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Clinical Trial Results:
A phase II, open-label, randomized controlled study of PDR001 in patients with moderately differentiated/undifferentiated locally advanced recurrent or metastatic nasopharyngeal carcinoma who progressed on standard treatment

Summary
EudraCT number	2015-000454-38
Trial protocol	FR
Global end of trial date	19 Feb 2021

Results information
Results version number	v2(current)
This version publication date	01 Mar 2022
First version publication date	13 Dec 2021
Other versions	v1
Version creation reason	Correction of full data set Minor corrections in the number of participants analyzed in four outcome measures.

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

CPDR001X2201

ISRCTN number

US NCT number

NCT02605967

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

19 Feb 2021

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

19 Feb 2021

Was the trial ended prematurely?

Main objective of the trial

To assess the efficacy of spartalizumab versus investigator’s choice of chemotherapy in subjects with moderately differentiated/ undifferentiated locally advanced recurrent or metastatic nasopharyngeal cancer (NPC) who progressed on or after first-line therapy.

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

20 Apr 2016

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Hong Kong: 27

Country: Number of subjects enrolled

Singapore: 14

Country: Number of subjects enrolled

Thailand: 18

Country: Number of subjects enrolled

China: 8

Country: Number of subjects enrolled

Taiwan: 33

Country: Number of subjects enrolled

United States: 7

Country: Number of subjects enrolled

France: 15

Worldwide total number of subjects

122

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)

103

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Participants took part in 19 investigative sites in 7 countries.

Screening details

The screening period began once patients had signed the study informed consent. All screening evaluations were performed as closely as possible to the beginning of treatment and never more than 4 weeks before the beginning of the study treatment. After screening, the treatment period started on Cycle 1 Day 1.

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

Spartalizumab 400 mg Q4W

Arm description

anti-PD1 humanized monoclonal antibody. Participants treated with spartalizumab who remained on spartalizumab

Arm type

Experimental

Investigational medicinal product name

Spartalizumab

Investigational medicinal product code

PDR001

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Spartalizumab was administered via intravenous infusion at a dose of 400 mg every 4 weeks (Q4W).

Chemotherapy

Arm description

Commonly used chemotherapy as per investigator's choice

Arm type

Active comparator

Investigational medicinal product name

Chemotherapy

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet, Solution for infusion

Routes of administration

Oral use, Intravenous use

Dosage and administration details

Commonly used chemotherapy as per investigator's choice. The dose and route of administration was the one described in each drug's label.

Number of subjects in period 1	Spartalizumab 400 mg Q4W	Chemotherapy
Started	82	40
Safety Set	82	39
Crossover to spartalizumab	0	27
Completed	0	0
Not completed	82	40
Adverse event, serious fatal	4	2
Physician decision	10	1
Adverse event, non-fatal	1	-
progressive disease	66	35
subject / guardian decision	1	2

Baseline characteristics

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Reporting group title

Spartalizumab 400 mg Q4W

Reporting group description

anti-PD1 humanized monoclonal antibody. Participants treated with spartalizumab who remained on spartalizumab

Reporting group title

Chemotherapy

Reporting group description

Commonly used chemotherapy as per investigator's choice

Reporting group values	Spartalizumab 400 mg Q4W	Chemotherapy	Total
Number of subjects	82	40	122
Age categorical
Units: Subjects
In utero	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0
Newborns (0-27 days)	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0
Children (2-11 years)	0	0	0
Adolescents (12-17 years)	0	0	0
Adults (18-64 years)	70	33	103
From 65-84 years	12	7	19
85 years and over	0	0	0
Age Continuous
Units: years
arithmetic mean (standard deviation)	51.1 ± 11.54	50.5 ± 12.32	-
Sex: Female, Male
Units: participants
Female	14	7	21
Male	68	33	101
Race/Ethnicity, Customized
Units: Subjects
Caucasian	12	2	14
Black	0	1	1
Asian	70	37	107

Subject analysis set title

Crossover to spartalizumab

Subject analysis set type

Full analysis

Subject analysis set description

Patients treated with chemotherapy who crossed over to spartalizumab

Subject analysis sets values	Crossover to spartalizumab
Number of subjects	27
Age categorical
Units: Subjects
In utero	0
Preterm newborn infants (gestational age < 37 wks)	0
Newborns (0-27 days)	0
Infants and toddlers (28 days-23 months)	0
Children (2-11 years)	0
Adolescents (12-17 years)	0
Adults (18-64 years)	24
From 65-84 years	3
85 years and over	0
Age Continuous
Units: years
arithmetic mean (standard deviation)	49.2 ± 11.48
Sex: Female, Male
Units: participants
Female	5
Male	22
Race/Ethnicity, Customized
Units: Subjects
Caucasian	1
Black	1
Asian	25

End points

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Reporting group title

Spartalizumab 400 mg Q4W

Reporting group description

anti-PD1 humanized monoclonal antibody. Participants treated with spartalizumab who remained on spartalizumab

Reporting group title

Chemotherapy

Reporting group description

Commonly used chemotherapy as per investigator's choice

Subject analysis set title

Crossover to spartalizumab

Subject analysis set type

Full analysis

Subject analysis set description

Patients treated with chemotherapy who crossed over to spartalizumab

Primary: Progression-free survival (PFS) as per RECIST v 1.1 using central assessment – Number of participants with progression or death

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End point title

Progression-free survival (PFS) as per RECIST v 1.1 using central assessment – Number of participants with progression or death ^[1]

End point description

PFS is the time from the date of randomization to the date of event defined as the first documented confirmed progression or death due to any cause. If a patient has not had an event, progression-free survival is censored at the date of last adequate tumor assessment. Tumor response was based on central review of tumor scan and the assessment criteria was Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Progressive disease is 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. Number of participants in each category (progression, death, censored) is reported in this record.

End point type

Primary

End point timeframe

From randomization up to maximum 3.3 years

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 analysis were planned for this primary endpoint.

End point values	Spartalizumab 400 mg Q4W	Chemotherapy
Number of subjects analysed	82	40
Units: participants
number of progression	62	32
number of deaths	3	1
number of censored	17	7

No statistical analyses for this end point

Primary: Progression-free survival (PFS) as per RECIST v 1.1 using central assessment – Median PFS

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End point title

Progression-free survival (PFS) as per RECIST v 1.1 using central assessment – Median PFS ^[2]

End point description

End point type

Primary

End point timeframe

From randomization up to maximum 3.3 years

Notes
[2] - 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 analysis were planned for this primary endpoint.

End point values	Spartalizumab 400 mg Q4W	Chemotherapy
Number of subjects analysed	82	40
Units: months
median (confidence interval 95%)	1.9 (1.8 to 2.9)	5.6 (3.7 to 9.2)

No statistical analyses for this end point

Secondary: Overall Survival (OS)

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End point title

Overall Survival (OS)

End point description

Overall survival (OS) is defined as the time from date of randomization to date of death due to any cause. If a patient is not known to have died, survival is censored at the date of last known date the patient was alive.

End point type

Secondary

End point timeframe

From randomization up to maximum 4.8 years.

