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Clinical Trial Results:
A Double-Blind, Placebo-Controlled, Randomized, Multicenter Phase III Study Evaluating the Efficacy and Safety of Pertuzumab in Combination With Trastuzumab and Chemotherapy in Patients With HER2-Positive Metastatic Gastroesophageal Junction and Gastric Cancer

Summary
EudraCT number	2012-003554-83
Trial protocol	ES AT DE FI NL IT BE HU BG PL
Global end of trial date	31 Dec 2019

Results information
Results version number	v2(current)
This version publication date	19 Dec 2020
First version publication date	24 Dec 2017
Other versions	v1
Version creation reason

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

Collapse all Expand all

Trial information

Top of page

Sponsor protocol code

BO25114

ISRCTN number

-

US NCT number

NCT01774786

WHO universal trial number (UTN)

-

Sponsor organisation name

F. Hoffmann-La Roche, Ltd.

Sponsor organisation address

Grenzacherstrasse 124, Basel, Switzerland, CH-4070

Public contact

F. Hoffmann-La Roche, Ltd., F. Hoffmann-La Roche, Ltd., 41 616878333, global.trial_information@roche.com

Scientific contact

F. Hoffmann-La Roche, Ltd., F. Hoffmann-La Roche, Ltd., 41 616878333, global.trial_information@roche.com

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

No

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

No

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

No

Analysis stage

Final

Date of interim/final analysis

31 Dec 2019

Is this the analysis of the primary completion data?

Yes

Primary completion date

09 Dec 2016

Global end of trial reached?

Yes

Global end of trial date

31 Dec 2019

Was the trial ended prematurely?

No

Main objective of the trial

The primary objective of this study was to compare overall survival in subjects treated with pertuzumab in addition to trastuzumab, fluoropyrimidine and cisplatin (TFP) versus subjects treated with placebo in addition to TFP.

Protection of trial subjects

All subjects (or authorized representatives) signed an informed consent form before participating in the study.

Background therapy

-

Evidence for comparator

-

Actual start date of recruitment

10 Jun 2013

Long term follow-up planned

Yes

Long term follow-up rationale

Efficacy, Safety

Long term follow-up duration

5 Years

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

China: 163

Country: Number of subjects enrolled

Kazakhstan: 2

Country: Number of subjects enrolled

Korea, Republic of: 94

Country: Number of subjects enrolled

Malaysia: 2

Country: Number of subjects enrolled

Thailand: 8

Country: Number of subjects enrolled

Taiwan: 20

Country: Number of subjects enrolled

Japan: 80

Country: Number of subjects enrolled

Australia: 11

Country: Number of subjects enrolled

Austria: 3

Country: Number of subjects enrolled

Belgium: 3

Country: Number of subjects enrolled

Canada: 18

Country: Number of subjects enrolled

Switzerland: 8

Country: Number of subjects enrolled

Germany: 38

Country: Number of subjects enrolled

Spain: 51

Country: Number of subjects enrolled

Finland: 1

Country: Number of subjects enrolled

Italy: 44

Country: Number of subjects enrolled

Netherlands: 8

Country: Number of subjects enrolled

Turkey: 57

Country: Number of subjects enrolled

United States: 24

Country: Number of subjects enrolled

Bulgaria: 6

Country: Number of subjects enrolled

Brazil: 22

Country: Number of subjects enrolled

Croatia: 4

Country: Number of subjects enrolled

Hungary: 16

Country: Number of subjects enrolled

Mexico: 3

Country: Number of subjects enrolled

North Macedonia: 10

Country: Number of subjects enrolled

Panama: 2

Country: Number of subjects enrolled

Peru: 14

Country: Number of subjects enrolled

Poland: 31

Country: Number of subjects enrolled

Romania: 16

Country: Number of subjects enrolled

Russian Federation: 21

Worldwide total number of subjects

780

EEA total number of subjects

221

Number of subjects enrolled per age group

In utero

0

Preterm newborn - gestational age < 37 wk

0

Newborns (0-27 days)

0

Infants and toddlers (28 days-23 months)

0

Children (2-11 years)

0

Adolescents (12-17 years)

0

Adults (18-64 years)

475

From 65 to 84 years

304

85 years and over

1

Subject disposition

Top of page

Recruitment details

-

Screening details

A total of 780 participants were enrolled in the study.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Pertuzumab + Trastuzumab + Chemotherapy

Arm description

Subjects received pertuzumab in combination with trastuzumab and chemotherapy (cisplatin and fluoropyrimidine [capecitabine or 5-fluorouracil]) for the first 6 treatment cycles (cycle length = 21 days). Thereafter, subjects continued to receive pertuzumab and trastuzumab until disease progression, occurrence of unacceptable toxicity, or withdrawal from the study for another reason.

Arm type

Experimental

Investigational medicinal product name

Pertuzumab

Investigational medicinal product code

RO4368451

Other name

Perjeta

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects will receive pertuzumab 840 milligrams (mg) intravenously (IV) every 3 weeks (q3w) until disease progression, occurrence of unacceptable toxicity, or withdrawal from the study for another reason.

Investigational medicinal product name

Trastuzumab

Investigational medicinal product code

RO0452317

Other name

Herceptin

Pharmaceutical forms

Powder for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects will receive 8 milligrams per kilogram (mg/kg) IV initial dose on Day 1, followed by 6 mg/kg IV q3w until disease progression, occurrence of unacceptable toxicity, or withdrawal from the study for another reason.

Investigational medicinal product name

5-Fluorouracil

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects were to receive either capecitabine or 5-fluorouracil. 5-fluorouracil was administered at 800 milligrams per meter square (mg/m^2)/24 hour IV infusion for 120 hours (Days 1-5) q3w for 6 cycles.

Investigational medicinal product name

Capecitabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects were to receive either capecitabine or 5-fluorouracil. Capecitabine 1000 mg/m^2 was administered orally twice daily, evening of Day 1 to morning of Day 15 (28 doses) q3w for 6 cycles.

Investigational medicinal product name

Cisplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects will receive cisplatin 80 mg/m^2 IV q3w for 6 cycles.

Placebo + Trastuzumab + Chemotherapy

Arm description

Subjects received placebo in combination with trastuzumab and chemotherapy (cisplatin and fluoropyrimidine [capecitabine or 5-fluorouracil]) for the first 6 treatment cycles (cycle length = 21 days). Thereafter, subjects continued to receive placebo and trastuzumab until disease progression, occurrence of unacceptable toxicity, or withdrawal from the study for another reason.

Arm type

Placebo

Investigational medicinal product name

Trastuzumab

Investigational medicinal product code

RO0452317

Other name

Herceptin

Pharmaceutical forms

Powder for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects will receive 8 mg/kg IV initial dose on Day 1, followed by 6 mg/kg IV q3w until disease progression, occurrence of unacceptable toxicity, or withdrawal from the study for another reason.

Investigational medicinal product name

5-Fluorouracil

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects were to receive either capecitabine or 5-fluorouracil. 5-fluorouracil was administered at 800 milligrams per meter square (mg/m^2)/24 hour IV infusion for 120 hours (Days 1-5) q3w for 6 cycles.

Investigational medicinal product name

Capecitabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects were to receive either capecitabine or 5-fluorouracil. Capecitabine 1000 mg/m^2 was administered orally twice daily, evening of Day 1 to morning of Day 15 (28 doses) q3w for 6 cycles.

Investigational medicinal product name

Cisplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects will receive cisplatin 80 mg/m^2 IV q3w for 6 cycles.

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects will receive pertuzumab placebo IV q3w until disease progression, occurrence of unacceptable toxicity, or withdrawal from the study for another reason.

Number of subjects in period 1	Pertuzumab + Trastuzumab + Chemotherapy	Placebo + Trastuzumab + Chemotherapy
Started	388	392
Did Not Receive Any Study Treatment	4 ^[1]	3 ^[2]
Received at Least One Dose of Pertuzumab	384	1 ^[3]
Received Placebo (No Pertuzumab)	0 ^[4]	388
Completed	60	46
Not completed	328	346
Consent withdrawn by subject	18	14
Physician decision	2	-
Death	300	319
Reason Not Specified	2	5
Non-compliance	-	1
Lost to follow-up	6	7

Notes
[1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: The safety population (for adverse events analysis) included all subjects who received any amount of study treatment: those who received any pertuzumab were included in the Pertuzumab arm; all others treated were included in the Placebo arm. 5 subjects (3 in the Placebo arm and 2 in the Pertuzumab arm) were found to be ineligible after enrolment into the study and 2 subjects in the Pertuzumab arm died before receiving any treatment; these 7 subjects were excluded from safety analysis.
[2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: The safety population (for adverse events analysis) included all subjects who received any amount of study treatment: those who received any pertuzumab were included in the Pertuzumab arm; all others treated were included in the Placebo arm. 5 subjects (3 in the Placebo arm and 2 in the Pertuzumab arm) were found to be ineligible after enrolment into the study and 2 subjects in the Pertuzumab arm died before receiving any treatment; these 7 subjects were excluded from safety analysis.
[3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: The safety population (for adverse events analysis) included all subjects who received any amount of study treatment: those who received any pertuzumab were included in the Pertuzumab arm; all others treated were included in the Placebo arm. 5 subjects (3 in the Placebo arm and 2 in the Pertuzumab arm) were found to be ineligible after enrolment into the study and 2 subjects in the Pertuzumab arm died before receiving any treatment; these 7 subjects were excluded from safety analysis.
[4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: The safety population (for adverse events analysis) included all subjects who received any amount of study treatment: those who received any pertuzumab were included in the Pertuzumab arm; all others treated were included in the Placebo arm. 5 subjects (3 in the Placebo arm and 2 in the Pertuzumab arm) were found to be ineligible after enrolment into the study and 2 subjects in the Pertuzumab arm died before receiving any treatment; these 7 subjects were excluded from safety analysis.

Baseline characteristics

Top of page

Reporting group title

Pertuzumab + Trastuzumab + Chemotherapy

Reporting group description

Subjects received pertuzumab in combination with trastuzumab and chemotherapy (cisplatin and fluoropyrimidine [capecitabine or 5-fluorouracil]) for the first 6 treatment cycles (cycle length = 21 days). Thereafter, subjects continued to receive pertuzumab and trastuzumab until disease progression, occurrence of unacceptable toxicity, or withdrawal from the study for another reason.

Reporting group title

Placebo + Trastuzumab + Chemotherapy

Reporting group description

Subjects received placebo in combination with trastuzumab and chemotherapy (cisplatin and fluoropyrimidine [capecitabine or 5-fluorouracil]) for the first 6 treatment cycles (cycle length = 21 days). Thereafter, subjects continued to receive placebo and trastuzumab until disease progression, occurrence of unacceptable toxicity, or withdrawal from the study for another reason.

Reporting group values	Pertuzumab + Trastuzumab + Chemotherapy	Placebo + Trastuzumab + Chemotherapy	Total
Number of subjects	388	392	780
Age categorical
Units: Subjects
Adults (18-64 years)	228	247	475
From 65-84 years	159	145	304
85 years and over	1	0	1
Age Continuous
Units: years
arithmetic mean (standard deviation)	60.9 ± 11.3	60.1 ± 10.7	-
Sex: Female, Male
Units: Subjects
Female	94	69	163
Male	294	323	617
Geographic Region
Subjects were stratified at randomization according to geographic region, prior gastrectomy, and HER2 status.
Units: Subjects
Asia (excluding Japan)	143	146	289
Japan	40	40	80
North America/Western Europe/Australia	133	133	266
South America/Eastern Europe	72	73	145
Prior Gastrectomy
Subjects were stratified at randomization according to geographic region, prior gastrectomy, and HER2 status.
Units: Subjects
Prior Gastrectomy	105	102	207
No Prior Gastrectomy	283	290	573
Human Epidermal Growth Factor Receptor 2 (HER2) Status
Subjects were stratified at randomization according to geographic region, prior gastrectomy, and HER2 status. HER2 positivity of tumor specimens from each subject were determined by central laboratory testing. The IHC gives a score of 0 to 3+ that measures the amount of HER2 proteins on the surface of cells. A subject's cancer was considered HER2-positive with an IHC score of 2+ that was confirmed by ISH positivity or by an IHC score of 3+. IHC = immunohistochemistry; ISH = in-situ hybridization
Units: Subjects
IHC 2+/ISH+	129	130	259
IHC 3+	259	262	521
Measurability of Disease, per RECIST v1.1
Units: Subjects
Measurable Disease	351	352	703
Non-Measurable Evaluable Disease Only	37	40	77
EORTC QLQ-C30 Scores at Baseline - Appetite Loss
European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life-Core 30 (QLQ-C30) Appetite Loss Symptom Scale score at baseline (Cycle 1, Day 1)
Units: score on a scale
arithmetic mean (standard deviation)	26.68 ± 28.65	27.59 ± 29.96	-
EORTC QLQ-C30 Scores at Baseline - Cognitive Functional Scale
EORTC QLQ-C30 Cognitive Functional Scale score at baseline (Cycle 1, Day 1)
Units: score on a scale
arithmetic mean (standard deviation)	87.95 ± 17.32	88.22 ± 16.18	-
EORTC QLQ-C30 Scores at Baseline - Constipation Symptom Scale
EORTC QLQ-C30 Constipation Symptom Scale score at baseline (Cycle 1, Day 1)
Units: score on a scale
arithmetic mean (standard deviation)	20.43 ± 28.45	18.41 ± 27.13	-
EORTC QLQ-C30 Scores at Baseline - Diarrhea Symptom Scale
EORTC QLQ-C30 Diarrhea Symptom Scale score at baseline (Cycle 1, Day 1)
Units: score on a scale
arithmetic mean (standard deviation)	8.87 ± 17.70	9.16 ± 18.87	-
EORTC QLQ-C30 Scores at Baseline - Dyspnoea Symptom Scale
EORTC QLQ-C30 Dyspnoea Symptom Scale score at baseline (Cycle 1, Day 1)
Units: score on a scale
arithmetic mean (standard deviation)	12.07 ± 17.99	12.65 ± 20.20	-
EORTC QLQ-C30 Scores at Baseline - Emotional Functional Scale
EORTC QLQ-C30 Emotional Functional Scale score at baseline (Cycle 1, Day 1)
Units: score on a scale
arithmetic mean (standard deviation)	76.90 ± 20.21	76.56 ± 19.84	-
EORTC QLQ-C30 Scores at Baseline - Fatigue Symptom Scale
EORTC QLQ-C30 Fatigue Symptom Scale score at baseline (Cycle 1, Day 1)
Units: score on a scale
arithmetic mean (standard deviation)	31.96 ± 23.46	32.27 ± 21.92	-
EORTC QLQ-C30 Scores at Baseline - Financial Difficulties Symptom Scale
EORTC QLQ-C30 Financial Difficulties Symptom Scale score at baseline (Cycle 1, Day 1)
Units: score on a scale
arithmetic mean (standard deviation)	26.67 ± 30.32	26.21 ± 29.78	-
EORTC QLQ-C30 Scores at Baseline - Nausea and Vomiting Symptom Scale
EORTC QLQ-C30 Nausea and Vomiting Symptom Scale score at baseline (Cycle 1, Day 1)
Units: score on a scale
arithmetic mean (standard deviation)	11.14 ± 19.11	11.92 ± 18.76	-
EORTC QLQ-C30 Scores at Baseline - Pain Symptom Scale
EORTC QLQ-C30 Pain Symptom Scale score at baseline (Cycle 1, Day 1)
Units: score on a scale
arithmetic mean (standard deviation)	23.92 ± 25.92	23.72 ± 24.82	-
EORTC QLQ-C30 Scores at Baseline - Physical Functional Scale
EORTC QLQ-C30 Physical Functional Scale score at baseline (Cycle 1, Day 1)
Units: score on a scale
arithmetic mean (standard deviation)	80.86 ± 19.53	82.05 ± 18.32	-
EORTC QLQ-C30 Scores at Baseline - Global Health Status Scale
EORTC QLQ-C30 Global Health Status Scale score at baseline (Cycle 1, Day 1)
Units: score on a scale
arithmetic mean (standard deviation)	59.77 ± 22.88	59.90 ± 22.11	-
EORTC QLQ-C30 Scores at Baseline - Role Functional Scale
EORTC QLQ-C30 Role Functional Scale score at baseline (Cycle 1, Day 1)
Units: score on a scale
arithmetic mean (standard deviation)	77.06 ± 27.02	79.33 ± 25.12	-
EORTC QLQ-C30 Scores at Baseline - Social Functional Scale
EORTC QLQ-C30 Social Functional Scale score at baseline (Cycle 1, Day 1)
Units: score on a scale
arithmetic mean (standard deviation)	77.96 ± 24.09	75.90 ± 24.69	-
EORTC QLQ-C30 Scores at Baseline - Insomnia Symptom Scale
EORTC QLQ-C30 Insomnia Symptom Scale score at baseline (Cycle 1, Day 1)
Units: score on a scale
arithmetic mean (standard deviation)	22.94 ± 28.00	25.41 ± 28.81	-
EORTC QLQ-STO22 Scores at Baseline - Anxiety
European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Gastric Cancer Module (EORTC QLQ-STO22) Anxiety score at baseline (Cycle 1, Day 1)
Units: score on a scale
arithmetic mean (standard deviation)	40.10 ± 25.85	40.48 ± 25.32	-
EORTC QLQ-STO22 Scores at Baseline - Body Image
EORTC QLQ-STO22 Body Image score at baseline (Cycle 1, Day 1)
Units: score on a scale
arithmetic mean (standard deviation)	23.53 ± 28.40	23.68 ± 27.47	-
EORTC QLQ-STO22 Scores at Baseline - Dry Mouth
EORTC QLQ-STO22 Dry Mouth score at baseline (Cycle 1, Day 1)
Units: score on a scale
arithmetic mean (standard deviation)	21.80 ± 25.07	23.32 ± 26.79	-
EORTC QLQ-STO22 Scores at Baseline - Dysphagia
EORTC QLQ-STO22 Dysphagia score at baseline (Cycle 1, Day 1)
Units: score on a scale
arithmetic mean (standard deviation)	16.29 ± 21.46	14.15 ± 18.93	-
EORTC QLQ-STO22 Scores at Baseline - Eating Restrictions
EORTC QLQ-STO22 Eating Restrictions score at baseline (Cycle 1, Day 1)
Units: score on a scale
arithmetic mean (standard deviation)	23.26 ± 21.78	22.33 ± 20.22	-
EORTC QLQ-STO22 Scores at Baseline - Hair Loss
EORTC QLQ-STO22 Hair Loss score at baseline (Cycle 1, Day 1)
Units: score on a scale
arithmetic mean (standard deviation)	4.73 ± 13.28	4.04 ± 13.20	-
EORTC QLQ-STO22 Scores at Baseline - Pain
EORTC QLQ-STO22 Pain score at baseline (Cycle 1, Day 1)
Units: score on a scale
arithmetic mean (standard deviation)	26.48 ± 21.34	26.47 ± 20.70	-
EORTC QLQ-STO22 Scores at Baseline - Reflux Symptoms
EORTC QLQ-STO22 Reflux Symptoms score at baseline (Cycle 1, Day 1)
Units: score on a scale
arithmetic mean (standard deviation)	16.68 ± 19.03	17.34 ± 18.31	-
EORTC QLQ-STO22 Scores at Baseline - Taste
EORTC QLQ-STO22 Taste score at baseline (Cycle 1, Day 1)
Units: score on a scale
arithmetic mean (standard deviation)	13.79 ± 23.99	16.22 ± 25.49	-

