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Clinical Trial Results:
INtegratioN of trastuzumab, with or without pertuzumab, into periOperatiVe chemotherApy of HER-2 posiTIve stOmach caNcer: the INNOVATION-TRIAL

Summary
EudraCT number	2014-000722-38
Trial protocol	EE DE BE NO PT GB ES NL FR IT
Global end of trial date	30 Sep 2024

Results information
Results version number	v1(current)
This version publication date	07 Jun 2026
First version publication date	07 Jun 2026
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

1203-GITCG

ISRCTN number

US NCT number

NCT02205047

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

Regulatory Affairs Department, European Organisation for Research and Treatment of Cancer (EORTC), +32 27741586, regulatory@eortc.org

Scientific contact

Regulatory Affairs Department, European Organisation for Research and Treatment of Cancer (EORTC), +32 27741586, regulatory@eortc.org

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

06 Jun 2022

Is this the analysis of the primary completion data?

Yes

Primary completion date

06 Jun 2022

Global end of trial reached?

Yes

Global end of trial date

30 Sep 2024

Was the trial ended prematurely?

Main objective of the trial

To increase the major pathological response rate (< 10% vital tumor cells) to neoadjuvant treatment by integrating both trastuzumab and pertuzumab or trastuzumab alone into perioperative chemotherapy for HER-2 positive, resectable gastric cancer.

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

Background therapy

Adjuvant chemotherapy based on the latest ESMO guidelines.

Evidence for comparator

Actual start date of recruitment

13 Nov 2015

Long term follow-up planned

Yes

Long term follow-up rationale

Efficacy, Scientific research

Long term follow-up duration

6 Years

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Belgium: 1

Country: Number of subjects enrolled

Estonia: 7

Country: Number of subjects enrolled

France: 28

Country: Number of subjects enrolled

Germany: 65

Country: Number of subjects enrolled

Italy: 22

Country: Number of subjects enrolled

Korea, Republic of: 16

Country: Number of subjects enrolled

Netherlands: 3

Country: Number of subjects enrolled

Norway: 1

Country: Number of subjects enrolled

Singapore: 1

Country: Number of subjects enrolled

Spain: 20

Country: Number of subjects enrolled

Switzerland: 4

Country: Number of subjects enrolled

United Kingdom: 4

Worldwide total number of subjects

172

EEA total number of subjects

147

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

Top of page

Recruitment details

A total of 621 patients were recruited from Belgium, Estonia, France, Germany, Israel, Italy, Korea, Netherlands, Norway, Portugal, Singapore, Spain, Switzerland and the United Kingdom between the 13/11/2015 and 27/12/2021.

Screening details

A total of 621 patients were registered in the study and signed an informed consent for further testing of their HER2 status. This status was assessed locally and/or centrally. After assessment, 172 patients were found eligible.

Period 1 title

Randomized study period (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Control Arm

Arm description

Patients were treated with chemotherapy alone. In protocol v1.0, all patients were treated with cisplatin and capecitabine or 5-FU. The protocol was amended (v 4.0) on 19/10/2017 to mandate that patients were given FLOT, CapOX or mFOLFOX6 in European centers.

Arm type

Active comparator

Investigational medicinal product name

Capecitabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Capecitabine was administered for three cycles of 3 weeks before and after surgery. Capecitabine was given orally at a dose of 1000 mg/m2 twice daily on days 1 to 14 out of 21 days.

Investigational medicinal product name

Cisplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Infusion

Dosage and administration details

Cisplatin was administered for three cycles of 3 weeks before and after surgery. Cisplatin was administered at the dose of 80 mg/m2 every three weeks by IV infusion.

Investigational medicinal product name

5-FU

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Infusion

Dosage and administration details

5-FU was administered for three cycles of 3 weeks before and after surgery. 5-FU was given at a dose of 800 mg/m2/day by continuous infusion on days 1 to 5 every 21 days (for patients with contraindications for capecitabine) and is given after cisplatin.

Investigational medicinal product name

FLOT

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Infusion

Dosage and administration details

FLOT was 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 was given as 1 hour infusion, followed by Oxaliplatin 85 mg/m2 diluted with 250 to 500 ml of 5% glucose solution as a 2-hour infusion, leucovorin 200 mg/m2 over 2 hours and 5-FU 2600mg/m2 as a 24 hour-infusion, with oral dexamethasone for prevention of fluid retention and allergic reactions for example at a dose of 8 mg in the morning (8am) and evening (8pm) on the day before administration of FLOT, and a third dose together with antiemetic premedication on the day of chemotherapy administration.

Investigational medicinal product name

CapOx

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Infusion

Dosage and administration details

CapOx was given for 3 cycles of 3 weeks (= 9 weeks) on day 1, 22 and 43 pre- and postoperatively. Oxaliplatin was given as a 2-hour intravenous infusion at a dose of 130 mg/m2 on day 1. Oxaliplatin needed to be diluted with 250 to 500 ml of 5% glucose solution, followed by capecitabine given orally at a dose of 1000 mg/m2 twice daily from the evening of day 1 to the morning of day 15 every 3 weeks.

Investigational medicinal product name

mFOLFOX6

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Infusion

Dosage and administration details

mFOLFOX6 was given for 4 cycles of 2 weeks (=8 weeks) on day 1, 15, 29 and 43 pre- and postoperatively. Oxaliplatin diluted with 250 to 500 ml of 5% glucose solution was given as a 2-hour intravenous infusion at a dose of 85mg/m2, followed by leucovorin 400 mg/m2 iv over 2 hours on day 1, and 5-FU 400mg/m2 iv bolus on day 1, then 1200 mg/m2/d x 2 days over 46-48 hours continuous infusion every 2 weeks.

Experimental Arm 1

Arm description

Experimental arm 1 consisted of perioperative chemotherapy plus trastuzumab. Trastuzumab was administered independently of the chemotherapy regimen at day 1 of each cycle, with an 8 mg/kg loading dose followed by 6 mg/kg every 3 weeks. Trastuzumab was given in combination with pre and postoperative chemotherapy for three 3 week cycles and was continued after completion of adjuvant chemotherapy as maintenance treatment. Antibody therapy was planned to continue up to a total of 17 cycles from the start of neoadjuvant treatment.

Arm type

Experimental

Investigational medicinal product name

Trastuzumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Infusion

Dosage and administration details

Trastuzumab was administered at a 8 mg/kg loading dose, followed by 6 mg/kg every 3 weeks at day 1, independent of the chemotherapy regimen chosen for 3 cycles of 3 weeks before and after surgery and for up to 17 cycles from the start of neoadjuvant treatment.

Investigational medicinal product name

Capecitabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Capecitabine was given orally at a dose of 1000 mg/m2 twice daily on days 1 to 14 out of 21 days. Capecitabine was administered for three cycles of 3 weeks before and after surgery.

Investigational medicinal product name

Cisplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Infusion

Dosage and administration details

Cisplatin was administered for three cycles of 3 weeks before and after surgery. Cisplatin was administered at the dose of 80 mg/m2 every three weeks by IV infusion.

Investigational medicinal product name

5-FU

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Infusion

Dosage and administration details

Investigational medicinal product name

FLOT

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Infusion

Dosage and administration details

Investigational medicinal product name

CapOx

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Infusion

Dosage and administration details

Investigational medicinal product name

mFOLFOX6

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Infusion

Dosage and administration details

Experimental Arm 2

Arm description

Experimental arm 2 consisted of perioperative chemotherapy plus trastuzumab and pertuzumab, with pertuzumab administered at a fixed dose of 840 mg every 3 weeks on day 1, independent of the chemotherapy regimen chosen. Trastuzumab and pertuzumab were administered for three 3‑week cycles in combination with pre‑ and postoperative chemotherapy, followed by maintenance antibody therapy. After completion of adjuvant chemotherapy, trastuzumab and pertuzumab were continued as maintenance treatment up to a total of 17 cycles from the start of neoadjuvant therapy.

Arm type

Experimental

Investigational medicinal product name

Pertuzumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Infusion

Dosage and administration details

Pertuzumab was administered as an infusion at a dose of 840 mg every 3 weeks at day 1, for 3 cycles of 3 weeks before and after surgery and for up to 17 cycles from the start of neoadjuvant treatment.

Investigational medicinal product name

Trastuzumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Infusion

Dosage and administration details

Investigational medicinal product name

Capecitabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Capecitabine was administered for three cycles of 3 weeks before and after surgery. Capecitabine was given orally at a dose of 1000 mg/m2 twice daily on days 1 to 14 out of 21 days.

Investigational medicinal product name

Cisplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Infusion

Dosage and administration details

Cisplatin was administered for three cycles of 3 weeks before and after surgery. Cisplatin was administered at the dose of 80 mg/m2 every three weeks by IV infusion.