End point values	Spartalizumab 400 mg Q4W	Chemotherapy
Number of subjects analysed	82	40
Units: months
median (confidence interval 95%)	20.1 (13.6 to 25.5)	16.0 (8.8 to 22.5)

No statistical analyses for this end point

Secondary: Overall Response Rate (ORR) as per RECIST v 1.1

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End point title

Overall Response Rate (ORR) as per RECIST v 1.1

End point description

ORR is defined as the percentage of participants with a best overall response of Complete Response (CR) or Partial Response (PR). Tumor response was based on central review of overall lesion response according to RECIST 1.1. For RECIST v1.1, 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 randomization up to maximum 3.3 years

End point values	Spartalizumab 400 mg Q4W	Chemotherapy
Number of subjects analysed	82	40
Units: percentage of participants
number (not applicable)	18.3	32.5

No statistical analyses for this end point

Secondary: Duration of Response (DOR) as per RECIST v 1.1

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End point title

Duration of Response (DOR) as per RECIST v 1.1

End point description

DOR only applies to subjects for whom best overall response is complete response (CR) or partial response (PR) based on central review of overall lesion response according to RECIST 1.1. DOR is defined as the time between the date of first documented response (confirmed CR or confirmed PR) and the date of first documented disease progression or death due to underlying cancer. If a patient not had an event, duration was censored at the date of last adequate tumor assessment. Due to EudraCT system limitations, data fields in the table cannot contain letters (eg. NA indicating ‘not available’). Therefore, not applicable values because of insufficient number of participants with events are indicated as ‘999’.

End point type

Secondary

End point timeframe

From randomization up to maximum 3.3 years

End point values	Spartalizumab 400 mg Q4W	Chemotherapy
Number of subjects analysed	15	13
Units: months
median (confidence interval 95%)	10.2 (7.4 to 999)	5.7 (3.7 to 7.4)

No statistical analyses for this end point

Secondary: Time to Progression (TTP) as per RECIST v 1.1

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End point title

Time to Progression (TTP) as per RECIST v 1.1

End point description

TTP is defined as time from date of randomization to the date of event defined as the first documented progression or death due to underlying cancer. If a subject did not had an event, TTP was censored at the date of last adequate tumor assessment. Tumor response was based on central review of tumor scan and the assessment criteria was RECIST v1.1. Progressive disease is 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.

End point type

Secondary

End point timeframe

From randomization up to maximum 3.3 years

End point values	Spartalizumab 400 mg Q4W	Chemotherapy
Number of subjects analysed	82	40
Units: months
median (confidence interval 95%)	1.9 (1.8 to 2.9)	5.6 (3.7 to 9.3)

No statistical analyses for this end point

Secondary: Immune-related progression-free survival (irPFS) as per irRC

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End point title

Immune-related progression-free survival (irPFS) as per irRC

End point description

irPFS is the time from the date of randomization to the date of event defined as the first documented progression or death due to any cause. If a patient has not had an event, progression-free survival is censored at the date of last adequate tumor assessment. Tumor response was based on central review of tumor scan and the assessment criteria was immune-related Response Criteria (irRC). Immune-related progressive disease is at least a 20% increase in the sum of diameters of all measured target lesions including new measurable lesions.

End point type

Secondary

End point timeframe

From randomization up to maximum 3.3 years

End point values	Spartalizumab 400 mg Q4W	Chemotherapy
Number of subjects analysed	82	0 ^[3]
Units: months
median (confidence interval 95%)	1.9 (1.8 to 3.6)	( to )

Notes
[3] - Tumor scans for efficacy assessment as per irRC were not planned in this arm.

No statistical analyses for this end point

Secondary: Maximum observed serum concentration (Cmax) of spartalizumab

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End point title

Maximum observed serum concentration (Cmax) of spartalizumab ^[4]

End point description

Pharmacokinetic (PK) parameters were calculated based on spartalizumab serum concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed serum concentration following a dose.

End point type

Secondary

End point timeframe

pre-dose, 1, 24, 168, 336 and 672 hours post spartalizumab dose on Cycle 1 and Cycle 3. The duration of one cycle was 28 days.

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: PK samples were only collected in participants to whom spartalizumab was assigned by randomization.

End point values	Spartalizumab 400 mg Q4W
Number of subjects analysed	82
Units: ug/mL
geometric mean (geometric coefficient of variation)
Cycle 1 (n=78)	116 ± 21.9
Cycle 3 (n=47)	149 ± 25.8

No statistical analyses for this end point

Secondary: Time to reach maximum serum concentration (Tmax) of spartalizumab

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End point title

Time to reach maximum serum concentration (Tmax) of spartalizumab ^[5]

End point description

Pharmacokinetic (PK) parameters were calculated based on spartalizumab serum concentrations by using non-compartmental methods. Tmax is defined as the time to reach maximum (peak) serum concentration following a dose. Actual recorded sampling times were considered for the calculations.

End point type

Secondary

End point timeframe

pre-dose, 1, 24, 168, 336 and 672 hours post spartalizumab dose on Cycle 1 and Cycle 3. The duration of one cycle was 28 days.

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: PK samples were only collected in participants to whom spartalizumab was assigned by randomization.

End point values	Spartalizumab 400 mg Q4W
Number of subjects analysed	82
Units: hours
median (full range (min-max))
Cycle 1 (n=78)	1.57 (0.58 to 3.17)
Cycle 3 (n=47)	1.57 (1.00 to 14.9)

No statistical analyses for this end point

Secondary: Area under the serum concentration-time curve from time zero to the end of the dosing interval tau (AUCtau) of spartalizumab

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End point title

Area under the serum concentration-time curve from time zero to the end of the dosing interval tau (AUCtau) of spartalizumab ^[6]

End point description

End point type

Secondary

End point timeframe

pre-dose, 1, 24, 168, 336 and 672 hours post spartalizumab dose on Cycle 1 and Cycle 3. The duration of one cycle was 28 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: PK samples were only collected in participants to whom spartalizumab was assigned by randomization.

End point values	Spartalizumab 400 mg Q4W
Number of subjects analysed	82
Units: day*ug/mL
geometric mean (geometric coefficient of variation)
Cycle 1 (n=73)	1340 ± 25.8
Cycle 3 (n=39)	2260 ± 30.6

No statistical analyses for this end point

Secondary: Area under the serum concentration-time curve from time zero to infinity (AUCinf) of spartalizumab

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End point title

Area under the serum concentration-time curve from time zero to infinity (AUCinf) of spartalizumab ^[7]

End point description

Pharmacokinetic (PK) parameters were calculated based on spartalizumab serum concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUC calculation. The extrapolation of AUC to infinity could be calculated if the percentage of area extrapolated was less than 20% and the regression analysis of the terminal serum elimination phase met a pre-defined criteria of goodness of fit.

End point type

Secondary

End point timeframe

pre-dose, 1, 24, 168, 336 and 672 hours post spartalizumab dose on Cycle 1 and Cycle 3. The duration of one cycle was 28 days.

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: PK samples were only collected in participants to whom spartalizumab was assigned by randomization.

End point values	Spartalizumab 400 mg Q4W
Number of subjects analysed	7
Units: day*ug/mL
geometric mean (geometric coefficient of variation)
Cycle 1 (n=6)	1180 ± 23.9
Cycle 3 (n=2)	1090 ± 84.8

No statistical analyses for this end point

Secondary: Accumulation ratio (Racc) of spartalizumab

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End point title

Accumulation ratio (Racc) of spartalizumab ^[8]

End point description

Pharmacokinetic (PK) parameters were calculated based on spartalizumab serum concentrations by using non-compartmental methods. Racc was calculated as the ratio between AUCtau Cycle 3 and AUCtau Cycle 1.

End point type

Secondary

End point timeframe

pre-dose, 1, 24, 168, 336 and 672 hours post spartalizumab dose on Cycle 1 and Cycle 3. The duration of one cycle was 28 days.

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: PK samples were only collected in participants to whom spartalizumab was assigned by randomization.

End point values	Spartalizumab 400 mg Q4W
Number of subjects analysed	39
Units: ratio
geometric mean (geometric coefficient of variation)	1.61 ± 19.6

No statistical analyses for this end point

Secondary: Terminal elimination half-life (T1/2) of spartalizumab

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End point title

Terminal elimination half-life (T1/2) of spartalizumab ^[9]

End point description

Pharmacokinetic (PK) parameters were calculated based on spartalizumab serum concentrations by using non-compartmental methods. Elimination half-life (T1/2) values were calculated as 0.693/terminal elimination rate constant.