End points

Top of page

Reporting group title

Pertuzumab + Trastuzumab + Chemotherapy

Reporting group description

Subjects received pertuzumab in combination with trastuzumab and chemotherapy (cisplatin and fluoropyrimidine [capecitabine or 5-fluorouracil]) for the first 6 treatment cycles (cycle length = 21 days). Thereafter, subjects continued to receive pertuzumab and trastuzumab until disease progression, occurrence of unacceptable toxicity, or withdrawal from the study for another reason.

Reporting group title

Placebo + Trastuzumab + Chemotherapy

Reporting group description

Subjects received placebo in combination with trastuzumab and chemotherapy (cisplatin and fluoropyrimidine [capecitabine or 5-fluorouracil]) for the first 6 treatment cycles (cycle length = 21 days). Thereafter, subjects continued to receive placebo and trastuzumab until disease progression, occurrence of unacceptable toxicity, or withdrawal from the study for another reason.

Primary: Overall Survival

Top of page

End point title

Overall Survival

End point description

Overall survival (OS) was defined as the time from randomization to death from any cause. For participants who were still alive on the date of clinical data cut-off for the OS analysis, the last date when the participant was known to be alive on, or prior to the clinical cut-off date, was used to determine the censoring date. Participants who did not have any post-baseline data (e.g., dosing records, imaging dates, visit dates) were censored at the date of randomization plus 1 day.

End point type

Primary

End point timeframe

From Baseline until death from any cause (Median [full range] duration of follow-up in Pertuzumab vs. Placebo arms for Primary Analysis: 24.4 [0-42] months vs. 25.0 [0-41] months; Final Analysis: 46.1 [0-70] months vs. 44.4 [0-68] months)

End point values	Pertuzumab + Trastuzumab + Chemotherapy	Placebo + Trastuzumab + Chemotherapy
Number of subjects analysed	388	392
Units: Months
median (confidence interval 95%)
Primary Analysis	17.5 (16.2 to 19.3)	14.2 (12.9 to 15.5)
Final Analysis	18.1 (16.2 to 19.5)	14.2 (12.9 to 15.7)

OS Primary Analysis

Statistical analysis description

The null hypothesis is that the survival distribution of OS is the same in the two treatment arms.

Comparison groups

Placebo + Trastuzumab + Chemotherapy v Pertuzumab + Trastuzumab + Chemotherapy

Number of subjects included in analysis

780

Analysis specification

Pre-specified

Analysis type

superiority ^[1]

P-value

= 0.0565 ^[2]

Method

Stratified Log-Rank

Parameter type

Hazard ratio (HR)

Point estimate

0.84

Confidence interval

level

95%

sides

2-sided

lower limit

0.71

upper limit

1

Notes
[1] - The study was designed to have 80% power to show a significant difference with respect to the primary endpoint.
[2] - The actual p-value significance threshold required for OS was 0.0455, after alpha spent at the interim analysis was taken into account. Stratified analysis by geographic region, HER2 status, and prior gastrectomy.

OS Final Analysis

Statistical analysis description

Stratified analysis by geographic region, HER2 status, and prior gastrectomy.

Comparison groups

Pertuzumab + Trastuzumab + Chemotherapy v Placebo + Trastuzumab + Chemotherapy

Number of subjects included in analysis

780

Analysis specification

Pre-specified

Analysis type

other ^[3]

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.85

Confidence interval

level

95%

sides

2-sided

lower limit

0.72

upper limit

0.99

Notes
[3] - Exploratory

Secondary: Progression-Free Survival, as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) Criteria

Top of page

End point title

Progression-Free Survival, as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) Criteria

End point description

Progression-free survival (PFS) is defined as the time from randomization to the first occurrence of progressive disease (PD), as determined by the investigator using RECIST v1.1, or death from any cause, whichever occurred first. Tumor assessments with CT or MRI scans of the chest, abdomen, and pelvis were performed every 9 weeks. Participants without documented PD or death were censored at the tumor assessment date for which the participant was last known to be progression-free. Participants who did not have any post-baseline tumor assessment data were censored at the date of randomization plus 1 day. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline; an absolute increase of at least 5 millimeters (mm) in the sum of diameters of target lesions; the appearance of one or more new lesions.

End point type

Secondary

End point timeframe

Baseline to death or progressive disease (PD), whichever occurred first (Median [full range] duration of follow-up in Pertuzumab vs. Placebo arms for Primary Analysis: 24.9 [0-41] vs. 21.3 [0-39] months; Final Analysis: 50.4 [0-70] vs. 47.4 [0-66] months)

End point values	Pertuzumab + Trastuzumab + Chemotherapy	Placebo + Trastuzumab + Chemotherapy
Number of subjects analysed	388	392
Units: months
median (confidence interval 95%)
Primary Analysis	8.5 (8.2 to 9.7)	7.0 (6.4 to 8.2)
Final Analysis	8.5 (8.3 to 9.7)	7.2 (6.4 to 8.2)

PFS Primary Analysis

Statistical analysis description

A stratified Cox proportional hazards regression model was used to estimate the HR between the pertuzumab arm vs. the placebo arm.

Comparison groups

Pertuzumab + Trastuzumab + Chemotherapy v Placebo + Trastuzumab + Chemotherapy

Number of subjects included in analysis

780

Analysis specification

Pre-specified

Analysis type

superiority ^[4]

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.73

Confidence interval

level

95%

sides

2-sided

lower limit

0.62

upper limit

0.86

Notes
[4] - Given the hierarchical testing procedure and non-statistical significant OS result, confirmatory statistical significance of PFS based on the Log-Rank test p-value cannot be concluded.

PFS Final Analysis

Statistical analysis description

A stratified Cox proportional hazards regression model was used to estimate the HR between the pertuzumab arm vs. the placebo arm.

Comparison groups

Pertuzumab + Trastuzumab + Chemotherapy v Placebo + Trastuzumab + Chemotherapy

Number of subjects included in analysis

780

Analysis specification

Pre-specified

Analysis type

other ^[5]

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.73

Confidence interval

level

95%

sides

2-sided

lower limit

0.62

upper limit

0.85

Notes
[5] - Exploratory

Secondary: Primary Analysis of the Percentage of Subjects With Overall Objective Response, as Determined by the Investigator According to RECIST v1.1 Criteria

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End point title

Primary Analysis of the Percentage of Subjects With Overall Objective Response, as Determined by the Investigator According to RECIST v1.1 Criteria

End point description

The overall objective response rate was defined as the percentage of subjects with partial response (PR) or complete response (CR) occurring on two consecutive occasions ≥4 weeks apart, as determined by the investigator using RECIST v1.1. Tumor assessments with computed tomography (CT) or magnetic resonance imaging (MRI) scans of the chest, abdomen, and pelvis were performed every 9 weeks. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. CR: disappearance of all target lesions. Measurable disease is defined as tumor lesions measured in at least one dimension (longest diameter in plane of measurement) with a minimum size of: 10 mm by CT or MRI scan; 10 mm caliper measurement by clinical examination; 20 mm by chest X-ray. For a malignant lymph node to be considered pathologically enlarged and measurable, it must be greater than or equal to (≥) 15 mm in short axis when assessed by CT scan.

End point type

Secondary

End point timeframe

Baseline up to death or progressive disease, whichever occurred first (Median [full range] duration of follow-up in Pertuzumab vs. Placebo arms for Primary Analysis: 24.9 [0-41] months vs. 21.3 [0-39] months)

End point values	Pertuzumab + Trastuzumab + Chemotherapy	Placebo + Trastuzumab + Chemotherapy
Number of subjects analysed	351	352
Units: Percentage of subjects
number (confidence interval 95%)
Objective Response (CR + PR)	56.7 (51.33 to 61.95)	48.3 (42.97 to 53.65)
Complete Response (CR)	5.1 (3.07 to 7.98)	0.9 (0.18 to 2.47)
Partial Response (PR)	51.6 (46.20 to 56.91)	47.4 (42.13 to 52.80)
Stable Disease (SD)	27.9 (23.29 to 32.93)	33.0 (28.06 to 38.14)
Progressive Disease (PD)	4.8 (2.85 to 7.64)	8.0 (5.35 to 11.29)
Not Evaluable/Missing	10.5 (7.53 to 14.24)	10.8 (7.75 to 14.52)

Primary Analysis: Difference in Objective Response

Statistical analysis description

The difference in objective response was calculated as the pertuzumab arm minus placebo arm.

Comparison groups

Pertuzumab + Trastuzumab + Chemotherapy v Placebo + Trastuzumab + Chemotherapy

Number of subjects included in analysis

703

Analysis specification

Pre-specified

Analysis type

other ^[6]

Method

Parameter type

Difference in Objective Response

Point estimate

8.4

Confidence interval

level

95%

sides

2-sided

lower limit

0.89

upper limit

15.91

Notes
[6] - Exploratory

Primary Analysis: Odds Ratio of Objective Response

Statistical analysis description

Odds ratio was calculated as the pertuzumab arm vs. placebo arm.

Comparison groups

Pertuzumab + Trastuzumab + Chemotherapy v Placebo + Trastuzumab + Chemotherapy

Number of subjects included in analysis

703

Analysis specification

Pre-specified

Analysis type

other ^[7]

Method

Parameter type

Odds ratio (OR)

Point estimate

1.4

Confidence interval

level

95%

sides

2-sided

lower limit

1.04

upper limit

1.89

Notes
[7] - Exploratory

Secondary: Final Analysis of the Percentage of Subjects With Overall Objective Response, as Determined by the Investigator According to RECIST v1.1 Criteria

Top of page

End point title

Final Analysis of the Percentage of Subjects With Overall Objective Response, as Determined by the Investigator According to RECIST v1.1 Criteria

End point description

The overall objective response rate was defined as the percentage of subjects with partial response (PR) or complete response (CR) occurring on two consecutive occasions ≥4 weeks apart, as determined by the investigator using RECIST v1.1. Tumor assessments with computed tomography (CT) or magnetic resonance imaging (MRI) scans of the chest, abdomen, and pelvis were performed every 9 weeks. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. CR: disappearance of all target lesions. Measurable disease is defined as tumor lesions measured in at least one dimension (longest diameter in plane of measurement) with a minimum size of: 10 mm by CT or MRI scan; 10 mm caliper measurement by clinical examination; 20 mm by chest X-ray. For a malignant lymph node to be considered pathologically enlarged and measurable, it must be greater than or equal to (≥) 15 mm in short axis when assessed by CT scan.

End point type

Secondary

End point timeframe

Baseline up to death or progressive disease, whichever occurred first (Median [full range] duration of follow-up in Pertuzumab vs. Placebo arms for Final Analysis: 50.4 [0-70] months vs. 47.4 [0-66] months)

End point values	Pertuzumab + Trastuzumab + Chemotherapy	Placebo + Trastuzumab + Chemotherapy
Number of subjects analysed	351 ^[8]	352 ^[9]
Units: Percentage of subjects
number (confidence interval 95%)
Objective Response (CR + PR)	57.0 (51.62 to 62.22)	48.6 (43.25 to 53.94)
Complete Response (CR)	5.7 (3.51 to 8.66)	2.0 (0.80 to 4.05)
Partial Response (PR)	51.3 (45.92 to 56.62)	46.6 (41.29 to 51.95)
Stable Disease (SD)	27.6 (23.02 to 32.63)	32.7 (27.79 to 37.84)
Progressive Disease (PD)	4.8 (2.85 to 7.64)	8.2 (5.59 to 11.62)
Not Evaluable/Missing	10.5 (7.53 to 14.24)	10.5 (7.51 to 14.20)

Notes
[8] - Subjects with measurable disease at baseline, according to RECIST v1.1 criteria
[9] - Subjects with measurable disease at baseline, according to RECIST v1.1 criteria

Final Analysis: Difference in Objective Response

Statistical analysis description

The difference in objective response was calculated as the pertuzumab arm minus placebo arm.