Investigational medicinal product name

5-FU

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Infusion

Dosage and administration details

Investigational medicinal product name

FLOT

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Infusion

Dosage and administration details

Investigational medicinal product name

CapOx

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Infusion

Dosage and administration details

Investigational medicinal product name

mFOLFOX6

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Infusion

Dosage and administration details

Number of subjects in period 1	Control Arm	Experimental Arm 1	Experimental Arm 2
Started	35	67	70
Completed	20	30	24
Not completed	15	37	46
Adverse event, serious fatal	-	2	2
Consent withdrawn by subject	1	4	7
Physician decision	1	4	6
Adverse event, non-fatal	6	12	20
Spondylodiscitis	1	-	-
Covid-19	1	-	-
Treatment never started due to GI bleeding	1	-	-
Poor clinical condition	1	1	-
Protocol deviation	1	5	4
Lack of efficacy	2	9	7

Baseline characteristics

Top of page

Reporting group title

Control Arm

Reporting group description

Reporting group title

Experimental Arm 1

Reporting group description

Reporting group title

Experimental Arm 2

Reporting group description

Reporting group values	Control Arm	Experimental Arm 1	Experimental Arm 2	Total
Number of subjects	35	67	70	172
Age categorical
Units: Subjects
In utero	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0
Newborns (0-27 days)	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0
Children (2-11 years)	0	0	0	0
Adolescents (12-17 years)	0	0	0	0
Adults (18-64 years)	19	35	38	92
From 65-84 years	16	32	32	80
85 years and over	0	0	0	0
Age continuous
Units: years
median (inter-quartile range (Q1-Q3))	63.0 (52.0 to 70.0)	63.0 (55.0 to 72.0)	64.0 (59.0 to 70.0)	-
Gender categorical
Units: Subjects
Female	2	21	7	30
Male	33	46	63	142
Site of the tumor
Units: Subjects
Stomach	13	26	26	65
Esophagogastric junction	22	41	44	107
Histological subtype
Units: Subjects
Intestinal	25	46	50	121
Non-intestinal	10	21	20	51
Clinical UICC stage as defined by CT-scan and/or MRI and endosonography if applicable
Units: Subjects
Stage IB	2	4	3	9
Stage IIA	4	7	5	16
Stage IIB	6	11	14	31
Stage IIIA	11	22	31	64
Stage IIIB	4	13	5	22
Stage IIIC	7	10	11	28
Stage IV	1	0	1	2
Histological grade
Units: Subjects
GI	3	9	7	19
GII	23	35	36	94
GIII	7	17	13	37
Missing	2	6	14	22
T-Stage
Units: Subjects
cT1	0	1	2	3
cT2	8	10	10	28
cT3	16	42	46	104
cT4	0	1	2	3
cT1b	2	0	0	2
cTX	0	2	3	5
cT4a	7	10	5	22
cT4b	1	1	2	4
Missing	1	0	0	1
N-Stage
Units: Subjects
cN0	6	12	10	28
cN1	14	29	33	76
cN2	10	14	14	38
cN3	1	4	6	11
cN3a	0	2	1	3
cN3b	1	1	0	2
cNX	3	5	5	13
Missing	0	0	1	1
M-Stage
Units: Subjects
cM0	34	67	70	171
cM1	1	0	0	1

Subject analysis set title

Per Protocol Population

Subject analysis set type

Per protocol

Subject analysis set description

All patients who met the important eligibility criteria (as assessed during medical review) and have started their allocated treatment (at least one dose of the study drug(s) planned as pre-operative treatment).

Subject analysis set title

Safety Population

Subject analysis set type

Safety analysis

Subject analysis set description

All patients who have started their allocated treatment (at least one dose of the study drug(s) planned as pre-operative treatment).

Subject analysis set title

Resected Population

Subject analysis set type

Sub-group analysis

Subject analysis set description

All patients who met the important eligibility criteria (as assessed during medical review, have started the allocated pre-operative treatment, were operated and achieved an R0 or R1 resection.

Subject analysis sets values	Per Protocol Population	Safety Population	Resected Population
Number of subjects	161	169	148
Age categorical
Units: Subjects
In utero	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0
Newborns (0-27 days)	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0
Children (2-11 years)	0	0	0
Adolescents (12-17 years)	0	0	0
Adults (18-64 years)	86	80	91
From 65-84 years	75	65	78
85 years and over	0	0	0
Age continuous
Units: years
median (inter-quartile range (Q1-Q3))	64.0 (57.0 to 71.0)
Gender categorical
Units: Subjects
Female	30
Male	131
Site of the tumor
Units: Subjects
Stomach	61
Esophagogastric junction	100
Histological subtype
Units: Subjects
Intestinal	116
Non-intestinal	45
Clinical UICC stage as defined by CT-scan and/or MRI and endosonography if applicable
Units: Subjects
Stage IB	9
Stage IIA	16
Stage IIB	28
Stage IIIA	60
Stage IIIB	22
Stage IIIC	26
Stage IV
Histological grade
Units: Subjects
GI	18
GII	86
GIII	35
Missing	22
T-Stage
Units: Subjects
cT1	3
cT2	27
cT3	99
cT4	3
cT1b	2
cTX	3
cT4a	19
cT4b	4
Missing	1
N-Stage
Units: Subjects
cN0	27
cN1	68
cN2	38
cN3	11
cN3a	3
cN3b	2
cNX	11
Missing	1
M-Stage
Units: Subjects
cM0	161
cM1	0

End points

Top of page

Reporting group title

Control Arm

Reporting group description

Reporting group title

Experimental Arm 1

Reporting group description

Reporting group title

Experimental Arm 2

Reporting group description

Subject analysis set title

Per Protocol Population

Subject analysis set type

Per protocol

Subject analysis set description

Subject analysis set title

Safety Population

Subject analysis set type

Safety analysis

Subject analysis set description

All patients who have started their allocated treatment (at least one dose of the study drug(s) planned as pre-operative treatment).

Subject analysis set title

Resected Population

Subject analysis set type

Sub-group analysis

Subject analysis set description

All patients who met the important eligibility criteria (as assessed during medical review, have started the allocated pre-operative treatment, were operated and achieved an R0 or R1 resection.

Primary: Major Pathological Response (mpR) rate

Top of page

End point title

Major Pathological Response (mpR) rate

End point description

Pathological response was assessed centrally using the Becker regression grading. Histopathologists were blinded to treatment allocation. Major pathological response is defined as major tumor regression (<10% vital residual tumor cells). The mpR rate is computed in each arm as the percentage of patients who had mpR after neoadjuvant treatment. Patients not resected were considered as not having major pathological response. MpR rate in each arm is calculated in the per protocol population with its exact 2-sided 95% confidence interval.

End point type

Primary

End point timeframe

Pathological response is assessed after neoadjuvant therapy and surgery.

End point values	Control Arm	Experimental Arm 1	Experimental Arm 2
Number of subjects analysed	30 ^[1]	54 ^[2]	53 ^[3]
Units: % of patients with mpR
number (confidence interval 95%)	23.3 (9.9 to 42.3)	37.0 (24.3 to 51.3)	26.4 (15.3 to 40.3)

Notes
[1] - For 3 patients operated in the Control Arm, sample was missing or judged of insufficient quality
[2] - For 10 patients operated in Experimental Arm 1, sample was missing or judged of insufficient quality
[3] - For 11 patients operated in Experimental Arm 2, sample was missing or judged of insufficient quality

Primary Analysis: Exp Arm 1 vs Control arm

Statistical analysis description

The primary analysis was done in the per protocol analysis. Difference in major Pathological Response Rate (% of patients with mpR) between experimental arm 1 (Chemo + Trastuzumab) and chemo only arm was tested at a one-sided 10% level of significance. The asymptotic one-sided 90% confidence interval was calculated. Results are expressed in %.

Comparison groups

Control Arm v Experimental Arm 1

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

13.7

Confidence interval

level

90%

sides

1-sided

lower limit

0.7

upper limit

Primary Analysis: Exp Arm 2 vs Control arm

Statistical analysis description

The primary analysis was done in the per protocol analysis. Difference in major Pathological Response Rate (% of patients with mpR) between experimental arm 2 (Chemo + Trastuzumab + Pertuzumab) and chemo only arm was tested at a one-sided 10% level of significance. The asymptotic one-sided 90% confidence interval was calculated. Results are expressed in %.

