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The European Union Clinical Trials Register allows you to search for protocol and results information on:

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Clinical Trial Results:
A Randomized Phase 2 Study of the Combination of Pembrolizumab (MK- 3475) Plus Epacadostat (INCB024360) with Platinum-based Chemotherapy Versus Pembrolizumab Plus Platinum-based Chemotherapy Plus Placebo as First-Line Treatment in Patients with Metastatic Non-Small Cell Lung Cancer

Summary
EudraCT number	2017-001810-27
Trial protocol	IE ES DE HU GB FR IT
Global end of trial date	16 Oct 2020

Results information
Results version number	v1(current)
This version publication date	04 Dec 2021
First version publication date	04 Dec 2021
Other versions

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

Collapse all Expand all

Trial information

Top of page

Sponsor protocol code

KEYNOTE-715-06/ECHO-306-06

ISRCTN number

-

US NCT number

-

WHO universal trial number (UTN)

-

Sponsor organisation name

Incyte

Sponsor organisation address

1801 Augustine Cutoff drive, Wilmington, United States, 19803

Public contact

Study Director, Incyte Corporation, +1 8554633463, medinfo@incyte.com

Scientific contact

Study Director, Incyte Corporation, +1 8554633463, medinfo@incyte.com

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

No

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

No

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

No

Analysis stage

Final

Date of interim/final analysis

16 Oct 2020

Is this the analysis of the primary completion data?

No

Global end of trial reached?

Yes

Global end of trial date

16 Oct 2020

Was the trial ended prematurely?

No

Main objective of the trial

The purpose of this study was to evaluate the efficacy and safety of pembrolizumab plus epacadostat with platinum-based chemotherapy versus pembrolizumab plus platinum-based chemotherapy plus placebo as first-line therapy in participants with metastatic non-small cell lung cancer (NSCLC).

Protection of trial subjects

This study was conducted in conformance with applicable country or local requirements regarding ethical committee review, informed consent, and other statutes or regulations regarding the protection of the rights and welfare of human participants in biomedical research.

Background therapy

-

Evidence for comparator

-

Actual start date of recruitment

09 Jan 2018

Long term follow-up planned

No

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 39

Country: Number of subjects enrolled

Canada: 13

Country: Number of subjects enrolled

Spain: 15

Country: Number of subjects enrolled

United Kingdom: 7

Country: Number of subjects enrolled

Hungary: 11

Country: Number of subjects enrolled

Israel: 41

Country: Number of subjects enrolled

Italy: 13

Country: Number of subjects enrolled

Mexico: 1

Country: Number of subjects enrolled

Russian Federation: 24

Country: Number of subjects enrolled

Turkey: 27

Country: Number of subjects enrolled

Taiwan: 17

Country: Number of subjects enrolled

United States: 25

Worldwide total number of subjects

233

EEA total number of subjects

39

Number of subjects enrolled per age group

In utero

0

Preterm newborn - gestational age < 37 wk

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)

129

From 65 to 84 years

104

85 years and over

0

Subject disposition

Top of page

Recruitment details

Participants took part in the study at 65 investigative sites in 12 countries.

Screening details

The original planned enrollment was 1062 participants across 3 treatment arms. With Protocol Amendment 05 the Epacadostat + Pembrolizumab (E+P) arm was dropped, and the planned sample size was reduced to a total of 148 participants randomized into the 2 remaining arms. 233 participants were randomized and 228 participants received study treatment.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Data analyst, Carer

Are arms mutually exclusive

Yes

Pembrolizumab + Chemotherapy + Epacadostat

Arm description

Participant received pembrolizumab 200 mg intravenous (IV) infusion, every 3 weeks (Q3W) on Day 1 of each 21 day cycle for up to 35 cycles + epacadostat 100 mg tablets, orally, twice daily (BID) in each 21 day cycle for up to 35 cycles + platinum-doublet chemotherapy (pemetrexed 500 mg/m^2 IV infusion, Q3W + cisplatin 75 mg/m^2 IV infusion, Q3W or carboplatin 5-6 mg/mL/min IV infusion Q3W for 4 cycles followed by pemetrexed maintenance; or paclitaxel 200 mg /m^2 IV infusion, Q3W + carboplatin 5-6 mg/mL/min IV infusion Q3W for 4 cycles).

Arm type

Experimental

Investigational medicinal product name

pembrolizumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

200 mg every 3 weeks

Investigational medicinal product name

platinum based chemotherapy

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

every 3 weeks

Investigational medicinal product name

epacadostat

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

100 mg twice a day

Pembrolizumab + Chemotherapy + Placebo

Arm description

Participant received pembrolizumab 200 mg IV infusion, Q3W on Day 1 of each 21 day cycle for up to 35 cycles + epacadostat matching placebo tablets, orally, BID in each 21 day cycle for up to 35 cycles + platinum-doublet chemotherapy (pemetrexed 500 mg/m^2 IV infusion, Q3W + cisplatin 75 mg/m^2 IV infusion, Q3W or carboplatin 5-6 mg/mL/min IV infusion Q3W for 4 cycles followed by pemetrexed maintenance; or paclitaxel 200 mg /m^2 IV infusion, Q3W + carboplatin 5-6 mg/mL/min IV infusion Q3W for 4 cycles).

Arm type

Placebo

Investigational medicinal product name

pembrolizumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate and solvent for solution for injection, Injection

Routes of administration

Intravenous use

Dosage and administration details

200 mg IV every 3 weeks

Investigational medicinal product name

placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Buccal tablet, Tablet

Routes of administration

Oral use

Dosage and administration details

twice a day

Investigational medicinal product name

platinum based chemotherapy

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

every 3 weeks

Pembrolizumab + Epacadostat

Arm description

Participant received pembrolizumab 200 mg IV infusion, Q3W on Day 1 of each 21 day cycle for up to 35 cycles + epacadostat 100 mg tablets, orally, BID in each 21 day cycle for up to 35 cycles.

