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Clinical Trial Results:
Adjuvant immunotherapy in patients with resected gastric cancer following preoperative chemotherapy with high risk for recurrence (N+ and/or R1): an open label randomized controlled phase-2-study (VESTIGE)

Summary
EudraCT number	2018-000406-36
Trial protocol	GB DE PL NO ES IT
Global end of trial date	11 Aug 2023

Results information
Results version number	v1(current)
This version publication date	08 Sep 2024
First version publication date	08 Sep 2024
Other versions

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

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Trial information

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Sponsor protocol code

EORTC-1707-GITCG

ISRCTN number

US NCT number

NCT03443856

WHO universal trial number (UTN)

Sponsor organisation name

European Organisation for the Research and Treatment of Cancer

Sponsor organisation address

Avenue Emmanuel Mounier 83/11, Brussels, Belgium, 1200

Public contact

Clinical Operations Department, European Organisation for the Research and Treatment of Cancer, 0032 27741334, murielle.mauer@gmail.com

Scientific contact

Clinical Operations Department, European Organisation for the Research and Treatment of Cancer, 0471693363 27741334, murielle.mauer@gmail.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

12 Mar 2024

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

11 Aug 2023

Was the trial ended prematurely?

Yes

Main objective of the trial

The primary objective of the trial is to investigate if nivolumab plus ipilimumab given as adjuvant treatment improve disease free survival (DFS) in patients with stage Ib-IVa gastric and esophagogastric junction (EGJ) adenocarcinoma and high risk of recurrence (defined by ypN1-3 and/or R1 status) following neoadjuvant chemotherapy and resection.

Protection of trial subjects

This study was conducted in agreement with either the Declaration of Helsinki (available on the World Medical Association web site (http://www.wma.net)) and/or the laws and regulations of the country, whichever provides the greatest protection of the patient. The protocol had been written, and the study was conducted according to the ICH Harmonized Tripartite Guideline on Good Clinical Practice (ICH-GCP, available online at https://www.ema.europa.eu/documents/scientific-guideline/ich-e6-r1-guideline-good-clinical-practice_en.pdf). The protocol was approved by the competent ethics committee(s) as required by the applicable national legislation.

Background therapy

Adjuvant chemotherapy based on the latest ESMO guidelines. Perioperative chemotherapy consisted of FLOT (docetaxel 50 mg/m2 given as a 1 hour infusion, followed by oxaliplatin 85 mg/m2 given as a 2 hour infusion, leucovorin 200 mg/m2 over 2 hours and 5-FU 2600 mg/m2 given as a 24 hour infusion) or an established non-FLOT perioperative chemotherapy regimen according to the study protocol (ECX, FOLFOX). The duration of preoperative chemotherapy was a minimum of 6 weeks and a maximum of 12 weeks.

Evidence for comparator

The standard treatment is adjuvant chemotherapy as specified by the ESMO guidelines.

Actual start date of recruitment

09 Aug 2019

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Israel: 19

Country: Number of subjects enrolled

Norway: 12

Country: Number of subjects enrolled

Poland: 13

Country: Number of subjects enrolled

Spain: 25

Country: Number of subjects enrolled

United Kingdom: 20

Country: Number of subjects enrolled

Czechia: 9

Country: Number of subjects enrolled

France: 27

Country: Number of subjects enrolled

Germany: 48

Country: Number of subjects enrolled

Italy: 22

Worldwide total number of subjects

195

EEA total number of subjects

156

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)

123

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Between 09/08/2019 and 14/06/2022, 195 patients with resected gastro-oesophageal adenocarcinoma following preoperative chemotherapy with high risk for recurrence (ypN+ and/or R1) were randomized at 26 medical centres in 9 countries (Czech Republic, France, Germany, Israel, Italy, Norway, Poland, Spain, and UK).

Screening details

Upon signing the informed consent and after verification of eligibility, patients were centrally randomized between the two arms in a 1:1 ratio. Treatment allocation was open-label and stratified for location (gastric vs. OGJ), histology (intestinal vs. non-intestinal), R0 vs. R1 status, preoperative chemotherapy (FLOT vs. non-FLOT).

Period 1 title

From randomization (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Standard arm

Arm description

Adjuvant chemotherapy based on the latest ESMO guidelines. Perioperative treatment consisted of FLOT or an established non-FLOT perioperative chemotherapy regimen according to the study protocol (ECX, FOLFOX). The duration of preoperative chemotherapy was a minimum of 6 weeks and a maximum of 12 weeks.

Arm type

Active comparator

Investigational medicinal product name

Epirubicin

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

-Epirubicin + cisplatin + capecitabine (ECX): Epirubicin 50 mg/m2 intravenously day 1, cisplatin 60 mg/m2 intravenously day 1, and capecitabine 625 mg/m2 twice daily on days 1–21. Cycled every 21 days for 3 cycles preop and 3 cycles postop.

Investigational medicinal product name

Cisplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

Capecitabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Fluorouracil

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

-Fluorouracil + leucovorin + oxaliplatin (FOLFOX): day 1: oxaliplatin 85 mg/m2 IV infusion, 400 mg/m2 leucovorin IV infusion, followed by 5-FU 400 mg/m2 IV push then 5-FU 1200 mg/m2 IV infusion for 22 hours; day 2: 5-FU 1200 mg/m2 IV infusion for 24 hours daily on Days 1 and 2. Cycled every 14 days for 4 cycles. -Fluorouracil + leucovorin + oxaliplatin + docetaxel (FLOT): FLOT is administered in cycles of 2 weeks for 4 cycles (= 8 weeks) on day 1, 15, 29 and 43 pre- and postoperatively. Docetaxel 50 mg/m2 is given as 1 hour infusion, followed by oxaliplatin 85 mg/m2 as a 2 hour infusion, leucovorin 200 mg/m2 over 2 hours, and 5-FU 2600 mg/m2 as a 24 hour-infusion, with oral dexamethasone for prevention of fluid retention and allergic reactions.

Investigational medicinal product name

Leucovorin

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

Oxaliplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

Docetaxel

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

-Fluorouracil + leucovorin + oxaliplatin + docetaxel (FLOT): FLOT is administered in cycles of 2 weeks for 4 cycles (= 8 weeks) on day 1, 15, 29 and 43 pre- and postoperatively. Docetaxel 50 mg/m2 is given as 1 hour infusion, followed by oxaliplatin 85 mg/m2 as a 2 hour infusion, leucovorin 200 mg/m2 over 2 hours, and 5-FU 2600 mg/m2 as a 24 hour-infusion, with oral dexamethasone for prevention of fluid retention and allergic reactions.

Experimental arm

Arm description

- Nivolumab 3 mg/kg intravenously every 2 weeks on day 1 of each 14 day cycle for one year - Ipilimumab 1 mg/kg intravenously every 6 weeks on day 1 of each 42 day cycle for one year

Arm type

Experimental

Investigational medicinal product name

Nivolumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Nivolumab 3 mg/kg intravenously every 2 weeks on day 1 of each 14 day cycle for one year.

Investigational medicinal product name

Ipilimumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Ipilimumab 1 mg/kg intravenously every 6 weeks on day 1 of each 42 day cycle for one year.