Comparison groups

Control Arm v Experimental Arm 2

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

3.1

Confidence interval

level

90%

sides

1-sided

lower limit

-9.5

upper limit

Secondary: R0 resection rate (%)

Top of page

End point title

R0 resection rate (%)

End point description

R0 resection is defined as the absence of residual tumor at the resection margins. The R0 resection rate is computed in each arm as the percentage of patients who had a R0 resection after neoadjuvant treatment. Patients who did not undergo surgery or did not have a resection are considered as no R0 resection. R0 resection rate in each arm is calculated in the per protocol population with its exact 2-sided 95% confidence interval.

End point type

Secondary

End point timeframe

R0 resection is assessed after surgery.

End point values	Control Arm	Experimental Arm 1	Experimental Arm 2
Number of subjects analysed	32 ^[4]	63 ^[5]	64
Units: % of patients with R0 resection
number (confidence interval 95%)	87.5 (71.0 to 96.5)	90.5 (80.4 to 96.4)	85.9 (75.0 to 93.4)

Notes
[4] - 1 patient with unknow resection status in the Control Arm
[5] - 1 patient with unknow resection status in Experimental Arm 1

No statistical analyses for this end point

Secondary: Progression Free Survival (RECIST v1.1)

Top of page

End point title

Progression Free Survival (RECIST v1.1)

End point description

Progression free survival is defined as the time interval between randomization and the date of disease progression or death from any cause, whichever comes first. Patients alive with no disease progression are censored at the date of the last follow-up examination. The primary analysis of Progression-free survival was performed in the Per protocol population.

End point type

Secondary

End point timeframe

Disease evaluation was performed at end of neoadjuvant treatment, every 6 months after surgery for the first 2 years and every 12 months for additional 4 years until progression, death, lost to follow-up or end of study.

End point values	Control Arm	Experimental Arm 1	Experimental Arm 2
Number of subjects analysed	33	64	64
Units: PFS rate (%) at 3 years
number (confidence interval 95%)	63.6 (44.9 to 77.5)	64.7 (51.5 to 75.2)	52.0 (38.8 to 63.8)

Attachments

PFS_KM_PP

No statistical analyses for this end point

Secondary: Overall Survival

Top of page

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. The primary analysis of Overall survival was performed in the Per protocol population.

End point type

Secondary

End point timeframe

All patients were followed-up until death for 6 years following surgery or until lost to follow-up or end of study.

End point values	Control Arm	Experimental Arm 1	Experimental Arm 2
Number of subjects analysed	33	64	64
Units: OS rate (%) at 3 years
number (confidence interval 95%)	75.6 (57.1 to 87.0)	76.9 (64.1 to 85.6)	65.2 (51.3 to 76.1)

Attachments

OS_KM_PP

No statistical analyses for this end point

Secondary: Recurrence Free Survival (from surgery)

Top of page

End point title

Recurrence Free Survival (from surgery)

End point description

Recurrence-free survival was defined in resected patients who achieved a R0 or R1 resection as the time interval from surgery to the date of first recurrence (local, regional or distant) or death, whichever comes first. Patients alive and recurrence free at the time of data analysis were censored at the date of the most recent follow-up. Recurrence-free survival was analyzed in the resected population.

End point type

Secondary

End point timeframe

Post surgery, disease evaluation was performed every 6 months for the first 2 years and every 12 months for 4 additional years until recurrence, death, lost to follow-up or end of study.

End point values	Control Arm	Experimental Arm 1	Experimental Arm 2
Number of subjects analysed	28	62	58
Units: RFS rate (%) at 3 years
number (confidence interval 95%)	67.9 (47.3 to 81.8)	63.2 (49.7 to 74.1)	54.6 (40.5 to 66.8)

Attachments

RFS_KM_RES

Experimental Arm 1 vs Control Arm

Statistical analysis description

The primary analysis of the secondary endpoint RFS was conducted in the Resected Only population. 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

Control Arm v Experimental Arm 1

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.92

Confidence interval

level

95%

sides

2-sided

lower limit

0.45

upper limit

1.9

Experimental Arm 2 vs Control Arm

Statistical analysis description

Comparison groups

Experimental Arm 2 v Control Arm

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Hazard ratio (HR)

Point estimate

1.24

Confidence interval

level

95%

sides

2-sided

lower limit

0.61

upper limit

2.51

Secondary: Cumulative Incidence of Locoregional Failure

Top of page

End point title

Cumulative Incidence of Locoregional Failure

End point description

Locoregional failure is defined as local or regional recurrence/progression, a tumor that cannot be resected or R2 resection at surgery. Local recurrence/progression is defined as evidence/progression of tumor in the anastomotic area or as recurrence/progression in the locoregional lymph nodes. Death in absence of locoregional failure is considered as a competing risk in the estimation of the cumulative incidence of locoregional failure. Patients who have not had any such event at the time of data analysis are censored at the date of the most recent follow-up. Locoregional failure was analysed in the per protocol population.

End point type

Secondary

End point timeframe

End point values	Control Arm	Experimental Arm 1	Experimental Arm 2
Number of subjects analysed	33	64	64
Units: Cumulative incidence rate (%) at 3 years
number (confidence interval 95%)	21.3 (9.2 to 36.8)	19.3 (10.6 to 30.0)	20.1 (11.0 to 31.1)

Attachments

CUM_LRF_PP

No statistical analyses for this end point

Secondary: Cumulative Incidence of Distant Failure

Top of page

End point title

Cumulative Incidence of Distant Failure

End point description

Distant failure is defined as the appearance of distant metastases. Death in absence of distant failure will be considered as a competing risk in the estimation of the cumulative incidence of distant failure. Patients who have not had any such event at the time of data analysis are censored at the date of the most recent follow-up. Distant failure was analysed in the per protocol population.

End point type

Secondary

End point timeframe

End point values	Control Arm	Experimental Arm 1	Experimental Arm 2
Number of subjects analysed	33	64	64
Units: Cumulative incidence rate (%) at 3 years
number (confidence interval 95%)	33.3 (17.9 to 49.6)	25.7 (15.6 to 37.1)	28.3 (17.5 to 40.1)

Attachments

CUM_DF_PP

No statistical analyses for this end point

Secondary: Complete Pathological Response (cpR) rate (%)

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End point title

Complete Pathological Response (cpR) rate (%)

End point description

Pathological response was assessed centrally using the Becker regression grading. Histopathologists were blinded to treatment allocation. Complete pathological response (cpR) is defined as no residual invasive cancer detected of the resected primary tumor following neoadjuvant therapy. The cpR rate is computed in each arm as the percentage of patients who had cpR after neoadjuvant treatment. Patients not resected were considered as not having pathological complete response. CpR rate in each arm is calculated in the per protocol population with its exact 2-sided 95% confidence interval.

End point type

Secondary

End point timeframe

Pathological response is assessed after neoadjuvant therapy and surgery.

End point values	Control Arm	Experimental Arm 1	Experimental Arm 2
Number of subjects analysed	30 ^[6]	54 ^[7]	53 ^[8]
Units: % of patients with cpR
number (confidence interval 95%)	3.3 (0.1 to 17.2)	14.8 (6.6 to 27.1)	5.7 (1.2 to 15.7)

Notes
[6] - For 3 patients operated in the Control Arm, sample was missing or judged of insufficient quality
[7] - For 10 patients operated in Experimental Arm 1, sample was missing or judged of insufficient quality
[8] - For 11 patients operated in Experimental Arm 2, sample was missing or judged of insufficient quality

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Adverse events were collected starting from the registration of the patient until 28 days after the last dose of study treatment. SAEs are to be reported within 24 hours. All AEs and SAEs are to be followed until resolution or stabilisation.

Adverse event reporting additional description

CRF for AEs contains pre-specified items + additional boxes for all "other" AEs. (AEs reported as "other" are not reported as not available from the list of SOC). AEs are evaluated using CTC grading version 4.0, SAEs using MedDra version 25. Non-SAEs has not been collected specifically, all AEs will be reported in non-SAE section.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

Reporting group title

Control Arm

Reporting group description

Perioperative chemotherapy alone.

Reporting group title

Experimental Arm 2

Reporting group description

Experimental arm 2 consisted of perioperative chemotherapy plus trastuzumab and pertuzumab.

Reporting group title

Experimental Arm 1

Reporting group description

Experimental arm 1 consisted of perioperative chemotherapy plus trastuzumab.