Arm type

Experimental

Investigational medicinal product name

epacadostat

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

100 mg twice a day

Investigational medicinal product name

pembrolizumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

200 mg every 3 weeks

Number of subjects in period 1	Pembrolizumab + Chemotherapy + Epacadostat	Pembrolizumab + Chemotherapy + Placebo	Pembrolizumab + Epacadostat
Started	91	87	55
Completed	46	42	22
Not completed	45	45	33
Adverse event, serious fatal	34	35	23
Physician decision	6	7	2
Consent withdrawn by subject	4	3	6
Study terminated by sponsor	1	-	1
Lost to follow-up	-	-	1

Baseline characteristics

Top of page

Reporting group title

Pembrolizumab + Chemotherapy + Epacadostat

Reporting group description

Participant received pembrolizumab 200 mg intravenous (IV) infusion, every 3 weeks (Q3W) on Day 1 of each 21 day cycle for up to 35 cycles + epacadostat 100 mg tablets, orally, twice daily (BID) in each 21 day cycle for up to 35 cycles + platinum-doublet chemotherapy (pemetrexed 500 mg/m^2 IV infusion, Q3W + cisplatin 75 mg/m^2 IV infusion, Q3W or carboplatin 5-6 mg/mL/min IV infusion Q3W for 4 cycles followed by pemetrexed maintenance; or paclitaxel 200 mg /m^2 IV infusion, Q3W + carboplatin 5-6 mg/mL/min IV infusion Q3W for 4 cycles).

Reporting group title

Pembrolizumab + Chemotherapy + Placebo

Reporting group description

Participant received pembrolizumab 200 mg IV infusion, Q3W on Day 1 of each 21 day cycle for up to 35 cycles + epacadostat matching placebo tablets, orally, BID in each 21 day cycle for up to 35 cycles + platinum-doublet chemotherapy (pemetrexed 500 mg/m^2 IV infusion, Q3W + cisplatin 75 mg/m^2 IV infusion, Q3W or carboplatin 5-6 mg/mL/min IV infusion Q3W for 4 cycles followed by pemetrexed maintenance; or paclitaxel 200 mg /m^2 IV infusion, Q3W + carboplatin 5-6 mg/mL/min IV infusion Q3W for 4 cycles).

Reporting group title

Pembrolizumab + Epacadostat

Reporting group description

Participant received pembrolizumab 200 mg IV infusion, Q3W on Day 1 of each 21 day cycle for up to 35 cycles + epacadostat 100 mg tablets, orally, BID in each 21 day cycle for up to 35 cycles.

Reporting group values	Pembrolizumab + Chemotherapy + Epacadostat	Pembrolizumab + Chemotherapy + Placebo	Pembrolizumab + Epacadostat	Total
Number of subjects	91	87	55	233
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)	49	46	34	129
From 65-84 years	42	41	21	104
85 years and over	0	0	0	0
Age Continuous
Units: years
arithmetic mean (standard deviation)	63.0 ( 11.7 )	63.6 ( 8.8 )	62.8 ( 8.4 )	-
Sex: Female, Male
Units:
Female	33	30	16	79
Male	58	57	39	154
Race/Ethnicity, Customized
Units: Subjects
American Indian Or Alaska Native	1	0	0	1
Asian	11	10	2	23
Black Or African American	1	1	0	2
White	78	75	53	206
Missing	0	1	0	1
Race/Ethnicity, Customized
Units: Subjects
Hispanic or Latino	3	1	1	5
Not Hispanic or Latino	86	85	52	223
Unknown	2	1	1	4
Not Reported	0	0	1	1

End points

Top of page

Reporting group title

Pembrolizumab + Chemotherapy + Epacadostat

Reporting group description

Participant received pembrolizumab 200 mg intravenous (IV) infusion, every 3 weeks (Q3W) on Day 1 of each 21 day cycle for up to 35 cycles + epacadostat 100 mg tablets, orally, twice daily (BID) in each 21 day cycle for up to 35 cycles + platinum-doublet chemotherapy (pemetrexed 500 mg/m^2 IV infusion, Q3W + cisplatin 75 mg/m^2 IV infusion, Q3W or carboplatin 5-6 mg/mL/min IV infusion Q3W for 4 cycles followed by pemetrexed maintenance; or paclitaxel 200 mg /m^2 IV infusion, Q3W + carboplatin 5-6 mg/mL/min IV infusion Q3W for 4 cycles).

Reporting group title

Pembrolizumab + Chemotherapy + Placebo

Reporting group description

Participant received pembrolizumab 200 mg IV infusion, Q3W on Day 1 of each 21 day cycle for up to 35 cycles + epacadostat matching placebo tablets, orally, BID in each 21 day cycle for up to 35 cycles + platinum-doublet chemotherapy (pemetrexed 500 mg/m^2 IV infusion, Q3W + cisplatin 75 mg/m^2 IV infusion, Q3W or carboplatin 5-6 mg/mL/min IV infusion Q3W for 4 cycles followed by pemetrexed maintenance; or paclitaxel 200 mg /m^2 IV infusion, Q3W + carboplatin 5-6 mg/mL/min IV infusion Q3W for 4 cycles).

Reporting group title

Pembrolizumab + Epacadostat

Reporting group description

Participant received pembrolizumab 200 mg IV infusion, Q3W on Day 1 of each 21 day cycle for up to 35 cycles + epacadostat 100 mg tablets, orally, BID in each 21 day cycle for up to 35 cycles.

Primary: Objective Response Rate (ORR) of Pembrolizumab + Chemotherapy + Epacadostat Versus Pembrolizumab + Chemotherapy + Placebo

Top of page

End point title

Objective Response Rate (ORR) of Pembrolizumab + Chemotherapy + Epacadostat Versus Pembrolizumab + Chemotherapy + Placebo ^[1]

End point description

ORR is defined as the percentage of participants who have a confirmed complete response (CR) or partial response (PR) per Response Evaluation Criteria in Solid Tumors (RECIST 1.1) based on blinded independent central review (BICR).

End point type

Primary

End point timeframe

Assessed every 12 up to 24 months

Notes
[1] - 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: No statistical analysis for this endpoint.

End point values	Pembrolizumab + Chemotherapy + Epacadostat	Pembrolizumab + Chemotherapy + Placebo
Number of subjects analysed	91	87
Units: percentage of participants
number (confidence interval 95%)	26.4 (17.7 to 36.7)	44.8 (34.1 to 55.9)

Stratified Miettinen and Nurminen method

Comparison groups

Pembrolizumab + Chemotherapy + Epacadostat v Pembrolizumab + Chemotherapy + Placebo

Number of subjects included in analysis

178

Analysis specification

Pre-specified

Analysis type

P-value

= 0.9948 ^[2]

Method

Stratified Miettinen and Nurminen method

Parameter type

Difference in Percentages

Point estimate

-18.5

Confidence interval

level

95%

sides

2-sided

lower limit

-32

upper limit

-4.3

Notes
[2] - One-sided p-value for testing. H0: difference in % = 0 versus H1: difference in % > 0.