End point type

Secondary

End point timeframe

pre-dose, 1, 24, 168, 336 and 672 hours post spartalizumab dose on Cycle 1 and Cycle 3. The duration of one cycle was 28 days.

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: PK samples were only collected in participants to whom spartalizumab was assigned by randomization.

End point values	Spartalizumab 400 mg Q4W
Number of subjects analysed	82
Units: days
median (full range (min-max))
Cycle 1 (n=79)	20.1 (7.35 to 41.5)
Cycle 3 (n=48)	22.7 (5.29 to 48.9)

No statistical analyses for this end point

Secondary: Number of participants with anti-spartalizumab antibodies

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End point title

Number of participants with anti-spartalizumab antibodies ^[10]

End point description

Validated immunoassays were used for screening and confirmation of the presence of anti-spartalizumab antibodies (ADA, anti-drug antibodies) in serum. Number of participants with each ADA status is reported in this record.

End point type

Secondary

End point timeframe

Baseline (pre-dose on Cycle 1 Day 1) and post-baseline (assessed throughout the treatment up to maximum 655 days).

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: Immunogenicity samples were only collected in participants to whom spartalizumab was assigned by randomization.

End point values	Spartalizumab 400 mg Q4W
Number of subjects analysed	72
Units: participants
ADA-negative at baseline (n=72)	66
ADA-positive at baseline (n=72)	6
ADA-negative at post-baseline (n=72)	59
ADA-positive at post-baseline (n=72)	9

No statistical analyses for this end point

Secondary: PD-L1 percent positive tumor

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End point title

PD-L1 percent positive tumor ^[11]

End point description

The expression of programmed cell death-ligand 1 (PD-L1) was measured in tumor samples by immunohistochemical methods. This record summarizes the PD-L1 positivity percentage in tumor samples.

End point type

Secondary

End point timeframe

Baseline (screening), Cycle 3 Day 1. The duration of one cycle was 28 days.

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: Biomarker samples were only collected in participants to whom spartalizumab was assigned by randomization.

End point values	Spartalizumab 400 mg Q4W
Number of subjects analysed	78
Units: PD-L1 positivity percentage
median (full range (min-max))
Baseline (n=78)	20.00 (0 to 100)
Cycle 3 Day 1 (n=1)	90.00 (90.00 to 90.00)

No statistical analyses for this end point

Secondary: Percent marker area for CD8 expression in tumor samples

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End point title

Percent marker area for CD8 expression in tumor samples ^[12]

End point description

The expression of CD8 was measured in tumor samples by immunohistochemical methods. This record summarizes the percent marker area for CD8 expression in tumor samples.

End point type

Secondary

End point timeframe

Baseline (screening), Cycle 3 Day 1. The duration of one cycle was 28 days.

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: Biomarker samples were only collected in participants to whom spartalizumab was assigned by randomization.

End point values	Spartalizumab 400 mg Q4W
Number of subjects analysed	78
Units: CD8 percent marker area
median (full range (min-max))
Baseline (n=78)	4.23 (0.1 to 31.8)
Cycle 3 Day 1 (n=1)	2.22 (2.22 to 2.22)

No statistical analyses for this end point

Secondary: TIL count in tumor samples

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End point title

TIL count in tumor samples ^[13]

End point description

The count of tumor-infiltrating lymphocytes (TILs) was measured in baseline (screening) and post-baseline paired tumor samples by immunohistochemical methods. This record summarizes the TIL count in tumor samples.

End point type

Secondary

End point timeframe

Baseline (screening), Cycle 3 Day 1. The duration of one cycle was 28 days.

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: Biomarker samples were only collected in participants to whom spartalizumab was assigned by randomization.

End point values	Spartalizumab 400 mg Q4W
Number of subjects analysed	1
Units: TILs
Baseline (n=1)	10
Cycle 3 Day 1 (n=1)	15

No statistical analyses for this end point

Secondary: Fold change from baseline in IFN-gamma levels in plasma

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End point title

Fold change from baseline in IFN-gamma levels in plasma ^[14]

End point description

The levels of interferon-gamma (IFN-gamma) were measured in plasma samples by immunoassay methods. This record summarizes the fold change from baseline in IFN-gamma levels in plasma.

End point type

Secondary

End point timeframe

Baseline (pre-dose on Cycle 1 Day 1), Cycle 1 Day 15, Cycle 2 Day 15 and end of treatment (assessed up to maximum 4 years). The duration of one cycle was 28 days.

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: Biomarker samples were only collected in participants to whom spartalizumab was assigned by randomization.

End point values	Spartalizumab 400 mg Q4W
Number of subjects analysed	82
Units: fold change
median (full range (min-max))
Cycle 1 Day 15 (n=65)	1.53 (0.2 to 14.3)
Cycle 2 Day 15 (n=51)	1.31 (0.1 to 35.2)
End of treatment (n=34)	1.11 (0.1 to 3.8)

No statistical analyses for this end point

Secondary: Fold change from baseline in IL-6 levels in plasma

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End point title

Fold change from baseline in IL-6 levels in plasma ^[15]

End point description

The levels of interleukin-6 (IL-6) were measured in plasma samples by immunoassay methods. This record summarizes the fold change from baseline in IL-6 levels in plasma.

End point type

Secondary

End point timeframe

Baseline (pre-dose on Cycle 1 Day 1), Cycle 1 Day 15, Cycle 2 Day 15 and end of treatment (assessed up to maximum 4 years). The duration of one cycle was 28 days.

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: Biomarker samples were only collected in participants to whom spartalizumab was assigned by randomization.

End point values	Spartalizumab 400 mg Q4W
Number of subjects analysed	82
Units: fold change
median (full range (min-max))
Cycle 1 Day 15 (n=41)	1.10 (0.2 to 3.3)
Cycle 2 Day 15 (n=30)	1.35 (0.2 to 6.3)
End of treatment (n=26)	1.41 (0.2 to 7.7)

No statistical analyses for this end point

Secondary: Fold change from baseline in TNF-alfa levels in plasma

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End point title

Fold change from baseline in TNF-alfa levels in plasma ^[16]

End point description

The levels of tumor necrosis factor-alpha (TNF-alfa) were measured in plasma samples by immunoassay methods. This record summarizes the fold change from baseline in TNF-alfa levels in plasma.

End point type

Secondary

End point timeframe

Baseline (pre-dose on Cycle 1 Day 1), Cycle 1 Day 15, Cycle 2 Day 15 and end of treatment (assessed up to maximum 4 years). The duration of one cycle was 28 days.

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: Biomarker samples were only collected in participants to whom spartalizumab was assigned by randomization.

End point values	Spartalizumab 400 mg Q4W
Number of subjects analysed	82
Units: fold change
median (full range (min-max))
Cycle 1 Day 15 (n=73)	1.32 (0.4 to 2.2)
Cycle 2 Day 15 (n=62)	1.39 (0.3 to 3.1)
End of treatment (n=45)	1.67 (0.3 to 3.7)

No statistical analyses for this end point

Post-hoc: Progression-free survival (PFS) as per RECIST v 1.1 using central assessment in participants who crossed over – Number of participants with progression or death

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End point title

Progression-free survival (PFS) as per RECIST v 1.1 using central assessment in participants who crossed over – Number of participants with progression or death

End point description

PFS is the time from the date of first dose of spartalizumab to the date of event defined as the first documented confirmed progression or death due to any cause. If a patient has not had an event, progression-free survival is censored at the date of last adequate tumor assessment. Tumor response was based on central review of tumor scan and the assessment criteria was Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Progressive disease is 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. Number of participants in each category (progression, death, censored) is reported in this record.

