment according to RECIST v1.1

Secondary: Progression free survival (PFS)

Secondary: Progression free survival (PFS)

Secondary: Overall Survival (OS)

Secondary: Overall Survival (OS)

Secondary: Pharmacokinetics (PK) parameter, Area under the plasma concentration versus time curve from time 0 to 504 hours (AUC0-504h) of LAG525

Secondary: Pharmacokinetics (PK) parameter, Area under the plasma concentration versus time curve from time 0 to 504 hours (AUC0-504h) of LAG525

Secondary: PK parameter, Cmax of LAG525

Secondary: PK parameter, Cmax of LAG525

Secondary: PK parameter, AUClast of LAG525

Secondary: PK parameter, AUClast of LAG525

Secondary: PK parameter, Tmax of LAG525

Secondary: PK parameter, Tmax of LAG525

Secondary: PK parameter, AUC0-504h of PDR001

Secondary: PK parameter, AUC0-504h of PDR001

Secondary: PK parameter, Cmax of PDR001

Secondary: PK parameter, Cmax of PDR001

Secondary: PK parameter, AUClast of PDR001

Secondary: PK parameter, AUClast of PDR001

Secondary: PK parameter, Tmax of PDR001

Secondary: PK parameter, Tmax of PDR001

Secondary: PK parameter, AUC0-4h of carboplatin (total platinium)

Secondary: PK parameter, AUC0-4h of carboplatin (total platinium)

Secondary: PK parameter, Cmax of carboplatin (total platinium)

Secondary: PK parameter, Cmax of carboplatin (total platinium)

Secondary: PK parameter, AUClast of carboplatin (total platinium)

Secondary: PK parameter, AUClast of carboplatin (total platinium)

Secondary: PK parameter, Tmax of carboplatin (total platinium)

Secondary: PK parameter, Tmax of carboplatin (total platinium)

Secondary: PK parameter, AUC0-4h of carboplatin (ultrafilterable platinium)

Secondary: PK parameter, AUC0-4h of carboplatin (ultrafilterable platinium)

Secondary: PK parameter, Cmax of carboplatin (ultrafilterable platinium)

Secondary: PK parameter, Cmax of carboplatin (ultrafilterable platinium)

Secondary: PK parameter, AUClast of carboplatin (ultrafilterable platinium)

Secondary: PK parameter, AUClast of carboplatin (ultrafilterable platinium)

Secondary: PK parameter, Tmax of carboplatin (ultrafilterable platinium)

Secondary: PK parameter, Tmax of carboplatin (ultrafilterable platinium)

Secondary: Number of participants with Anti-drug antibodies (ADA) at baseline for LAG525

Secondary: Number of participants with Anti-drug antibodies (ADA) at baseline for LAG525

Secondary: Number of participants with Anti-drug antibodies (ADA) on treatment for LAG525

Secondary: Number of participants with Anti-drug antibodies (ADA) on treatment for LAG525

Secondary: Number of participants with Anti-drug antibodies (ADA) at baseline for PDR001

Secondary: Number of participants with Anti-drug antibodies (ADA) at baseline for PDR001

Secondary: Number of participants with Anti-drug antibodies (ADA) on treatment for PDR001

Secondary: Number of participants with Anti-drug antibodies (ADA) on treatment for PDR001

Post-hoc: All collected deaths

Post-hoc: All collected deaths

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
A phase II open-label, randomized, three-arm, multicenter study of LAG525 given in combination with spartalizumab (PDR001), or with spartalizumab and carboplatin, or with carboplatin, as first or second line therapy in patients with advanced triple-negative breast cancer