Secondary: Progression-free survival of Pembrolizumab + Chemotherapy + Epacadostat versus Pembrolizumab + Chemotherapy + Placebo

Top of page

End point title

Progression-free survival of Pembrolizumab + Chemotherapy + Epacadostat versus Pembrolizumab + Chemotherapy + Placebo ^[3]

End point description

Defined as the time from randomization to the first documented progressive disease (PD) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or death due to any cause, whichever occurs first.

End point type

Secondary

End point timeframe

Up to 24 months

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: No statistical analysis for this endpoint.

End point values	Pembrolizumab + Chemotherapy + Epacadostat	Pembrolizumab + Chemotherapy + Placebo
Number of subjects analysed	91	87
Units: months
median (confidence interval 95%)	8.0 (4.2 to 10.2)	8.2 (6.0 to 999999)

Regression, Cox

Comparison groups

Pembrolizumab + Chemotherapy + Epacadostat v Pembrolizumab + Chemotherapy + Placebo

Number of subjects included in analysis

178

Analysis specification

Pre-specified

Analysis type

P-value

= 0.94305 ^[4]

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

1.47

Confidence interval

level

95%

sides

2-sided

lower limit

0.91

upper limit

2.36

Notes
[4] - One-sided p-value based on log-rank test stratified by TPS (<50% vs >=50%) and predominant histology (squamous vs non-squamous), because of small sample size, the strata ‘TPS >= 50% Non-squamous’ and 'TPS >= 50% Squamous’ were combined into one.

Secondary: Overall survival of Pembrolizumab + Chemotherapy + Epacadostat versus Pembrolizumab + Chemotherapy + Placebo

Top of page

End point title

Overall survival of Pembrolizumab + Chemotherapy + Epacadostat versus Pembrolizumab + Chemotherapy + Placebo ^[5]

End point description

Defined as the time from randomization to death due to any cause.

End point type

Secondary

End point timeframe

Up to 24 months

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: No statistical analysis for this endpoint.

End point values	Pembrolizumab + Chemotherapy + Epacadostat	Pembrolizumab + Chemotherapy + Placebo
Number of subjects analysed	91	87
Units: months
median (confidence interval 95%)	9.9999 (0.9999 to 99.999)	9.9999 (0.99999 to 99.9999)

Regression, Cox

Comparison groups

Pembrolizumab + Chemotherapy + Epacadostat v Pembrolizumab + Chemotherapy + Placebo

Number of subjects included in analysis

178

Analysis specification

Pre-specified

Analysis type

P-value

= 0.96272 ^[6]

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

1.9

Confidence interval

level

95%

sides

2-sided

lower limit

0.93

upper limit

3.9

Notes
[6] - One-sided p-value based on log-rank test stratified by PD-L1 TPS (<50% vs >=50%) and predominant tumor histology (squamous vs non-squamous), because of small sample size, the strata (<50% vs >=50%) were combined into one stratum.

Secondary: Duration of response of Pembrolizumab + Chemotherapy + Epacadostat versus Pembrolizumab + Chemotherapy + Placebo

Top of page

End point title

Duration of response of Pembrolizumab + Chemotherapy + Epacadostat versus Pembrolizumab + Chemotherapy + Placebo ^[7]

End point description

Defined as the time from the earliest date of qualifying response until earliest date of disease progression, per RECIST v1.1, or death from any cause, whichever comes first.

End point type

Secondary

End point timeframe

Up to 24 months

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: No statistical analysis for this endpoint.

End point values	Pembrolizumab + Chemotherapy + Epacadostat	Pembrolizumab + Chemotherapy + Placebo
Number of subjects analysed	91	87
Units: months
median (confidence interval 95%)	2.2222 (1.1 to 7.0)	7.0 (1.2 to 8.0)

No statistical analyses for this end point

Secondary: Safety and tolerability of Pembrolizumab + Chemotherapy + Epacadostat versus Pembrolizumab + Chemotherapy + Placebo as measured by the number of participants experiencing adverse events (AEs)

Top of page

End point title

Safety and tolerability of Pembrolizumab + Chemotherapy + Epacadostat versus Pembrolizumab + Chemotherapy + Placebo as measured by the number of participants experiencing adverse events (AEs) ^[8]

End point description

An AE is defined as any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment.

End point type

Secondary

End point timeframe

Up to 25 months

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: No statistical analysis for this endpoint.

End point values	Pembrolizumab + Chemotherapy + Epacadostat	Pembrolizumab + Chemotherapy + Placebo
Number of subjects analysed	90	86
Units: number of participants	89	82

No statistical analyses for this end point

Secondary: Safety and tolerability of Pembrolizumab + Chemotherapy + Epacadostat versus Pembrolizumab + Chemotherapy + Placebo as measured by the number of participants discontinuing study drug due to AEs

Top of page

End point title

Safety and tolerability of Pembrolizumab + Chemotherapy + Epacadostat versus Pembrolizumab + Chemotherapy + Placebo as measured by the number of participants discontinuing study drug due to AEs ^[9]

End point description

An AE is defined as any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of any study drug, whether or not considered related to the study drug.

End point type

Secondary

End point timeframe

Up to 25 months

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analysis for this endpoint.

End point values	Pembrolizumab + Chemotherapy + Epacadostat	Pembrolizumab + Chemotherapy + Placebo
Number of subjects analysed	90	86
Units: Number of Participants	37	35

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

Up to 25 months

Adverse event reporting additional description

AE additional description

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

16

Reporting group title

Pembrolizumab + Chemotherapy + Epacadostat

Reporting group description

Participant received pembrolizumab 200 mg intravenous (IV) infusion, every 3 weeks (Q3W) on Day 1 of each 21 day cycle for up to 35 cycles + epacadostat 100 mg tablets, orally, twice daily (BID) in each 21 day cycle for up to 35 cycles + platinum-doublet chemotherapy (pemetrexed 500 mg/m^2 IV infusion, Q3W + cisplatin 75 mg/m^2 IV infusion, Q3W or carboplatin 5-6 mg/mL/min IV infusion Q3W for 4 cycles followed by pemetrexed maintenance; or paclitaxel 200 mg /m^2 IV infusion, Q3W + carboplatin 5-6 mg/mL/min IV infusion Q3W for 4 cycles).

Reporting group title

Pembrolizumab + Chemotherapy + Placebo

Reporting group description

Participant received pembrolizumab 200 mg IV infusion, Q3W on Day 1 of each 21 day cycle for up to 35 cycles + epacadostat matching placebo tablets, orally, BID in each 21 day cycle for up to 35 cycles + platinum-doublet chemotherapy (pemetrexed 500 mg/m^2 IV infusion, Q3W + cisplatin 75 mg/m^2 IV infusion, Q3W or carboplatin 5-6 mg/mL/min IV infusion Q3W for 4 cycles followed by pemetrexed maintenance; or paclitaxel 200 mg /m^2 IV infusion, Q3W + carboplatin 5-6 mg/mL/min IV infusion Q3W for 4 cycles).