Comparison groups

Pertuzumab + Trastuzumab + Chemotherapy v Placebo + Trastuzumab + Chemotherapy

Number of subjects included in analysis

703

Analysis specification

Pre-specified

Analysis type

other ^[10]

Method

Parameter type

Difference in Objective Response

Point estimate

8.4

Confidence interval

level

95%

sides

2-sided

lower limit

0.89

upper limit

15.91

Notes
[10] - Exploratory

Final Analysis: Odds Ratio for Objective Response

Statistical analysis description

Odds ratio was calculated as the pertuzumab arm vs. placebo arm.

Comparison groups

Pertuzumab + Trastuzumab + Chemotherapy v Placebo + Trastuzumab + Chemotherapy

Number of subjects included in analysis

703

Analysis specification

Pre-specified

Analysis type

other ^[11]

Method

Parameter type

Odds ratio (OR)

Point estimate

1.4

Confidence interval

level

95%

sides

2-sided

lower limit

1.04

upper limit

1.89

Notes
[11] - Exploratory

Secondary: Duration of Objective Response, as Determined by Investigator According to RECIST v1.1 Criteria

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End point title

Duration of Objective Response, as Determined by Investigator According to RECIST v1.1 Criteria

End point description

Duration of objective response is defined as the time from first occurrence of documented objective response to documented disease progression, as determined by the investigator using RECIST v1.1, or death from any cause. Objective response: PR or CR occurring on 2 consecutive occasions ≥4 weeks apart. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. CR: disappearance of all target lesions. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline; an absolute increase of at least 5 mm in the sum of diameters of target lesions; the appearance of one or more new lesions. Measurable disease defined as tumor lesions with a minimum size of: 10 mm by CT or MRI scan; 10 mm caliper measurement by clinical examination; 20 mm by chest X-ray. For a malignant lymph node, it must be ≥15 mm in short axis when assessed by CT scan.

End point type

Secondary

End point timeframe

Baseline to death or progressive disease (PD), whichever occurred first (Median [full range] duration of follow-up in Pertuzumab vs. Placebo arms for Primary Analysis: 24.9 [0-41] vs. 21.3 [0-39] months; Final Analysis: 50.4 [0-70] vs. 47.4 [0-66] months)

End point values	Pertuzumab + Trastuzumab + Chemotherapy	Placebo + Trastuzumab + Chemotherapy
Number of subjects analysed	200 ^[12]	171 ^[13]
Units: months
median (confidence interval 95%)
Primary Analysis (n = 199, 170)	10.2 (8.4 to 10.7)	8.4 (6.8 to 8.7)
Final Analysis (n = 200, 171)	10.2 (8.5 to 11.6)	8.4 (6.7 to 9.0)

Notes
[12] - Subjects with measurable disease at baseline who achieved a documented objective response
[13] - Subjects with measurable disease at baseline who achieved a documented objective response

DOR Primary Analysis - Stratified

Statistical analysis description

HR was calculated as pertuzumab arm vs. placebo arm. Stratified analysis by geographic region, HER2 status, and prior gastrectomy.

Comparison groups

Pertuzumab + Trastuzumab + Chemotherapy v Placebo + Trastuzumab + Chemotherapy

Number of subjects included in analysis

371

Analysis specification

Pre-specified

Analysis type

other ^[14]

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.82

Confidence interval

level

95%

sides

2-sided

lower limit

0.64

upper limit

1.06

Notes
[14] - Exploratory

DOR Final Analysis - Stratified

Statistical analysis description

HR was calculated as pertuzumab arm vs. placebo arm. Stratified analysis by geographic region, HER2 status, and prior gastrectomy.

Comparison groups

Pertuzumab + Trastuzumab + Chemotherapy v Placebo + Trastuzumab + Chemotherapy

Number of subjects included in analysis

371

Analysis specification

Pre-specified

Analysis type

other ^[15]

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.78

Confidence interval

level

95%

sides

2-sided

lower limit

0.62

upper limit

0.98

Notes
[15] - Exploratory

Secondary: Percentage of Subjects With Clinical Benefit, as Determined by the Investigator According to RECIST v1.1 Criteria

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End point title

Percentage of Subjects With Clinical Benefit, as Determined by the Investigator According to RECIST v1.1 Criteria

End point description

The clinical benefit rate was defined as best response of complete response (CR) or partial response (PR) or stable disease (SD) for 6 weeks or longer, as determined by the investigator using RECIST v1.1. CR: disappearance of all target lesions. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression, taking as reference the smallest sum diameters while on study. Measurable disease is defined as tumor lesions measured in at least one dimension (longest diameter in plane of measurement) with a minimum size of: 10 mm by CT or MRI scan; 10 mm caliper measurement by clinical examination; 20 mm by chest X-ray. For a malignant lymph node to be considered pathologically enlarged and measurable, it must be >/=15 mm in short axis when assessed by CT scan. The clinical benefit rate was not updated at the final analysis.

End point type

Secondary

End point timeframe

Baseline up to death or progressive disease, whichever occurred first (Median [full range] duration of follow-up in Pertuzumab vs. Placebo arms for Primary Analysis: 24.9 [0-41] months vs. 21.3 [0-39] months)

End point values	Pertuzumab + Trastuzumab + Chemotherapy	Placebo + Trastuzumab + Chemotherapy
Number of subjects analysed	351 ^[16]	352 ^[17]
Units: percentage of subjects
number (confidence interval 95%)	84.6 (80.41 to 88.23)	81.3 (76.77 to 85.19)

Notes
[16] - Subjects with measurable disease at baseline, according to RECIST v1.1 criteria
[17] - Subjects with measurable disease at baseline, according to RECIST v1.1 criteria

Difference in Clinical Benefit Rate

Statistical analysis description

The difference in clinical benefit rate was calculated as the pertuzumab arm minus placebo arm.

Comparison groups

Pertuzumab + Trastuzumab + Chemotherapy v Placebo + Trastuzumab + Chemotherapy

Number of subjects included in analysis

703

Analysis specification

Pre-specified

Analysis type

other ^[18]

Method

Parameter type

Difference in Clinical Benefit Rate

Point estimate

3.37

Confidence interval

level

95%

sides

2-sided

lower limit

-2.34

upper limit

9.07

Notes
[18] - Exploratory

Odds Ratio for Clinical Benefit Rate

Statistical analysis description

Odds ratio was calculated as the pertuzumab arm vs. placebo arm.

Comparison groups

Pertuzumab + Trastuzumab + Chemotherapy v Placebo + Trastuzumab + Chemotherapy

Number of subjects included in analysis

703

Analysis specification

Pre-specified

Analysis type

other ^[19]

Method

Parameter type

Odds ratio (OR)

Point estimate

1.27

Confidence interval

level

95%

sides

2-sided

lower limit

0.86

upper limit

1.88

Notes
[19] - Exploratory

Secondary: Overview of Safety: Percentage of Subjects With at Least One Adverse Event, Severity Determined According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 4.03

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End point title

Overview of Safety: Percentage of Subjects With at Least One Adverse Event, Severity Determined According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 4.03

End point description

An adverse event (AE) is any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. The investigator graded all AEs for severity per the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.03; if not listed, the AE was assessed as follows: Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening/disabling; Grade 5 = death. The investigator determined whether an AE was related to study drug and independently assessed severity and seriousness of each AE. The safety population included all subjects who received any amount of any study medication. Those who received any amount of pertuzumab were included in the pertuzumab arm; all other treated subjects were included in the placebo arm.

End point type

Secondary

End point timeframe

From Baseline until end of post-treatment follow-up (up to 70 months)

End point values	Pertuzumab + Trastuzumab + Chemotherapy	Placebo + Trastuzumab + Chemotherapy
Number of subjects analysed	385 ^[20]	388 ^[21]
Units: percentage of subjects
number (not applicable)
Any Adverse Event (AE)	99.0	99.2
AE with Fatal Outcome	7.0	8.0
Serious AE	46.2	40.2
Grade 3-5 AE	80.5	74.2
AE Leading to Pertuz/Pbo & Trastuz Discontinuation	12.5	11.9
AE Leading to Dose Interruption &/or Dose Delay	28.6	24.2

Notes
[20] - Safety population: subjects who received any amount of any study medication
[21] - Safety population: subjects who received any amount of any study medication

No statistical analyses for this end point

Secondary: Percentage of Subjects With Symptomatic or Asymptomatic Left Ventricular Systolic Dysfunction (LVSD)

Top of page

End point title

Percentage of Subjects With Symptomatic or Asymptomatic Left Ventricular Systolic Dysfunction (LVSD)

End point description

The percentage of subjects with symptomatic left ventricular systolic dysfunction (LVSD) and asymptomatic LVSD events (defined as a left ventricular ejection fraction [LVEF] ≥10% decrease from baseline to an absolute value <50%) at any time during the study was summarized by treatment arm. The safety population included all subjects who received any amount of any study medication. Those who received any amount of pertuzumab were included in the pertuzumab arm; all other treated subjects were included in the placebo arm.

End point type

Secondary

End point timeframe

From Baseline until end of post-treatment follow-up (up to 70 months)

End point values	Pertuzumab + Trastuzumab + Chemotherapy	Placebo + Trastuzumab + Chemotherapy
Number of subjects analysed	385 ^[22]	388 ^[23]
Units: percentage of subjects
number (not applicable)
Symptomatic LVSD	0.8	0.3
Asymptomatic LVSD	5.2	4.6

Notes
[22] - Safety population: subjects who received any amount of any study medication
[23] - Safety population: subjects who received any amount of any study medication

No statistical analyses for this end point

Secondary: Change from Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Score

Top of page

End point title

Change from Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Score

End point description

The EORTC QLQ-C30 included global health status, functional scales (physical, role, emotional, cognitive, and social), symptom scales (fatigue, nausea/vomiting, and pain) and single items (dyspnoea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Most questions used a 4-point scale (1 'Not at all' to 4 'Very much'; 2 questions used 7-point scale [1 'very poor' to 7 'Excellent']). Scores were averaged and transformed to 0 - 100 scale, whereby higher scores indicate greater functioning, greater quality of life, or a greater degree of symptoms, with changes of 5 - 10 points considered to be a minimally important difference to participants. A positive value means an increase, while a negative value means a decrease, in score at the indicated time-point relative to the score at baseline (Cycle 1, Day 1). Subjects in ITT population with both a baseline and at least 1 post-treatment assessment are included.

End point type

Secondary

End point timeframe

Day 1 of each 21-day treatment cycle up to 28 and 60-90 days after Day 1 of last treatment cycle (up to approximately 3.5 years)