Serious adverse events	Control Arm	Experimental Arm 2	Experimental Arm 1
Total subjects affected by serious adverse events
subjects affected / exposed	13 / 34 (38.24%)	47 / 69 (68.12%)	35 / 66 (53.03%)
number of deaths (all causes)	12	25	19
number of deaths resulting from adverse events	0	2	2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
TUMOUR HAEMORRHAGE
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
METASTASES TO CENTRAL NERVOUS SYSTEM
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
GASTROINTESTINAL STROMAL TUMOUR
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	2 / 66 (3.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular disorders
HAEMATOMA
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
LYMPHATIC FISTULA
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PERIPHERAL ARTERY THROMBOSIS
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PERIPHERAL VEIN THROMBOSIS
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
ASTHENIA
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PYREXIA
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 34 (2.94%)	1 / 69 (1.45%)	1 / 66 (1.52%)
occurrences causally related to treatment / all	0 / 1	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PERFORATION
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
GENERAL PHYSICAL HEALTH DETERIORATION
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DEHISCENCE
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
MUCOSAL INFLAMMATION
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	3 / 69 (4.35%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	3 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0
Respiratory, thoracic and mediastinal disorders
PULMONARY EMBOLISM
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	1 / 66 (1.52%)
occurrences causally related to treatment / all	0 / 0	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
RESPIRATORY FAILURE
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PNEUMOTHORAX
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	2 / 69 (2.90%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ASPHYXIA
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ASPIRATION
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	1 / 66 (1.52%)
occurrences causally related to treatment / all	0 / 0	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
BRONCHIAL FISTULA
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DYSPNOEA
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
INTERSTITIAL LUNG DISEASE
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PLEURAL EFFUSION
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	2 / 69 (2.90%)	1 / 66 (1.52%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PNEUMONITIS
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 34 (2.94%)	0 / 69 (0.00%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Investigations
WEIGHT DECREASED
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	2 / 69 (2.90%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
EJECTION FRACTION DECREASED
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	2 / 66 (3.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
BLOOD CREATININE INCREASED
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
BLOOD CHOLINESTERASE DECREASED
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
INCISIONAL HERNIA
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
VASCULAR PSEUDOANEURYSM
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
GASTROINTESTINAL ANASTOMOTIC COMPLICATION
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
FAILURE TO ANASTOMOSE
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
EXTRADURAL HAEMATOMA
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CRANIOFACIAL FRACTURE
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 34 (2.94%)	0 / 69 (0.00%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ANASTOMOTIC LEAK
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	2 / 69 (2.90%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ANASTOMOTIC FISTULA
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ANASTOMOTIC COMPLICATION
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 34 (2.94%)	0 / 69 (0.00%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
INFUSION RELATED REACTION
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
LIMB INJURY
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
POST PROCEDURAL COMPLICATION
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	1 / 66 (1.52%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
POST PROCEDURAL FISTULA
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
POST PROCEDURAL HAEMORRHAGE
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 34 (2.94%)	0 / 69 (0.00%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
STOMA SITE EXTRAVASATION
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 34 (2.94%)	0 / 69 (0.00%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
GASTROINTESTINAL ANASTOMOTIC LEAK
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 34 (2.94%)	2 / 69 (2.90%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	1 / 1	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
WOUND DEHISCENCE
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
CARDIAC FAILURE
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SINUS NODE DYSFUNCTION
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
MYOCARDITIS
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
LEFT VENTRICULAR DYSFUNCTION
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ARTERIOSPASM CORONARY
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SINUS TACHYCARDIA
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
CEREBRAL ISCHAEMIA
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0
CEREBROVASCULAR ACCIDENT
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SYNCOPE
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	2 / 69 (2.90%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
ANAEMIA
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SPLENIC HAEMORRHAGE
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 34 (2.94%)	0 / 69 (0.00%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
NEUTROPENIA
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	1 / 66 (1.52%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
FEBRILE NEUTROPENIA
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1
Ear and labyrinth disorders
VERTIGO
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Eye disorders
DIPLOPIA
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
FISTULA OF SMALL INTESTINE
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
GASTRIC PERFORATION
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
GASTRITIS
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	1 / 66 (1.52%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
GASTROINTESTINAL HAEMORRHAGE
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
GASTROINTESTINAL OBSTRUCTION
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DYSPHAGIA
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 34 (2.94%)	2 / 69 (2.90%)	2 / 66 (3.03%)
occurrences causally related to treatment / all	1 / 1	2 / 2	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DUODENAL ULCER
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DIARRHOEA
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	8 / 69 (11.59%)	1 / 66 (1.52%)
occurrences causally related to treatment / all	0 / 0	11 / 11	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DIAPHRAGMATIC HERNIA
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 34 (2.94%)	0 / 69 (0.00%)	2 / 66 (3.03%)
occurrences causally related to treatment / all	1 / 1	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ABDOMINAL WALL HAEMATOMA
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ABDOMINAL PAIN
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	1 / 66 (1.52%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HAEMOPERITONEUM
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 34 (2.94%)	0 / 69 (0.00%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HERNIAL EVENTRATION
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
IMPAIRED GASTRIC EMPTYING
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	2 / 66 (3.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
VOMITING
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 34 (2.94%)	4 / 69 (5.80%)	2 / 66 (3.03%)
occurrences causally related to treatment / all	1 / 1	4 / 4	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
UPPER GASTROINTESTINAL HAEMORRHAGE
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
TERMINAL ILEITIS
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SMALL INTESTINAL OBSTRUCTION
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	1 / 66 (1.52%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SMALL INTESTINAL HAEMORRHAGE
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PEPTIC ULCER HAEMORRHAGE
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PANCREATITIS
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
OESOPHAGEAL ULCER
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
OESOPHAGEAL STENOSIS
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
OESOPHAGEAL FISTULA
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
INTESTINAL OBSTRUCTION
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 34 (2.94%)	2 / 69 (2.90%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
MELAENA
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
NAUSEA
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 34 (2.94%)	4 / 69 (5.80%)	2 / 66 (3.03%)
occurrences causally related to treatment / all	1 / 1	4 / 4	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
PERFORATION BILE DUCT
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CHOLECYSTITIS
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
ACUTE KIDNEY INJURY
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 34 (2.94%)	3 / 69 (4.35%)	1 / 66 (1.52%)
occurrences causally related to treatment / all	0 / 1	3 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CYSTITIS HAEMORRHAGIC
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
BACK PAIN
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 34 (2.94%)	0 / 69 (0.00%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
ABDOMINAL INFECTION
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ENDOCARDITIS
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 34 (2.94%)	0 / 69 (0.00%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
EMPYEMA
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	3 / 69 (4.35%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	5 / 5	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DEVICE RELATED INFECTION
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 34 (2.94%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ATYPICAL PNEUMONIA
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ENDOCARDITIS BACTERIAL