End point type

Post-hoc

End point timeframe

From first dose of spartalizumab up to maximum 0.6 years

End point values	Crossover to spartalizumab
Number of subjects analysed	27
Units: participants
number of progression	20
number of deaths	5
number of censored	2

No statistical analyses for this end point

Post-hoc: Progression-free survival (PFS) as per RECIST v 1.1 using central assessment in participants who crossed over – Median PFS

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End point title

Progression-free survival (PFS) as per RECIST v 1.1 using central assessment in participants who crossed over – Median PFS

End point description

End point type

Post-hoc

End point timeframe

From first dose of spartalizumab up to maximum 0.6 years

End point values	Crossover to spartalizumab
Number of subjects analysed	27
Units: months
median (confidence interval 95%)	1.7 (1.6 to 1.9)

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 the start of treatment up to 30 days after study drug discontinuation, for a maximum duration of 4.0 years. Post-treatment deaths were collected after the on-treatment period (starting at day 31 after last dose of study treatment), up to 4.8 years. For the crossover patients, the deaths collected before crossing over are summarized in the chemotherapy arm and the deaths collected after the crossover are summarized in the crossover arm.

End point type

Post-hoc

End point timeframe

Up to 4.0 years (on-treatment deaths) and 4.8 years (all deaths).

End point values	Spartalizumab 400 mg Q4W	Chemotherapy	Crossover to spartalizumab
Number of subjects analysed	82	40	27
Units: participants
Total Deaths	48	9	19
Deaths on-treatment	5	3	3

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From first dose of study treatment up to 30 days after last dose (max 4yrs). For crossover patients, safety data collected before crossing over is summarized in the chemotherapy arm and data collected after the crossover is summarized in the crossover arm

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

23.1

Reporting group title

Spartalizumab 400 mg Q4W

Reporting group description

anti-PD1 humanized monoclonal antibody. Participants treated with spartalizumab who remained on spartalizumab

Reporting group title

All spartalizumab participants

Reporting group description

All participants who received at least one dose of spartalizumab

Reporting group title

Crossover to spartalizumab

Reporting group description

Patients treated with chemotherapy who crossed over to spartalizumab.