Reporting group title

Pembrolizumab + Epacadostat

Reporting group description

Participant received pembrolizumab 200 mg IV infusion, Q3W on Day 1 of each 21 day cycle for up to 35 cycles + epacadostat 100 mg tablets, orally, BID in each 21 day cycle for up to 35 cycles.

Reporting group title

Total

Reporting group description

Total

Serious adverse events	Pembrolizumab + Chemotherapy + Epacadostat	Pembrolizumab + Chemotherapy + Placebo	Pembrolizumab + Epacadostat	Total
Total subjects affected by serious adverse events
subjects affected / exposed	47 / 90 (52.22%)	41 / 86 (47.67%)	20 / 52 (38.46%)	108 / 228 (47.37%)
number of deaths (all causes)	38	35	26	99
number of deaths resulting from adverse events	12	6	10	28
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain
subjects affected / exposed	0 / 90 (0.00%)	1 / 86 (1.16%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypopharyngeal neoplasm
subjects affected / exposed	0 / 90 (0.00%)	1 / 86 (1.16%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
Malignant neoplasm progression
subjects affected / exposed	5 / 90 (5.56%)	2 / 86 (2.33%)	8 / 52 (15.38%)	15 / 228 (6.58%)
occurrences causally related to treatment / all	0 / 5	0 / 2	0 / 8	0 / 15
deaths causally related to treatment / all	0 / 4	0 / 0	0 / 5	0 / 9
Malignant pleural effusion
subjects affected / exposed	0 / 90 (0.00%)	1 / 86 (1.16%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatic carcinoma
subjects affected / exposed	1 / 90 (1.11%)	0 / 86 (0.00%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
Paraneoplastic syndrome
subjects affected / exposed	1 / 90 (1.11%)	0 / 86 (0.00%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Prostate cancer
subjects affected / exposed	0 / 90 (0.00%)	1 / 86 (1.16%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Embolism
subjects affected / exposed	1 / 90 (1.11%)	0 / 86 (0.00%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypertension
subjects affected / exposed	1 / 90 (1.11%)	0 / 86 (0.00%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral ischaemia
subjects affected / exposed	0 / 90 (0.00%)	1 / 86 (1.16%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Superior vena cava syndrome
subjects affected / exposed	1 / 90 (1.11%)	0 / 86 (0.00%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Breakthrough pain
subjects affected / exposed	1 / 90 (1.11%)	0 / 86 (0.00%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Chest pain
subjects affected / exposed	0 / 90 (0.00%)	1 / 86 (1.16%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Death
subjects affected / exposed	0 / 90 (0.00%)	0 / 86 (0.00%)	2 / 52 (3.85%)	2 / 228 (0.88%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 2
General physical health deterioration
subjects affected / exposed	0 / 90 (0.00%)	1 / 86 (1.16%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
Infusion site extravasation
subjects affected / exposed	1 / 90 (1.11%)	0 / 86 (0.00%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Malaise
subjects affected / exposed	0 / 90 (0.00%)	1 / 86 (1.16%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Mucosal inflammation
subjects affected / exposed	0 / 90 (0.00%)	1 / 86 (1.16%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	2 / 90 (2.22%)	0 / 86 (0.00%)	0 / 52 (0.00%)	2 / 228 (0.88%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Hypersensitivity
subjects affected / exposed	0 / 90 (0.00%)	1 / 86 (1.16%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease
subjects affected / exposed	0 / 90 (0.00%)	1 / 86 (1.16%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cough
subjects affected / exposed	0 / 90 (0.00%)	1 / 86 (1.16%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	0 / 90 (0.00%)	1 / 86 (1.16%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemoptysis
subjects affected / exposed	2 / 90 (2.22%)	1 / 86 (1.16%)	0 / 52 (0.00%)	3 / 228 (1.32%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
Haemothorax
subjects affected / exposed	1 / 90 (1.11%)	0 / 86 (0.00%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypoxia
subjects affected / exposed	1 / 90 (1.11%)	0 / 86 (0.00%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	2 / 90 (2.22%)	1 / 86 (1.16%)	2 / 52 (3.85%)	5 / 228 (2.19%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 2	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	1 / 90 (1.11%)	3 / 86 (3.49%)	0 / 52 (0.00%)	4 / 228 (1.75%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 2
Pulmonary embolism
subjects affected / exposed	1 / 90 (1.11%)	1 / 86 (1.16%)	0 / 52 (0.00%)	2 / 228 (0.88%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary oedema
subjects affected / exposed	1 / 90 (1.11%)	0 / 86 (0.00%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	1 / 90 (1.11%)	1 / 86 (1.16%)	0 / 52 (0.00%)	2 / 228 (0.88%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 2
Psychiatric disorders
Agitation
subjects affected / exposed	0 / 90 (0.00%)	1 / 86 (1.16%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Confusional state
subjects affected / exposed	0 / 90 (0.00%)	1 / 86 (1.16%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hallucination
subjects affected / exposed	0 / 90 (0.00%)	0 / 86 (0.00%)	1 / 52 (1.92%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	1 / 90 (1.11%)	0 / 86 (0.00%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Liver function test increased
subjects affected / exposed	1 / 90 (1.11%)	0 / 86 (0.00%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatic enzymes increased
subjects affected / exposed	1 / 90 (1.11%)	0 / 86 (0.00%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Platelet count decreased
subjects affected / exposed	0 / 90 (0.00%)	1 / 86 (1.16%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Femoral neck fracture
subjects affected / exposed	0 / 90 (0.00%)	1 / 86 (1.16%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hip fracture
subjects affected / exposed	0 / 90 (0.00%)	1 / 86 (1.16%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Humerus fracture
subjects affected / exposed	0 / 90 (0.00%)	0 / 86 (0.00%)	1 / 52 (1.92%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Radiation necrosis
subjects affected / exposed	1 / 90 (1.11%)	1 / 86 (1.16%)	0 / 52 (0.00%)	2 / 228 (0.88%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Spinal compression fracture
subjects affected / exposed	1 / 90 (1.11%)	0 / 86 (0.00%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Subdural haemorrhage
subjects affected / exposed	1 / 90 (1.11%)	0 / 86 (0.00%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute coronary syndrome
subjects affected / exposed	0 / 90 (0.00%)	1 / 86 (1.16%)	1 / 52 (1.92%)	2 / 228 (0.88%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Acute myocardial infarction