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 34 (2.94%)	0 / 69 (0.00%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
ENTEROCOLITIS INFECTIOUS
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
INFECTED SEROMA
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
INFECTION
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	2 / 66 (3.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
INFECTIOUS PLEURAL EFFUSION
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
INTERVERTEBRAL DISCITIS
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 34 (2.94%)	0 / 69 (0.00%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PERITONITIS
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1
PNEUMONIA
alternative dictionary used: MedDRA 25
subjects affected / exposed	2 / 34 (5.88%)	3 / 69 (4.35%)	2 / 66 (3.03%)
occurrences causally related to treatment / all	1 / 2	1 / 3	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PNEUMONIA KLEBSIELLA
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
PYELONEPHRITIS ACUTE
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SEPSIS
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 34 (2.94%)	2 / 69 (2.90%)	1 / 66 (1.52%)
occurrences causally related to treatment / all	1 / 1	1 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0
SEPTIC SHOCK
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	1 / 66 (1.52%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SERRATIA SEPSIS
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SPONTANEOUS BACTERIAL PERITONITIS
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
HYPOKALAEMIA
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	2 / 66 (3.03%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HYPERGLYCAEMIA
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DEHYDRATION
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	2 / 69 (2.90%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
DECREASED APPETITE
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	1 / 66 (1.52%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HYPOMAGNESAEMIA
alternative dictionary used: MedDRA 25
subjects affected / exposed	1 / 34 (2.94%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HYPONATRAEMIA
alternative dictionary used: MedDRA 25
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	1 / 66 (1.52%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Control Arm	Experimental Arm 2	Experimental Arm 1
Total subjects affected by non serious adverse events
subjects affected / exposed	34 / 34 (100.00%)	69 / 69 (100.00%)	66 / 66 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - OTHER, SPECIFY
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	3 / 69 (4.35%)	5 / 66 (7.58%)
occurrences all number	0	4	5
TUMOR PAIN
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	1 / 34 (2.94%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences all number	1	1	0
Vascular disorders
VASCULAR DISORDERS - OTHER, SPECIFY
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences all number	0	2	0
HEMATOMA
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	2 / 69 (2.90%)	1 / 66 (1.52%)
occurrences all number	0	2	1
HOT FLASHES
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	1 / 34 (2.94%)	0 / 69 (0.00%)	0 / 66 (0.00%)
occurrences all number	1	0	0
HYPERTENSION
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	5 / 34 (14.71%)	14 / 69 (20.29%)	14 / 66 (21.21%)
occurrences all number	6	32	36
HYPOTENSION
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	1 / 34 (2.94%)	1 / 69 (1.45%)	1 / 66 (1.52%)
occurrences all number	1	1	1
SUPERFICIAL THROMBOPHLEBITIS
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	2 / 69 (2.90%)	0 / 66 (0.00%)
occurrences all number	0	2	0
THROMBOEMBOLIC EVENT
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	2 / 34 (5.88%)	3 / 69 (4.35%)	7 / 66 (10.61%)
occurrences all number	2	4	10
General disorders and administration site conditions
CHILLS
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	3 / 69 (4.35%)	1 / 66 (1.52%)
occurrences all number	0	4	1
EDEMA LIMBS
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	2 / 69 (2.90%)	2 / 66 (3.03%)
occurrences all number	0	2	2
FATIGUE
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	16 / 34 (47.06%)	26 / 69 (37.68%)	27 / 66 (40.91%)
occurrences all number	28	50	50
FEVER
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	4 / 34 (11.76%)	9 / 69 (13.04%)	6 / 66 (9.09%)
occurrences all number	5	18	6
FLU LIKE SYMPTOMS
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	1 / 34 (2.94%)	3 / 69 (4.35%)	2 / 66 (3.03%)
occurrences all number	1	3	2
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - OTHER, SPECIFY
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	12 / 34 (35.29%)	12 / 69 (17.39%)	19 / 66 (28.79%)
occurrences all number	18	33	66
HEADACHE
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	2 / 34 (5.88%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences all number	2	0	1
HYPOTHERMIA
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	1 / 34 (2.94%)	0 / 69 (0.00%)	0 / 66 (0.00%)
occurrences all number	1	0	0
INFUSION RELATED REACTION
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	3 / 69 (4.35%)	2 / 66 (3.03%)
occurrences all number	0	3	2
INFUSION SITE EXTRAVASATION
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences all number	0	0	2
LOCALIZED EDEMA
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences all number	0	1	0
NON-CARDIAC CHEST PAIN
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	3 / 66 (4.55%)
occurrences all number	0	1	3
PAIN
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	3 / 66 (4.55%)
occurrences all number	0	1	4
Immune system disorders
ALLERGIC REACTION
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	2 / 34 (5.88%)	2 / 69 (2.90%)	1 / 66 (1.52%)
occurrences all number	2	2	1
IMMUNE SYSTEM DISORDERS - OTHER, SPECIFY
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences all number	0	0	1
Reproductive system and breast disorders
ERECTILE DYSFUNCTION
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	1 / 34 (2.94%)	0 / 69 (0.00%)	0 / 66 (0.00%)
occurrences all number	1	0	0
IRREGULAR MENSTRUATION
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences all number	0	1	0
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - OTHER, SPECIFY
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences all number	0	1	0
VAGINAL DRYNESS
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences all number	0	1	0
Respiratory, thoracic and mediastinal disorders
COUGH
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	1 / 34 (2.94%)	4 / 69 (5.80%)	3 / 66 (4.55%)
occurrences all number	1	5	3
ALLERGIC RHINITIS
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences all number	0	0	1
ASPIRATION
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	2 / 69 (2.90%)	1 / 66 (1.52%)
occurrences all number	0	3	1
BRONCHIAL FISTULA
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences all number	0	1	0
CHYLOTHORAX
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences all number	0	0	1
DYSPNEA
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	2 / 34 (5.88%)	3 / 69 (4.35%)	4 / 66 (6.06%)
occurrences all number	2	5	5
EPISTAXIS
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	2 / 34 (5.88%)	13 / 69 (18.84%)	1 / 66 (1.52%)
occurrences all number	2	14	1
HICCUPS
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	2 / 34 (5.88%)	1 / 69 (1.45%)	1 / 66 (1.52%)
occurrences all number	2	1	1
LUNG INFECTION
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	1 / 34 (2.94%)	0 / 69 (0.00%)	0 / 66 (0.00%)
occurrences all number	1	0	0
NASAL CONGESTION
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences all number	0	0	1
PLEURAL EFFUSION
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	3 / 34 (8.82%)	6 / 69 (8.70%)	7 / 66 (10.61%)
occurrences all number	3	9	10
PNEUMOTHORAX
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	4 / 69 (5.80%)	1 / 66 (1.52%)
occurrences all number	0	4	1
RESPIRATORY FAILURE
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	1 / 34 (2.94%)	1 / 69 (1.45%)	1 / 66 (1.52%)
occurrences all number	1	1	1
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - OTHER, SPECIFY
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	7 / 69 (10.14%)	5 / 66 (7.58%)
occurrences all number	0	8	5
RETINOIC ACID SYNDROME
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences all number	0	0	1
SORE THROAT
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	1 / 34 (2.94%)	1 / 69 (1.45%)	1 / 66 (1.52%)
occurrences all number	1	1	1
PNEUMONITIS
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	1 / 34 (2.94%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences all number	1	0	1
Psychiatric disorders
ANXIETY
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	1 / 34 (2.94%)	4 / 69 (5.80%)	2 / 66 (3.03%)
occurrences all number	1	4	2
DELIRIUM
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	1 / 34 (2.94%)	1 / 69 (1.45%)	1 / 66 (1.52%)
occurrences all number	1	1	1
DEPRESSION
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	2 / 66 (3.03%)
occurrences all number	0	1	2
INSOMNIA
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	6 / 66 (9.09%)
occurrences all number	0	1	6
PSYCHOSIS
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences all number	0	1	0
Investigations
ASPARTATE AMINOTRANSFERASE INCREASED
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	2 / 69 (2.90%)	3 / 66 (4.55%)
occurrences all number	0	6	3
CREATININE INCREASED
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	4 / 34 (11.76%)	5 / 69 (7.25%)	4 / 66 (6.06%)
occurrences all number	6	9	4
EJECTION FRACTION DECREASED
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	3 / 69 (4.35%)	2 / 66 (3.03%)
occurrences all number	0	3	2
ALANINE AMINOTRANSFERASE INCREASED
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	2 / 34 (5.88%)	2 / 69 (2.90%)	3 / 66 (4.55%)
occurrences all number	2	4	3
INVESTIGATIONS - OTHER, SPECIFY
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	1 / 34 (2.94%)	5 / 69 (7.25%)	3 / 66 (4.55%)
occurrences all number	1	8	3
LYMPHOCYTE COUNT DECREASED
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences all number	0	2	0
NEUTROPHIL COUNT DECREASED
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	18 / 34 (52.94%)	32 / 69 (46.38%)	36 / 66 (54.55%)
occurrences all number	27	74	80
PLATELET COUNT DECREASED
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	2 / 34 (5.88%)	8 / 69 (11.59%)	7 / 66 (10.61%)
occurrences all number	2	10	18
WEIGHT LOSS
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	5 / 34 (14.71%)	26 / 69 (37.68%)	13 / 66 (19.70%)
occurrences all number	6	34	14
WHITE BLOOD CELL DECREASED
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	2 / 34 (5.88%)	13 / 69 (18.84%)	7 / 66 (10.61%)
occurrences all number	2	38	40
Injury, poisoning and procedural complications
ESOPHAGEAL ANASTOMOTIC LEAK
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	1 / 34 (2.94%)	4 / 69 (5.80%)	1 / 66 (1.52%)
occurrences all number	1	4	1
BURN