Reporting group title

Chemotherapy

Reporting group description

Commonly used chemotherapy as per investigator's choice

Serious adverse events	Spartalizumab 400 mg Q4W	All spartalizumab participants	Crossover to spartalizumab	Chemotherapy
Total subjects affected by serious adverse events
subjects affected / exposed	28 / 82 (34.15%)	40 / 109 (36.70%)	12 / 27 (44.44%)	15 / 39 (38.46%)
number of deaths (all causes)	5	8	3	3
number of deaths resulting from adverse events	0	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour associated fever
subjects affected / exposed	0 / 82 (0.00%)	1 / 109 (0.92%)	1 / 27 (3.70%)	1 / 39 (2.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	1 / 82 (1.22%)	2 / 109 (1.83%)	1 / 27 (3.70%)	1 / 39 (2.56%)
occurrences causally related to treatment / all	0 / 1	1 / 2	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Fatigue
subjects affected / exposed	0 / 82 (0.00%)	1 / 109 (0.92%)	1 / 27 (3.70%)	1 / 39 (2.56%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Generalised oedema
subjects affected / exposed	0 / 82 (0.00%)	1 / 109 (0.92%)	1 / 27 (3.70%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oedema peripheral
subjects affected / exposed	0 / 82 (0.00%)	0 / 109 (0.00%)	0 / 27 (0.00%)	1 / 39 (2.56%)
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
Pain
subjects affected / exposed	0 / 82 (0.00%)	0 / 109 (0.00%)	0 / 27 (0.00%)	1 / 39 (2.56%)
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
Peripheral swelling
subjects affected / exposed	0 / 82 (0.00%)	1 / 109 (0.92%)	1 / 27 (3.70%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	3 / 82 (3.66%)	4 / 109 (3.67%)	1 / 27 (3.70%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	1 / 4	1 / 5	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Social circumstances
Miscarriage of partner
subjects affected / exposed	1 / 82 (1.22%)	1 / 109 (0.92%)	0 / 27 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure
subjects affected / exposed	0 / 82 (0.00%)	0 / 109 (0.00%)	0 / 27 (0.00%)	1 / 39 (2.56%)
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
Dyspnoea
subjects affected / exposed	0 / 82 (0.00%)	2 / 109 (1.83%)	2 / 27 (7.41%)	1 / 39 (2.56%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nasal congestion
subjects affected / exposed	1 / 82 (1.22%)	1 / 109 (0.92%)	0 / 27 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Epistaxis
subjects affected / exposed	1 / 82 (1.22%)	1 / 109 (0.92%)	0 / 27 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	1 / 82 (1.22%)	1 / 109 (0.92%)	0 / 27 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia aspiration
subjects affected / exposed	2 / 82 (2.44%)	3 / 109 (2.75%)	1 / 27 (3.70%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 3	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	2 / 82 (2.44%)	3 / 109 (2.75%)	1 / 27 (3.70%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	2 / 2	3 / 3	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	1 / 82 (1.22%)	1 / 109 (0.92%)	0 / 27 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Aspartate aminotransferase increased
subjects affected / exposed	2 / 82 (2.44%)	2 / 109 (1.83%)	0 / 27 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bilirubin conjugated increased
subjects affected / exposed	1 / 82 (1.22%)	1 / 109 (0.92%)	0 / 27 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood bilirubin increased
subjects affected / exposed	1 / 82 (1.22%)	1 / 109 (0.92%)	0 / 27 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood bilirubin unconjugated increased
subjects affected / exposed	1 / 82 (1.22%)	1 / 109 (0.92%)	0 / 27 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Electrical burn
subjects affected / exposed	1 / 82 (1.22%)	1 / 109 (0.92%)	0 / 27 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Angina pectoris
subjects affected / exposed	1 / 82 (1.22%)	1 / 109 (0.92%)	0 / 27 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	0 / 82 (0.00%)	0 / 109 (0.00%)	0 / 27 (0.00%)	1 / 39 (2.56%)
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
Pericardial effusion
subjects affected / exposed	1 / 82 (1.22%)	1 / 109 (0.92%)	0 / 27 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Diplegia
subjects affected / exposed	1 / 82 (1.22%)	1 / 109 (0.92%)	0 / 27 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hemiparesis
subjects affected / exposed	1 / 82 (1.22%)	1 / 109 (0.92%)	0 / 27 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 1	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	2 / 82 (2.44%)	2 / 109 (1.83%)	0 / 27 (0.00%)	1 / 39 (2.56%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	2 / 82 (2.44%)	3 / 109 (2.75%)	1 / 27 (3.70%)	1 / 39 (2.56%)
occurrences causally related to treatment / all	0 / 2	0 / 3	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	1 / 82 (1.22%)	1 / 109 (0.92%)	0 / 27 (0.00%)	4 / 39 (10.26%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	5 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	0 / 82 (0.00%)	0 / 109 (0.00%)	0 / 27 (0.00%)	1 / 39 (2.56%)
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
Normocytic anaemia
subjects affected / exposed	0 / 82 (0.00%)	0 / 109 (0.00%)	0 / 27 (0.00%)	1 / 39 (2.56%)
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
Thrombocytopenia
subjects affected / exposed	0 / 82 (0.00%)	0 / 109 (0.00%)	0 / 27 (0.00%)	1 / 39 (2.56%)
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
Eye disorders
Papilloedema
subjects affected / exposed	0 / 82 (0.00%)	0 / 109 (0.00%)	0 / 27 (0.00%)	1 / 39 (2.56%)
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
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	1 / 82 (1.22%)	2 / 109 (1.83%)	1 / 27 (3.70%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	1 / 82 (1.22%)	2 / 109 (1.83%)	1 / 27 (3.70%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ascites
subjects affected / exposed	1 / 82 (1.22%)	1 / 109 (0.92%)	0 / 27 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 82 (0.00%)	0 / 109 (0.00%)	0 / 27 (0.00%)	2 / 39 (5.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Duodenal ulcer
subjects affected / exposed	1 / 82 (1.22%)	1 / 109 (0.92%)	0 / 27 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dysphagia
subjects affected / exposed	1 / 82 (1.22%)	1 / 109 (0.92%)	0 / 27 (0.00%)	1 / 39 (2.56%)
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
Stomatitis
subjects affected / exposed	0 / 82 (0.00%)	0 / 109 (0.00%)	0 / 27 (0.00%)	1 / 39 (2.56%)
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
Vomiting
subjects affected / exposed	1 / 82 (1.22%)	2 / 109 (1.83%)	1 / 27 (3.70%)	2 / 39 (5.13%)
occurrences causally related to treatment / all	1 / 1	1 / 2	0 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Hepatocellular injury
subjects affected / exposed	1 / 82 (1.22%)	1 / 109 (0.92%)	0 / 27 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis acute
subjects affected / exposed	0 / 82 (0.00%)	1 / 109 (0.92%)	1 / 27 (3.70%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Angioedema
subjects affected / exposed	1 / 82 (1.22%)	1 / 109 (0.92%)	0 / 27 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rash maculo-papular
subjects affected / exposed	1 / 82 (1.22%)	1 / 109 (0.92%)	0 / 27 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Urinary retention
subjects affected / exposed	1 / 82 (1.22%)	1 / 109 (0.92%)	0 / 27 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Acute kidney injury
subjects affected / exposed	0 / 82 (0.00%)	1 / 109 (0.92%)	1 / 27 (3.70%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 82 (0.00%)	1 / 109 (0.92%)	1 / 27 (3.70%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bone pain
subjects affected / exposed	2 / 82 (2.44%)	2 / 109 (1.83%)	0 / 27 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Muscular weakness
subjects affected / exposed	0 / 82 (0.00%)	0 / 109 (0.00%)	0 / 27 (0.00%)	1 / 39 (2.56%)
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
Infections and infestations
Brain abscess
subjects affected / exposed	0 / 82 (0.00%)	0 / 109 (0.00%)	0 / 27 (0.00%)	1 / 39 (2.56%)
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
Conjunctivitis
subjects affected / exposed	0 / 82 (0.00%)	0 / 109 (0.00%)	0 / 27 (0.00%)	1 / 39 (2.56%)
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
Gastroenteritis
subjects affected / exposed	1 / 82 (1.22%)	1 / 109 (0.92%)	0 / 27 (0.00%)	1 / 39 (2.56%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	1 / 82 (1.22%)	1 / 109 (0.92%)	0 / 27 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	1 / 82 (1.22%)	2 / 109 (1.83%)	1 / 27 (3.70%)	1 / 39 (2.56%)
occurrences causally related to treatment / all	1 / 1	1 / 2	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	2 / 82 (2.44%)	3 / 109 (2.75%)	1 / 27 (3.70%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 3	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
Septic shock
subjects affected / exposed	0 / 82 (0.00%)	0 / 109 (0.00%)	0 / 27 (0.00%)	1 / 39 (2.56%)
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
Sinusitis
subjects affected / exposed	1 / 82 (1.22%)	1 / 109 (0.92%)	0 / 27 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	0 / 82 (0.00%)	1 / 109 (0.92%)	1 / 27 (3.70%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypercalcaemia
subjects affected / exposed	0 / 82 (0.00%)	1 / 109 (0.92%)	1 / 27 (3.70%)	1 / 39 (2.56%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyperkalaemia
subjects affected / exposed	0 / 82 (0.00%)	1 / 109 (0.92%)	1 / 27 (3.70%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	0 / 82 (0.00%)	0 / 109 (0.00%)	0 / 27 (0.00%)	2 / 39 (5.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Malnutrition
subjects affected / exposed	1 / 82 (1.22%)	1 / 109 (0.92%)	0 / 27 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	2 / 82 (2.44%)	3 / 109 (2.75%)	1 / 27 (3.70%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	1 / 2	2 / 3	1 / 1	0 / 0
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	Spartalizumab 400 mg Q4W	All spartalizumab participants	Crossover to spartalizumab	Chemotherapy
Total subjects affected by non serious adverse events
subjects affected / exposed	76 / 82 (92.68%)	101 / 109 (92.66%)	25 / 27 (92.59%)	37 / 39 (94.87%)
Vascular disorders
Hypertension
subjects affected / exposed	1 / 82 (1.22%)	3 / 109 (2.75%)	2 / 27 (7.41%)	2 / 39 (5.13%)
occurrences all number	2	4	2	2
General disorders and administration site conditions
Oedema peripheral
subjects affected / exposed	2 / 82 (2.44%)	2 / 109 (1.83%)	0 / 27 (0.00%)	5 / 39 (12.82%)
occurrences all number	3	3	0	8
Fatigue
subjects affected / exposed	14 / 82 (17.07%)	19 / 109 (17.43%)	5 / 27 (18.52%)	15 / 39 (38.46%)
occurrences all number	16	22	6	16
Asthenia
subjects affected / exposed	11 / 82 (13.41%)	12 / 109 (11.01%)	1 / 27 (3.70%)	2 / 39 (5.13%)