End point values	Pertuzumab + Trastuzumab + Chemotherapy	Placebo + Trastuzumab + Chemotherapy
Number of subjects analysed	388	392
Units: score on a scale
arithmetic mean (standard deviation)
Appetite Loss: Cycle 2	6.57 ± 33.18	0.97 ± 35.86
Appetite Loss: Cycle 3	3.63 ± 36.19	3.81 ± 36.76
Appetite Loss: Cycle 4	5.24 ± 34.20	0.79 ± 34.33
Appetite Loss: Cycle 5	4.55 ± 36.50	2.90 ± 35.85
Appetite Loss: Cycle 6	3.94 ± 36.07	-0.39 ± 36.86
Appetite Loss: Cycle 7	2.07 ± 38.05	1.61 ± 35.98
Appetite Loss: Cycle 8	-2.42 ± 33.81	-3.69 ± 34.20
Appetite Loss: Cycle 9	-6.67 ± 31.92	-4.76 ± 31.67
Appetite Loss: Cycle 10	-8.06 ± 32.52	-6.63 ± 28.48
Appetite Loss: Cycle 11	-9.36 ± 33.19	-9.68 ± 27.38
Appetite Loss: Cycle 12	-9.22 ± 33.73	-9.05 ± 28.51
Appetite Loss: Cycle 13	-10.17 ± 31.10	-10.81 ± 29.18
Appetite Loss: Cycle 14	-12.10 ± 31.96	-12.09 ± 30.32
Appetite Loss: Cycle 15	-8.21 ± 32.96	-9.18 ± 29.81
Appetite Loss: Cycle 16	-6.03 ± 33.07	-10.59 ± 28.74
Appetite Loss: Cycle 17	-6.55 ± 29.29	-9.91 ± 29.05
Appetite Loss: Cycle 18	-4.90 ± 31.25	-14.08 ± 27.98
Appetite Loss: Cycle 19	-8.33 ± 31.34	-13.13 ± 28.57
Appetite Loss: Cycle 20	-3.97 ± 31.65	-13.23 ± 29.66
Appetite Loss: Cycle 21	-5.91 ± 31.01	-14.20 ± 32.76
Appetite Loss: Cycle 22	-4.98 ± 34.45	-16.31 ± 29.38
Appetite Loss: Cycle 23	-6.35 ± 36.84	-11.36 ± 35.90
Appetite Loss: Cycle 24	-7.78 ± 33.82	-13.33 ± 30.00
Appetite Loss: Cycle 25	-7.05 ± 35.14	-12.04 ± 31.02
Appetite Loss: Cycle 26	-7.48 ± 34.87	-12.50 ± 32.52
Appetite Loss: Cycle 27	-10.08 ± 33.76	-9.20 ± 28.03
Appetite Loss: Cycle 28	-10.00 ± 32.20	-11.54 ± 29.73
Appetite Loss: Post-treatment Visit 1	7.30 ± 36.86	2.64 ± 33.14
Appetite Loss: Post-treatment Visit 2	-0.33 ± 33.83	4.55 ± 34.53
Cognitive Functional Scale: Cycle 2	-1.90 ± 17.82	-1.81 ± 16.93
Cognitive Functional Scale: Cycle 3	-0.83 ± 17.11	-3.17 ± 18.30
Cognitive Functional Scale: Cycle 4	-2.04 ± 17.78	-2.99 ± 19.28
Cognitive Functional Scale: Cycle 5	-3.04 ± 19.09	-4.59 ± 19.59
Cognitive Functional Scale: Cycle 6	-5.10 ± 19.23	-3.84 ± 19.00
Cognitive Functional Scale: Cycle 7	-4.34 ± 19.52	-4.31 ± 19.09
Cognitive Functional Scale: Cycle 8	-3.15 ± 17.90	-3.30 ± 17.59
Cognitive Functional Scale: Cycle 9	-2.22 ± 18.53	-4.59 ± 18.53
Cognitive Functional Scale: Cycle 10	-3.32 ± 19.44	-3.11 ± 18.50
Cognitive Functional Scale: Cycle 11	-2.83 ± 18.44	-3.44 ± 17.06
Cognitive Functional Scale: Cycle 12	-3.35 ± 20.00	-2.52 ± 18.16
Cognitive Functional Scale: Cycle 13	-1.79 ± 19.04	-3.60 ± 17.89
Cognitive Functional Scale: Cycle 14	-1.98 ± 19.00	-2.29 ± 17.56
Cognitive Functional Scale: Cycle 15	-1.15 ± 18.47	-2.38 ± 16.05
Cognitive Functional Scale: Cycle 16	-2.73 ± 17.16	-2.55 ± 17.16
Cognitive Functional Scale: Cycle 17	-2.53 ± 17.21	-1.13 ± 15.44
Cognitive Functional Scale: Cycle 18	-2.78 ± 18.18	0.47 ± 16.42
Cognitive Functional Scale: Cycle 19	-1.04 ± 18.07	0.00 ± 14.62
Cognitive Functional Scale: Cycle 20	-2.18 ± 19.67	0.79 ± 15.68
Cognitive Functional Scale: Cycle 21	-2.11 ± 20.56	0.62 ± 16.50
Cognitive Functional Scale: Cycle 22	-4.73 ± 18.98	-0.71 ± 18.04
Cognitive Functional Scale: Cycle 23	-2.38 ± 19.60	1.14 ± 17.75
Cognitive Functional Scale: Cycle 24	-2.78 ± 19.69	1.25 ± 16.18
Cognitive Functional Scale: Cycle 25	-5.45 ± 16.41	-0.93 ± 18.66
Cognitive Functional Scale: Cycle 26	-2.38 ± 16.32	-1.56 ± 18.63
Cognitive Functional Scale: Cycle 27	-3.88 ± 18.84	-1.15 ± 18.33
Cognitive Functional Scale: Cycle 28	-3.75 ± 15.78	0.00 ± 20.00
Cognitive Functional Scale: Post-treatment Visit 1	-9.13 ± 21.90	-9.16 ± 20.02
Cognitive Functional Scale: Post-treatment Visit 2	-8.42 ± 20.22	-11.21 ± 22.48
Constipation Symptom Scale: Cycle 2	-5.39 ± 27.05	0.29 ± 27.23
Constipation Symptom Scale: Cycle 3	-7.48 ± 28.98	-2.11 ± 27.65
Constipation Symptom Scale: Cycle 4	-5.32 ± 29.21	-3.73 ± 28.26
Constipation Symptom Scale: Cycle 5	-5.94 ± 29.15	-1.28 ± 27.64
Constipation Symptom Scale: Cycle 6	-7.13 ± 29.65	-2.33 ± 30.24
Constipation Symptom Scale: Cycle 7	-8.13 ± 30.11	-4.09 ± 29.06
Constipation Symptom Scale: Cycle 8	-8.05 ± 30.90	-4.45 ± 27.32
Constipation Symptom Scale: Cycle 9	-10.00 ± 27.10	-5.61 ± 26.74
Constipation Symptom Scale: Cycle 10	-9.32 ± 29.56	-7.43 ± 26.81
Constipation Symptom Scale: Cycle 11	-9.16 ± 29.60	-6.88 ± 27.84
Constipation Symptom Scale: Cycle 12	-10.27 ± 29.04	-7.25 ± 25.39
Constipation Symptom Scale: Cycle 13	-11.19 ± 29.55	-5.76 ± 26.27
Constipation Symptom Scale: Cycle 14	-11.60 ± 27.11	-6.21 ± 26.00
Constipation Symptom Scale: Cycle 15	-10.51 ± 26.59	-7.14 ± 24.52
Constipation Symptom Scale: Cycle 16	-8.62 ± 24.91	-7.45 ± 25.39
Constipation Symptom Scale: Cycle 17	-8.33 ± 24.30	-5.86 ± 18.59
Constipation Symptom Scale: Cycle 18	-7.52 ± 22.93	-6.57 ± 26.20
Constipation Symptom Scale: Cycle 19	-3.47 ± 25.81	-3.03 ± 25.97
Constipation Symptom Scale: Cycle 20	-3.97 ± 26.08	-4.76 ± 26.68
Constipation Symptom Scale: Cycle 21	-3.80 ± 29.23	-9.26 ± 25.42
Constipation Symptom Scale: Cycle 22	-4.98 ± 28.58	-8.51 ± 27.34
Constipation Symptom Scale: Cycle 23	-6.35 ± 28.62	-8.33 ± 26.04
Constipation Symptom Scale: Cycle 24	-7.78 ± 27.01	-10.00 ± 26.37
Constipation Symptom Scale: Cycle 25	-7.05 ± 29.77	-9.26 ± 28.30
Constipation Symptom Scale: Cycle 26	-6.12 ± 30.94	-6.25 ± 23.09
Constipation Symptom Scale: Cycle 27	-7.75 ± 28.95	-10.34 ± 26.88
Constipation Symptom Scale: Cycle 28	-6.67 ± 26.37	-6.41 ± 21.12
Constipation Symptom Scale: Post-treatment Visit 1	-6.78 ± 31.45	-4.62 ± 26.19
Constipation Symptom Scale: Post-treatment Visit 2	-6.93 ± 28.41	-0.91 ± 31.11
Diarrhea Symptom Scale: Cycle 2	15.12 ± 30.42	5.20 ± 23.79
Diarrhea Symptom Scale: Cycle 3	14.64 ± 27.71	4.99 ± 26.10
Diarrhea Symptom Scale: Cycle 4	14.13 ± 27.15	4.63 ± 24.07
Diarrhea Symptom Scale: Cycle 5	13.17 ± 25.47	4.99 ± 23.70
Diarrhea Symptom Scale: Cycle 6	14.81 ± 27.01	2.47 ± 23.76
Diarrhea Symptom Scale: Cycle 7	12.26 ± 23.74	2.92 ± 23.44
Diarrhea Symptom Scale: Cycle 8	8.91 ± 23.56	2.61 ± 23.53
Diarrhea Symptom Scale: Cycle 9	6.83 ± 23.76	2.04 ± 21.25
Diarrhea Symptom Scale: Cycle 10	6.63 ± 23.97	0.60 ± 20.91
Diarrhea Symptom Scale: Cycle 11	5.26 ± 21.80	2.60 ± 20.36
Diarrhea Symptom Scale: Cycle 12	3.98 ± 22.30	1.92 ± 19.97
Diarrhea Symptom Scale: Cycle 13	4.29 ± 24.27	1.50 ± 19.27
Diarrhea Symptom Scale: Cycle 14	3.95 ± 24.45	0.98 ± 20.15
Diarrhea Symptom Scale: Cycle 15	3.33 ± 23.79	1.02 ± 19.42
Diarrhea Symptom Scale: Cycle 16	5.46 ± 21.06	3.14 ± 15.10
Diarrhea Symptom Scale: Cycle 17	2.68 ± 21.05	2.25 ± 14.94
Diarrhea Symptom Scale: Cycle 18	3.59 ± 21.95	3.29 ± 17.95
Diarrhea Symptom Scale: Cycle 19	3.82 ± 19.86	2.02 ± 16.41
Diarrhea Symptom Scale: Cycle 20	5.95 ± 19.47	3.70 ± 17.05
Diarrhea Symptom Scale: Cycle 21	3.80 ± 23.26	1.85 ± 16.40
Diarrhea Symptom Scale: Cycle 22	6.97 ± 24.98	4.26 ± 17.88
Diarrhea Symptom Scale: Cycle 23	6.88 ± 21.72	8.33 ± 20.49
Diarrhea Symptom Scale: Cycle 24	7.22 ± 22.21	3.33 ± 16.54
Diarrhea Symptom Scale: Cycle 25	8.97 ± 23.91	2.78 ± 14.64
Diarrhea Symptom Scale: Cycle 26	5.44 ± 21.89	5.21 ± 20.93
Diarrhea Symptom Scale: Cycle 27	3.88 ± 22.07	3.45 ± 16.29
Diarrhea Symptom Scale: Cycle 28	7.50 ± 27.72	2.56 ± 16.12
Diarrhea Symptom Scale: Post-treatment Visit 1	8.14 ± 26.00	1.98 ± 24.35
Diarrhea Symptom Scale: Post-treatment Visit 2	7.26 ± 25.65	4.24 ± 29.65
Dyspnoea Symptom Scale: Cycle 2	-0.50 ± 19.04	0.29 ± 19.72
Dyspnoea Symptom Scale: Cycle 3	-0.31 ± 20.18	-0.32 ± 20.38
Dyspnoea Symptom Scale: Cycle 4	1.23 ± 20.31	1.81 ± 21.08
Dyspnoea Symptom Scale: Cycle 5	2.58 ± 20.62	1.39 ± 21.18
Dyspnoea Symptom Scale: Cycle 6	3.20 ± 23.79	0.39 ± 20.55
Dyspnoea Symptom Scale: Cycle 7	0.00 ± 21.94	0.59 ± 20.07
Dyspnoea Symptom Scale: Cycle 8	-0.14 ± 21.99	0.93 ± 20.56
Dyspnoea Symptom Scale: Cycle 9	-1.12 ± 20.51	0.17 ± 18.95
Dyspnoea Symptom Scale: Cycle 10	-0.54 ± 21.56	1.00 ± 16.99
Dyspnoea Symptom Scale: Cycle 11	-2.16 ± 19.58	-1.29 ± 17.77
Dyspnoea Symptom Scale: Cycle 12	-2.53 ± 19.75	-0.71 ± 18.95
Dyspnoea Symptom Scale: Cycle 13	-1.43 ± 20.34	-1.20 ± 16.77
Dyspnoea Symptom Scale: Cycle 14	-1.98 ± 19.00	-2.61 ± 17.98
Dyspnoea Symptom Scale: Cycle 15	-2.84 ± 21.26	2.72 ± 18.95
Dyspnoea Symptom Scale: Cycle 16	-1.45 ± 20.42	1.18 ± 18.86
Dyspnoea Symptom Scale: Cycle 17	-1.82 ± 20.61	0.90 ± 19.87
Dyspnoea Symptom Scale: Cycle 18	-0.98 ± 20.15	-2.35 ± 18.10
Dyspnoea Symptom Scale: Cycle 19	-1.74 ± 20.73	0.51 ± 18.15
Dyspnoea Symptom Scale: Cycle 20	-1.19 ± 20.98	-1.06 ± 16.90
Dyspnoea Symptom Scale: Cycle 21	1.27 ± 22.29	-0.62 ± 19.95
Dyspnoea Symptom Scale: Cycle 22	-1.99 ± 22.38	0.71 ± 14.73
Dyspnoea Symptom Scale: Cycle 23	-1.59 ± 21.94	1.52 ± 14.30
Dyspnoea Symptom Scale: Cycle 24	1.11 ± 22.10	-1.67 ± 12.96
Dyspnoea Symptom Scale: Cycle 25	0.64 ± 21.38	-3.70 ± 15.49
Dyspnoea Symptom Scale: Cycle 26	0.00 ± 22.57	1.04 ± 23.16
Dyspnoea Symptom Scale: Cycle 27	0.78 ± 21.19	3.45 ± 22.44
Dyspnoea Symptom Scale: Cycle 28	1.67 ± 21.28	3.85 ± 17.20
Dyspnoea Symptom Scale: Post-treatment Visit 1	6.97 ± 26.98	6.77 ± 23.82
Dyspnoea Symptom Scale: Post-treatment Visit 2	3.30 ± 23.81	9.39 ± 26.76
Emotional Functional Scale: Cycle 2	3.53 ± 16.84	3.05 ± 18.49
Emotional Functional Scale: Cycle 3	2.65 ± 18.63	3.96 ± 19.95
Emotional Functional Scale: Cycle 4	3.10 ± 21.11	3.67 ± 20.44
Emotional Functional Scale: Cycle 5	2.62 ± 19.97	2.74 ± 21.72
Emotional Functional Scale: Cycle 6	1.01 ± 19.64	4.93 ± 21.00
Emotional Functional Scale: Cycle 7	1.72 ± 21.09	4.41 ± 20.18
Emotional Functional Scale: Cycle:8	3.43 ± 20.66	5.66 ± 19.63
Emotional Functional Scale: Cycle 9	4.72 ± 20.10	4.78 ± 19.45
Emotional Functional Scale: Cycle 10	3.72 ± 21.76	6.74 ± 18.13
Emotional Functional Scale: Cycle 11	5.85 ± 19.64	4.96 ± 19.21
Emotional Functional Scale: Cycle 12	4.93 ± 21.38	5.24 ± 19.14
Emotional Functional Scale: Cycle 13	5.00 ± 23.07	5.18 ± 17.95
Emotional Functional Scale: Cycle 14	5.93 ± 22.90	6.29 ± 19.03
Emotional Functional Scale: Cycle 15	6.03 ± 22.13	5.19 ± 19.61
Emotional Functional Scale: Cycle 16	5.17 ± 23.20	5.29 ± 20.81
Emotional Functional Scale: Cycle 17	6.01 ± 23.55	6.31 ± 18.70
Emotional Functional Scale: Cycle 18	3.68 ± 24.11	5.87 ± 19.39
Emotional Functional Scale: Cycle 19	4.69 ± 26.01	5.56 ± 18.68
Emotional Functional Scale: Cycle 20	3.47 ± 26.92	5.42 ± 17.91
Emotional Functional Scale: Cycle 21	4.54 ± 26.55	6.48 ± 22.00
Emotional Functional Scale: Cycle 22	5.35 ± 28.67	6.91 ± 18.66
Emotional Functional Scale: Cycle 23	5.82 ± 28.42	6.63 ± 21.00
Emotional Functional Scale: Cycle 24	5.28 ± 26.22	8.54 ± 19.57
Emotional Functional Scale: Cycle 25	5.93 ± 25.48	8.80 ± 20.89
Emotional Functional Scale: Cycle 26	5.44 ± 27.77	5.99 ± 16.15
Emotional Functional Scale: Cycle 27	7.56 ± 28.34	5.75 ± 18.51
Emotional Functional Scale: Cycle 28	7.08 ± 25.43	7.05 ± 18.96
Emotional Functional Scale: Post-treatment Visit 1	-5.48 ± 23.16	-3.92 ± 23.28
Emotional Functional Scale: Post-treatment Visit 2	-2.64 ± 23.33	-4.47 ± 23.34
Fatigue Symptom Scale: Cycle 2	3.13 ± 19.80	2.32 ± 21.57
Fatigue Symptom Scale: Cycle 3	1.41 ± 22.65	3.19 ± 22.97
Fatigue Symptom Scale: Cycle 4	2.77 ± 23.14	1.58 ± 24.04
Fatigue Symptom Scale: Cycle 5	3.87 ± 25.75	3.05 ± 24.29
Fatigue Symptom Scale: Cycle 6	4.37 ± 25.64	2.62 ± 23.68
Fatigue Symptom Scale: Cycle 7	2.36 ± 26.79	0.97 ± 23.44
Fatigue Symptom Scale: Cycle 8	-0.19 ± 25.00	-1.18 ± 22.74
Fatigue Symptom Scale: Cycle 9	-2.38 ± 22.69	-2.01 ± 22.84
Fatigue Symptom Scale: Cycle 10	-3.41 ± 24.69	-3.08 ± 22.41
Fatigue Symptom Scale: Cycle 11	-4.35 ± 22.66	-3.44 ± 21.21
Fatigue Symptom Scale: Cycle 12	-3.14 ± 24.56	-4.60 ± 24.39
Fatigue Symptom Scale: Cycle 13	-4.57 ± 23.31	-4.50 ± 21.47
Fatigue Symptom Scale: Cycle 14	-6.75 ± 24.32	-6.54 ± 22.89
Fatigue Symptom Scale: Cycle 15	-5.47 ± 24.68	-4.99 ± 22.40
Fatigue Symptom Scale: Cycle 16	-3.54 ± 24.81	-6.93 ± 21.89
Fatigue Symptom Scale: Cycle 17	-4.27 ± 25.50	-3.45 ± 21.91
Fatigue Symptom Scale: Cycle 18	-4.14 ± 24.42	-8.92 ± 20.54
Fatigue Symptom Scale: Cycle 19	-5.32 ± 27.83	-9.01 ± 20.71
Fatigue Symptom Scale: Cycle 20	-5.56 ± 26.64	-6.53 ± 21.83
Fatigue Symptom Scale: Cycle 21	-3.94 ± 25.97	-7.41 ± 23.45
Fatigue Symptom Scale: Cycle 22	-1.49 ± 25.58	-10.64 ± 22.22
Fatigue Symptom Scale: Cycle 23	-5.82 ± 25.23	-9.60 ± 28.01
Fatigue Symptom Scale: Cycle 24	-1.67 ± 27.05	-12.50 ± 24.29
Fatigue Symptom Scale: Cycle 25	-4.70 ± 26.16	-12.35 ± 22.03
Fatigue Symptom Scale: Cycle 26	-4.99 ± 24.85	-11.46 ± 22.84
Fatigue Symptom Scale: Cycle 27	-6.98 ± 23.76	-5.36 ± 23.87
Fatigue Symptom Scale: Cycle 28	-6.39 ± 18.98	-4.70 ± 26.14
Fatigue Symptom Scale: Post-treatment Visit 1	10.02 ± 28.48	5.25 ± 24.00
Fatigue Symptom Scale: Post-treatment Visit 2	7.70 ± 27.65	9.70 ± 25.01
Financial Difficulties Symptom Scale: Cycle 2	-0.90 ± 26.85	-2.46 ± 25.46
Financial Difficulties Symptom Scale: Cycle 3	0.31 ± 27.62	0.00 ± 26.33
Financial Difficulties Symptom Scale: Cycle 4	0.89 ± 25.95	0.11 ± 25.10
Financial Difficulties Symptom Scale: Cycle 5	1.75 ± 27.71	2.58 ± 26.46
Financial Difficulties Symptom Scale: Cycle 6	1.11 ± 27.62	0.92 ± 26.36
Financial Difficulties Symptom Scale: Cycle 7	1.11 ± 31.08	0.30 ± 26.41
Financial Difficulties Symptom Scale: Cycle 8	1.15 ± 30.21	0.47 ± 25.27
Financial Difficulties Symptom Scale: Cycle 9	1.11 ± 29.78	-0.51 ± 24.75
Financial Difficulties Symptom Scale: Cycle 10	0.90 ± 30.10	-2.42 ± 24.30
Financial Difficulties Symptom Scale: Cycle 11	0.39 ± 29.37	-0.22 ± 24.84
Financial Difficulties Symptom Scale: Cycle 12	-1.05 ± 28.91	-0.97 ± 26.39
Financial Difficulties Symptom Scale: Cycle 13	-0.95 ± 28.82	0.30 ± 24.82
Financial Difficulties Symptom Scale: Cycle 14	-1.73 ± 29.74	-0.98 ± 25.02
Financial Difficulties Symptom Scale: Cycle 15	-1.81 ± 28.96	1.36 ± 26.18
Financial Difficulties Symptom Scale: Cycle 16	-3.16 ± 30.13	0.39 ± 25.97
Financial Difficulties Symptom Scale: Cycle 17	-3.87 ± 29.59	1.35 ± 27.28