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences all number	0	1	0
FALL
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	1 / 34 (2.94%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences all number	1	1	0
FRACTURE
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	1 / 34 (2.94%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences all number	1	0	1
GASTRIC ANASTOMOTIC LEAK
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	1 / 34 (2.94%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences all number	1	1	0
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - OTHER, SPECIFY
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	1 / 34 (2.94%)	4 / 69 (5.80%)	7 / 66 (10.61%)
occurrences all number	1	5	9
INTRAOPERATIVE HEMORRHAGE
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences all number	0	0	1
POSTOPERATIVE HEMORRHAGE
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	1 / 34 (2.94%)	0 / 69 (0.00%)	0 / 66 (0.00%)
occurrences all number	1	0	0
WOUND COMPLICATION
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	1 / 34 (2.94%)	0 / 69 (0.00%)	2 / 66 (3.03%)
occurrences all number	1	0	2
WOUND DEHISCENCE
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	2 / 34 (5.88%)	2 / 69 (2.90%)	3 / 66 (4.55%)
occurrences all number	2	2	5
GASTROINTESTINAL ANASTOMOTIC LEAK
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	1 / 34 (2.94%)	0 / 69 (0.00%)	2 / 66 (3.03%)
occurrences all number	1	0	2
Cardiac disorders
HEART FAILURE
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences all number	0	2	0
CONDUCTION DISORDER
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	1 / 34 (2.94%)	0 / 69 (0.00%)	0 / 66 (0.00%)
occurrences all number	1	0	0
CARDIAC DISORDERS - OTHER, SPECIFY
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	4 / 69 (5.80%)	2 / 66 (3.03%)
occurrences all number	0	4	2
ATRIAL FIBRILLATION
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	3 / 66 (4.55%)
occurrences all number	0	1	3
MITRAL VALVE DISEASE
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences all number	0	1	0
ACUTE CORONARY SYNDROME
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	1 / 34 (2.94%)	0 / 69 (0.00%)	0 / 66 (0.00%)
occurrences all number	1	0	0
LEFT VENTRICULAR SYSTOLIC DYSFUNCTION
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	2 / 66 (3.03%)
occurrences all number	0	1	2
AORTIC VALVE DISEASE
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences all number	0	1	0
VENTRICULAR TACHYCARDIA
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences all number	0	0	1
VENTRICULAR ARRHYTHMIA
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences all number	0	0	1
SINUS TACHYCARDIA
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	1 / 34 (2.94%)	1 / 69 (1.45%)	4 / 66 (6.06%)
occurrences all number	1	1	4
SINUS BRADYCARDIA
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	2 / 66 (3.03%)
occurrences all number	0	0	2
PALPITATIONS
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	2 / 66 (3.03%)
occurrences all number	0	0	2
MYOCARDITIS
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences all number	0	2	0
Nervous system disorders
HEADACHE
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	4 / 69 (5.80%)	1 / 66 (1.52%)
occurrences all number	0	5	1
AMNESIA
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences all number	0	0	1
APHONIA
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences all number	0	0	1
DIZZINESS
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	2 / 34 (5.88%)	5 / 69 (7.25%)	6 / 66 (9.09%)
occurrences all number	3	5	6
DYSESTHESIA
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	2 / 69 (2.90%)	2 / 66 (3.03%)
occurrences all number	0	5	4
DYSGEUSIA
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	7 / 34 (20.59%)	8 / 69 (11.59%)	9 / 66 (13.64%)
occurrences all number	14	11	11
DYSPHAGIA
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences all number	0	1	0
HEMATOMA
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences all number	0	1	0
NERVOUS SYSTEM DISORDERS - OTHER, SPECIFY
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	1 / 34 (2.94%)	8 / 69 (11.59%)	2 / 66 (3.03%)
occurrences all number	1	14	2
NEURALGIA
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	2 / 69 (2.90%)	0 / 66 (0.00%)
occurrences all number	0	3	0
PARESTHESIA
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	8 / 34 (23.53%)	11 / 69 (15.94%)	14 / 66 (21.21%)
occurrences all number	10	15	24
PERIPHERAL MOTOR NEUROPATHY
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	2 / 69 (2.90%)	3 / 66 (4.55%)
occurrences all number	0	2	4
PERIPHERAL SENSORY NEUROPATHY
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	8 / 34 (23.53%)	12 / 69 (17.39%)	17 / 66 (25.76%)
occurrences all number	10	25	30
PRESYNCOPE
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences all number	0	1	0
REVERSIBLE POSTERIOR LEUKOENCEPHALOPATHY SYNDROME
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences all number	0	1	0
STROKE
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	1 / 34 (2.94%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences all number	1	0	1
SYNCOPE
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	1 / 34 (2.94%)	3 / 69 (4.35%)	0 / 66 (0.00%)
occurrences all number	1	3	0
ISCHEMIA CEREBROVASCULAR
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences all number	0	2	0
Blood and lymphatic system disorders
ANEMIA
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	2 / 34 (5.88%)	15 / 69 (21.74%)	8 / 66 (12.12%)
occurrences all number	5	51	25
LEUKOCYTOSIS
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	3 / 69 (4.35%)	0 / 66 (0.00%)
occurrences all number	0	3	0
FEBRILE NEUTROPENIA
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences all number	0	0	2
BLOOD AND LYMPHATIC SYSTEM DISORDERS - OTHER, SPECIFY
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	1 / 34 (2.94%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences all number	1	0	1
Ear and labyrinth disorders
VERTIGO
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	3 / 34 (8.82%)	3 / 69 (4.35%)	2 / 66 (3.03%)
occurrences all number	3	3	3
TINNITUS
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	1 / 34 (2.94%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences all number	1	0	1
HEARING IMPAIRED
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	3 / 66 (4.55%)
occurrences all number	0	1	4
Eye disorders
EYE DISORDERS - OTHER, SPECIFY
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	1 / 34 (2.94%)	0 / 69 (0.00%)	2 / 66 (3.03%)
occurrences all number	2	0	2
DRY EYE
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	1 / 34 (2.94%)	1 / 69 (1.45%)	1 / 66 (1.52%)
occurrences all number	1	1	2
CONJUNCTIVITIS
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	2 / 66 (3.03%)
occurrences all number	0	1	2
BLURRED VISION
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	1 / 34 (2.94%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences all number	1	0	2
Gastrointestinal disorders
CHEILITIS
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	1 / 66 (1.52%)
occurrences all number	0	1	1
BLOATING
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	2 / 66 (3.03%)
occurrences all number	0	0	2
ANAL HEMORRHAGE
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences all number	0	2	0
ABDOMINAL PAIN
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	5 / 34 (14.71%)	9 / 69 (13.04%)	8 / 66 (12.12%)
occurrences all number	6	11	16
COLITIS
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences all number	0	1	0
CONSTIPATION
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	3 / 34 (8.82%)	5 / 69 (7.25%)	10 / 66 (15.15%)
occurrences all number	4	6	12
DIARRHEA
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	16 / 34 (47.06%)	55 / 69 (79.71%)	45 / 66 (68.18%)
occurrences all number	24	179	93
DRY MOUTH
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	1 / 34 (2.94%)	1 / 69 (1.45%)	1 / 66 (1.52%)
occurrences all number	1	1	1
DUODENAL FISTULA
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	2 / 66 (3.03%)
occurrences all number	0	0	3
ESOPHAGEAL PAIN
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	1 / 34 (2.94%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences all number	1	0	1
ESOPHAGEAL STENOSIS
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences all number	0	2	0
ESOPHAGEAL FISTULA
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	3 / 69 (4.35%)	0 / 66 (0.00%)
occurrences all number	0	5	0
ENTEROCOLITIS
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences all number	0	0	1
DYSPHAGIA
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	5 / 34 (14.71%)	8 / 69 (11.59%)	9 / 66 (13.64%)
occurrences all number	7	10	11
DYSPEPSIA
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	4 / 69 (5.80%)	3 / 66 (4.55%)
occurrences all number	0	4	4
DYSGEUSIA
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences all number	0	0	1
DUODENAL ULCER
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	1 / 66 (1.52%)
occurrences all number	0	1	1
ESOPHAGEAL HEMORRHAGE
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences all number	0	1	0
ILEAL OBSTRUCTION
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences all number	0	2	0
ESOPHAGEAL ULCER
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	1 / 34 (2.94%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences all number	1	2	0
HEMORRHOIDAL HEMORRHAGE
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences all number	0	0	1
GINGIVAL PAIN
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences all number	0	1	0
GASTROPARESIS
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences all number	0	0	1
GASTROINTESTINAL PAIN
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	2 / 69 (2.90%)	0 / 66 (0.00%)
occurrences all number	0	2	0
GASTROINTESTINAL DISORDERS - OTHER, SPECIFY
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	7 / 34 (20.59%)	6 / 69 (8.70%)	10 / 66 (15.15%)
occurrences all number	11	7	16
GASTROESOPHAGEAL REFLUX DISEASE
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	2 / 34 (5.88%)	5 / 69 (7.25%)	2 / 66 (3.03%)
occurrences all number	2	5	2
GASTRITIS
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	1 / 66 (1.52%)
occurrences all number	0	3	1
GASTRIC STENOSIS
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences all number	0	0	1
GASTRIC HEMORRHAGE
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences all number	0	1	0
GASTRIC FISTULA
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences all number	0	0	1
FLATULENCE
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	3 / 69 (4.35%)	0 / 66 (0.00%)
occurrences all number	0	3	0
ESOPHAGITIS
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	1 / 34 (2.94%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences all number	1	0	1
HEMORRHOIDS
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	1 / 66 (1.52%)
occurrences all number	0	1	1
TOOTHACHE
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	2 / 66 (3.03%)
occurrences all number	0	0	2
STOMACH PAIN