subjects affected / exposed	0 / 90 (0.00%)	1 / 86 (1.16%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	1 / 90 (1.11%)	2 / 86 (2.33%)	0 / 52 (0.00%)	3 / 228 (1.32%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Atrioventricular block complete
subjects affected / exposed	1 / 90 (1.11%)	0 / 86 (0.00%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	0 / 90 (0.00%)	2 / 86 (2.33%)	0 / 52 (0.00%)	2 / 228 (0.88%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
Cardiac failure acute
subjects affected / exposed	1 / 90 (1.11%)	0 / 86 (0.00%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardio-respiratory arrest
subjects affected / exposed	1 / 90 (1.11%)	0 / 86 (0.00%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
Myocardial infarction
subjects affected / exposed	1 / 90 (1.11%)	0 / 86 (0.00%)	1 / 52 (1.92%)	2 / 228 (0.88%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 2
Pericardial effusion
subjects affected / exposed	0 / 90 (0.00%)	0 / 86 (0.00%)	1 / 52 (1.92%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cerebrovascular accident
subjects affected / exposed	2 / 90 (2.22%)	1 / 86 (1.16%)	0 / 52 (0.00%)	3 / 228 (1.32%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Embolic stroke
subjects affected / exposed	1 / 90 (1.11%)	0 / 86 (0.00%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Encephalopathy
subjects affected / exposed	0 / 90 (0.00%)	1 / 86 (1.16%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral sensory neuropathy
subjects affected / exposed	0 / 90 (0.00%)	1 / 86 (1.16%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sciatica
subjects affected / exposed	0 / 90 (0.00%)	1 / 86 (1.16%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	0 / 90 (0.00%)	1 / 86 (1.16%)	1 / 52 (1.92%)	2 / 228 (0.88%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	1 / 90 (1.11%)	0 / 86 (0.00%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vocal cord paralysis
subjects affected / exposed	0 / 90 (0.00%)	0 / 86 (0.00%)	1 / 52 (1.92%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	1 / 90 (1.11%)	1 / 86 (1.16%)	0 / 52 (0.00%)	2 / 228 (0.88%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	5 / 90 (5.56%)	0 / 86 (0.00%)	0 / 52 (0.00%)	5 / 228 (2.19%)
occurrences causally related to treatment / all	0 / 5	0 / 0	0 / 0	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lymphadenopathy
subjects affected / exposed	1 / 90 (1.11%)	0 / 86 (0.00%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	2 / 90 (2.22%)	0 / 86 (0.00%)	0 / 52 (0.00%)	2 / 228 (0.88%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancytopenia
subjects affected / exposed	1 / 90 (1.11%)	0 / 86 (0.00%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 1	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 / 90 (0.00%)	1 / 86 (1.16%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain upper
subjects affected / exposed	0 / 90 (0.00%)	1 / 86 (1.16%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Colitis
subjects affected / exposed	0 / 90 (0.00%)	2 / 86 (2.33%)	1 / 52 (1.92%)	3 / 228 (1.32%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	0 / 90 (0.00%)	1 / 86 (1.16%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	2 / 90 (2.22%)	2 / 86 (2.33%)	0 / 52 (0.00%)	4 / 228 (1.75%)
occurrences causally related to treatment / all	0 / 3	0 / 2	0 / 0	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal toxicity
subjects affected / exposed	0 / 90 (0.00%)	0 / 86 (0.00%)	1 / 52 (1.92%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Odynophagia
subjects affected / exposed	1 / 90 (1.11%)	0 / 86 (0.00%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	1 / 90 (1.11%)	1 / 86 (1.16%)	0 / 52 (0.00%)	2 / 228 (0.88%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Stomatitis
subjects affected / exposed	1 / 90 (1.11%)	1 / 86 (1.16%)	0 / 52 (0.00%)	2 / 228 (0.88%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	2 / 90 (2.22%)	0 / 86 (0.00%)	0 / 52 (0.00%)	2 / 228 (0.88%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Autoimmune hepatitis
subjects affected / exposed	1 / 90 (1.11%)	0 / 86 (0.00%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis
subjects affected / exposed	1 / 90 (1.11%)	0 / 86 (0.00%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis acute
subjects affected / exposed	0 / 90 (0.00%)	1 / 86 (1.16%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gallbladder rupture
subjects affected / exposed	1 / 90 (1.11%)	0 / 86 (0.00%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatotoxicity
subjects affected / exposed	1 / 90 (1.11%)	0 / 86 (0.00%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Exfoliative rash
subjects affected / exposed	1 / 90 (1.11%)	0 / 86 (0.00%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Purpura
subjects affected / exposed	0 / 90 (0.00%)	1 / 86 (1.16%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rash
subjects affected / exposed	1 / 90 (1.11%)	0 / 86 (0.00%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin ulcer
subjects affected / exposed	1 / 90 (1.11%)	0 / 86 (0.00%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Stevens-Johnson syndrome
subjects affected / exposed	0 / 90 (0.00%)	1 / 86 (1.16%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	2 / 90 (2.22%)	0 / 86 (0.00%)	0 / 52 (0.00%)	2 / 228 (0.88%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Endocrine disorders
Hyperthyroidism
subjects affected / exposed	0 / 90 (0.00%)	0 / 86 (0.00%)	1 / 52 (1.92%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthropathy
subjects affected / exposed	1 / 90 (1.11%)	0 / 86 (0.00%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Myalgia
subjects affected / exposed	0 / 90 (0.00%)	1 / 86 (1.16%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pain in extremity
subjects affected / exposed	1 / 90 (1.11%)	0 / 86 (0.00%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rhabdomyolysis
subjects affected / exposed	1 / 90 (1.11%)	0 / 86 (0.00%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Bronchitis
subjects affected / exposed	3 / 90 (3.33%)	1 / 86 (1.16%)	0 / 52 (0.00%)	4 / 228 (1.75%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	1 / 90 (1.11%)	0 / 86 (0.00%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Encephalitis
subjects affected / exposed	1 / 90 (1.11%)	0 / 86 (0.00%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	1 / 90 (1.11%)	0 / 86 (0.00%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gingivitis
subjects affected / exposed	1 / 90 (1.11%)	0 / 86 (0.00%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Herpes zoster
subjects affected / exposed	0 / 90 (0.00%)	1 / 86 (1.16%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	3 / 90 (3.33%)	1 / 86 (1.16%)	0 / 52 (0.00%)	4 / 228 (1.75%)