occurrences all number	15	16	1	3
Pyrexia
subjects affected / exposed	16 / 82 (19.51%)	24 / 109 (22.02%)	8 / 27 (29.63%)	3 / 39 (7.69%)
occurrences all number	25	33	8	3
Peripheral swelling
subjects affected / exposed	0 / 82 (0.00%)	2 / 109 (1.83%)	2 / 27 (7.41%)	0 / 39 (0.00%)
occurrences all number	0	3	3	0
Swelling face
subjects affected / exposed	0 / 82 (0.00%)	1 / 109 (0.92%)	1 / 27 (3.70%)	3 / 39 (7.69%)
occurrences all number	0	1	1	3
Malaise
subjects affected / exposed	6 / 82 (7.32%)	7 / 109 (6.42%)	1 / 27 (3.70%)	2 / 39 (5.13%)
occurrences all number	7	8	1	2
Respiratory, thoracic and mediastinal disorders
Dysphonia
subjects affected / exposed	4 / 82 (4.88%)	4 / 109 (3.67%)	0 / 27 (0.00%)	2 / 39 (5.13%)
occurrences all number	4	4	0	2
Cough
subjects affected / exposed	17 / 82 (20.73%)	18 / 109 (16.51%)	1 / 27 (3.70%)	12 / 39 (30.77%)
occurrences all number	21	22	1	15
Dyspnoea
subjects affected / exposed	12 / 82 (14.63%)	15 / 109 (13.76%)	3 / 27 (11.11%)	3 / 39 (7.69%)
occurrences all number	12	16	4	3
Epistaxis
subjects affected / exposed	10 / 82 (12.20%)	10 / 109 (9.17%)	0 / 27 (0.00%)	3 / 39 (7.69%)
occurrences all number	15	15	0	5
Nasal congestion
subjects affected / exposed	3 / 82 (3.66%)	4 / 109 (3.67%)	1 / 27 (3.70%)	2 / 39 (5.13%)
occurrences all number	3	4	1	2
Productive cough
subjects affected / exposed	1 / 82 (1.22%)	2 / 109 (1.83%)	1 / 27 (3.70%)	2 / 39 (5.13%)
occurrences all number	1	2	1	2
Pleural effusion
subjects affected / exposed	2 / 82 (2.44%)	5 / 109 (4.59%)	3 / 27 (11.11%)	0 / 39 (0.00%)
occurrences all number	2	5	3	0
Rhinorrhoea
subjects affected / exposed	2 / 82 (2.44%)	3 / 109 (2.75%)	1 / 27 (3.70%)	3 / 39 (7.69%)
occurrences all number	2	3	1	4
Psychiatric disorders
Insomnia
subjects affected / exposed	9 / 82 (10.98%)	12 / 109 (11.01%)	3 / 27 (11.11%)	3 / 39 (7.69%)
occurrences all number	9	12	3	3
Investigations
Blood creatinine increased
subjects affected / exposed	5 / 82 (6.10%)	6 / 109 (5.50%)	1 / 27 (3.70%)	2 / 39 (5.13%)
occurrences all number	6	8	2	3
Blood alkaline phosphatase increased
subjects affected / exposed	4 / 82 (4.88%)	6 / 109 (5.50%)	2 / 27 (7.41%)	1 / 39 (2.56%)
occurrences all number	4	6	2	1
Aspartate aminotransferase increased
subjects affected / exposed	15 / 82 (18.29%)	17 / 109 (15.60%)	2 / 27 (7.41%)	7 / 39 (17.95%)
occurrences all number	17	19	2	12
Alanine aminotransferase increased
subjects affected / exposed	7 / 82 (8.54%)	8 / 109 (7.34%)	1 / 27 (3.70%)	6 / 39 (15.38%)
occurrences all number	8	9	1	14
Platelet count decreased
subjects affected / exposed	1 / 82 (1.22%)	3 / 109 (2.75%)	2 / 27 (7.41%)	7 / 39 (17.95%)
occurrences all number	1	3	2	27
Neutrophil count decreased
subjects affected / exposed	1 / 82 (1.22%)	1 / 109 (0.92%)	0 / 27 (0.00%)	2 / 39 (5.13%)
occurrences all number	1	1	0	6
Lymphocyte count decreased
subjects affected / exposed	3 / 82 (3.66%)	4 / 109 (3.67%)	1 / 27 (3.70%)	2 / 39 (5.13%)
occurrences all number	3	4	1	6
White blood cell count decreased
subjects affected / exposed	1 / 82 (1.22%)	1 / 109 (0.92%)	0 / 27 (0.00%)	8 / 39 (20.51%)
occurrences all number	1	1	0	46
Weight decreased
subjects affected / exposed	9 / 82 (10.98%)	9 / 109 (8.26%)	0 / 27 (0.00%)	5 / 39 (12.82%)
occurrences all number	9	9	0	7
Blood thyroid stimulating hormone increased
subjects affected / exposed	6 / 82 (7.32%)	6 / 109 (5.50%)	0 / 27 (0.00%)	1 / 39 (2.56%)
occurrences all number	7	7	0	1
Nervous system disorders
Dizziness
subjects affected / exposed	5 / 82 (6.10%)	8 / 109 (7.34%)	3 / 27 (11.11%)	1 / 39 (2.56%)
occurrences all number	7	10	3	1
Headache
subjects affected / exposed	12 / 82 (14.63%)	13 / 109 (11.93%)	1 / 27 (3.70%)	4 / 39 (10.26%)
occurrences all number	14	15	1	5
Hypoaesthesia
subjects affected / exposed	4 / 82 (4.88%)	6 / 109 (5.50%)	2 / 27 (7.41%)	5 / 39 (12.82%)
occurrences all number	5	7	2	5
Neuropathy peripheral
subjects affected / exposed	3 / 82 (3.66%)	5 / 109 (4.59%)	2 / 27 (7.41%)	5 / 39 (12.82%)
occurrences all number	3	5	2	5
Peripheral sensory neuropathy
subjects affected / exposed	0 / 82 (0.00%)	0 / 109 (0.00%)	0 / 27 (0.00%)	4 / 39 (10.26%)
occurrences all number	0	0	0	5
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	19 / 82 (23.17%)	25 / 109 (22.94%)	6 / 27 (22.22%)	19 / 39 (48.72%)
occurrences all number	22	28	6	32
Lymphopenia
subjects affected / exposed	0 / 82 (0.00%)	1 / 109 (0.92%)	1 / 27 (3.70%)	2 / 39 (5.13%)
occurrences all number	0	1	1	4
Leukopenia
subjects affected / exposed	2 / 82 (2.44%)	2 / 109 (1.83%)	0 / 27 (0.00%)	3 / 39 (7.69%)
occurrences all number	2	2	0	4
Neutropenia
subjects affected / exposed	1 / 82 (1.22%)	1 / 109 (0.92%)	0 / 27 (0.00%)	12 / 39 (30.77%)
occurrences all number	1	1	0	36
Thrombocytopenia
subjects affected / exposed	1 / 82 (1.22%)	1 / 109 (0.92%)	0 / 27 (0.00%)	3 / 39 (7.69%)
occurrences all number	1	1	0	3
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	0 / 82 (0.00%)	1 / 109 (0.92%)	1 / 27 (3.70%)	2 / 39 (5.13%)
occurrences all number	0	1	1	2
Abdominal pain upper
subjects affected / exposed	8 / 82 (9.76%)	11 / 109 (10.09%)	3 / 27 (11.11%)	3 / 39 (7.69%)
occurrences all number	8	11	3	3
Abdominal distension
subjects affected / exposed	5 / 82 (6.10%)	6 / 109 (5.50%)	1 / 27 (3.70%)	0 / 39 (0.00%)
occurrences all number	5	6	1	0
Abdominal pain
subjects affected / exposed	5 / 82 (6.10%)	9 / 109 (8.26%)	4 / 27 (14.81%)	2 / 39 (5.13%)
occurrences all number	5	9	4	2
Diarrhoea
subjects affected / exposed	5 / 82 (6.10%)	6 / 109 (5.50%)	1 / 27 (3.70%)	5 / 39 (12.82%)
occurrences all number	7	8	1	7
Dry mouth
subjects affected / exposed	3 / 82 (3.66%)	4 / 109 (3.67%)	1 / 27 (3.70%)	3 / 39 (7.69%)
occurrences all number	3	4	1	3
Constipation
subjects affected / exposed	13 / 82 (15.85%)	16 / 109 (14.68%)	3 / 27 (11.11%)	7 / 39 (17.95%)
occurrences all number	17	21	4	8
Dyspepsia
subjects affected / exposed	0 / 82 (0.00%)	1 / 109 (0.92%)	1 / 27 (3.70%)	2 / 39 (5.13%)
occurrences all number	0	1	1	2
Mouth ulceration
subjects affected / exposed	0 / 82 (0.00%)	0 / 109 (0.00%)	0 / 27 (0.00%)	2 / 39 (5.13%)
occurrences all number	0	0	0	2
Nausea
subjects affected / exposed	13 / 82 (15.85%)	17 / 109 (15.60%)	4 / 27 (14.81%)	8 / 39 (20.51%)
occurrences all number	15	19	4	9
Vomiting
subjects affected / exposed	14 / 82 (17.07%)	21 / 109 (19.27%)	7 / 27 (25.93%)	6 / 39 (15.38%)
occurrences all number	21	29	8	7
Oral pain
subjects affected / exposed	0 / 82 (0.00%)	0 / 109 (0.00%)	0 / 27 (0.00%)	2 / 39 (5.13%)
occurrences all number	0	0	0	2
Stomatitis
subjects affected / exposed	6 / 82 (7.32%)	6 / 109 (5.50%)	0 / 27 (0.00%)	9 / 39 (23.08%)
occurrences all number	6	6	0	14
Dysphagia
subjects affected / exposed	5 / 82 (6.10%)	5 / 109 (4.59%)	0 / 27 (0.00%)	1 / 39 (2.56%)
occurrences all number	6	6	0	1
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	0 / 82 (0.00%)	0 / 109 (0.00%)	0 / 27 (0.00%)	9 / 39 (23.08%)
occurrences all number	0	0	0	9
Palmar-plantar erythrodysaesthesia syndrome
subjects affected / exposed	0 / 82 (0.00%)	1 / 109 (0.92%)	1 / 27 (3.70%)	6 / 39 (15.38%)
occurrences all number	0	1	1	6
Pruritus
subjects affected / exposed	10 / 82 (12.20%)	14 / 109 (12.84%)	4 / 27 (14.81%)	3 / 39 (7.69%)
occurrences all number	14	18	4	3
Dry skin
subjects affected / exposed	5 / 82 (6.10%)	7 / 109 (6.42%)	2 / 27 (7.41%)	0 / 39 (0.00%)
occurrences all number	6	8	2	0
Urticaria
subjects affected / exposed	0 / 82 (0.00%)	0 / 109 (0.00%)	0 / 27 (0.00%)	2 / 39 (5.13%)
occurrences all number	0	0	0	2
Rash
subjects affected / exposed	15 / 82 (18.29%)	16 / 109 (14.68%)	1 / 27 (3.70%)	6 / 39 (15.38%)
occurrences all number	21	22	1	8
Renal and urinary disorders
Urinary retention
subjects affected / exposed	0 / 82 (0.00%)	2 / 109 (1.83%)	2 / 27 (7.41%)	0 / 39 (0.00%)
occurrences all number	0	2	2	0
Endocrine disorders
Hypothyroidism
subjects affected / exposed	10 / 82 (12.20%)	13 / 109 (11.93%)	3 / 27 (11.11%)	2 / 39 (5.13%)
occurrences all number	10	13	3	2
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	9 / 82 (10.98%)	14 / 109 (12.84%)	5 / 27 (18.52%)	2 / 39 (5.13%)
occurrences all number	11	17	6	2
Muscular weakness
subjects affected / exposed	2 / 82 (2.44%)	2 / 109 (1.83%)	0 / 27 (0.00%)	2 / 39 (5.13%)
occurrences all number	2	2	0	2
Bone pain
subjects affected / exposed	4 / 82 (4.88%)	5 / 109 (4.59%)	1 / 27 (3.70%)	2 / 39 (5.13%)
occurrences all number	4	5	1	2
Back pain
subjects affected / exposed	9 / 82 (10.98%)	13 / 109 (11.93%)	4 / 27 (14.81%)	6 / 39 (15.38%)
occurrences all number	9	14	5	7
Musculoskeletal chest pain
subjects affected / exposed	4 / 82 (4.88%)	4 / 109 (3.67%)	0 / 27 (0.00%)	3 / 39 (7.69%)
occurrences all number	4	4	0	3
Myalgia
subjects affected / exposed	1 / 82 (1.22%)	1 / 109 (0.92%)	0 / 27 (0.00%)	3 / 39 (7.69%)
occurrences all number	1	1	0	3
Infections and infestations
Nasopharyngitis
subjects affected / exposed	3 / 82 (3.66%)	3 / 109 (2.75%)	0 / 27 (0.00%)	2 / 39 (5.13%)
occurrences all number	3	3	0	2
Herpes zoster
subjects affected / exposed	3 / 82 (3.66%)	3 / 109 (2.75%)	0 / 27 (0.00%)	2 / 39 (5.13%)
occurrences all number	3	3	0	2
Sinusitis
subjects affected / exposed	1 / 82 (1.22%)	1 / 109 (0.92%)	0 / 27 (0.00%)	2 / 39 (5.13%)
occurrences all number	4	4	0	2
Upper respiratory tract infection
subjects affected / exposed	9 / 82 (10.98%)	10 / 109 (9.17%)	1 / 27 (3.70%)	2 / 39 (5.13%)
occurrences all number	11	12	1	2
Urinary tract infection
subjects affected / exposed	1 / 82 (1.22%)	1 / 109 (0.92%)	0 / 27 (0.00%)	2 / 39 (5.13%)
occurrences all number	4	4	0	3
Pneumonia
subjects affected / exposed	3 / 82 (3.66%)	3 / 109 (2.75%)	0 / 27 (0.00%)	2 / 39 (5.13%)
occurrences all number	3	3	0	3
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	3 / 82 (3.66%)	3 / 109 (2.75%)	0 / 27 (0.00%)	2 / 39 (5.13%)
occurrences all number	3	3	0	2
Decreased appetite
subjects affected / exposed	16 / 82 (19.51%)	24 / 109 (22.02%)	8 / 27 (29.63%)	9 / 39 (23.08%)
occurrences all number	18	26	8	12
Hypoalbuminaemia
subjects affected / exposed	6 / 82 (7.32%)	9 / 109 (8.26%)	3 / 27 (11.11%)	2 / 39 (5.13%)
occurrences all number	6	9	3	2
Hypomagnesaemia
subjects affected / exposed	7 / 82 (8.54%)	9 / 109 (8.26%)	2 / 27 (7.41%)	6 / 39 (15.38%)
occurrences all number	8	10	2	6
Hypokalaemia
subjects affected / exposed	5 / 82 (6.10%)	9 / 109 (8.26%)	4 / 27 (14.81%)	13 / 39 (33.33%)
occurrences all number	7	12	5	20
Hyponatraemia
subjects affected / exposed	14 / 82 (17.07%)	18 / 109 (16.51%)	4 / 27 (14.81%)	6 / 39 (15.38%)
occurrences all number	19	24	5	8
Hypophosphataemia
subjects affected / exposed	0 / 82 (0.00%)	1 / 109 (0.92%)	1 / 27 (3.70%)	2 / 39 (5.13%)
occurrences all number	0	1	1	6
Hyperglycaemia
subjects affected / exposed	5 / 82 (6.10%)	5 / 109 (4.59%)	0 / 27 (0.00%)	1 / 39 (2.56%)
occurrences all number	9	9	0	1