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	1 / 34 (2.94%)	0 / 69 (0.00%)	3 / 66 (4.55%)
occurrences all number	1	0	3
SMALL INTESTINAL OBSTRUCTION
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	1 / 34 (2.94%)	1 / 69 (1.45%)	1 / 66 (1.52%)
occurrences all number	1	1	1
RECTAL MUCOSITIS
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences all number	0	0	1
PERIODONTAL DISEASE
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	1 / 66 (1.52%)
occurrences all number	0	1	1
PANCREATITIS
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences all number	0	0	1
PANCREATIC FISTULA
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences all number	0	0	1
ORAL PAIN
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences all number	0	0	1
ORAL DYSESTHESIA
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences all number	0	1	0
NAUSEA
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	20 / 34 (58.82%)	38 / 69 (55.07%)	37 / 66 (56.06%)
occurrences all number	33	71	69
MUCOSITIS ORAL
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	5 / 34 (14.71%)	22 / 69 (31.88%)	17 / 66 (25.76%)
occurrences all number	7	46	26
JEJUNAL HEMORRHAGE
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences all number	0	0	1
JEJUNAL FISTULA
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences all number	0	1	0
INTRA-ABDOMINAL HEMORRHAGE
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	1 / 34 (2.94%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences all number	1	0	1
UPPER GASTROINTESTINAL HEMORRHAGE
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	2 / 69 (2.90%)	0 / 66 (0.00%)
occurrences all number	0	3	0
ILEUS
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences all number	0	0	1
VOMITING
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	6 / 34 (17.65%)	20 / 69 (28.99%)	15 / 66 (22.73%)
occurrences all number	7	37	20
Hepatobiliary disorders
CHOLECYSTITIS
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	1 / 34 (2.94%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences all number	1	1	0
HEPATITIS VIRAL
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	1 / 66 (1.52%)
occurrences all number	0	1	1
HEPATOBILIARY DISORDERS - OTHER, SPECIFY
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	2 / 66 (3.03%)
occurrences all number	0	1	2
Skin and subcutaneous tissue disorders
ALOPECIA
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	6 / 34 (17.65%)	8 / 69 (11.59%)	10 / 66 (15.15%)
occurrences all number	7	8	12
DRY SKIN
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	2 / 34 (5.88%)	8 / 69 (11.59%)	5 / 66 (7.58%)
occurrences all number	2	12	5
HYPERHIDROSIS
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences all number	0	1	0
NAIL DISCOLORATION
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	2 / 66 (3.03%)
occurrences all number	0	1	2
NAIL RIDGING
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	1 / 34 (2.94%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences all number	1	1	0
PALMAR-PLANTAR ERYTHRODYSESTHESIA SYNDROME
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	2 / 34 (5.88%)	7 / 69 (10.14%)	8 / 66 (12.12%)
occurrences all number	4	9	13
PRURITUS
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	3 / 69 (4.35%)	4 / 66 (6.06%)
occurrences all number	0	3	5
RASH ACNEIFORM
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	1 / 34 (2.94%)	2 / 69 (2.90%)	1 / 66 (1.52%)
occurrences all number	1	2	3
RASH MACULO-PAPULAR
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	6 / 69 (8.70%)	3 / 66 (4.55%)
occurrences all number	0	6	3
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - OTHER, SPECIFY
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	2 / 34 (5.88%)	9 / 69 (13.04%)	7 / 66 (10.61%)
occurrences all number	2	11	10
SKIN HYPOPIGMENTATION
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences all number	0	0	1
URTICARIA
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences all number	0	0	1
ERYTHEMA MULTIFORME
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences all number	0	1	0
Renal and urinary disorders
ACUTE KIDNEY INJURY
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	1 / 34 (2.94%)	9 / 69 (13.04%)	3 / 66 (4.55%)
occurrences all number	1	15	15
CHRONIC KIDNEY DISEASE
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	2 / 66 (3.03%)
occurrences all number	0	1	4
HEMATURIA
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	1 / 34 (2.94%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences all number	1	0	1
RENAL AND URINARY DISORDERS - OTHER, SPECIFY
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	2 / 34 (5.88%)	5 / 69 (7.25%)	1 / 66 (1.52%)
occurrences all number	2	5	1
URINARY FREQUENCY
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences all number	0	0	2
URINARY RETENTION
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences all number	0	0	1
CYSTITIS NONINFECTIVE
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences all number	0	0	1
Endocrine disorders
HYPERTHYROIDISM
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences all number	0	0	2
HYPOTHYROIDISM
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences all number	0	1	0
Musculoskeletal and connective tissue disorders
GENERALIZED MUSCLE WEAKNESS
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences all number	0	1	0
ARTHRITIS
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	1 / 66 (1.52%)
occurrences all number	0	2	1
BACK PAIN
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	3 / 34 (8.82%)	1 / 69 (1.45%)	1 / 66 (1.52%)
occurrences all number	3	1	2
BONE PAIN
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	2 / 69 (2.90%)	2 / 66 (3.03%)
occurrences all number	0	2	2
BUTTOCK PAIN
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences all number	0	1	0
FLANK PAIN
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	1 / 34 (2.94%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences all number	1	0	1
ARTHRALGIA
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	1 / 34 (2.94%)	0 / 69 (0.00%)	0 / 66 (0.00%)
occurrences all number	2	0	0
JOINT EFFUSION
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences all number	0	1	0
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDER - OTHER, SPECIFY
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	1 / 34 (2.94%)	5 / 69 (7.25%)	2 / 66 (3.03%)
occurrences all number	1	7	2
MYALGIA
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	2 / 69 (2.90%)	1 / 66 (1.52%)
occurrences all number	0	2	3
NECK PAIN
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences all number	0	0	1
PAIN IN EXTREMITY
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	1 / 66 (1.52%)
occurrences all number	0	1	1
MUSCLE WEAKNESS RIGHT-SIDED
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences all number	0	0	1
Infections and infestations
LUNG INFECTION
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	3 / 34 (8.82%)	8 / 69 (11.59%)	6 / 66 (9.09%)
occurrences all number	3	8	6
CATHETER RELATED INFECTION
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	3 / 69 (4.35%)	2 / 66 (3.03%)
occurrences all number	0	3	3
ENDOCARDITIS INFECTIVE
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	1 / 34 (2.94%)	0 / 69 (0.00%)	0 / 66 (0.00%)
occurrences all number	2	0	0
ENTEROCOLITIS INFECTIOUS
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences all number	0	0	1
ESOPHAGEAL INFECTION
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	1 / 34 (2.94%)	0 / 69 (0.00%)	0 / 66 (0.00%)
occurrences all number	1	0	0
INFECTIONS AND INFESTATIONS - OTHER, SPECIFY
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	3 / 34 (8.82%)	16 / 69 (23.19%)	13 / 66 (19.70%)
occurrences all number	3	19	18
ABDOMINAL INFECTION
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences all number	0	0	1
MEDIASTINAL INFECTION
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences all number	0	1	0
NAIL INFECTION
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences all number	0	1	0
PARONYCHIA
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences all number	0	1	0
PHARYNGITIS
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences all number	0	0	1
PLEURAL INFECTION
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences all number	0	1	0
RHINITIS INFECTIVE
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	2 / 66 (3.03%)
occurrences all number	0	0	2
SINUSITIS
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences all number	0	0	1
SKIN INFECTION
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	3 / 69 (4.35%)	1 / 66 (1.52%)
occurrences all number	0	3	1
UPPER RESPIRATORY INFECTION
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	2 / 69 (2.90%)	4 / 66 (6.06%)
occurrences all number	0	2	4
URINARY TRACT INFECTION
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	1 / 34 (2.94%)	2 / 69 (2.90%)	4 / 66 (6.06%)
occurrences all number	1	2	6
WOUND INFECTION
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	2 / 69 (2.90%)	2 / 66 (3.03%)
occurrences all number	0	2	2
SEPSIS
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	2 / 34 (5.88%)	4 / 69 (5.80%)	3 / 66 (4.55%)
occurrences all number	2	5	3
Metabolism and nutrition disorders
HYPOALBUMINEMIA
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences all number	0	1	0
DEHYDRATION
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	4 / 69 (5.80%)	0 / 66 (0.00%)
occurrences all number	0	7	0
GLUCOSE INTOLERANCE
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences all number	0	0	1
HYPERGLYCEMIA
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	3 / 69 (4.35%)	1 / 66 (1.52%)
occurrences all number	0	3	1
HYPERKALEMIA
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences all number	0	0	1
HYPERNATREMIA
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	1 / 69 (1.45%)	0 / 66 (0.00%)
occurrences all number	0	2	0
HYPERURICEMIA
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	1 / 34 (2.94%)	0 / 69 (0.00%)	0 / 66 (0.00%)
occurrences all number	1	0	0
ANOREXIA
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	12 / 34 (35.29%)	21 / 69 (30.43%)	20 / 66 (30.30%)
occurrences all number	18	37	44
HYPOCALCEMIA
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	3 / 69 (4.35%)	2 / 66 (3.03%)
occurrences all number	0	3	3
HYPOKALEMIA
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	5 / 34 (14.71%)	15 / 69 (21.74%)	5 / 66 (7.58%)
occurrences all number	6	23	8
HYPOMAGNESEMIA
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	1 / 34 (2.94%)	7 / 69 (10.14%)	3 / 66 (4.55%)
occurrences all number	3	8	4
HYPONATREMIA
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	0 / 34 (0.00%)	3 / 69 (4.35%)	3 / 66 (4.55%)
occurrences all number	0	5	6
HYPOPHOSPHATEMIA
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	1 / 34 (2.94%)	0 / 69 (0.00%)	1 / 66 (1.52%)
occurrences all number	1	0	2
METABOLISM AND NUTRITION DISORDERS - OTHER, SPECIFY
alternative dictionary used: CTCAE 4.0
subjects affected / exposed	1 / 34 (2.94%)	5 / 69 (7.25%)	0 / 66 (0.00%)
occurrences all number	2	6	0