occurrences causally related to treatment / all	0 / 4	0 / 1	0 / 0	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ophthalmic herpes zoster
subjects affected / exposed	1 / 90 (1.11%)	0 / 86 (0.00%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumocystis jirovecii pneumonia
subjects affected / exposed	0 / 90 (0.00%)	0 / 86 (0.00%)	1 / 52 (1.92%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
Pneumonia
subjects affected / exposed	5 / 90 (5.56%)	12 / 86 (13.95%)	4 / 52 (7.69%)	21 / 228 (9.21%)
occurrences causally related to treatment / all	0 / 5	0 / 12	0 / 4	0 / 21
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
Sepsis
subjects affected / exposed	3 / 90 (3.33%)	0 / 86 (0.00%)	1 / 52 (1.92%)	4 / 228 (1.75%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 1	0 / 4
deaths causally related to treatment / all	0 / 2	0 / 0	0 / 1	0 / 3
Urinary tract infection
subjects affected / exposed	1 / 90 (1.11%)	1 / 86 (1.16%)	0 / 52 (0.00%)	2 / 228 (0.88%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	0 / 90 (0.00%)	1 / 86 (1.16%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vascular device infection
subjects affected / exposed	1 / 90 (1.11%)	0 / 86 (0.00%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	0 / 90 (0.00%)	1 / 86 (1.16%)	1 / 52 (1.92%)	2 / 228 (0.88%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dehydration
subjects affected / exposed	2 / 90 (2.22%)	0 / 86 (0.00%)	1 / 52 (1.92%)	3 / 228 (1.32%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diabetes mellitus
subjects affected / exposed	0 / 90 (0.00%)	1 / 86 (1.16%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diabetic ketoacidosis
subjects affected / exposed	1 / 90 (1.11%)	0 / 86 (0.00%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	0 / 90 (0.00%)	0 / 86 (0.00%)	1 / 52 (1.92%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyperkalaemia
subjects affected / exposed	0 / 90 (0.00%)	1 / 86 (1.16%)	0 / 52 (0.00%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	0 / 90 (0.00%)	0 / 86 (0.00%)	1 / 52 (1.92%)	1 / 228 (0.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Pembrolizumab + Chemotherapy + Epacadostat	Pembrolizumab + Chemotherapy + Placebo	Pembrolizumab + Epacadostat	Total
Total subjects affected by non serious adverse events
subjects affected / exposed	87 / 90 (96.67%)	81 / 86 (94.19%)	51 / 52 (98.08%)	219 / 228 (96.05%)
Vascular disorders
Hypertension
subjects affected / exposed	5 / 90 (5.56%)	3 / 86 (3.49%)	0 / 52 (0.00%)	8 / 228 (3.51%)
occurrences all number	7	4	0	11
General disorders and administration site conditions
Asthenia
subjects affected / exposed	12 / 90 (13.33%)	18 / 86 (20.93%)	6 / 52 (11.54%)	36 / 228 (15.79%)
occurrences all number	14	24	9	47
Chest pain
subjects affected / exposed	3 / 90 (3.33%)	13 / 86 (15.12%)	10 / 52 (19.23%)	26 / 228 (11.40%)
occurrences all number	3	13	11	27
Fatigue
subjects affected / exposed	28 / 90 (31.11%)	25 / 86 (29.07%)	14 / 52 (26.92%)	67 / 228 (29.39%)
occurrences all number	40	32	16	88
Mucosal inflammation
subjects affected / exposed	5 / 90 (5.56%)	7 / 86 (8.14%)	0 / 52 (0.00%)	12 / 228 (5.26%)
occurrences all number	7	8	0	15
Oedema peripheral
subjects affected / exposed	14 / 90 (15.56%)	10 / 86 (11.63%)	4 / 52 (7.69%)	28 / 228 (12.28%)
occurrences all number	20	11	4	35
Peripheral swelling
subjects affected / exposed	6 / 90 (6.67%)	2 / 86 (2.33%)	1 / 52 (1.92%)	9 / 228 (3.95%)
occurrences all number	9	3	1	13
Pyrexia
subjects affected / exposed	15 / 90 (16.67%)	10 / 86 (11.63%)	9 / 52 (17.31%)	34 / 228 (14.91%)
occurrences all number	21	12	13	46
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	10 / 90 (11.11%)	11 / 86 (12.79%)	12 / 52 (23.08%)	33 / 228 (14.47%)
occurrences all number	10	13	14	37
Dyspnoea
subjects affected / exposed	12 / 90 (13.33%)	11 / 86 (12.79%)	7 / 52 (13.46%)	30 / 228 (13.16%)
occurrences all number	14	11	7	32
Epistaxis
subjects affected / exposed	7 / 90 (7.78%)	6 / 86 (6.98%)	1 / 52 (1.92%)	14 / 228 (6.14%)
occurrences all number	7	8	1	16
Haemoptysis
subjects affected / exposed	4 / 90 (4.44%)	7 / 86 (8.14%)	3 / 52 (5.77%)	14 / 228 (6.14%)
occurrences all number	4	9	3	16
Oropharyngeal pain
subjects affected / exposed	5 / 90 (5.56%)	2 / 86 (2.33%)	1 / 52 (1.92%)	8 / 228 (3.51%)
occurrences all number	5	2	1	8
Pneumonitis
subjects affected / exposed	2 / 90 (2.22%)	6 / 86 (6.98%)	0 / 52 (0.00%)	8 / 228 (3.51%)
occurrences all number	2	7	0	9
Productive cough
subjects affected / exposed	5 / 90 (5.56%)	1 / 86 (1.16%)	4 / 52 (7.69%)	10 / 228 (4.39%)
occurrences all number	5	1	4	10
Rhinorrhoea
subjects affected / exposed	10 / 90 (11.11%)	0 / 86 (0.00%)	2 / 52 (3.85%)	12 / 228 (5.26%)
occurrences all number	12	0	2	14
Psychiatric disorders
Anxiety
subjects affected / exposed	3 / 90 (3.33%)	5 / 86 (5.81%)	2 / 52 (3.85%)	10 / 228 (4.39%)
occurrences all number	3	5	2	10
Insomnia
subjects affected / exposed	16 / 90 (17.78%)	7 / 86 (8.14%)	2 / 52 (3.85%)	25 / 228 (10.96%)
occurrences all number	16	7	2	25
Investigations
Alanine aminotransferase increased
subjects affected / exposed	15 / 90 (16.67%)	10 / 86 (11.63%)	1 / 52 (1.92%)	26 / 228 (11.40%)
occurrences all number	20	12	3	35
Amylase increased
subjects affected / exposed	10 / 90 (11.11%)	10 / 86 (11.63%)	7 / 52 (13.46%)	27 / 228 (11.84%)
occurrences all number	14	10	8	32
Aspartate aminotransferase increased
subjects affected / exposed	15 / 90 (16.67%)	8 / 86 (9.30%)	3 / 52 (5.77%)	26 / 228 (11.40%)
occurrences all number	22	10	5	37
Blood alkaline phosphatase increased
subjects affected / exposed	7 / 90 (7.78%)	3 / 86 (3.49%)	2 / 52 (3.85%)	12 / 228 (5.26%)
occurrences all number	7	4	2	13
Blood creatinine increased
subjects affected / exposed	7 / 90 (7.78%)	7 / 86 (8.14%)	4 / 52 (7.69%)	18 / 228 (7.89%)
occurrences all number	8	11	4	23
Gamma-glutamyltransferase increased
subjects affected / exposed	5 / 90 (5.56%)	7 / 86 (8.14%)	3 / 52 (5.77%)	15 / 228 (6.58%)
occurrences all number	5	12	3	20
Lipase increased
subjects affected / exposed	7 / 90 (7.78%)	6 / 86 (6.98%)	5 / 52 (9.62%)	18 / 228 (7.89%)
occurrences all number	9	7	5	21
Neutrophil count decreased
subjects affected / exposed	4 / 90 (4.44%)	14 / 86 (16.28%)	0 / 52 (0.00%)	18 / 228 (7.89%)
occurrences all number	8	20	0	28
Platelet count decreased
subjects affected / exposed	5 / 90 (5.56%)	9 / 86 (10.47%)	0 / 52 (0.00%)	14 / 228 (6.14%)
occurrences all number	9	12	0	21
Weight decreased
subjects affected / exposed	10 / 90 (11.11%)	8 / 86 (9.30%)	7 / 52 (13.46%)	25 / 228 (10.96%)
occurrences all number	10	9	7	26
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	3 / 90 (3.33%)	5 / 86 (5.81%)	1 / 52 (1.92%)	9 / 228 (3.95%)