Number of subjects in period 1	Standard arm	Experimental arm
Started	97	98
Completed	71	20
Not completed	26	78
Adverse event, serious fatal	-	1
Adverse event, non-fatal	9	30
Patient's decision not to start treatment	10	1
Treatment not started due to patient ineligibility	2	-
Progression of disease	-	33
Patient's decision to stop treatment	4	13
Treatment not started due to other malignancy	1	-

Baseline characteristics

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Reporting group title

Standard arm

Reporting group description

Reporting group title

Experimental arm

Reporting group description

- Nivolumab 3 mg/kg intravenously every 2 weeks on day 1 of each 14 day cycle for one year - Ipilimumab 1 mg/kg intravenously every 6 weeks on day 1 of each 42 day cycle for one year

Reporting group values	Standard arm	Experimental arm	Total
Number of subjects	97	98	195
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)			0
From 65-84 years			0
85 years and over			0
Age continuous
Units: years
median (inter-quartile range (Q1-Q3))	60 (26 to 82)	61 (35 to 80)	-
Gender categorical
Units: Subjects
Female	37	29	66
Male	60	69	129
WHO performance status
Units: Subjects
PS 0	51	55	106
PS 1	46	43	89
Histologically proven gastric, lower oesophageal or OGJ adenocarcinoma (Siewert I-III)
Units: Subjects
Gastric adenocarcinoma	57	58	115
Lower oesophageal adenocarcinoma	8	11	19
OGJ adenocarcinoma	32	29	61
Histological subtype
Units: Subjects
Intestinal	49	52	101
Non-intestinal	48	46	94
Total or distal gastrectomy with D2 lymphadenectomy or oesophagectomy with two-field lymphadenectomy
done according to the ESMO guidelines
Units: Subjects
Yes	97	98	195
Resection status of primary tumor
according to TNM version 8
Units: Subjects
R0	81	84	165
R1	16	14	30
ypN stage
according to TNM version 8
Units: Subjects
ypN0	4	2	6
ypN1	31	24	55
ypN2	25	22	47
ypN3	37	50	87
Pre-operative chemotherapy regimen
Units: Subjects
non-FLOT	7	8	15
FLOT	90	90	180
Neoadjuvant chemotherapy duration
Units: weeks
median (inter-quartile range (Q1-Q3))	8 (6 to 8)	8 (6 to 8)	-

End points

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Reporting group title

Standard arm

Reporting group description

Reporting group title

Experimental arm

Reporting group description

- Nivolumab 3 mg/kg intravenously every 2 weeks on day 1 of each 14 day cycle for one year - Ipilimumab 1 mg/kg intravenously every 6 weeks on day 1 of each 42 day cycle for one year

Subject analysis set title

Per protocol population - standard arm

Subject analysis set type

Per protocol

Subject analysis set description

All patients who are eligible and have started their allocated treatment (at least one dose of the study drugs).

Subject analysis set title

Per protocol population - experimental arm

Subject analysis set type

Per protocol

Subject analysis set description

All patients who are eligible and have started their allocated treatment (at least one dose of the study drugs).

Primary: Disease free survival

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End point title

Disease free survival

End point description

Disease free survival is defined as the time interval between randomization and the date of disease recurrence or death from any cause, whichever comes first. Patients alive with no disease recurrence are censored at the date of the last follow-up examination.

End point type

Primary

End point timeframe

Disease evaluation was to be performed every 3 months during the treatment period for 2 years after randomization and every 6 months during follow up for consecutive 3 years until PD/death/lost to follow-up whichever occurs first.

End point values	Standard arm	Experimental arm	Per protocol population - standard arm	Per protocol population - experimental arm
Number of subjects analysed	97 ^[1]	98 ^[2]	79 ^[3]	93 ^[4]
Units: Months
median (confidence interval 95%)	20.8 (15.0 to 29.9)	11.4 (8.4 to 16.8)	20.8 (15.0 to 29.9)	11.7 (8.5 to 17.3)

Attachments

Disease free survival - ITT population
Disease free survival - per protocol population

Notes
[1] - The primary analysis of DFS was conducted in the Intention-to-treat population.
[2] - The primary analysis of DFS was conducted in the Intention-to-treat population.
[3] - A sensitivity analysis was performed in the per protocol population.
[4] - A sensitivity analysis was performed in the per protocol population.

Primary analysis (ITT)

Statistical analysis description

The primary test for the primary endpoint DFS was conducted in the Intention-to-treat population according to the intent to treat principle. The superiority of the experimental arm against the control arm was tested for DFS at a 1-sided level of significance of 0.1 using an unstratified log-rank test. A Cox regression model with treatment as covariate was used to provide an estimate of the treatment effect (hazard ratio) together its 1-sided 90% confidence interval.

Comparison groups

Standard arm v Experimental arm

Number of subjects included in analysis

195

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9902 ^[5]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.55

Confidence interval

level

80%

sides

2-sided

lower limit

1.22

upper limit

1.98

Notes
[5] - The one-sided p-value from the one-tailed unstratified log-rank test (primary analysis) is 0.99 and therefore not below the level of significance of 0.1. The primary endpoint, prolonged DFS in the experimental arm, was not met.

Sensitivity analysis (per protocol)

Statistical analysis description

A sensitivity analysis consisted in repeating the primary analysis in the per protocol population.

Comparison groups

Per protocol population - standard arm v Per protocol population - experimental arm

Number of subjects included in analysis

172

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9803 ^[6]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.49

Confidence interval

level

80%

sides

2-sided

lower limit

1.16

upper limit

1.92

Notes
[6] - The one-sided p-value from the one-tailed unstratified log-rank test (primary analysis) is 0.98 and therefore not below the level of significance of 0.1.

Secondary: Overall survival

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End point title

Overall survival

End point description

Overall survival is defined as the time interval between the date of randomization and the date of death from any cause. Patients who are still alive when last traced are censored at the date of last follow up.

End point type

Secondary

End point timeframe

After the end of treatment, patients were to be followed up for survival. Each patient was to be followed until death or for approximately 5 years following randomization in order to document the long-term outcomes.

End point values	Standard arm	Experimental arm	Per protocol population - standard arm	Per protocol population - experimental arm
Number of subjects analysed	97 ^[7]	98 ^[8]	79 ^[9]	93 ^[10]
Units: Months
median (confidence interval 95%)	38.0 (25.8 to 999)	27.6 (25.4 to 999)	38.0 (25.8 to 999)	27.6 (25.4 to 999)

Attachments

Overall survival - ITT population
Overall survival - per protocol population

Notes
[7] - The primary analysis of OS was conducted in the Intention-to-treat population. 999=Not reached
[8] - The primary analysis of OS was conducted in the Intention-to-treat population. 999=Not reached
[9] - A sensitivity analysis was performed in the per protocol population. 999=Not reached
[10] - A sensitivity analysis was performed in the per protocol population. 999=Not reached

Primary analysis (ITT)

Statistical analysis description

The primary analysis of the secondary endpoint OS was conducted in the Intention-to-treat population according to the intent to treat principle. A Cox regression model with treatment as covariate was used to provide an estimate of the treatment effect (hazard ratio) together its two-sided 95% confidence interval.

Comparison groups

Standard arm v Experimental arm

Number of subjects included in analysis

195

Analysis specification

Pre-specified

Analysis type

other ^[11]

Method

Parameter type

Hazard ratio (HR)

Point estimate

1.32

Confidence interval

level

95%

sides

2-sided

lower limit

0.83

upper limit

2.1

Notes
[11] - descriptive analysis

Sensitivity analysis (per protocol)

Statistical analysis description

A sensitivity analysis consisted in repeating the primary analysis in the per protocol population.

Comparison groups

Per protocol population - experimental arm v Per protocol population - standard arm

Number of subjects included in analysis

172

Analysis specification

Pre-specified

Analysis type

other ^[12]

Method

Parameter type

Hazard ratio (HR)

Point estimate

1.29

Confidence interval

level

95%

sides

2-sided

lower limit

0.8

upper limit

2.1

Notes
[12] - descriptive analysis

Secondary: 12-month disease-free survival rate

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End point title

12-month disease-free survival rate

End point description

DFS rates at 12 months and its two-sided 95% confidence interval were estimated in both treatment arms using the log-log transformation of the Kaplan-Meier estimates and the standard deviation of the Kaplan Meier estimate based on the Greenwood formula.