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Were there any global substantial amendments to the protocol? Yes

03 Mar 2015

1. To address comments received after the VHP submission to competent authorities about the minimization procedure used for randomization, it was specified that no random component was added to the minimization algorithm and a reference to appendix K was added in the corresponding protocol section. 2. To address the comment received after the VHP submission to competent authorities that the trial protocol does not state how missing values will be handled, it was clarified in the protocol section on “Statistical methods” that the primary analysis of the major pathological response rate will be performed in the per-protocol population with a non-missing assessment of pathological response. This will include all patients in the per protocol population who: ♦ have been resected, and for whom the tumor regression according to Becker et al. has been assessed by the central pathology laboratory or ♦ have not been operated or resected for any reason and will be considered as not having a major pathological response in the analysis. Missing data for the primary endpoint will only occur if a patient is resected and the pathological assessment of the resection specimen is not possible. These patients will be removed from the analysis. 3. The maximum total number of patients to be screened in order to randomize the required 225 patients with HER-2 positive disease was modified to reflect the recent knowledge published in the literature about the frequency of HER-2 positivity in Gastric cancer. This frequency could indeed be as low as 10% and therefore a maximum of 2250 patients will have to be screened. 4. ISH (In Situ Hybridization) has been mentioned instead of FISH (Fluorescence In Situ Hybridization) for South Korea.

30 Nov 2015

Roche Protocol Review Committee feedback led to a decision to follow patients longer after pertuzumab and trastuzumab exposure in terms of pregnancy. In the amendment, any new pregnancy within 6 months after last dose of pertuzumab (within 7 months after last dose of trastuzumab as per the Herceptin Global Enhanced PV Pregnancy Program) must be reported to the EORTC Pharmacovigilance Unit. The current protocol requires reporting up to 180 days, and this time frame was extended up to 7 months with this amendment.

19 Oct 2017

1. Change of chemotherapy backbone: in Europe, the regimen was to be selected between FLOT, CapOX por mFOLFOX6; in Asia, cisplatin + capecitabine or 5-FU. This scientific amendment was necessary after the presentation of the results of the FLOT-4-trial at ASCO 2017, which demonstrated a significantly better progression-free and overall survival for perioperative treatment with FLOT, as compared to ECF. Both, dose modification and supportive care recommendations for treatment with FLOT have been inspired by those used in the FLOT-4 study, which were generously provided by the author. Cisplatin is being kept as an option as it is still standard of care in Korea, and efficacy benefit of other regimen yet have to be demonstrated in these patients. 2. A safety run has been introduced in the protocol, given the change of background chemotherapies. 3. A definition of ‘high dose corticosteroids’ was inserted. 4. Clarification was added, that Dihydropyrimidine dehydrogenase deficiency (DPD) testing should be done according to local guidelines. 5. Dose reduction upon grade 2 or 3 nausea or vomiting has been adapted. 6. Recommendations regarding the procedures in case of tubular damage and low Mg/Ca were added. 7. Measures to be taken after assessment of ototoxicity and sensory neural damage were clarified.

25 Feb 2019

1. Upon update of the Trastuzumab's IB the following changes have been implemented in the protocol and PISIC Eligibility criteria: - Protocol eligibility: exclusion of patients with interstitial lung disease - Clinical evaluation: adding additional monitoring for cardiac function after the chemotherapies in adjuvant and during the follow-up period with 6 monthly assessment for 2 years after last dose of trastuzumab. 2. Swiss Competent Authorities requires to specify side effects related to Leucoverin 3. Clarification of dose banding 4. Annex 3/GDPR adaptation of the PISIC.

10 May 2019

1. Upon update of the Trastuzumab's Summary of Product Characteristics (SmPC) and Pertuzumab's SmPC the side effects in the patient information sheet have been updated 2. Wording on the timing of surgery was aligned with the wording in the protocol summary 3. A change in biobank was implemented.

02 Feb 2021

1. Upon update of the Herceptin’s SmPC and and Pertuzumab's SmPC the side effects in the patient information sheet have been updated 2. COVID-19 Addendum to patient information sheets 3. Protocol: assessments during the follow up period were updated.

07 Dec 2021

1. Patient information sheets and addenda to patient information sheets Risk and side effects related to trastuzumab and Risk and side effects related to pertuzumab have been updated according to the new version of the IB. 2. Protocol • To confirm progression by pathological assessment (regarding the primary endpoint) at surgery. In case of local progression by imaging during the neo-adjuvant treatment, if the patient is judged operable, every effort were to be made to confirm the progression at surgery. If progression was not confirmed, patients could stay under protocol treatment and start adjuvant treatment as per protocol. • To specify prerequisites for central pathology review. Pathology report was to be sent to EORTC. Personal data of the patient must have been anonymized and replaced by the EORTC sequential identification number allocated to this patient at the time of randomization. • Elderly Minimal Dataset Comprehensive Geriatric Assessment only once before randomization was needed.

20 Jun 2022

1. Patient information sheets and addenda to patient information sheets • To align PISIC cisplatin and PISIC flot-folfox-capox. Safety information from the Trial Petrarca were added. • Risk and side effects related to pertuzumab have been updated according to the new version of the IB. 2. Protocol • Additional clarification wished from the supporting company. In case of local progression diagnosed by imaging during the neo-adjuvant treatment, if the patient was judged operable, every effort should have been made to confirm the microscopic/macroscopic progression at surgery • Implementation of the updated IB. Serious adverse events (incl. life-threatening events) compatible with infusion-related reactions with pertuzumab have been infrequently reported (less than 1% of patients).

13 Oct 2023

1. The end of the study was clarified. Indeed, due to the early termination of the study, this phase II study will not transition to phase III and no IDMC will occur at the end of phase II. The study will not be transitioned to CTR. 2. A new translational research project and exploratory endpoints were added following the surgical quality assurance. In addition, further clarification was made on the end of treatment and minor updates were implemented such as the name and address of the company performing the central assessment of HER-2 expression.

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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INtegratioN of trastuzumab, with or without pertuzumab, into periOperatiVe chemotherApy of HER-2 posiTIve stOmach caNcer: the INNOVATION-TRIAL

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Clinical trials

Clinical Trial Results: INtegratioN of trastuzumab, with or without pertuzumab, into periOperatiVe chemotherApy of HER-2 posiTIve stOmach caNcer: the INNOVATION-TRIAL

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Major Pathological Response (mpR) rate

Primary: Major Pathological Response (mpR) rate

Secondary: R0 resection rate (%)

Secondary: R0 resection rate (%)

Secondary: Progression Free Survival (RECIST v1.1)

Secondary: Progression Free Survival (RECIST v1.1)

Secondary: Overall Survival

Secondary: Overall Survival

Secondary: Recurrence Free Survival (from surgery)

Secondary: Recurrence Free Survival (from surgery)

Secondary: Cumulative Incidence of Locoregional Failure

Secondary: Cumulative Incidence of Locoregional Failure

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Secondary: Cumulative Incidence of Distant Failure

Secondary: Complete Pathological Response (cpR) rate (%)

Secondary: Complete Pathological Response (cpR) rate (%)

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
INtegratioN of trastuzumab, with or without pertuzumab, into periOperatiVe chemotherApy of HER-2 posiTIve stOmach caNcer: the INNOVATION-TRIAL