occurrences all number	3	6	1	10
Nervous system disorders
Dizziness
subjects affected / exposed	16 / 90 (17.78%)	13 / 86 (15.12%)	5 / 52 (9.62%)	34 / 228 (14.91%)
occurrences all number	17	17	7	41
Dysgeusia
subjects affected / exposed	8 / 90 (8.89%)	5 / 86 (5.81%)	0 / 52 (0.00%)	13 / 228 (5.70%)
occurrences all number	9	6	0	15
Headache
subjects affected / exposed	14 / 90 (15.56%)	11 / 86 (12.79%)	5 / 52 (9.62%)	30 / 228 (13.16%)
occurrences all number	18	13	7	38
Hypoaesthesia
subjects affected / exposed	7 / 90 (7.78%)	7 / 86 (8.14%)	0 / 52 (0.00%)	14 / 228 (6.14%)
occurrences all number	7	8	0	15
Neuropathy peripheral
subjects affected / exposed	14 / 90 (15.56%)	10 / 86 (11.63%)	1 / 52 (1.92%)	25 / 228 (10.96%)
occurrences all number	14	10	2	26
Paraesthesia
subjects affected / exposed	6 / 90 (6.67%)	1 / 86 (1.16%)	0 / 52 (0.00%)	7 / 228 (3.07%)
occurrences all number	6	1	0	7
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	24 / 90 (26.67%)	37 / 86 (43.02%)	8 / 52 (15.38%)	69 / 228 (30.26%)
occurrences all number	34	56	11	101
Leukopenia
subjects affected / exposed	6 / 90 (6.67%)	4 / 86 (4.65%)	0 / 52 (0.00%)	10 / 228 (4.39%)
occurrences all number	25	7	0	32
Neutropenia
subjects affected / exposed	16 / 90 (17.78%)	15 / 86 (17.44%)	2 / 52 (3.85%)	33 / 228 (14.47%)
occurrences all number	24	25	3	52
Thrombocytopenia
subjects affected / exposed	9 / 90 (10.00%)	2 / 86 (2.33%)	0 / 52 (0.00%)	11 / 228 (4.82%)
occurrences all number	14	3	0	17
Eye disorders
Lacrimation increased
subjects affected / exposed	11 / 90 (12.22%)	8 / 86 (9.30%)	0 / 52 (0.00%)	19 / 228 (8.33%)
occurrences all number	13	8	0	21
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	6 / 90 (6.67%)	3 / 86 (3.49%)	5 / 52 (9.62%)	14 / 228 (6.14%)
occurrences all number	8	3	5	16
Abdominal pain upper
subjects affected / exposed	3 / 90 (3.33%)	7 / 86 (8.14%)	0 / 52 (0.00%)	10 / 228 (4.39%)
occurrences all number	3	8	0	11
Constipation
subjects affected / exposed	26 / 90 (28.89%)	23 / 86 (26.74%)	8 / 52 (15.38%)	57 / 228 (25.00%)
occurrences all number	40	35	9	84
Diarrhoea
subjects affected / exposed	23 / 90 (25.56%)	23 / 86 (26.74%)	14 / 52 (26.92%)	60 / 228 (26.32%)
occurrences all number	36	35	19	90
Dry mouth
subjects affected / exposed	1 / 90 (1.11%)	5 / 86 (5.81%)	0 / 52 (0.00%)	6 / 228 (2.63%)
occurrences all number	1	5	0	6
Dyspepsia
subjects affected / exposed	6 / 90 (6.67%)	1 / 86 (1.16%)	3 / 52 (5.77%)	10 / 228 (4.39%)
occurrences all number	11	2	5	18
Dysphagia
subjects affected / exposed	5 / 90 (5.56%)	4 / 86 (4.65%)	0 / 52 (0.00%)	9 / 228 (3.95%)
occurrences all number	5	4	0	9
Nausea
subjects affected / exposed	38 / 90 (42.22%)	37 / 86 (43.02%)	10 / 52 (19.23%)	85 / 228 (37.28%)
occurrences all number	80	101	13	194
Vomiting
subjects affected / exposed	19 / 90 (21.11%)	11 / 86 (12.79%)	6 / 52 (11.54%)	36 / 228 (15.79%)
occurrences all number	29	14	6	49
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	11 / 90 (12.22%)	16 / 86 (18.60%)	0 / 52 (0.00%)	27 / 228 (11.84%)
occurrences all number	11	16	0	27
Pruritus
subjects affected / exposed	12 / 90 (13.33%)	11 / 86 (12.79%)	6 / 52 (11.54%)	29 / 228 (12.72%)
occurrences all number	13	14	11	38
Rash
subjects affected / exposed	22 / 90 (24.44%)	18 / 86 (20.93%)	10 / 52 (19.23%)	50 / 228 (21.93%)
occurrences all number	35	25	13	73
Rash maculo-papular
subjects affected / exposed	5 / 90 (5.56%)	2 / 86 (2.33%)	0 / 52 (0.00%)	7 / 228 (3.07%)
occurrences all number	5	2	0	7
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	4 / 90 (4.44%)	6 / 86 (6.98%)	0 / 52 (0.00%)	10 / 228 (4.39%)
occurrences all number	4	6	0	10
Endocrine disorders
Hyperthyroidism
subjects affected / exposed	6 / 90 (6.67%)	6 / 86 (6.98%)	3 / 52 (5.77%)	15 / 228 (6.58%)
occurrences all number	8	6	3	17
Hypothyroidism
subjects affected / exposed	10 / 90 (11.11%)	9 / 86 (10.47%)	7 / 52 (13.46%)	26 / 228 (11.40%)
occurrences all number	10	9	8	27
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	14 / 90 (15.56%)	10 / 86 (11.63%)	5 / 52 (9.62%)	29 / 228 (12.72%)
occurrences all number	21	13	5	39
Back pain
subjects affected / exposed	14 / 90 (15.56%)	10 / 86 (11.63%)	8 / 52 (15.38%)	32 / 228 (14.04%)
occurrences all number	18	10	9	37
Bone pain
subjects affected / exposed	5 / 90 (5.56%)	0 / 86 (0.00%)	3 / 52 (5.77%)	8 / 228 (3.51%)
occurrences all number	8	0	3	11
Muscular weakness
subjects affected / exposed	6 / 90 (6.67%)	3 / 86 (3.49%)	2 / 52 (3.85%)	11 / 228 (4.82%)
occurrences all number	6	3	3	12
Myalgia
subjects affected / exposed	5 / 90 (5.56%)	3 / 86 (3.49%)	2 / 52 (3.85%)	10 / 228 (4.39%)
occurrences all number	5	3	2	10
Neck pain
subjects affected / exposed	5 / 90 (5.56%)	2 / 86 (2.33%)	1 / 52 (1.92%)	8 / 228 (3.51%)
occurrences all number	5	2	1	8
Pain in extremity
subjects affected / exposed	11 / 90 (12.22%)	5 / 86 (5.81%)	2 / 52 (3.85%)	18 / 228 (7.89%)
occurrences all number	12	5	3	20
Infections and infestations
Nasopharyngitis
subjects affected / exposed	5 / 90 (5.56%)	5 / 86 (5.81%)	3 / 52 (5.77%)	13 / 228 (5.70%)
occurrences all number	8	9	3	20
Pneumonia
subjects affected / exposed	7 / 90 (7.78%)	1 / 86 (1.16%)	2 / 52 (3.85%)	10 / 228 (4.39%)
occurrences all number	7	1	2	10
Upper respiratory tract infection
subjects affected / exposed	11 / 90 (12.22%)	6 / 86 (6.98%)	1 / 52 (1.92%)	18 / 228 (7.89%)
occurrences all number	14	7	1	22
Urinary tract infection
subjects affected / exposed	5 / 90 (5.56%)	9 / 86 (10.47%)	4 / 52 (7.69%)	18 / 228 (7.89%)
occurrences all number	8	10	4	22
Viral infection
subjects affected / exposed	5 / 90 (5.56%)	2 / 86 (2.33%)	0 / 52 (0.00%)	7 / 228 (3.07%)
occurrences all number	6	3	0	9
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	19 / 90 (21.11%)	20 / 86 (23.26%)	8 / 52 (15.38%)	47 / 228 (20.61%)
occurrences all number	23	23	11	57
Dehydration
subjects affected / exposed	4 / 90 (4.44%)	2 / 86 (2.33%)	3 / 52 (5.77%)	9 / 228 (3.95%)
occurrences all number	5	2	6	13
Hypercalcaemia
subjects affected / exposed	5 / 90 (5.56%)	1 / 86 (1.16%)	1 / 52 (1.92%)	7 / 228 (3.07%)
occurrences all number	6	1	1	8
Hyperglycaemia
subjects affected / exposed	4 / 90 (4.44%)	6 / 86 (6.98%)	2 / 52 (3.85%)	12 / 228 (5.26%)
occurrences all number	6	6	5	17
Hypoalbuminaemia
subjects affected / exposed	1 / 90 (1.11%)	5 / 86 (5.81%)	0 / 52 (0.00%)	6 / 228 (2.63%)
occurrences all number	3	6	0	9
Hypokalaemia
subjects affected / exposed	9 / 90 (10.00%)	8 / 86 (9.30%)	1 / 52 (1.92%)	18 / 228 (7.89%)
occurrences all number	13	12	1	26
Hypomagnesaemia
subjects affected / exposed	8 / 90 (8.89%)	7 / 86 (8.14%)	1 / 52 (1.92%)	16 / 228 (7.02%)
occurrences all number	12	10	1	23
Hyponatraemia
subjects affected / exposed	4 / 90 (4.44%)	6 / 86 (6.98%)	1 / 52 (1.92%)	11 / 228 (4.82%)
occurrences all number	4	11	1	16