Financial Difficulties Symptom Scale: Cycle 18	-2.29 ± 27.46	2.35 ± 26.02
Financial Difficulties Symptom Scale: Cycle 19	-0.35 ± 28.41	-0.51 ± 27.73
Financial Difficulties Symptom Scale: Cycle 20	1.19 ± 29.47	1.59 ± 27.71
Financial Difficulties Symptom Scale: Cycle 21	1.27 ± 28.96	-4.94 ± 27.78
Financial Difficulties Symptom Scale: Cycle 22	2.49 ± 26.79	-4.26 ± 23.69
Financial Difficulties Symptom Scale: Cycle 23	-0.53 ± 26.43	-2.27 ± 29.11
Financial Difficulties Symptom Scale: Cycle 24	1.11 ± 24.52	-5.83 ± 26.03
Financial Difficulties Symptom Scale: Cycle 25	3.21 ± 27.42	-4.63 ± 25.39
Financial Difficulties Symptom Scale: Cycle 26	2.72 ± 28.74	-2.22 ± 26.16
Financial Difficulties Symptom Scale: Cycle 27	-3.10 ± 23.92	1.15 ± 24.37
Financial Difficulties Symptom Scale: Cycle 28	-1.67 ± 23.81	-1.28 ± 24.00
Financial Difficulties: Post-treatment Visit 1	1.70 ± 29.66	1.33 ± 26.21
Financial Difficulties: Post-treatment Visit 2	1.98 ± 26.17	4.24 ± 31.32
Nausea And Vomiting Symptom Scale: Cycle 2	5.85 ± 22.65	4.08 ± 22.25
Nausea And Vomiting Symptom Scale: Cycle 3	5.12 ± 23.62	5.06 ± 21.14
Nausea And Vomiting Symptom Scale: Cycle 4	4.10 ± 21.85	3.56 ± 23.76
Nausea And Vomiting Symptom Scale: Cycle 5	5.13 ± 22.58	5.15 ± 23.81
Nausea And Vomiting Symptom Scale: Cycle 6	4.11 ± 23.36	2.59 ± 21.24
Nausea And Vomiting Symptom Scale: Cycle 7	2.07 ± 23.58	2.49 ± 22.31
Nausea And Vomiting Symptom Scale: Cycle 8	-0.86 ± 20.80	-0.77 ± 20.21
Nausea And Vomiting Symptom Scale: Cycle 9	-2.54 ± 20.85	-2.98 ± 19.78
Nausea And Vomiting Symptom Scale: Cycle 10	-4.30 ± 18.81	-2.81 ± 20.57
Nausea And Vomiting Symptom Scale: Cycle 11	-3.51 ± 18.01	-3.66 ± 20.04
Nausea And Vomiting Symptom Scale: Cycle 12	-3.04 ± 18.07	-3.45 ± 20.34
Nausea And Vomiting Symptom Scale: Cycle 13	-4.02 ± 16.29	-3.60 ± 19.25
Nausea And Vomiting Symptom Scale: Cycle 14	-3.46 ± 19.54	-5.72 ± 18.54
Nausea And Vomiting Symptom Scale: Cycle 15	-3.59 ± 16.34	-3.91 ± 16.55
Nausea And Vomiting Symptom Scale: Cycle 16	-0.43 ± 20.32	-2.55 ± 20.00
Nausea And Vomiting Symptom Scale: Cycle 17	-0.60 ± 17.46	-3.15 ± 16.48
Nausea And Vomiting Symptom Scale: Cycle 18	-0.65 ± 16.90	-3.52 ± 18.24
Nausea And Vomiting Symptom Scale: Cycle 19	-0.87 ± 18.32	-4.04 ± 19.62
Nausea And Vomiting Symptom Scale: Cycle 20	-1.79 ± 18.48	-3.97 ± 17.89
Nausea And Vomiting Symptom Scale: Cycle 21	-1.05 ± 20.03	-6.48 ± 19.80
Nausea And Vomiting Symptom Scale: Cycle 22	-3.48 ± 19.14	-8.16 ± 18.99
Nausea And Vomiting Symptom Scale: Cycle 23	-4.23 ± 17.70	-6.44 ± 24.70
Nausea And Vomiting Symptom Scale: Cycle 24	-4.72 ± 16.26	-7.92 ± 17.70
Nausea And Vomiting Symptom Scale: Cycle 25	-4.17 ± 20.84	-7.41 ± 19.29
Nausea And Vomiting Symptom Scale: Cycle 26	-3.40 ± 24.29	-9.38 ± 19.37
Nausea And Vomiting Symptom Scale: Cycle 27	-5.04 ± 22.58	-7.47 ± 20.70
Nausea And Vomiting Symptom Scale: Cycle 28	-1.25 ± 20.11	-6.41 ± 17.69
Nausea/Vomiting Scale: Post-treatment Visit 1	4.68 ± 22.20	4.13 ± 23.91
Nausea/Vomiting Scale: Post-treatment Visit 2	4.29 ± 23.05	2.73 ± 21.60
Pain Symptom Scale: Cycle 2	-6.80 ± 24.69	-6.38 ± 23.58
Pain Symptom Scale: Cycle 3	-9.89 ± 25.16	-7.23 ± 25.78
Pain Symptom Scale: Cycle 4	-10.26 ± 24.78	-7.46 ± 26.06
Pain Symptom Scale: Cycle 5	-8.86 ± 25.88	-6.25 ± 25.42
Pain Symptom Scale: Cycle 6	-8.95 ± 25.73	-7.33 ± 24.85
Pain Symptom Scale: Cycle 7	-10.95 ± 26.13	-7.46 ± 24.79
Pain Symptom Scale: Cycle 8	-9.97 ± 25.80	-8.53 ± 22.86
Pain Symptom Scale: Cycle 9	-9.29 ± 24.83	-7.82 ± 22.98
Pain Symptom Scale: Cycle 10	-9.41 ± 26.10	-8.13 ± 22.75
Pain Symptom Scale: Cycle 11	-10.33 ± 25.77	-6.34 ± 22.97
Pain Symptom Scale: Cycle 12	-10.27 ± 23.10	-5.24 ± 25.29
Pain Symptom Scale: Cycle 13	-10.28 ± 25.79	-4.80 ± 20.27
Pain Symptom Scale: Cycle 14	-10.49 ± 25.49	-5.56 ± 23.37
Pain Symptom Scale: Cycle 15	-11.15 ± 22.86	-3.74 ± 22.77
Pain Symptom Scale: Cycle 16	-9.91 ± 22.94	-4.71 ± 23.66
Pain Symptom Scale: Cycle 17	-7.59 ± 25.00	-5.63 ± 22.63
Pain Symptom Scale: Cycle 18	-8.82 ± 23.42	-8.22 ± 20.68
Pain Symptom Scale: Cycle 19	-8.16 ± 25.13	-5.05 ± 21.48
Pain Symptom Scale: Cycle 20	-6.94 ± 25.90	-6.08 ± 19.24
Pain Symptom Scale: Cycle 21	-9.92 ± 27.15	-6.48 ± 23.44
Pain Symptom Scale: Cycle 22	-7.71 ± 26.96	-8.51 ± 19.62
Pain Symptom Scale: Cycle 23	-10.85 ± 22.03	-7.95 ± 26.29
Pain Symptom Scale: Cycle 24	-10.00 ± 24.39	-10.00 ± 17.21
Pain Symptom Scale: Cycle 25	-9.94 ± 24.09	-12.96 ± 19.96
Pain Symptom Scale: Cycle 26	-10.54 ± 22.49	-8.33 ± 18.45
Pain Symptom Scale: Cycle 27	-11.24 ± 22.34	-5.75 ± 21.95
Pain Symptom Scale: Cycle 28	-10.42 ± 27.91	-9.62 ± 19.54
Pain Symptom Scale: Post-treatment Visit 1	1.13 ± 27.27	2.06 ± 28.70
Pain Symptom Scale: Post-treatment Visit 2	-1.49 ± 28.39	5.45 ± 29.96
Physical Functional Scale: Cycle 2	-3.58 ± 14.56	-3.01 ± 15.34
Physical Functional Scale: Cycle 3	-2.99 ± 17.19	-3.92 ± 17.03
Physical Functional Scale: Cycle 4	-3.28 ± 18.87	-3.50 ± 17.99
Physical Functional Scale: Cycle 5	-3.10 ± 19.35	-4.62 ± 17.62
Physical Functional Scale: Cycle 6	-5.00 ± 20.30	-3.84 ± 18.65
Physical Functional Scale: Cycle 7	-3.66 ± 20.75	-3.79 ± 19.82
Physical Functional Scale: Cycle 8	-2.24 ± 21.14	-1.56 ± 18.55
Physical Functional Scale: Cycle 9	-1.59 ± 20.21	-0.75 ± 18.44
Physical Functional Scale: Cycle 10	0.11 ± 19.93	-0.27 ± 17.16
Physical Functional Scale: Cycle 11	0.35 ± 19.43	0.27 ± 17.09
Physical Functional Scale: Cycle 12	-1.05 ± 20.06	0.89 ± 16.35
Physical Functional Scale: Cycle 13	-0.80 ± 20.65	0.27 ± 17.41
Physical Functional Scale: Cycle 14	-0.02 ± 20.14	1.70 ± 18.09
Physical Functional Scale: Cycle 15	0.41 ± 18.91	-0.95 ± 17.99
Physical Functional Scale: Cycle 16	-1.08 ± 19.85	-0.08 ± 18.18
Physical Functional Scale: Cycle 17	-0.46 ± 19.43	-0.81 ± 17.55
Physical Functional Scale: Cycle 18	0.13 ± 19.74	0.75 ± 16.85
Physical Functional Scale: Cycle 19	1.39 ± 19.82	1.31 ± 14.38
Physical Functional Scale: Cycle 20	0.71 ± 21.08	0.85 ± 16.74
Physical Functional Scale: Cycle 21	0.42 ± 22.20	0.25 ± 18.18
Physical Functional Scale: Cycle 22	-2.79 ± 21.90	1.42 ± 16.79
Physical Functional Scale: Cycle 23	-1.48 ± 21.47	0.61 ± 19.60
Physical Functional Scale: Cycle 24	-2.67 ± 22.27	3.00 ± 16.47
Physical Functional Scale: Cycle 25	-2.18 ± 20.61	4.81 ± 15.91
Physical Functional Scale: Cycle 26	-1.90 ± 20.09	-1.88 ± 20.69
Physical Functional Scale: Cycle 27	0.16 ± 18.66	-3.68 ± 19.40
Physical Functional Scale: Cycle 28	-1.17 ± 17.79	-2.82 ± 18.97
Physical Functional Scale: Post-treatment Visit 1	-11.37 ± 23.67	-7.51 ± 20.53
Physical Functional Scale: Post-treatment Visit 2	-11.49 ± 24.31	-11.82 ± 20.27
Global Health Status Scale: Cycle 2	1.81 ± 23.35	4.29 ± 23.42
Global Health Status Scale: Cycle 3	1.56 ± 25.05	2.86 ± 25.03
Global Health Status Scale: Cycle 4	1.39 ± 25.26	4.15 ± 23.79
Global Health Status Scale: Cycle 5	1.17 ± 25.70	3.92 ± 23.05
Global Health Status Scale: Cycle 6	0.68 ± 27.89	3.61 ± 23.13
Global Health Status Scale: Cycle 7	1.83 ± 27.81	3.33 ± 22.77
Global Health Status Scale: Cycle 8	3.06 ± 27.09	5.18 ± 23.18
Global Health Status Scale: Cycle 9	4.39 ± 26.25	4.68 ± 22.99
Global Health Status Scale: Cycle 10	4.80 ± 25.35	5.07 ± 22.77
Global Health Status Scale: Cycle 11	5.78 ± 26.62	3.82 ± 23.75
Global Health Status Scale: Cycle 12	3.11 ± 24.89	5.34 ± 24.47
Global Health Status Scale: Cycle 13	3.51 ± 23.82	3.83 ± 23.78
Global Health Status Scale: Cycle 14	5.97 ± 23.09	4.82 ± 24.86
Global Health Status Scale: Cycle 15	4.26 ± 25.98	1.70 ± 24.46
Global Health Status Scale: Cycle 16	3.12 ± 25.16	3.04 ± 23.77
Global Health Status Scale: Cycle 17	2.93 ± 24.84	3.83 ± 24.84
Global Health Status Scale: Cycle 18	3.02 ± 23.88	2.58 ± 27.08
Global Health Status Scale: Cycle 19	3.25 ± 26.39	3.97 ± 25.43
Global Health Status Scale: Cycle 20	5.12 ± 24.20	4.89 ± 25.69
Global Health Status Scale: Cycle 21	5.38 ± 23.87	5.40 ± 24.72
Global Health Status Scale: Cycle 22	3.79 ± 22.56	3.19 ± 25.57
Global Health Status Scale: Cycle 23	4.03 ± 23.85	4.07 ± 27.18
Global Health Status Scale: Cycle 24	4.24 ± 22.66	2.92 ± 30.58
Global Health Status Scale: Cycle 25	3.59 ± 22.38	8.10 ± 25.39
Global Health Status Scale: Cycle 26	7.27 ± 24.55	5.47 ± 26.91
Global Health Status Scale: Cycle 27	7.54 ± 23.19	1.72 ± 28.38
Global Health Status Scale: Cycle 28	4.49 ± 22.69	4.81 ± 28.98
Global Health Status Scale: Post-treatment Visit 1	-7.24 ± 27.24	-6.14 ± 24.97
Global Health Status Scale: Post-treatment Visit 2	-2.72 ± 27.46	-5.68 ± 26.57
Role Functional Scale: Cycle 2	-3.78 ± 24.99	-2.82 ± 24.35
Role Functional Scale: Cycle 3	-3.62 ± 25.96	-4.55 ± 28.00
Role Functional Scale: Cycle 4	-4.64 ± 27.69	-5.99 ± 26.87
Role Functional Scale: Cycle 5	-4.72 ± 27.68	-7.41 ± 27.25
Role Functional Scale: Cycle 6	-6.13 ± 28.94	-6.03 ± 28.51
Role Functional Scale: Cycle 7	-4.82 ± 29.75	-5.34 ± 26.31
Role Functional Scale: Cycle 8	-1.85 ± 28.87	-2.38 ± 26.41
Role Functional Scale: Cycle 9	-1.19 ± 28.57	-2.47 ± 27.29
Role Functional Scale: Cycle 10	-1.79 ± 28.10	0.90 ± 25.97
Role Functional Scale: Cycle 11	-0.78 ± 28.34	-2.69 ± 24.94
Role Functional Scale: Cycle 12	-1.05 ± 27.28	0.24 ± 24.07
Role Functional Scale: Cycle 13	-2.01 ± 26.61	-2.40 ± 24.91
Role Functional Scale: Cycle 14	-0.86 ± 27.27	-1.31 ± 25.66
Role Functional Scale: Cycle 15	-1.03 ± 27.51	-3.23 ± 25.40
Role Functional Scale: Cycle 16	-3.16 ± 28.73	-2.35 ± 25.48
Role Functional Scale: Cycle 17	-1.04 ± 26.69	-3.38 ± 25.88
Role Functional Scale: Cycle 18	-0.16 ± 27.10	0.23 ± 26.05
Role Functional Scale: Cycle 19	1.04 ± 27.55	-0.25 ± 23.48
Role Functional Scale: Cycle 20	-1.19 ± 30.04	0.79 ± 23.46
Role Functional Scale: Cycle 21	-0.84 ± 28.98	0.00 ± 27.47
Role Functional Scale: Cycle 22	-2.24 ± 27.96	1.06 ± 22.63
Role Functional Scale: Cycle 23	-3.44 ± 30.11	1.14 ± 25.01
Role Functional Scale: Cycle 24	-4.44 ± 29.73	2.08 ± 24.22
Role Functional Scale: Cycle 25	-3.53 ± 29.21	4.63 ± 26.91
Role Functional Scale: Cycle 26	-1.36 ± 28.02	0.52 ± 26.60
Role Functional Scale: Cycle 27	-1.55 ± 30.82	-4.02 ± 29.77
Role Functional Scale: Cycle 28	-0.42 ± 27.86	-3.85 ± 29.56
Role Functional Scale: Post-Treatment Visit 1	-14.61 ± 30.41	-9.49 ± 28.64
Role Functional Scale: Post-Treatment Visit 2	-10.73 ± 31.94	-15.45 ± 31.82
Social Functional Scale: Cycle 2	-3.45 ± 24.07	-0.44 ± 23.09
Social Functional Scale: Cycle 3	-4.62 ± 25.25	-2.07 ± 25.35
Social Functional Scale: Cycle 4	-2.59 ± 25.08	-1.70 ± 26.58
Social Functional Scale: Cycle 5	-5.54 ± 27.03	-3.26 ± 27.24
Social Functional Scale: Cycle 6	-5.72 ± 27.87	-1.04 ± 27.20
Social Functional Scale: Cycle 7	-2.69 ± 27.13	-0.15 ± 26.00
Social Functional Scale: Cycle 8	-1.72 ± 26.93	1.08 ± 26.49
Social Functional Scale: Cycle 9	0.56 ± 27.59	0.77 ± 25.11
Social Functional Scale: Cycle 10	-0.81 ± 27.31	2.31 ± 25.75
Social Functional Scale: Cycle 11	0.58 ± 27.35	1.94 ± 24.39
Social Functional Scale: Cycle 12	0.52 ± 28.59	2.40 ± 24.70
Social Functional Scale: Cycle 13	0.83 ± 25.31	2.10 ± 25.73
Social Functional Scale: Cycle 14	1.98 ± 26.71	2.12 ± 24.89
Social Functional Scale: Cycle 15	1.79 ± 27.24	0.00 ± 27.08
Social Functional Scale: Cycle 16	-0.72 ± 25.76	0.39 ± 25.84
Social Functional Scale: Cycle 17	-0.45 ± 26.51	1.58 ± 24.39
Social Functional Scale: Cycle 18	-0.98 ± 25.99	2.11 ± 26.42
Social Functional Scale: Cycle 19	2.26 ± 26.56	3.28 ± 21.53
Social Functional Scale: Cycle 20	1.59 ± 27.09	0.79 ± 22.88
Social Functional Scale: Cycle 21	1.27 ± 28.09	5.86 ± 22.00
Social Functional Scale: Cycle 22	1.24 ± 27.72	2.84 ± 24.16
Social Functional Scale: Cycle 23	6.08 ± 27.32	1.89 ± 22.51
Social Functional Scale: Cycle 24	5.83 ± 25.64	4.17 ± 24.39
Social Functional Scale: Cycle 25	1.60 ± 27.27	2.78 ± 23.40
Social Functional Scale: Cycle 26	3.74 ± 26.19	1.56 ± 24.45
Social Functional Scale: Cycle 27	5.81 ± 24.37	-1.72 ± 26.85
Social Functional Scale: Cycle 28	6.25 ± 23.48	-0.64 ± 24.26
Social Functional Scale: Post-Treatment Visit 1	-9.13 ± 26.47	-3.80 ± 28.74
Social Functional Scale: Post-Treatment Visit 2	-5.45 ± 28.49	-8.48 ± 28.98
Insomnia Symptom Scale: Cycle 2	-0.69 ± 26.82	-0.39 ± 28.27
Insomnia Symptom Scale: Cycle 3	-3.53 ± 27.03	-3.48 ± 30.14
Insomnia Symptom Scale: Cycle 4	-2.88 ± 28.14	-3.62 ± 30.40
Insomnia Symptom Scale: Cycle 5	-2.21 ± 29.27	-2.66 ± 30.17
Insomnia Symptom Scale: Cycle 6	-2.94 ± 28.63	-5.58 ± 32.53
Insomnia Symptom Scale: Cycle 7	-4.56 ± 28.42	-4.82 ± 32.98
Insomnia Symptom Scale: Cycle 8	-6.13 ± 27.72	-6.45 ± 30.75
Insomnia Symptom Scale: Cycle 9	-8.97 ± 25.69	-6.12 ± 30.32
Insomnia Symptom Scale: Cycle 10	-8.24 ± 26.69	-4.42 ± 28.79
Insomnia Symptom Scale: Cycle 11	-8.97 ± 28.19	-5.81 ± 27.69
Insomnia Symptom Scale: Cycle 12	-8.81 ± 27.67	-6.43 ± 26.49
Insomnia Symptom Scale: Cycle 13	-10.17 ± 26.71	-5.11 ± 24.29
Insomnia Symptom Scale: Cycle 14	-9.14 ± 26.84	-7.84 ± 24.45
Insomnia Symptom Scale: Cycle 15	-9.74 ± 28.89	-5.10 ± 21.59
Insomnia Symptom Scale: Cycle 16	-8.91 ± 26.14	-4.31 ± 26.62
Insomnia Symptom Scale: Cycle 17	-11.01 ± 26.62	-5.41 ± 26.48
Insomnia Symptom Scale: Cycle 18	-8.82 ± 28.12	-8.45 ± 20.09
Insomnia Symptom Scale: Cycle 19	-11.46 ± 29.35	-7.58 ± 22.49
Insomnia Symptom Scale: Cycle 20	-10.32 ± 27.37	-5.29 ± 25.55
Insomnia Symptom Scale: Cycle 21	-11.81 ± 27.24	-4.94 ± 27.02
Insomnia Symptom Scale: Cycle 22	-10.95 ± 31.46	-7.80 ± 19.92
Insomnia Symptom Scale: Cycle 23	-10.58 ± 34.82	-6.06 ± 23.04
Insomnia Symptom Scale: Cycle 24	-9.44 ± 31.94	-7.50 ± 21.99
Insomnia Symptom Scale: Cycle 25	-10.26 ± 28.42	-8.33 ± 26.87
Insomnia Symptom Scale: Cycle 26	-9.52 ± 32.63	-4.17 ± 20.30
Insomnia Symptom Scale: Cycle 27	-13.18 ± 30.11	-4.60 ± 19.36
Insomnia Symptom Scale: Cycle 28	-11.67 ± 31.62	-1.28 ± 22.07
Insomnia Symptom Scale: Post-Treatment Visit 1	2.81 ± 29.19	-1.32 ± 30.81
Insomnia Symptom Scale: Post-Treatment Visit 2	5.67 ± 29.23	3.03 ± 31.13