End point type

Secondary

End point timeframe

Disease evaluation was to be performed every 3 months during the treatment period for 2 years after randomization.

End point values	Standard arm	Experimental arm	Per protocol population - standard arm	Per protocol population - experimental arm
Number of subjects analysed	97 ^[13]	98 ^[14]	79 ^[15]	93 ^[16]
Units: Percentage
number (confidence interval 95%)	64.0 (52.7 to 73.2)	47.1 (36.8 to 56.8)	64.5 (52.7 to 74.1)	48.1 (37.5 to 57.9)

Notes
[13] - The primary analysis was conducted in the Intention-to-treat population.
[14] - The primary analysis was conducted in the Intention-to-treat population.
[15] - A sensitivity analysis was performed in the per protocol population.
[16] - A sensitivity analysis was performed in the per protocol population.

No statistical analyses for this end point

Secondary: Pattern and rate of relapse

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End point title

Pattern and rate of relapse

End point description

-Loco-regional failure: Local recurrence is defined as evidence of tumor in the anastomotic area. Regional recurrence is defined as evidence of tumor in the locoregional lymph nodes or other surrounding structures apart from the anastomotic site. -Distant failure: Distant recurrence is defined as recurrence not considered as local or regional.

End point type

Secondary

End point timeframe

End point values	Standard arm	Experimental arm	Per protocol population - standard arm	Per protocol population - experimental arm
Number of subjects analysed	97 ^[17]	98 ^[18]	79 ^[19]	93 ^[20]
Units: Patients
Loco-regional recurrence	12	19	12	18
Distant recurrence	30	39	27	37
Both	4	6	4	6
Death	2	2	2	2
No DFS event	49	32	34	30

Notes
[17] - The primary analysis was conducted in the Intention-to-treat population.
[18] - The primary analysis was conducted in the Intention-to-treat population.
[19] - A sensitivity analysis was performed in the per protocol population.
[20] - A sensitivity analysis was performed in the per protocol population.

No statistical analyses for this end point

Secondary: 12-month loco-regional failure rate

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End point title

12-month loco-regional failure rate

End point description

Time to loco-regional failure is defined as the time interval between randomization and the date of loco-regional recurrence. Distant failure as first recurrence or death in absence of loco-regional failure is considered as a competing risk in the estimation of the cumulative incidence of loco-regional failures. Patients alive with no disease recurrence are censored at the date of the last follow-up examination. The 1-year cumulative incidence rates together with their two-sided 95% confidence intervals are estimated in each arm using the competing risk methodology by means of a Fine-and-Gray model.

End point type

Secondary

End point timeframe

End point values	Standard arm	Experimental arm	Per protocol population - standard arm	Per protocol population - experimental arm
Number of subjects analysed	97 ^[21]	98 ^[22]	79 ^[23]	93 ^[24]
Units: Percent
number (confidence interval 95%)	10.8 (5.3 to 18.6)	20.2 (12.8 to 28.9)	11.8 (5.8 to 20.2)	20.0 (12.4 to 28.9)

Notes
[21] - The primary analysis was conducted in the Intention-to-treat population.
[22] - The primary analysis was conducted in the Intention-to-treat population.
[23] - A sensitivity analysis was performed in the per protocol population.
[24] - A sensitivity analysis was performed in the per protocol population.

Primary analysis (ITT)

Statistical analysis description

The primary analysis of this secondary endpoint was conducted in the Intention-to-treat population according to the intent to treat principle. Locoregional failure was analyzed using the competing risk methodology by means of a Fine-and-Gray model. Competing risk hazard ratios with their two-sided 95% confidence intervals will be provided.

Comparison groups

Standard arm v Experimental arm

Number of subjects included in analysis

195

Analysis specification

Pre-specified

Analysis type

other ^[25]

Method

Parameter type

Hazard ratio (HR)

Point estimate

1.48

Confidence interval

level

95%

sides

2-sided

lower limit

0.8

upper limit

2.76

Notes
[25] - descriptive analysis

Sensitivity analysis (per protocol)

Statistical analysis description

A sensitivity analysis consisted in repeating the primary analysis in the per protocol population.

Comparison groups

Per protocol population - standard arm v Per protocol population - experimental arm

Number of subjects included in analysis

172

Analysis specification

Pre-specified

Analysis type

other ^[26]

Method

Parameter type

Hazard ratio (HR)

Point estimate

1.35

Confidence interval

level

95%

sides

2-sided

lower limit

0.72

upper limit

2.52

Notes
[26] - descriptive analysis

Secondary: 12 months distant failure rate

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End point title

12 months distant failure rate

End point description

Time to distant failure is defined as the time interval between randomization and the date of distant recurrence. Loco-regional failure as first recurrence or death in absence of distant failure is considered as a competing risk in the estimation of the cumulative incidence of distant failures. Patients alive with no disease recurrence are censored at the date of the last follow-up examination. The 1-year cumulative incidence rates together with their two-sided 95% confidence intervals are estimated in each arm using the competing risk methodology by means of a Fine-and-Gray model.

End point type

Secondary

End point timeframe

End point values	Standard arm	Experimental arm	Per protocol population - standard arm	Per protocol population - experimental arm
Number of subjects analysed	97 ^[27]	98 ^[28]	79 ^[29]	93 ^[30]
Units: Percent
number (confidence interval 95%)	26.4 (17.4 to 36.3)	35.8 (26.2 to 45.5)	25.0 (15.8 to 35.1)	35.2 (25.5 to 45.1)

Notes
[27] - The primary analysis was conducted in the Intention-to-treat population.
[28] - The primary analysis was conducted in the Intention-to-treat population.
[29] - A sensitivity analysis was performed in the per protocol population.
[30] - A sensitivity analysis was performed in the per protocol population.

Primary analysis (ITT)

Statistical analysis description

The primary analysis of this secondary endpoint was conducted in the Intention-to-treat population according to the intent to treat principle. Distant failure was analyzed using the competing risk methodology by means of a Fine-and-Gray model. Competing risk hazard ratios with their two-sided 95% confidence intervals are provided.

Comparison groups

Standard arm v Experimental arm

Number of subjects included in analysis

195

Analysis specification

Pre-specified

Analysis type

other ^[31]

Method

Parameter type

Hazard ratio (HR)

Point estimate

1.35

Confidence interval

level

95%

sides

2-sided

lower limit

0.87

upper limit

2.08

Notes
[31] - descriptive analysis

Sensitivity analysis (per protocol)

Statistical analysis description

A sensitivity analysis consisted in repeating the primary analysis in the per protocol population.

Comparison groups

Per protocol population - standard arm v Per protocol population - experimental arm

Number of subjects included in analysis

172

Analysis specification

Pre-specified

Analysis type

other ^[32]

Method

Parameter type

Hazard ratio (HR)

Point estimate

1.34

Confidence interval

level

95%

sides

2-sided

lower limit

0.85

upper limit

2.11

Notes
[32] - descriptive analysis

Adverse events

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Timeframe for reporting adverse events

Adverse events were collected on a CRF to be submitted at pre-specified timepoint : Adverse events are reported from day 1 of study treatment (after the "Baseline" period) till the end of the follow-up period for safety.