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

17 Jul 2017

Updates to SoA; Serotonin syndrome; clarity to DMC review

17 Oct 2017

Dose modification and toxicity management guidelines for myocarditis. Melatonin and propofol removed from exclusion criteria and from the list of prohibited medications.

01 May 2018

Amended from a Phase 3 to a Phase 2 design, with ORR as the primary endpoint and PFS, OS, DOR as secondary endpoints due data from the Phase 3 KEYNOTE-252/ECHO-301. Removed Pembro + Epa arm, reduced number of patients to be enrolled to 148 and removed interim analysis.

04 Mar 2019

Data from the final analysis of KEYNOTE-715/ECHO-306 (data cutoff: 13-DEC-2018) indicated that the study did not meet the prespecified endpoint of improvement in objective response rate (ORR) for the combination of pembrolizumab plus epacadostat plus chemotherapy compared with pembrolizumab plus chemotherapy plus placebo. Based upon these data from the final analysis, the Sponsor and MSD implemented this Amendment 06 to direct that all epacadostat and placebo administration stop and to reflect that the study is no longer blinded. The study remained open so participants still on study will have continued access to pembrolizumab.

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.

Data from the final analysis of KEYNOTE-715/ECHO-306 (data cutoff: 13-DEC-2018) indicated that the study did not meet the pre-specified endpoint of improvement in objective response rate (ORR).

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