No statistical analyses for this end point

Secondary: Change from Baseline in EORTC QLQ-Gastric Cancer Module (EORTC QLQ-STO22) Questionnaire Score

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End point title

Change from Baseline in EORTC QLQ-Gastric Cancer Module (EORTC QLQ-STO22) Questionnaire Score

End point description

The EORTC QLQ-STO22 is a gastric cancer quality of life questionnaire. There are 22 questions concerning disease, treatment related symptoms, side effects, dysphagia, nutritional aspects, and questions about the emotional problems of gastric cancer (dysphagia, pain, reflux, eating restrictions, anxiety, dry mouth, body image, and hair loss). The questions are grouped into five scales and 4 single items which are related to the symptoms of the disease. Most questions used 4-point scale (1 'Not at all' to 4 'Very much'; 1 question was a yes or no answer). A linear transformation was used to standardize all scores and single-items to a scale of 0 to 100; higher score=better level of functioning or greater degree of symptoms. Positive value means increase, while negative value means decrease, in score at indicated time-point relative to score at baseline (Cycle 1, Day 1). Subjects in ITT population with both a baseline and at least 1 post-treatment assessment are included.

End point type

Secondary

End point timeframe

Day 1 of each 21-day treatment cycle up to 28 and 60-90 days after Day 1 of last treatment cycle (up to approximately 3.5 years)