Adverse event reporting additional description

AEs are evaluated using CTC grading, SAEs using MedDra. Non-SAEs has not been collected specifically, all AEs will be reported in non-SAE section. 1 SAE with SOC Product issues and PT Device dislocation occurred in the experimental arm and is not reported as no matching EudraCT ID for the MedDra coding was identified.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

Reporting group title

Experimental arm

Reporting group description

- Nivolumab 3 mg/kg intravenously every 2 weeks on day 1 of each 14 day cycle for one year - Ipilimumab 1 mg/kg intravenously every 6 weeks on day 1 of each 42 day cycle for one year

Reporting group title

Standard arm

Reporting group description

Serious adverse events	Experimental arm	Standard arm
Total subjects affected by serious adverse events
subjects affected / exposed	41 / 97 (42.27%)	19 / 84 (22.62%)
number of deaths (all causes)	41	30
number of deaths resulting from adverse events	0	0
Vascular disorders
ORTHOSTATIC HYPOTENSION
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 97 (0.00%)	1 / 84 (1.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
HYPOTENSION
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 97 (0.00%)	1 / 84 (1.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
PHLEBITIS
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 97 (0.00%)	1 / 84 (1.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
PYREXIA
alternative dictionary used: MedDRA 25
subjects affected / exposed	2 / 97 (2.06%)	2 / 84 (2.38%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
ASTHENIA
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
MUCOSAL INFLAMMATION
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 97 (0.00%)	1 / 84 (1.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
FATIGUE
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
DISEASE PROGRESSION
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
CHILLS
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Immune system disorders
DRUG HYPERSENSITIVITY
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 97 (0.00%)	2 / 84 (2.38%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
IMMUNE-MEDIATED LUNG DISEASE
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
PLEURAL EFFUSION
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 97 (0.00%)	1 / 84 (1.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
RESPIRATORY FAILURE
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
PULMONARY EMBOLISM
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 97 (0.00%)	1 / 84 (1.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
PNEUMONITIS ASPIRATION
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
PNEUMONITIS
alternative dictionary used: MedDRA 25
subjects affected / exposed	2 / 97 (2.06%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Investigations
NEUTROPHIL COUNT DECREASED
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 97 (0.00%)	1 / 84 (1.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
ASPARTATE AMINOTRANSFERASE INCREASED
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
ALANINE AMINOTRANSFERASE INCREASED
alternative dictionary used: MedDRA 25
subjects affected / exposed	2 / 97 (2.06%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
ANIMAL BITE
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
HUMERUS FRACTURE
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
PERICARDIAL EFFUSION
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 97 (0.00%)	1 / 84 (1.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
CARDIAC TAMPONADE
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 97 (0.00%)	1 / 84 (1.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
CARDIAC FAILURE
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 97 (0.00%)	1 / 84 (1.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
ATRIAL FIBRILLATION
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 97 (0.00%)	2 / 84 (2.38%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
PERIPHERAL SENSORY NEUROPATHY
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
NEUROPATHY PERIPHERAL
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
ISCHAEMIC CEREBRAL INFARCTION
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
CEREBRAL INFARCTION
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
ANAEMIA
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
NEUTROPENIA
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 97 (0.00%)	1 / 84 (1.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
FEBRILE NEUTROPENIA
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 97 (0.00%)	2 / 84 (2.38%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
GASTROINTESTINAL DISORDER
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
DUMPING SYNDROME
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
DIARRHOEA
alternative dictionary used: MedDRA 25
subjects affected / exposed	5 / 97 (5.15%)	2 / 84 (2.38%)
occurrences causally related to treatment / all	0 / 5	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
CONSTIPATION
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
COLITIS
alternative dictionary used: MedDRA 25
subjects affected / exposed	5 / 97 (5.15%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 5	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
ABDOMINAL PAIN
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
GASTROINTESTINAL TOXICITY
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 97 (0.00%)	1 / 84 (1.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
IMMUNE-MEDIATED ENTEROCOLITIS
alternative dictionary used: MedDRA 25
subjects affected / exposed	3 / 97 (3.09%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
ILEUS
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
HAEMORRHOIDAL HAEMORRHAGE
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 97 (0.00%)	1 / 84 (1.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
GASTROOESOPHAGEAL REFLUX DISEASE
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
INTESTINAL OBSTRUCTION
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
LARGE INTESTINAL OBSTRUCTION
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
NAUSEA
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 97 (0.00%)	2 / 84 (2.38%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
OESOPHAGEAL STENOSIS
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
PANCREATITIS ACUTE
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
SMALL INTESTINAL OBSTRUCTION
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 97 (1.03%)	2 / 84 (2.38%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
VOMITING
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 97 (0.00%)	2 / 84 (2.38%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
AUTOIMMUNE HEPATITIS
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
HEPATITIS
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
HYPERTRANSAMINASAEMIA
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
IMMUNE-MEDIATED HEPATITIS
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
DERMATITIS ALLERGIC
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
URINARY RETENTION
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
CHRONIC KIDNEY DISEASE
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
ACUTE KIDNEY INJURY
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Endocrine disorders
HYPOPHYSITIS
alternative dictionary used: MedDRA 25
subjects affected / exposed	2 / 97 (2.06%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
HYPOTHYROIDISM
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
HYPOPITUITARISM
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
ARTHRITIS
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
CERVICAL SPINAL STENOSIS
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
ABSCESS
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
APPENDICITIS
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
BACTERIAL INFECTION
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
DEVICE RELATED INFECTION
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
ENTERITIS INFECTIOUS
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 97 (0.00%)	1 / 84 (1.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
HERPES ZOSTER
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
VIRAL INFECTION
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 97 (0.00%)	1 / 84 (1.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
SKIN INFECTION
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 97 (0.00%)	1 / 84 (1.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
SEPSIS
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
PNEUMONIA
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
LOWER RESPIRATORY TRACT INFECTION
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
INFECTION
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
DIABETIC METABOLIC DECOMPENSATION
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
DIABETIC KETOACIDOSIS
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
ACIDOSIS
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	Experimental arm	Standard arm
Total subjects affected by non serious adverse events
subjects affected / exposed	95 / 97 (97.94%)	81 / 84 (96.43%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MALIGNANT FRACTURE
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
CYST IN LEG
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
PERITONEAL CARCINOMATOSIS
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
TUMOR PAIN
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
SUSPECTED BONE METASTASES
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
Vascular disorders
VASCULITIS
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
HOT FLASHES
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	2 / 97 (2.06%)	0 / 84 (0.00%)
occurrences all number	2	0
HYPERTENSION
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	6 / 97 (6.19%)	0 / 84 (0.00%)
occurrences all number	9	0
HYPOTENSION
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	3 / 84 (3.57%)
occurrences all number	1	3
PHLEBITIS
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	0 / 97 (0.00%)	1 / 84 (1.19%)
occurrences all number	0	1
SUPERFICIAL THROMBOPHLEBITIS
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
THROMBOEMBOLIC EVENT
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	2 / 97 (2.06%)	1 / 84 (1.19%)
occurrences all number	3	1
Surgical and medical procedures
WOUND HEALING DEFICIT
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