More information

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Were there any global substantial amendments to the protocol? Yes

09 Nov 2015

To revise exclusion criteria to exclude subjects receiving systemic corticosteroids at dose of > 10mg/day prednisone; To specify in more detail guidelines and criteria about immune related and non-immune related AE management and study treatment recommendations; To clarify the criterion that subjects beyond initial RECIST v1.1 defined disease progression were allowed to continue study treatment; To specify more frequent evaluations may be performed at investigator’s discretion or if recommended by drug product information.

21 Jan 2016

The primary purpose of this amendment was to introduce the RP2D of spartalizumab established in the Phase I (first-in-human) Study X2101. Based on PK and safety data from Study X2101, the RP2D for spartalizumab had been declared as a flat dose of 400 mg iv Q4W; The safety follow-up period had been extended to 90 days after the last dose of spartalizumab treatment (based on preliminary PK data from Study X2101 and the possibility of delayed appearance of immune-related AEs); Subjects who were HBV or HCV positive were eligible. As PD-1 blocking antibodies were not immunosuppressive, there was no specific contraindication to recruit subjects who were HBV and HCV positive, provided their active disease was adequately controlled by antiviral therapy; Subjects who had previously received CTLA-4-antagonists were eligible providing they did not have hepatic, diarrhea/colitis or endocrine AEs grade ≥ 2, any other non-laboratory immune-related AE grade ≥ 3. Subjects must have had minimum 8-week washout period between the last dose of anti-CTLA4 and the first dose of spartalizumab. The 8 weeks washout period was needed to resolve the anti-CTLA4 induced irAE, which could have a delayed onset; For monitoring of thyroid function, the measurement of free T4 a more specific parameter as compared to total T4 was included, whereas total T4 was removed; The tumor assessment should include the head and neck if clinically relevant.