End point values	Pertuzumab + Trastuzumab + Chemotherapy	Placebo + Trastuzumab + Chemotherapy
Number of subjects analysed	388	392
Units: score on a scale
arithmetic mean (standard deviation)
Anxiety: Cycle 2	-2.58 ± 21.72	-4.11 ± 21.19
Anxiety: Cycle 3	-4.14 ± 22.45	-3.87 ± 23.19
Anxiety: Cycle 4	-4.52 ± 23.01	-7.25 ± 23.16
Anxiety: Cycle 5	-4.10 ± 22.94	-7.39 ± 24.36
Anxiety: Cycle 6	-4.54 ± 23.97	-8.42 ± 25.21
Anxiety: Cycle 7	-6.40 ± 24.00	-10.40 ± 24.37
Anxiety: Cycle 8	-9.00 ± 23.17	-11.92 ± 24.50
Anxiety: Cycle 9	-10.09 ± 23.30	-11.43 ± 23.24
Anxiety: Cycle 10	-11.17 ± 25.05	-12.64 ± 22.09
Anxiety: Cycle 11	-10.78 ± 23.47	-12.09 ± 21.84
Anxiety: Cycle 12	-12.62 ± 26.24	-13.16 ± 23.11
Anxiety: Cycle 13	-13.32 ± 25.93	-13.33 ± 22.47
Anxiety: Cycle 14	-14.32 ± 26.49	-12.43 ± 23.59
Anxiety: Cycle 15	-13.42 ± 26.64	-10.65 ± 25.74
Anxiety: Cycle 16	-12.75 ± 26.87	-12.57 ± 23.89
Anxiety: Cycle 17	-13.41 ± 27.30	-12.79 ± 21.01
Anxiety: Cycle 18	-13.53 ± 28.05	-12.38 ± 22.90
Anxiety: Cycle 19	-14.50 ± 27.41	-12.48 ± 20.08
Anxiety: Cycle 20	-15.34 ± 29.21	-12.37 ± 23.73
Anxiety: Cycle 21	-16.03 ± 28.84	-14.47 ± 25.00
Anxiety: Cycle 22	-13.30 ± 30.77	-15.46 ± 23.83
Anxiety: Cycle 23	-17.28 ± 30.64	-14.47 ± 29.55
Anxiety: Cycle 24	-16.11 ± 30.65	-17.09 ± 23.76
Anxiety: Cycle 25	-16.03 ± 29.47	-17.78 ± 23.68
Anxiety: Cycle 26	-19.73 ± 30.28	-13.26 ± 22.11
Anxiety: Cycle 27	-21.71 ± 29.89	-12.70 ± 20.67
Anxiety: Cycle 28	-22.51 ± 29.34	-12.89 ± 22.38
Anxiety: Post-treatment Monitoring Visit 1	-0.73 ± 25.18	-4.73 ± 27.21
Anxiety: Post-treatment Monitoring Visit 2	-4.04 ± 28.24	-3.98 ± 25.02
Body Image: Cycle 2	1.33 ± 28.19	1.20 ± 26.44
Body Image: Cycle 3	1.48 ± 29.06	3.88 ± 28.03
Body Image: Cycle 4	4.20 ± 28.51	1.15 ± 27.19
Body Image: Cycle 5	2.86 ± 30.91	1.06 ± 25.74
Body Image: Cycle 6	0.75 ± 30.11	2.78 ± 28.48
Body Image: Cycle 7	-0.56 ± 28.94	0.29 ± 25.53
Body Image: Cycle 8	-1.74 ± 29.83	0.00 ± 26.30
Body Image: Cycle 9	-3.58 ± 28.74	-0.69 ± 24.52
Body Image: Cycle 10	-5.07 ± 30.15	-3.25 ± 24.55
Body Image: Cycle 11	-4.62 ± 30.24	-1.53 ± 25.46
Body Image: Cycle 12	-5.31 ± 31.92	-2.66 ± 27.04
Body Image: Cycle 13	-4.73 ± 30.23	-2.73 ± 25.99
Body Image: Cycle 14	-5.43 ± 29.70	-4.62 ± 24.05
Body Image: Cycle 15	-3.08 ± 30.63	-2.43 ± 27.03
Body Image: Cycle 16	-1.74 ± 32.99	-1.19 ± 26.10
Body Image: Cycle 17	-2.70 ± 32.76	-2.28 ± 21.75
Body Image: Cycle 18	-2.64 ± 30.44	-5.71 ± 23.38
Body Image: Cycle 19	-2.81 ± 33.57	-5.21 ± 20.76
Body Image: Cycle 20	-3.97 ± 30.79	-5.38 ± 22.74
Body Image: Cycle 21	1.69 ± 30.15	-8.18 ± 26.07
Body Image: Cycle 22	-1.49 ± 32.01	-10.87 ± 22.28
Body Image: Cycle 23	-5.82 ± 24.35	-8.53 ± 29.18
Body Image: Cycle 24	-0.56 ± 31.25	-11.11 ± 23.36
Body Image: Cycle 25	-3.21 ± 28.97	-11.43 ± 24.18
Body Image: Cycle 26	-4.76 ± 29.66	-6.45 ± 18.09
Body Image: Cycle 27	0.78 ± 24.65	-7.14 ± 21.00
Body Image: Cycle 28	-4.27 ± 26.69	-4.00 ± 24.19
Body Image: Post-treatment Monitoring Visit 1	2.48 ± 31.57	3.42 ± 29.31
Body Image: Post-treatment Monitoring Visit 2	2.36 ± 35.40	6.35 ± 27.38
Dry Mouth: Cycle 2	7.72 ± 28.70	3.00 ± 25.43
Dry Mouth: Cycle 3	6.10 ± 28.65	4.87 ± 27.33
Dry Mouth: Cycle 4	4.76 ± 29.40	2.66 ± 31.06
Dry Mouth: Cycle 5	2.47 ± 29.67	2.57 ± 28.68
Dry Mouth: Cycle 6	2.96 ± 30.14	1.19 ± 27.65
Dry Mouth: Cycle 7	-1.96 ± 28.82	0.44 ± 28.54
Dry Mouth: Cycle 8	-2.43 ± 28.68	-2.66 ± 26.27
Dry Mouth: Cycle 9	-3.70 ± 25.70	-4.32 ± 24.74
Dry Mouth: Cycle 10	-6.27 ± 25.04	-3.46 ± 23.53
Dry Mouth: Cycle 11	-7.69 ± 25.46	-1.96 ± 26.56
Dry Mouth: Cycle 12	-8.18 ± 24.22	-4.35 ± 26.36
Dry Mouth: Cycle 13	-9.69 ± 24.08	-8.48 ± 26.50
Dry Mouth: Cycle 14	-8.33 ± 24.60	-3.63 ± 29.78
Dry Mouth: Cycle 15	-7.89 ± 22.20	-7.29 ± 26.58
Dry Mouth: Cycle 16	-6.32 ± 24.44	-8.33 ± 27.80
Dry Mouth: Cycle 17	-7.44 ± 23.12	-3.20 ± 24.32
Dry Mouth: Cycle 18	-5.56 ± 24.86	-8.10 ± 28.62
Dry Mouth: Cycle 19	-5.90 ± 24.18	-7.69 ± 25.53
Dry Mouth: Cycle 20	-6.35 ± 26.62	-9.68 ± 27.25
Dry Mouth: Cycle 21	-7.17 ± 24.27	-9.43 ± 20.02
Dry Mouth: Cycle 22	-3.98 ± 26.29	-8.70 ± 23.76
Dry Mouth: Cycle 23	-7.94 ± 23.73	-3.88 ± 25.42
Dry Mouth: Cycle 24	-6.67 ± 25.15	-9.40 ± 28.56
Dry Mouth: Cycle 25	-8.33 ± 22.75	-9.52 ± 28.66
Dry Mouth: Cycle 26	-2.72 ± 23.41	-7.53 ± 26.82
Dry Mouth: Cycle 27	-6.98 ± 21.28	-7.14 ± 27.75
Dry Mouth: Cycle 28	-8.55 ± 21.24	-8.00 ± 22.11
Dry Mouth: Post-treatment Monitoring Visit 1	0.19 ± 28.70	2.38 ± 31.58
Dry Mouth: Post-treatment Monitoring Visit 2	-1.35 ± 30.09	1.89 ± 25.95
Dysphagia: Cycle 2	-2.27 ± 17.64	-0.53 ± 19.32
Dysphagia: Cycle 3	-3.39 ± 18.57	-2.15 ± 19.67
Dysphagia: Cycle 4	-2.94 ± 18.93	-1.08 ± 18.79
Dysphagia: Cycle 5	-3.22 ± 19.92	-1.83 ± 18.99
Dysphagia: Cycle 6	-4.20 ± 18.99	-2.25 ± 18.70
Dysphagia: Cycle 7	-4.83 ± 20.56	-1.97 ± 19.94
Dysphagia: Cycle 8	-5.96 ± 18.80	-3.29 ± 18.48
Dysphagia: Cycle 9	-6.17 ± 18.21	-3.86 ± 18.49
Dysphagia: Cycle 10	-6.03 ± 17.37	-4.61 ± 16.87
Dysphagia: Cycle 11	-6.25 ± 17.09	-2.83 ± 17.03
Dysphagia: Cycle 12	-7.06 ± 17.65	-4.19 ± 15.84
Dysphagia: Cycle 13	-6.93 ± 18.71	-3.54 ± 17.61
Dysphagia: Cycle 14	-8.01 ± 18.53	-4.95 ± 18.22
Dysphagia: Cycle 15	-6.45 ± 17.38	-2.14 ± 18.69
Dysphagia: Cycle 16	-4.41 ± 18.29	-3.70 ± 21.08
Dysphagia: Cycle 17	-5.36 ± 16.87	-3.20 ± 14.99
Dysphagia: Cycle 18	-4.90 ± 16.44	-3.33 ± 19.78
Dysphagia: Cycle 19	-4.40 ± 17.10	-3.59 ± 14.31
Dysphagia: Cycle 20	-2.51 ± 16.21	-3.76 ± 15.83
Dysphagia: Cycle 21	-3.80 ± 19.24	-2.10 ± 17.84
Dysphagia: Cycle 22	-3.65 ± 20.41	-4.83 ± 15.65
Dysphagia: Cycle 23	-4.23 ± 18.87	-3.88 ± 17.63
Dysphagia: Cycle 24	-5.00 ± 18.35	-3.70 ± 13.08
Dysphagia: Cycle 25	-5.98 ± 19.61	-2.22 ± 16.79
Dysphagia: Cycle 26	-5.67 ± 20.43	-2.87 ± 16.22
Dysphagia: Cycle 27	-5.68 ± 20.91	-4.37 ± 12.22
Dysphagia: Cycle 28	-8.26 ± 19.86	-3.56 ± 11.44
Dysphagia: Post-treatment Monitoring Visit 1	0.44 ± 24.15	2.83 ± 22.63
Dysphagia: Post-treatment Monitoring Visit 2	-2.81 ± 24.40	3.25 ± 19.81
Eating Restrictions: Cycle 2	-1.41 ± 19.36	-1.54 ± 19.62
Eating Restrictions: Cycle 3	-1.04 ± 21.09	-2.20 ± 20.94
Eating Restrictions: Cycle 4	-2.24 ± 20.81	-1.39 ± 23.36
Eating Restrictions: Cycle 5	-1.39 ± 22.10	-0.09 ± 23.31
Eating Restrictions: Cycle 6	-1.35 ± 22.77	-3.32 ± 23.14
Eating Restrictions: Cycle 7	-2.45 ± 22.68	-2.67 ± 21.66
Eating Restrictions: Cycle 8	-4.29 ± 22.70	-5.56 ± 19.87
Eating Restrictions: Cycle 9	-6.99 ± 21.16	-6.48 ± 19.69
Eating Restrictions: Cycle 10	-7.06 ± 21.32	-5.89 ± 19.30
Eating Restrictions: Cycle 11	-8.22 ± 21.25	-5.05 ± 19.98
Eating Restrictions: Cycle 12	-7.74 ± 21.16	-6.34 ± 19.87
Eating Restrictions: Cycle 13	-8.55 ± 20.41	-8.41 ± 19.57
Eating Restrictions: Cycle 14	-8.62 ± 19.16	-8.58 ± 21.16
Eating Restrictions: Cycle 15	-6.85 ± 20.92	-5.56 ± 21.21
Eating Restrictions: Cycle 16	-5.77 ± 22.01	-6.94 ± 20.36
Eating Restrictions: Cycle 17	-5.56 ± 21.95	-7.42 ± 17.76
Eating Restrictions: Cycle 18	-7.27 ± 20.40	-6.90 ± 21.14
Eating Restrictions: Cycle 19	-7.03 ± 21.78	-5.38 ± 18.07
Eating Restrictions: Cycle 20	-4.56 ± 21.03	-4.44 ± 16.72
Eating Restrictions: Cycle 21	-5.80 ± 22.58	-5.03 ± 19.97
Eating Restrictions: Cycle 22	-3.65 ± 21.79	-6.16 ± 16.80
Eating Restrictions: Cycle 23	-3.70 ± 22.74	-5.23 ± 20.25
Eating Restrictions: Cycle 24	-5.00 ± 20.77	-7.91 ± 15.76
Eating Restrictions: Cycle 25	-5.77 ± 21.10	-5.95 ± 16.61
Eating Restrictions: Cycle 26	-6.80 ± 21.22	-2.42 ± 22.89
Eating Restrictions: Cycle 27	-5.62 ± 23.48	-3.87 ± 10.26
Eating Restrictions: Cycle 28	-7.91 ± 21.79	-5.00 ± 11.02
Eating Restrictions: Post-treatment Visit 1	1.52 ± 24.48	0.94 ± 24.70
Eating Restrictions: Post-treatment Visit 2	-2.10 ± 25.32	0.94 ± 21.46
Hair Loss: Cycle 2	0.20 ± 14.85	1.27 ± 16.59
Hair Loss: Cycle 3	4.34 ± 17.51	4.52 ± 18.71
Hair Loss: Cycle 4	5.40 ± 18.46	6.53 ± 20.99
Hair Loss: Cycle 5	6.12 ± 19.38	7.18 ± 19.49
Hair Loss: Cycle 6	6.93 ± 18.87	10.07 ± 22.94
Hair Loss: Cycle 7	5.72 ± 19.91	9.26 ± 22.92
Hair Loss: Cycle 8	5.00 ± 18.96	7.38 ± 23.05
Hair Loss: Cycle 9	2.38 ± 17.43	6.46 ± 21.06
Hair Loss: Cycle 10	0.64 ± 16.88	4.22 ± 19.51
Hair Loss: Cycle 11	-0.10 ± 17.02	2.54 ± 17.51
Hair Loss: Cycle 12	0.21 ± 19.70	1.96 ± 15.72
Hair Loss: Cycle 13	0.36 ± 18.91	2.29 ± 15.46
Hair Loss: Cycle 14	-1.37 ± 17.59	1.83 ± 15.15
Hair Loss: Cycle 15	-0.39 ± 15.65	1.58 ± 12.65
Hair Loss: Cycle 16	-1.47 ± 17.47	1.42 ± 13.91
Hair Loss: Cycle 17	-1.07 ± 17.75	0.23 ± 12.57
Hair Loss: Cycle 18	-1.68 ± 17.58	-0.71 ± 13.14
Hair Loss: Cycle 19	-0.90 ± 18.12	0.51 ± 14.12
Hair Loss: Cycle 20	-0.20 ± 19.21	-1.61 ± 12.70
Hair Loss: Cycle 21	-1.07 ± 19.43	-1.57 ± 8.81
Hair Loss: Cycle 22	-0.50 ± 16.66	-3.26 ± 11.98
Hair Loss: Cycle 23	-0.54 ± 16.79	-1.19 ± 11.28
Hair Loss: Cycle 24	-1.39 ± 17.44	1.71 ± 16.13
Hair Loss: Cycle 25	-1.96 ± 18.75	-0.95 ± 9.85
Hair Loss: Cycle 26	-1.02 ± 19.37	-0.54 ± 10.08
Hair Loss: Cycle 27	-3.10 ± 15.96	-0.60 ± 10.62
Hair Loss: Cycle 28	-4.70 ± 20.57	-1.33 ± 10.67
Hair Loss: Post-Treatment Monitoring Visit 1	4.98 ± 19.73	4.51 ± 20.39
Hair Loss: Post-Treatment Monitoring Visit 2	15.82 ± 25.35	22.22 ± 30.81
Pain: Cycle 2	-4.63 ± 20.30	-5.86 ± 19.15
Pain: Cycle 3	-6.96 ± 20.37	-5.86 ± 20.68
Pain: Cycle 4	-6.45 ± 21.47	-7.48 ± 21.23
Pain: Cycle 5	-7.28 ± 20.95	-6.89 ± 22.10
Pain: Cycle 6	-7.24 ± 20.84	-7.22 ± 21.62
Pain: Cycle 7	-9.52 ± 21.18	-6.62 ± 21.63
Pain: Cycle 8	-10.53 ± 21.62	-8.16 ± 20.11
Pain: Cycle 9	-10.08 ± 19.60	-8.98 ± 20.29
Pain: Cycle 10	-10.63 ± 19.23	-8.59 ± 20.38
Pain: Cycle 11	-11.65 ± 19.35	-8.01 ± 18.97
Pain: Cycle 12	-11.76 ± 19.87	-7.19 ± 19.11
Pain: Cycle 13	-11.92 ± 18.93	-9.24 ± 19.79
Pain: Cycle 14	-11.66 ± 19.51	-9.82 ± 19.91
Pain: Cycle 15	-11.15 ± 18.16	-8.51 ± 20.94
Pain: Cycle 16	-8.72 ± 18.02	-10.52 ± 21.30
Pain: Cycle 17	-8.88 ± 18.17	-9.93 ± 17.27
Pain: Cycle 18	-8.31 ± 18.33	-11.19 ± 18.16
Pain: Cycle 19	-6.63 ± 17.25	-10.38 ± 14.51
Pain: Cycle 20	-5.72 ± 19.98	-10.35 ± 16.65
Pain: Cycle 21	-8.19 ± 18.27	-7.55 ± 16.77
Pain: Cycle 22	-9.08 ± 18.10	-9.42 ± 16.72
Pain: Cycle 23	-9.66 ± 20.75	-8.53 ± 19.96
Pain: Cycle 24	-9.86 ± 21.56	-8.76 ± 15.53
Pain: Cycle 25	-10.58 ± 19.88	-8.10 ± 18.69
Pain: Cycle 26	-9.01 ± 17.99	-9.41 ± 17.58
Pain: Cycle 27	-12.02 ± 17.28	-9.23 ± 14.58
Pain: Cycle 28	-11.54 ± 18.20	-7.33 ± 13.46
Pain: Post-Treatment Monitoring Visit 1	-1.70 ± 23.07	-2.99 ± 23.86
Pain: Post-Treatment Monitoring Visit 2	-7.49 ± 24.09	-0.03 ± 22.04
Reflux Symptoms: Cycle 2	-0.13 ± 16.33	-1.99 ± 18.03
Reflux Symptoms: Cycle 3	-0.52 ± 18.95	-2.28 ± 19.53
Reflux Symptoms: Cycle 4	-0.98 ± 19.18	-1.90 ± 19.93
Reflux Symptoms: Cycle 5	-1.92 ± 18.98	-1.72 ± 20.10
Reflux Symptoms: Cycle 6	-2.90 ± 20.42	-3.59 ± 19.04
Reflux Symptoms: Cycle 7	-4.18 ± 18.36	-3.20 ± 20.21
Reflux Symptoms: Cycle 8	-4.96 ± 19.39	-5.74 ± 19.53
Reflux Symptoms: Cycle 9	-5.02 ± 18.97	-5.18 ± 19.81
Reflux Symptoms: Cycle 10	-6.12 ± 17.81	-6.48 ± 18.55
Reflux Symptoms: Cycle 11	-6.44 ± 18.74	-6.03 ± 18.07
Reflux Symptoms: Cycle 12	-4.82 ± 18.00	-7.49 ± 16.99
Reflux Symptoms: Cycle 13	-6.42 ± 17.09	-6.77 ± 18.19
Reflux Symptoms: Cycle 14	-5.39 ± 18.24	-7.37 ± 17.45
Reflux Symptoms: Cycle 15	-5.00 ± 16.66	-4.98 ± 18.72
Reflux Symptoms: Cycle 16	-3.07 ± 18.39	-4.89 ± 22.31
Reflux Symptoms: Cycle 17	-3.35 ± 18.38	-4.57 ± 20.44
Reflux Symptoms: Cycle 18	-2.94 ± 18.36	-6.51 ± 20.33
Reflux Symptoms: Cycle 19	-2.43 ± 16.38	-6.15 ± 18.43
Reflux Symptoms: Cycle 20	-1.85 ± 18.32	-5.38 ± 18.63
Reflux Symptoms: Cycle 21	-1.83 ± 18.44	-4.19 ± 17.73
Reflux Symptoms: Cycle 22	-3.81 ± 19.30	-7.00 ± 19.65
Reflux Symptoms: Cycle 23	-5.11 ± 17.03	-6.98 ± 19.70
Reflux Symptoms: Cycle 24	-4.07 ± 19.30	-7.98 ± 18.19
Reflux Symptoms: Cycle 25	-5.56 ± 18.86	-5.71 ± 16.69
Reflux Symptoms: Cycle 26	-4.99 ± 20.67	-4.30 ± 21.98
Reflux Symptoms: Cycle 27	-7.75 ± 20.51	-6.75 ± 16.10
Reflux Symptoms: Cycle 28	-7.12 ± 18.64	-4.44 ± 11.56
Reflux Symptoms: Post-Treatment Visit 1	0.88 ± 20.01	-0.45 ± 22.92
Reflux Symptoms: Post-Treatment Visit 2	0.56 ± 18.67	-1.47 ± 22.28
Taste: Cycle 2	12.09 ± 28.78	6.61 ± 26.94
Taste: Cycle 3	16.72 ± 32.11	9.99 ± 30.16
Taste: Cycle 4	18.43 ± 34.70	11.07 ± 31.93
Taste: Cycle 5	17.61 ± 32.93	11.85 ± 30.25
Taste: Cycle 6	17.97 ± 31.20	11.82 ± 32.21
Taste: Cycle 7	16.25 ± 33.51	9.19 ± 31.09
Taste: Cycle 8	11.64 ± 29.81	3.29 ± 28.13
Taste: Cycle 9	9.22 ± 28.25	1.73 ± 26.30
Taste: Cycle 10	7.93 ± 26.41	1.63 ± 28.79
Taste: Cycle 11	4.96 ± 26.72	2.61 ± 26.91
Taste: Cycle 12	5.27 ± 24.82	0.24 ± 24.66
Taste: Cycle 13	4.08 ± 25.53	-0.91 ± 25.33
Taste: Cycle 14	0.49 ± 25.66	-5.28 ± 24.37
Taste: Cycle 15	3.08 ± 24.36	-1.04 ± 26.25
Taste: Cycle 16	5.51 ± 27.90	-3.57 ± 20.71
Taste: Cycle 17	4.80 ± 24.96	-3.65 ± 23.28
Taste: Cycle 18	3.59 ± 23.87	-4.29 ± 23.34
Taste: Cycle 19	3.13 ± 25.17	-4.62 ± 15.45
Taste: Cycle 20	5.56 ± 27.78	-3.76 ± 18.21
Taste: Cycle 21	6.33 ± 27.26	-5.03 ± 17.78
Taste: Cycle 22	9.45 ± 30.04	-4.35 ± 16.64
Taste: Cycle 23	8.99 ± 30.06	0.00 ± 23.00
Taste: Cycle 24	7.78 ± 28.37	-5.13 ± 19.55
Taste: Cycle 25	3.21 ± 28.97	-4.76 ± 18.33
Taste: Cycle 26	4.08 ± 34.45	-3.23 ± 21.70
Taste: Cycle 27	4.65 ± 29.62	-3.57 ± 20.96
Taste: Cycle 28	3.42 ± 21.35	-6.67 ± 25.46
Taste: Post-Treatment Monitoring Visit 1	12.76 ± 34.59	9.06 ± 33.56
Taste: Post-Treatment Monitoring Visit 2	8.42 ± 31.35	6.67 ± 28.64