General disorders and administration site conditions
EXERCISE INTOLERANCE
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
EDEMA LIMBS
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	4 / 97 (4.12%)	3 / 84 (3.57%)
occurrences all number	4	4
EDEMA FACE
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
DETERIORATION OF GENERAL CONDITION
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
COLD INTOLERANCE
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	0 / 97 (0.00%)	1 / 84 (1.19%)
occurrences all number	0	1
CLINICAL PROGRESSIVE DISEASE
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	2	0
CHILLS
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	3 / 97 (3.09%)	1 / 84 (1.19%)
occurrences all number	4	1
FACIAL PAIN
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	0 / 97 (0.00%)	1 / 84 (1.19%)
occurrences all number	0	2
WORSENING OF GENERAL CONDITION
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
PAIN
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	2 / 97 (2.06%)	1 / 84 (1.19%)
occurrences all number	2	1
NON-CARDIAC CHEST PAIN
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	2 / 97 (2.06%)	1 / 84 (1.19%)
occurrences all number	2	1
MUCOSITIS
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	0 / 97 (0.00%)	1 / 84 (1.19%)
occurrences all number	0	1
INFUSION RELATED REACTION
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
HEADACHE
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
FLU LIKE SYMPTOMS
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	0 / 97 (0.00%)	2 / 84 (2.38%)
occurrences all number	0	2
FEVER
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	15 / 97 (15.46%)	5 / 84 (5.95%)
occurrences all number	18	7
FATIGUE
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	48 / 97 (49.48%)	37 / 84 (44.05%)
occurrences all number	66	54
Immune system disorders
SARCOIDOSIS
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
ALLERGIC REACTION
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	0 / 97 (0.00%)	4 / 84 (4.76%)
occurrences all number	0	4
Reproductive system and breast disorders
ERECTILE DYSFUNCTION
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	0 / 97 (0.00%)	1 / 84 (1.19%)
occurrences all number	0	1
Respiratory, thoracic and mediastinal disorders
SORE THROAT
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
ALLERGIC RHINITIS
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
COMMON COLD
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	2 / 97 (2.06%)	0 / 84 (0.00%)
occurrences all number	2	0
COMMON COLD SYMTOMS
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
COUGH
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	9 / 97 (9.28%)	2 / 84 (2.38%)
occurrences all number	11	2
DYSPNEA
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	3 / 97 (3.09%)	2 / 84 (2.38%)
occurrences all number	4	3
EPISTAXIS
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	5 / 84 (5.95%)
occurrences all number	3	6
HICCUPS
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	0 / 97 (0.00%)	1 / 84 (1.19%)
occurrences all number	0	1
HOARSENESS
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	0 / 97 (0.00%)	1 / 84 (1.19%)
occurrences all number	0	1
INFLAMED MUCOUS MEMBRANE IN THE NOSE
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
PLEURAL EFFUSION
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	1 / 84 (1.19%)
occurrences all number	1	2
PNEUMONITIS
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	10 / 97 (10.31%)	0 / 84 (0.00%)
occurrences all number	15	0
POSTNASAL DRIP
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
PRODUCTIVE COUGH
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	0 / 97 (0.00%)	1 / 84 (1.19%)
occurrences all number	0	1
RHINITIS - NON INFECTIVE
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
RHINORRHEA
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	1 / 84 (1.19%)
occurrences all number	1	1
SARCOIDOSIS
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
Psychiatric disorders
CONFUSION
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	2	0
DEPRESSION
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	2 / 97 (2.06%)	0 / 84 (0.00%)
occurrences all number	2	0
INSOMNIA
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	8 / 97 (8.25%)	2 / 84 (2.38%)
occurrences all number	8	3
LOW MOOD
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	0 / 97 (0.00%)	1 / 84 (1.19%)
occurrences all number	0	1
ANXIETY
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	1 / 84 (1.19%)
occurrences all number	1	1
Investigations
ALANINE AMINOTRANSFERASE INCREASED
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	10 / 97 (10.31%)	0 / 84 (0.00%)
occurrences all number	27	0
ALKALINE PHOSPHATASE INCREASED
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	3 / 97 (3.09%)	2 / 84 (2.38%)
occurrences all number	4	2
ASPARTATE AMINOTRANSFERASE INCREASED
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	10 / 97 (10.31%)	0 / 84 (0.00%)
occurrences all number	21	0
BLOOD BILIRUBIN INCREASED
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	0 / 97 (0.00%)	1 / 84 (1.19%)
occurrences all number	0	1
BLOOD CORTICOTROPHIN DECREASED
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	0 / 97 (0.00%)	1 / 84 (1.19%)
occurrences all number	0	1
BLOOD LACTATE DEHYDROGENASE INCREASED
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
CPK INCREASED
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
CREATININE INCREASED
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	3 / 97 (3.09%)	0 / 84 (0.00%)
occurrences all number	3	0
CRP INCREASED
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
ELECTROLYTE IMBALANCE
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
FOLINAT ACID DECREASE
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
GGT INCREASED
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	2 / 97 (2.06%)	1 / 84 (1.19%)
occurrences all number	4	1
GRANULOCYTOPENIA
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	0 / 97 (0.00%)	1 / 84 (1.19%)
occurrences all number	0	3
HYPERTRANSAMINASEMIA
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	2 / 97 (2.06%)	0 / 84 (0.00%)
occurrences all number	10	0
HYPERTRANSAMINEMIA
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
INTERMITTENT LEUKOCYTOSIS
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
LIPASE INCREASED
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	2	0
NEUTROPHIL COUNT DECREASED
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	5 / 97 (5.15%)	33 / 84 (39.29%)
occurrences all number	8	57
PLATELET COUNT DECREASED
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	3 / 97 (3.09%)	6 / 84 (7.14%)
occurrences all number	8	9
SERUM AMYLASE INCREASED
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
THYROID STIMULATING HORMONE INCREASED
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
TRANSAMINASE INCREASE
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
TRANSAMINASE INCREASED
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
TSH DECREASED
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	3	0
WEIGHT GAIN
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
WEIGHT LOSS
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	6 / 97 (6.19%)	7 / 84 (8.33%)
occurrences all number	8	11
WHITE BLOOD CELL DECREASED
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	10 / 84 (11.90%)
occurrences all number	4	19
LYMPHOCYTE COUNT DECREASED
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	0 / 97 (0.00%)	1 / 84 (1.19%)
occurrences all number	0	1
Injury, poisoning and procedural complications
PEJ LEAKAGE
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	2	0
INFUSION RELATED REACTION
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	1 / 84 (1.19%)
occurrences all number	1	1
FRACTURE
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
ESOPHAGEAL ANASTOMOTIC LEAK
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
BURN
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
BRUISING
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	0 / 97 (0.00%)	2 / 84 (2.38%)
occurrences all number	0	2
A BITE WOUND INFLICTED BY A DOG
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
PAIN AT THE SURGICAL SUTURE
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
PULLING OUT PEJ AFTER FALL
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
SEROMA
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
WOUND INCISED CONTUSED
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
Cardiac disorders
CORONARY ARTERY DISEASE
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	0 / 97 (0.00%)	1 / 84 (1.19%)
occurrences all number	0	1
TACHYCARDIA
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
ATRIAL FIBRILLATION
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	2 / 84 (2.38%)
occurrences all number	1	2
HEART FAILURE
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	0 / 97 (0.00%)	1 / 84 (1.19%)
occurrences all number	0	1
PALPITATIONS
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	0 / 97 (0.00%)	1 / 84 (1.19%)
occurrences all number	0	1
PERICARDIAL EFFUSION
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	0 / 97 (0.00%)	1 / 84 (1.19%)
occurrences all number	0	1
PERICARDIAL TAMPONADE
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	0 / 97 (0.00%)	1 / 84 (1.19%)
occurrences all number	0	1
RIGHT BUNDLE BRANCH BLOCK
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	0 / 97 (0.00%)	1 / 84 (1.19%)
occurrences all number	0	1
SINUS BRADYCARDIA
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
SINUS TACHYCARDIA
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
CARDIOMYOPAHTY
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
VENTRICULAR ARRHYTHMIA
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
Nervous system disorders
STROKE
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	3	0
COGNITIVE DISTURBANCE
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
DIZZINESS
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	3 / 97 (3.09%)	3 / 84 (3.57%)
occurrences all number	3	4
DYSARTHRIA
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	0 / 97 (0.00%)	1 / 84 (1.19%)
occurrences all number	0	1
DYSESTHESIA
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
DYSGEUSIA
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	4 / 84 (4.76%)
occurrences all number	1	4
DYSPHAGIA
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	0 / 97 (0.00%)	1 / 84 (1.19%)
occurrences all number	0	1
HEADACHE
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	10 / 97 (10.31%)	4 / 84 (4.76%)
occurrences all number	11	4