27 Jul 2016

With the available PK data obtained from the single agent first-in-human Study X2101, an exploratory population PK (PopPK) analysis showed that the T1/2 of spartalizumab in man was 20 (17, 23) days (mean (90% CI)). Using 5 times the upper limit of the half-life of 23 days and an added safety margin, the protocol was amended to increase the duration of contraception and safety follow-up period post spartalizumab treatment from 90 days to 150 days. These changes were related to an Urgent Safety Measure communicated on 08-Jun-2016 to all investigators; This amendment also introduced the following key changes: Clarification of inclusion criterion 8: Specified that lesions in previously irradiated areas should not be considered measurable unless there was clear evidence of progression in such lesions since the radiotherapy; Modification of exclusion criterion 8: Subjects who had previously received an investigational therapeutic cancer vaccine could be eligible. This change had been introduced considering the limited efficacy evidence available for cancer vaccines and the high-unmet medical need in this subject population; Clarification of exclusion criterion 10: Subjects who had previously received an investigational therapeutic cancer vaccine were eligible providing there was a minimum 4-week washout period between the last dose of the vaccine and the first dose of spartalizumab; ECG monitoring plan was simplified to collection of ECGs at screening, C1D1, C3D1 and as clinically indicated, because no signal of QT interval prolongation was observed in the first in human Study X2101 or other currently approved anti-PD-1 antibodies. Concentration-QT analysis plan in Section 10.6.1 was removed accordingly.

07 Dec 2017

Addition of safety evaluations on 30 and 90 days to the 150-day safety follow-up visit, in order to ensure regular safety follow-up of subjects after the last administration of spartalizumab; To ensure a consistent approach in the reporting of the safety profile of study treatment, the main data analysis focused on the period from the first dose of study treatment to 30 days after the date of the last administration of study treatment. Data collected beyond this period (i.e. post-treatment period) were summarized separately; irAEs had been included in the AEs part as secondary endpoints. To avoid redundant description and reporting, the irAEs were removed as standalone secondary endpoint but continued to be analyzed as part of the AEs analysis (secondary endpoint); In order to explore the durability of disease control by spartalizumab in subjects with NPC, the analysis of long-term endpoints was added to the primary CSR. This analysis included all subjects data up to the date when each subject had reached a minimum of 12 months of follow-up after the first dose of study treatment or had lost to follow-up. There were no changes to the pre-defined study endpoints; In order to better characterize PK through population approach, one more sample collection was added for PK and IG at the 150-day safety follow-up visit for the spartalizumab arm subjects who come on site.

30 Aug 2018

After the occurrence of a case of Steven Johnson Syndrome in a study with spartalizumab in combination with another investigational agent, the dose modification guidelines for protocols using spartalizumab were updated to mandate permanent discontinuation of study treatment for subjects who experience Stevens–Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN); The independent central review of imaging data were terminated for the whole study when both criteria were met, 1) decisions were made based on central review results for all the chemotherapy arm subjects on whether to crossover; 2) all subject had reached a minimum of 12 months follow-up after the first dose of study treatment (unless have been lost to follow-up). Because the purposes of applying the central review service had been fulfilled; Serology tests (anti-DNA antibodies (Abs), anti-nuclear abs, anti-phospholipid abs, antimitochondrial abs, c-Reactive protein (CRP), Rheumatoid factor (RF)) were no longer mandated. The available safety data from clinical studies indicate that spartalizumab was generally well tolerated; ECG was no longer centrally reviewed; PK and IG sample collection was terminated after the Cycle 4 samples were collected from all the spartalizumab arm subjects, as sufficient PK and IG samples had been collected for characterization of the PK and IG profile of spartalizumab in NPC subjects.

24 Jun 2019

The definition of end of study was revised to include the option for subjects still on study treatment and who in the opinion of the Investigator were still deriving clinical benefit at the time of end of study, to transfer to another study or to an alternative treatment option to continue providing study treatment to these subjects; In addition, the blood sample collection was removed for the assessment of serum cytokines used for retrospective analysis of a CRS AE. Blood samples for serum cytokines were included due to the unknown risk of CRS with IO agents alone and in combination, and to allow an assessment of any association between cytokines and clinical events. These samples were drawn at baseline and at the time of a potential CRS event, stored, and analyzed retrospectively. Due to this, results were not intended to be used to support clinical decision-making for subjects with possible CRS. There were no unexpected clinically assessed events of CRS observed across 19 studies including more than 2200 subjects. The risk of CRS in the current study was deemed to be low, thus supporting the removal of this blood sample collection.

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 for complete trial results.

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Clinical trials

Clinical Trial Results: A phase II, open-label, randomized controlled study of PDR001 in patients with moderately differentiated/undifferentiated locally advanced recurrent or metastatic nasopharyngeal carcinoma who progressed on standard treatment

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Progression-free survival (PFS) as per RECIST v 1.1 using central assessment – Number of participants with progression or death

Primary: Progression-free survival (PFS) as per RECIST v 1.1 using central assessment – Number of participants with progression or death

Primary: Progression-free survival (PFS) as per RECIST v 1.1 using central assessment – Median PFS

Primary: Progression-free survival (PFS) as per RECIST v 1.1 using central assessment – Median PFS

Secondary: Overall Survival (OS)

Secondary: Overall Survival (OS)

Secondary: Overall Response Rate (ORR) as per RECIST v 1.1

Secondary: Overall Response Rate (ORR) as per RECIST v 1.1

Secondary: Duration of Response (DOR) as per RECIST v 1.1

Secondary: Duration of Response (DOR) as per RECIST v 1.1

Secondary: Time to Progression (TTP) as per RECIST v 1.1

Secondary: Time to Progression (TTP) as per RECIST v 1.1

Secondary: Immune-related progression-free survival (irPFS) as per irRC

Secondary: Immune-related progression-free survival (irPFS) as per irRC

Secondary: Maximum observed serum concentration (Cmax) of spartalizumab

Secondary: Maximum observed serum concentration (Cmax) of spartalizumab

Secondary: Time to reach maximum serum concentration (Tmax) of spartalizumab

Secondary: Time to reach maximum serum concentration (Tmax) of spartalizumab

Secondary: Area under the serum concentration-time curve from time zero to the end of the dosing interval tau (AUCtau) of spartalizumab

Secondary: Area under the serum concentration-time curve from time zero to the end of the dosing interval tau (AUCtau) of spartalizumab

Secondary: Area under the serum concentration-time curve from time zero to infinity (AUCinf) of spartalizumab

Secondary: Area under the serum concentration-time curve from time zero to infinity (AUCinf) of spartalizumab

Secondary: Accumulation ratio (Racc) of spartalizumab

Secondary: Accumulation ratio (Racc) of spartalizumab

Secondary: Terminal elimination half-life (T1/2) of spartalizumab

Secondary: Terminal elimination half-life (T1/2) of spartalizumab

Secondary: Number of participants with anti-spartalizumab antibodies

Secondary: Number of participants with anti-spartalizumab antibodies

Secondary: PD-L1 percent positive tumor

Secondary: PD-L1 percent positive tumor

Secondary: Percent marker area for CD8 expression in tumor samples

Secondary: Percent marker area for CD8 expression in tumor samples

Secondary: TIL count in tumor samples

Secondary: TIL count in tumor samples

Secondary: Fold change from baseline in IFN-gamma levels in plasma

Secondary: Fold change from baseline in IFN-gamma levels in plasma

Secondary: Fold change from baseline in IL-6 levels in plasma

Secondary: Fold change from baseline in IL-6 levels in plasma

Secondary: Fold change from baseline in TNF-alfa levels in plasma

Secondary: Fold change from baseline in TNF-alfa levels in plasma

Post-hoc: Progression-free survival (PFS) as per RECIST v 1.1 using central assessment in participants who crossed over – Number of participants with progression or death

Post-hoc: Progression-free survival (PFS) as per RECIST v 1.1 using central assessment in participants who crossed over – Number of participants with progression or death

Post-hoc: Progression-free survival (PFS) as per RECIST v 1.1 using central assessment in participants who crossed over – Median PFS

Post-hoc: Progression-free survival (PFS) as per RECIST v 1.1 using central assessment in participants who crossed over – Median PFS

Post-hoc: All Collected Deaths

Post-hoc: All Collected Deaths

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A phase II, open-label, randomized controlled study of PDR001 in patients with moderately differentiated/undifferentiated locally advanced recurrent or metastatic nasopharyngeal carcinoma who progressed on standard treatment