HYPOESTHESIA
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	0 / 97 (0.00%)	2 / 84 (2.38%)
occurrences all number	0	2
LOSS OF CONTACT
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	0 / 97 (0.00%)	1 / 84 (1.19%)
occurrences all number	0	2
NEURALGIA
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
PARESTHESIA
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	7 / 97 (7.22%)	9 / 84 (10.71%)
occurrences all number	7	12
PERIPHERAL MOTOR NEUROPATHY
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	1 / 84 (1.19%)
occurrences all number	1	1
PERIPHERAL SENSORY NEUROPATHY
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	8 / 97 (8.25%)	24 / 84 (28.57%)
occurrences all number	11	39
PRESYNCOPE
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	0 / 97 (0.00%)	1 / 84 (1.19%)
occurrences all number	0	1
TREMOR
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
Blood and lymphatic system disorders
LEUKOCYTOSIS
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	1 / 84 (1.19%)
occurrences all number	1	1
IRON DEFICIENCY ANEMIA
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
FEBRILE NEUTROPENIA
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	0 / 97 (0.00%)	2 / 84 (2.38%)
occurrences all number	0	2
EOSINOPHILIA
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	2 / 97 (2.06%)	0 / 84 (0.00%)
occurrences all number	3	0
ANEMIA
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	9 / 97 (9.28%)	11 / 84 (13.10%)
occurrences all number	12	12
Ear and labyrinth disorders
VERTIGO
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	2 / 97 (2.06%)	0 / 84 (0.00%)
occurrences all number	3	0
TINNITUS
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	2 / 97 (2.06%)	0 / 84 (0.00%)
occurrences all number	2	0
MUFFLED HEARING
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	0 / 97 (0.00%)	1 / 84 (1.19%)
occurrences all number	0	1
HEARING IMPAIRED
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
EAR PAIN
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
Eye disorders
DRY EYE
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	2 / 97 (2.06%)	0 / 84 (0.00%)
occurrences all number	2	0
DOUBLE VISION
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
BLURRED VISION
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	3 / 97 (3.09%)	1 / 84 (1.19%)
occurrences all number	3	1
EYE PAIN
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	1 / 84 (1.19%)
occurrences all number	1	1
VISION DECREASED
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	1 / 84 (1.19%)
occurrences all number	1	1
WATERING EYES
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	0 / 97 (0.00%)	1 / 84 (1.19%)
occurrences all number	0	1
XEROPHTHALMIA
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
STY
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	0 / 97 (0.00%)	1 / 84 (1.19%)
occurrences all number	0	1
Gastrointestinal disorders
DYSPEPSIA
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	3 / 97 (3.09%)	0 / 84 (0.00%)
occurrences all number	3	0
ABDOMINAL PAIN
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	23 / 97 (23.71%)	10 / 84 (11.90%)
occurrences all number	35	15
ANAL FISSURE
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
ASCITES
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	0 / 97 (0.00%)	1 / 84 (1.19%)
occurrences all number	0	1
BLOATING
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	2 / 97 (2.06%)	2 / 84 (2.38%)
occurrences all number	2	2
CHOLANGITIS
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
DUMPING SYNDROME
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	2 / 97 (2.06%)	1 / 84 (1.19%)
occurrences all number	2	1
DRY MOUTH
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	4 / 97 (4.12%)	0 / 84 (0.00%)
occurrences all number	4	0
DIARRHEA
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	43 / 97 (44.33%)	53 / 84 (63.10%)
occurrences all number	81	86
COPROSTASIS
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	2	0
CONSTIPATION
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	7 / 97 (7.22%)	4 / 84 (4.76%)
occurrences all number	11	6
COLONIC OBSTRUCTION
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	2 / 97 (2.06%)	0 / 84 (0.00%)
occurrences all number	2	0
COLITIS
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	11 / 97 (11.34%)	0 / 84 (0.00%)
occurrences all number	23	0
ILEAL OBSTRUCTION
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	0 / 97 (0.00%)	2 / 84 (2.38%)
occurrences all number	0	2
ILEUS
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	3	0
DYSPHAGIA
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	3 / 97 (3.09%)	6 / 84 (7.14%)
occurrences all number	3	7
ENTEROCOLITIS
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
EPIGASTRIC INTERMITTENT FEELING OF PRESSURE
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	0 / 97 (0.00%)	1 / 84 (1.19%)
occurrences all number	0	2
ESOPHAGEAL PAIN
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	0 / 97 (0.00%)	1 / 84 (1.19%)
occurrences all number	0	1
ESOPHAGEAL STENOSIS
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	2 / 97 (2.06%)	0 / 84 (0.00%)
occurrences all number	9	0
FAT STOOLS
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
FATTY STOOLS
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
FLATULENCE
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	2 / 84 (2.38%)
occurrences all number	2	3
GASTRITIS
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	2 / 97 (2.06%)	0 / 84 (0.00%)
occurrences all number	2	0
GASTROESOPHAGEAL REFLUX DISEASE
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	10 / 97 (10.31%)	7 / 84 (8.33%)
occurrences all number	12	7
GASTROINTESTINAL TOXICITY
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	0 / 97 (0.00%)	1 / 84 (1.19%)
occurrences all number	0	2
HEARTBURN
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	0 / 97 (0.00%)	1 / 84 (1.19%)
occurrences all number	0	1
HEMORRHOIDAL HEMORRHAGE
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	0 / 97 (0.00%)	1 / 84 (1.19%)
occurrences all number	0	2
HEMORRHOIDS
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	2 / 84 (2.38%)
occurrences all number	1	3
SMALL INTESTINAL OBSTRUCTION
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	2 / 97 (2.06%)	1 / 84 (1.19%)
occurrences all number	4	1
TOOTHACHE
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	2 / 97 (2.06%)	0 / 84 (0.00%)
occurrences all number	2	0
RECTAL TENESMUS
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
RECTAL PAIN
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
PANCREATITIS
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	3 / 97 (3.09%)	0 / 84 (0.00%)
occurrences all number	3	0
NAUSEA
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	21 / 97 (21.65%)	34 / 84 (40.48%)
occurrences all number	30	53
MUCOSITIS ORAL
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	2 / 97 (2.06%)	7 / 84 (8.33%)
occurrences all number	2	10
MUCOSITIS
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	0 / 97 (0.00%)	1 / 84 (1.19%)
occurrences all number	0	1
MOUTH SORE
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
INTESTINAL VOLVULUS
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
SOFT STOOL
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
STEATORRHEA
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	1 / 84 (1.19%)
occurrences all number	1	2
STEATORRHOEA
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
STOMACH PAIN
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	2	0
SIALORRHEA
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	2 / 97 (2.06%)	0 / 84 (0.00%)
occurrences all number	2	0
WOUND IN THE LIPS
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
VOMITING
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	10 / 97 (10.31%)	10 / 84 (11.90%)
occurrences all number	13	14
TRANSVERSE TOOTH FRACTURE
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
Hepatobiliary disorders
CHOLESTASIS
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	2 / 97 (2.06%)	0 / 84 (0.00%)
occurrences all number	2	0
HEPATITIS
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	4 / 97 (4.12%)	0 / 84 (0.00%)
occurrences all number	9	0
IMMUNE RELATED HEPATITIS
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	2 / 97 (2.06%)	0 / 84 (0.00%)
occurrences all number	2	0
IMMUNE-MEDIATED HEPATITIS
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
TRANSAMINASES INCREASED
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
TRANSAMINITIS
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	2	0
HEPATIC CYTOLYSIS
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
Skin and subcutaneous tissue disorders
ALOPECIA
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	6 / 84 (7.14%)
occurrences all number	2	6
RASH ACNEIFORM
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	4 / 97 (4.12%)	1 / 84 (1.19%)
occurrences all number	4	1
CONTACT DERMATITIS, BOTH HANDS
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
DRY SKIN
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	2 / 97 (2.06%)	4 / 84 (4.76%)
occurrences all number	3	4
ECZEMA
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	2 / 97 (2.06%)	1 / 84 (1.19%)
occurrences all number	2	1
ERYTHEMA MULTIFORME
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	3 / 97 (3.09%)	0 / 84 (0.00%)
occurrences all number	3	0
ERYTHEMA, LEFT ARM AROUND PICC LINE
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
ERYTHRODERMA
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	0 / 97 (0.00%)	1 / 84 (1.19%)
occurrences all number	0	1
EXCORIATION OF THE RIGHT CLAVICLE
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
HYPERKERATOTIC RHAGADIFORM HAND ECZEMA
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
IMMUNE-INDUCED SKIN PATHOLOGY
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
NAIL CHANGES
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	1 / 84 (1.19%)
occurrences all number	1	1
NAIL RIDGING
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	1 / 84 (1.19%)
occurrences all number	1	1
PALMAR-PLANTAR ERYTHRODYSESTHESIA SYNDROME
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	0 / 97 (0.00%)	3 / 84 (3.57%)
occurrences all number	0	4
PRURITUS
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	24 / 97 (24.74%)	1 / 84 (1.19%)
occurrences all number	34	1
PSORIASIS
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	2 / 97 (2.06%)	0 / 84 (0.00%)
occurrences all number	2	0
RASH
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
RASH (NOS)
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
BULLOUS DERMATITIS
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
RASH MACULO-PAPULAR
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	14 / 97 (14.43%)	1 / 84 (1.19%)
occurrences all number	20	1
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - OTHER, RASH
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
SKIN RASH
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
SUBCUTANEOUS ABSCESS
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
URTICARIA
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
VITILIGO
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
SKIN AND SUBCUTANEOUS TISSUE DISORDERS
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
Renal and urinary disorders
URINARY STONES
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
ACUTE KIDNEY FAILURE
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
ACUTE KIDNEY INJURY
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
CHRONIC KIDNEY DISEASE
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	2 / 97 (2.06%)	0 / 84 (0.00%)
occurrences all number	4	0
CYSTITIS NONINFECTIVE
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
DYSURIA
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	0 / 97 (0.00%)	1 / 84 (1.19%)
occurrences all number	0	1
HEMATURIA
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
NEPHRITIS
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	2 / 97 (2.06%)	0 / 84 (0.00%)
occurrences all number	2	0
PROTEINURIA
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
RENAL INSUFFICIENCY
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	0 / 97 (0.00%)	1 / 84 (1.19%)
occurrences all number	0	1
URINARY FREQUENCY
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
URINARY INCONTINENCE
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
URINARY RETENTION
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	1 / 84 (1.19%)
occurrences all number	1	1
URINARY TRACT OBSTRUCTION
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	2 / 97 (2.06%)	0 / 84 (0.00%)
occurrences all number	2	0
Endocrine disorders
ADRENALITIS
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
ADRENAL INSUFFICIENCY
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	5 / 97 (5.15%)	0 / 84 (0.00%)
occurrences all number	6	0
HYPERTHYROIDISM
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	20 / 97 (20.62%)	2 / 84 (2.38%)
occurrences all number	22	2
THYROIDITIS
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
HYPOTHYROIDISM
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	20 / 97 (20.62%)	1 / 84 (1.19%)
occurrences all number	28	1
HYPOPITUITARISM
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	3 / 97 (3.09%)	0 / 84 (0.00%)
occurrences all number	4	0
HYPOPHYSITIS
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	8 / 97 (8.25%)	0 / 84 (0.00%)
occurrences all number	11	0
Musculoskeletal and connective tissue disorders
BONE PAIN
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
ALGIC SYNDROME
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
ARTHRALGIA
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	9 / 97 (9.28%)	0 / 84 (0.00%)
occurrences all number	10	0
ARTHRITIS
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	5 / 97 (5.15%)	0 / 84 (0.00%)
occurrences all number	7	0
ARTHROMYALGIA
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
BACK PAIN
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	9 / 97 (9.28%)	3 / 84 (3.57%)
occurrences all number	10	3
BURSITIS IN THE RIGHT FOREARM
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
CHEST WALL PAIN
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
COLD TOE
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	0 / 97 (0.00%)	1 / 84 (1.19%)
occurrences all number	0	1
CRITICAL-ILLNESS-MYOPATHIE
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
GENERALIZED MUSCLE WEAKNESS
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	2 / 97 (2.06%)	2 / 84 (2.38%)
occurrences all number	2	2
GOUT ATTACK
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
GOUT ATTACK LEFT KNEE
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
MUSCLE WEAKNESS UPPER LIMB
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	3	0
MYALGIA
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	5 / 97 (5.15%)	1 / 84 (1.19%)
occurrences all number	5	1
NECK PAIN
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
PAIN IN EXTREMITY
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	6 / 97 (6.19%)	1 / 84 (1.19%)
occurrences all number	7	1
PULLED GROIN MUSCLE
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	0 / 97 (0.00%)	1 / 84 (1.19%)
occurrences all number	0	1
RIGHT ILIAC FOSSA PAIN
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
SPINE PAIN
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
TENDONITIS
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
CERVICAL SPINAL STENOSIS C5-6 AND C6-7
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
Infections and infestations
COVID-19
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
COVID INFECTION
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
COVID 19 INFECTION
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	3 / 97 (3.09%)	0 / 84 (0.00%)
occurrences all number	3	0
COLD SYMPTOMS
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
CATHETER RELATED INFECTION
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	2 / 97 (2.06%)	0 / 84 (0.00%)
occurrences all number	2	0
BRONCHIAL INFECTION
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	2 / 84 (2.38%)
occurrences all number	1	2
APPENDICITIS
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
ABSCESS RIGHT THORACIC
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
COVID-19 INFECTION
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	4 / 97 (4.12%)	2 / 84 (2.38%)
occurrences all number	4	2
COVID-19 VIRUS
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	0 / 97 (0.00%)	1 / 84 (1.19%)
occurrences all number	0	1
PYELONEFRITIS-CYSTITIS
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
POSITIVE ANTIGENURIA FOR PNEUMOCOCCUS
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	0 / 97 (0.00%)	1 / 84 (1.19%)
occurrences all number	0	1
PARONYCHIA
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	1 / 84 (1.19%)
occurrences all number	1	1
OTITIS MEDIA
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	2	0
OTITIS EXTERNA
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
LUNG INFECTION
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	5 / 97 (5.15%)	2 / 84 (2.38%)
occurrences all number	7	3
LOWER RESPIRATORY TRACT INFECTION
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	3	0
KIDNEY INFECTION
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
INFLAMMATORY NIDUS CHEST RIGHT SITE
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
INFECTION WITHOUT FOCUS
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
INFECTION OF UNCLEAR ORIGIN
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
INFECTION JEJUNAL TUBE
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	0 / 97 (0.00%)	1 / 84 (1.19%)
occurrences all number	0	1
HERPES SIMPLEX REACTIVATION
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	1 / 84 (1.19%)
occurrences all number	1	1
GASTROENTERITIS
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	0 / 97 (0.00%)	1 / 84 (1.19%)
occurrences all number	0	1
GALLBLADDER INFECTION
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
CYSTITIS
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
RASH PUSTULAR
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
WOUND INFECTION
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	2	0
VIRAL INFECTION (FLU)
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	0 / 97 (0.00%)	1 / 84 (1.19%)
occurrences all number	0	1
URINARY TRACT INFECTION
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	4 / 97 (4.12%)	1 / 84 (1.19%)
occurrences all number	7	2
UPPER RESPIRATORY INFECTION
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	2 / 84 (2.38%)
occurrences all number	1	2
UNSPECIFIED BACTERIAL INFECTION
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
SKIN INFECTION
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	1 / 84 (1.19%)
occurrences all number	1	1
SHINGLES
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	2 / 97 (2.06%)	0 / 84 (0.00%)
occurrences all number	3	0
SEPSIS
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	2 / 97 (2.06%)	0 / 84 (0.00%)
occurrences all number	2	0
SARS COVID-19 INFECTION
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
Metabolism and nutrition disorders
HYPERGLYCEMIA DECOMPENSATION OF DIABETES
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
ACIDOSIS
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	2 / 97 (2.06%)	0 / 84 (0.00%)
occurrences all number	3	0
ANOREXIA
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	17 / 97 (17.53%)	7 / 84 (8.33%)
occurrences all number	20	9
DEHYDRATION
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
DIABETIC KETOACIDOSIS
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
HYPERGLYCEMIA
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	2 / 84 (2.38%)
occurrences all number	1	5
HYPERKALEMIA
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	2 / 97 (2.06%)	0 / 84 (0.00%)
occurrences all number	3	0
HYPERPHOSPHATEMIA
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	2 / 97 (2.06%)	0 / 84 (0.00%)
occurrences all number	2	0
HYPOALBUMINEMIA
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	1 / 84 (1.19%)
occurrences all number	1	1
HYPOCALCEMIA
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	3	0
HYPOGLYCEMIA
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	2	0
HYPOKALEMIA
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	7 / 97 (7.22%)	2 / 84 (2.38%)
occurrences all number	11	3
HYPOMAGNESEMIA
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	0 / 97 (0.00%)	1 / 84 (1.19%)
occurrences all number	0	1
HYPONATREMIA
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	4	0
HYPOPHOSPHATEMIA
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	3 / 97 (3.09%)	0 / 84 (0.00%)
occurrences all number	3	0
IRON DEFICIENCY
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
POSTPRANDIAL SYNDROME
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	0 / 97 (0.00%)	1 / 84 (1.19%)
occurrences all number	0	1
STORAGE IRON DEFICIENCY
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	1 / 97 (1.03%)	0 / 84 (0.00%)
occurrences all number	1	0
HYPERLIPIDEMIA
alternative dictionary used: CTCAE 5.0
subjects affected / exposed	0 / 97 (0.00%)	1 / 84 (1.19%)
occurrences all number	0	1

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Were there any global substantial amendments to the protocol? Yes

03 Aug 2018

SCIENTIFIC AMENDMENT 1 -Amendment of PISIC following new GDPR Regulation in May 2018. -Amendment of dosing of immunotherapy in the experimental arm (Protocol and PISIC) based on DMC recommendation to close the Nivolumab 1 mg/kg + ipilimumab 3 mg/kg of the CHECKMATE 649 study. Dosing is changed back to IB recommendations: Nivolumab 3 mg/kg + ipilimumab 1 mg/kg. -Clarification of the assessment schedule.

06 Apr 2020

SCIENTIFIC AMENDMENT 2 -Added text discussing the balance between benefit versus life-threatening and fatal SARs listed for nivo+ipi in SmpC (requested by NL and and Norway competent authorities) -Added possible men contraception methods (requested by regulatory bodies) -Pregnancy testing for 6 months after EOT added as per IB/SMPC -Positive testing to HIV according to local practice (requested by German regulatory bodies) -Clarification of timelines and time windows for evaluation -Safety updated according to new nivolumab IB -Capecitabine dosage corrected - now aligned with ESMO guidelines

15 Oct 2020

-COVID-19 addendum -Safety guidelines clarified based on safety guidance of the Investigator's brochures (IBs) -Risks and side effects related to nivolumab and ipilimumab updated based on CTFG recommendations (v1.1) -Clarification of timeline of FU assessments by our DM following feedback from sites

03 Mar 2021

SCIENTIFIC AMENDMENT 4 -Eligibility criteria: inclusion of patients with prior malignancies provided they have no impact on patient's prognosis -Removal of BP monitoring post immunotherapy infusion except for cycle 1 -Authorization of off-site lab assessments for Biochemistry, hematology, pregnancy, thyroid function, except for Screening assessment -Update of toxicity management algorithms to CTCAE V5 as per ipi IB addendum 01 & 02 -COVID addendum to PISIC: to inform patients about potential measures specific to the COVID health crisis -Update of PIS/IC: mention of Pelvic imaging during treatment and follow for consistency with protocol and database

25 Oct 2021

SCIENTIFIC AMENDMENT 5 -Eligibility criteria: inclusion of patients with partial DPD deficiency and clarification of surgery timelines. -Update of toxicity management algorithms as per ipilimumab and nivolumab IBs v24 and v20. -Statistical analysis: Given the low frequencies of patients with R1 resection (17.5%) and receiving other regimen than FLOT (8.3%) and the phase of the study (phase II with no intent for regulatory submission), an unstratified log-rank test will be used for the primary analysis. -Update of pregnancy reporting: Within 12 months (for a female subject) or 9 months (for a female partner of a male subject); possibility to report by e-mail in addition to fax. -Update of PIS/IC: New safety information for nivolumab and ipilimumab; update of duration of contraception.

29 Apr 2022

SCIENTIFIC AMENDMENT 6 -Clarification of inclusion of partially deficient patients based on SoC testing (genetic or uracil levels) as per request of French CA

05 Oct 2022

SCIENTIFIC AMENDMENT 7 -Update of PISIC: The investigator brochures of both nivolumab and ipilimumab were updated, leading to Nivo IB v 21.0 and ipilimumab IB v 25.0. The safety language of the study PISIC was updated accordingly. Clarification of duration of pregnancy testing during treatment and after end of treatment depending on treatment arm.

27 Jan 2023

ADMINISTRATIVE AMENDMENT 8 -To specify TR laboratory -To clarify TR lab responsibilities

Were there any global interruptions to the trial? No

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

None reported

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Clinical Trial Results:
Adjuvant immunotherapy in patients with resected gastric cancer following preoperative chemotherapy with high risk for recurrence (N+ and/or R1): an open label randomized controlled phase-2-study (VESTIGE)

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Baseline characteristics

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Primary: Disease free survival

Primary: Disease free survival

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Secondary: Overall survival

Secondary: 12-month disease-free survival rate

Secondary: 12-month disease-free survival rate

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Secondary: Pattern and rate of relapse

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Secondary: 12-month loco-regional failure rate

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Secondary: 12 months distant failure rate

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Clinical trials

Clinical Trial Results: Adjuvant immunotherapy in patients with resected gastric cancer following preoperative chemotherapy with high risk for recurrence (N+ and/or R1): an open label randomized controlled phase-2-study (VESTIGE)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Disease free survival

Primary: Disease free survival

Secondary: Overall survival

Secondary: Overall survival

Secondary: 12-month disease-free survival rate

Secondary: 12-month disease-free survival rate

Secondary: Pattern and rate of relapse

Secondary: Pattern and rate of relapse

Secondary: 12-month loco-regional failure rate

Secondary: 12-month loco-regional failure rate

Secondary: 12 months distant failure rate

Secondary: 12 months distant failure rate

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
Adjuvant immunotherapy in patients with resected gastric cancer following preoperative chemotherapy with high risk for recurrence (N+ and/or R1): an open label randomized controlled phase-2-study (VESTIGE)