No statistical analyses for this end point

Secondary: Maximum Serum Concentrations (Cmax) of Pertuzumab

Top of page

End point title

Maximum Serum Concentrations (Cmax) of Pertuzumab ^[24]

End point description

The pharmacokinetic analysis included all subjects who were treated with study medication and who had at least one measurable concentration of pertuzumab or trastuzumab. In this analysis, results are reported only for evaluable subjects who received pertuzumab.

End point type

Secondary

End point timeframe

Post-dose (0.5 hour after end of 30-60 minutes infusion) on Day 1 of Cycles 1, 2, 4, and 8 (1 cycle = 21 days)

Notes
[24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only applicable to the Pertuzumab arm of the study; no data was collected from subjects in the Placebo arm for this endpoint.

End point values	Pertuzumab + Trastuzumab + Chemotherapy
Number of subjects analysed	374
Units: micrograms per milliliter (μg/mL)
arithmetic mean (standard deviation)
Cycle 1 (n = 374)	258 ± 90.3
Cycle 2 (n = 346)	288 ± 83.7
Cycle 4 (n = 302)	341 ± 111
Cycle 8 (n = 106)	371 ± 127

No statistical analyses for this end point

Secondary: Cmax of Trastuzumab

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End point title

Cmax of Trastuzumab

End point description

The pharmacokinetic analysis included all subjects who were treated with study medication and who had at least one measurable concentration of pertuzumab or trastuzumab. Data are reported for evaluable subjects.

End point type

Secondary

End point timeframe

Post-dose (0.5 hour after end of 30-60 minutes infusion) on Day 1 of Cycles 1, 2, 4, and 8 (1 cycle = 21 days)

End point values	Pertuzumab + Trastuzumab + Chemotherapy	Placebo + Trastuzumab + Chemotherapy
Number of subjects analysed	372	375
Units: μg/mL
arithmetic mean (standard deviation)
Cycle 1 (n = 372, 375)	142 ± 86.8	139 ± 58.6
Cycle 2 (n = 346, 354)	120 ± 46.6	120 ± 44.3
Cycle 4 (n = 304, 299)	127 ± 50.9	129 ± 58.1
Cycle 8 (n = 115, 90)	130 ± 50.8	147 ± 90.2

No statistical analyses for this end point

Secondary: Minimum Serum Concentration (Cmin) of Pertuzumab

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End point title

Minimum Serum Concentration (Cmin) of Pertuzumab ^[25]

End point description

The pharmacokinetic analysis included all subjects who were treated with study medication and who had at least one measurable concentration of pertuzumab or trastuzumab. In this analysis, results are reported only for evaluable subjects who received pertuzumab. The value '999999' indicates that the Cmin mean and standard deviation at Cycle 1 (before first dose) is non-reportable (i.e., lower than quantifiable).

End point type

Secondary

End point timeframe

Pre-dose (0-6 hours before infusion) on Day 1 of Cycles 1, 2, 3, 4, 6, and 8 (1 cycle = 21 days)

Notes
[25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only applicable to the Pertuzumab arm of the study; no data was collected from subjects in the Placebo arm for this endpoint.

End point values	Pertuzumab + Trastuzumab + Chemotherapy
Number of subjects analysed	376
Units: μg/mL
arithmetic mean (standard deviation)
Cycle 1 (n = 376)	999999 ± 999999
Cycle 2 (n = 349)	42.4 ± 24.8
Cycle 3 (n = 327)	74.0 ± 40.9
Cycle 4 (n = 305)	90.4 ± 42.4
Cycle 6 (n = 274)	114 ± 51.8
Cycle 8 (n = 114)	142 ± 67.9

No statistical analyses for this end point

Secondary: Cmin of Trastuzumab

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End point title

Cmin of Trastuzumab

End point description

The pharmacokinetic analysis included all subjects who were treated with study medication and who had at least one measurable concentration of pertuzumab or trastuzumab. Data are reported for evaluable subjects. The value '999999' indicates that the Cmin mean and standard deviation at Cycle 1 (before first dose) is non-reportable (i.e., lower than quantifiable).

End point type

Secondary

End point timeframe

Pre-dose (0-6 hours before infusion) on Day 1 of Cycles 1, 2, 3, 4, 6, and 8 (1 cycle = 21 days)

End point values	Pertuzumab + Trastuzumab + Chemotherapy	Placebo + Trastuzumab + Chemotherapy
Number of subjects analysed	379	381
Units: μg/mL
arithmetic mean (standard deviation)
Cycle 1 (n = 379, 381)	999999 ± 999999	999999 ± 999999
Cycle 2 (n = 345, 354)	15.4 ± 11.3	17.2 ± 15.4
Cycle 3 (n = 328, 326)	19.9 ± 13.4	20.7 ± 15.2
Cycle 4 (n = 305, 300)	22.9 ± 12.7	24.1 ± 19.0
Cycle 6 (n = 274, 254)	26.3 ± 14.8	29.8 ± 21.9
Cycle 8 (n = 114, 92)	32.7 ± 15.0	37.4 ± 20.3

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From Baseline until end of post-treatment follow-up (up to 70 months)

Adverse event reporting additional description

All adverse events that occurred during the study were recorded until the post-treatment safety follow-up visit 28 days after last study treatment. The safety population included all subjects who received any study treatment: those who received any pertuzumab were included in the pertuzumab arm; all others treated were included in the placebo arm.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

22.1

Reporting group title

Pertuzumab + Trastuzumab + Chemotherapy

Reporting group description

Subjects received pertuzumab in combination with trastuzumab and chemotherapy (cisplatin and fluoropyrimidine [capecitabine or 5-fluorouracil]) for the first 6 treatment cycles (cycle length = 21 days). Thereafter, subjects continued to receive pertuzumab and trastuzumab until disease progression, occurrence of unacceptable toxicity, or withdrawal from the study for another reason.

Reporting group title

Placebo + Trastuzumab + Chemotherapy

Reporting group description

Subjects received placebo in combination with trastuzumab and chemotherapy (cisplatin and fluoropyrimidine [capecitabine or 5-fluorouracil]) for the first 6 treatment cycles (cycle length = 21 days). Thereafter, subjects continued to receive placebo and trastuzumab until disease progression, occurrence of unacceptable toxicity, or withdrawal from the study for another reason.

Serious adverse events	Pertuzumab + Trastuzumab + Chemotherapy	Placebo + Trastuzumab + Chemotherapy
Total subjects affected by serious adverse events
subjects affected / exposed	178 / 385 (46.23%)	156 / 388 (40.21%)
number of deaths (all causes)	299	318
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Myelodysplastic syndrome
subjects affected / exposed	1 / 385 (0.26%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Rectosigmoid cancer stage 0
subjects affected / exposed	1 / 385 (0.26%)	0 / 388 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Second primary malignancy
subjects affected / exposed	0 / 385 (0.00%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Tumour haemorrhage
subjects affected / exposed	4 / 385 (1.04%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	2 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Plasma cell myeloma
subjects affected / exposed	0 / 385 (0.00%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Vascular disorders
Aortic aneurysm
subjects affected / exposed	0 / 385 (0.00%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Deep vein thrombosis
subjects affected / exposed	3 / 385 (0.78%)	0 / 388 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Embolism
subjects affected / exposed	2 / 385 (0.52%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0
Haemodynamic instability
subjects affected / exposed	0 / 385 (0.00%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	1 / 1
Hypertensive crisis
subjects affected / exposed	1 / 385 (0.26%)	0 / 388 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypotension
subjects affected / exposed	0 / 385 (0.00%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypovolaemic shock
subjects affected / exposed	0 / 385 (0.00%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Iliac artery occlusion
subjects affected / exposed	0 / 385 (0.00%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Orthostatic hypotension
subjects affected / exposed	1 / 385 (0.26%)	0 / 388 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral ischaemia
subjects affected / exposed	1 / 385 (0.26%)	0 / 388 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Subclavian vein thrombosis
subjects affected / exposed	0 / 385 (0.00%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Thrombosis
subjects affected / exposed	1 / 385 (0.26%)	0 / 388 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Varicose vein
subjects affected / exposed	1 / 385 (0.26%)	0 / 388 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Venous thrombosis limb
subjects affected / exposed	1 / 385 (0.26%)	0 / 388 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	5 / 385 (1.30%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	5 / 8	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Chest pain
subjects affected / exposed	0 / 385 (0.00%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Death
subjects affected / exposed	8 / 385 (2.08%)	9 / 388 (2.32%)
occurrences causally related to treatment / all	0 / 8	1 / 9
deaths causally related to treatment / all	0 / 8	1 / 9
Fatigue
subjects affected / exposed	4 / 385 (1.04%)	0 / 388 (0.00%)
occurrences causally related to treatment / all	4 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	1 / 385 (0.26%)	0 / 388 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Hypothermia
subjects affected / exposed	1 / 385 (0.26%)	0 / 388 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Malaise
subjects affected / exposed	0 / 385 (0.00%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Mucosal inflammation
subjects affected / exposed	4 / 385 (1.04%)	3 / 388 (0.77%)
occurrences causally related to treatment / all	4 / 4	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Multiple organ dysfunction syndrome
subjects affected / exposed	0 / 385 (0.00%)	2 / 388 (0.52%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	1 / 1
Non-cardiac chest pain
subjects affected / exposed	0 / 385 (0.00%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	2 / 385 (0.52%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	2 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Immune system disorders
Cytokine release syndrome
subjects affected / exposed	1 / 385 (0.26%)	0 / 388 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypersensitivity
subjects affected / exposed	1 / 385 (0.26%)	0 / 388 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Reproductive system and breast disorders
Benign prostatic hyperplasia
subjects affected / exposed	1 / 385 (0.26%)	0 / 388 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome
subjects affected / exposed	0 / 385 (0.00%)	2 / 388 (0.52%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 1
Bronchospasm
subjects affected / exposed	1 / 385 (0.26%)	0 / 388 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	2 / 385 (0.52%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0
Epistaxis
subjects affected / exposed	1 / 385 (0.26%)	0 / 388 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypoxia
subjects affected / exposed	0 / 385 (0.00%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	0 / 385 (0.00%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	6 / 385 (1.56%)	2 / 388 (0.52%)
occurrences causally related to treatment / all	2 / 6	2 / 2
deaths causally related to treatment / all	0 / 1	1 / 1
Respiratory failure
subjects affected / exposed	0 / 385 (0.00%)	2 / 388 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1
Psychiatric disorders
Delirium
subjects affected / exposed	1 / 385 (0.26%)	0 / 388 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Depression
subjects affected / exposed	0 / 385 (0.00%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Suicide attempt
subjects affected / exposed	0 / 385 (0.00%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Product issues
Device dislocation
subjects affected / exposed	0 / 385 (0.00%)	2 / 388 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Device occlusion
subjects affected / exposed	1 / 385 (0.26%)	0 / 388 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 385 (0.00%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Aspartate aminotransferase increased
subjects affected / exposed	0 / 385 (0.00%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Blood bilirubin increased
subjects affected / exposed	1 / 385 (0.26%)	0 / 388 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood creatine phosphokinase increased
subjects affected / exposed	1 / 385 (0.26%)	0 / 388 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood creatinine increased
subjects affected / exposed	1 / 385 (0.26%)	2 / 388 (0.52%)
occurrences causally related to treatment / all	1 / 1	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Creatinine renal clearance decreased
subjects affected / exposed	1 / 385 (0.26%)	0 / 388 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Weight decreased
subjects affected / exposed	1 / 385 (0.26%)	0 / 388 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Biopsy bone marrow
subjects affected / exposed	0 / 385 (0.00%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Anastomotic stenosis
subjects affected / exposed	1 / 385 (0.26%)	0 / 388 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Craniocerebral injury
subjects affected / exposed	1 / 385 (0.26%)	0 / 388 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Fall
subjects affected / exposed	2 / 385 (0.52%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Femoral neck fracture
subjects affected / exposed	0 / 385 (0.00%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Fracture
subjects affected / exposed	2 / 385 (0.52%)	0 / 388 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal anastomotic leak
subjects affected / exposed	0 / 385 (0.00%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Head injury
subjects affected / exposed	1 / 385 (0.26%)	0 / 388 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hip fracture
subjects affected / exposed	0 / 385 (0.00%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infusion related reaction
subjects affected / exposed	3 / 385 (0.78%)	2 / 388 (0.52%)
occurrences causally related to treatment / all	3 / 3	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Injury
subjects affected / exposed	1 / 385 (0.26%)	0 / 388 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Limb injury
subjects affected / exposed	1 / 385 (0.26%)	0 / 388 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal compression fracture
subjects affected / exposed	1 / 385 (0.26%)	0 / 388 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ankle fracture
subjects affected / exposed	1 / 385 (0.26%)	0 / 388 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Thermal burn
subjects affected / exposed	1 / 385 (0.26%)	0 / 388 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Acute myocardial infarction
subjects affected / exposed	4 / 385 (1.04%)	0 / 388 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0
Atrial fibrillation
subjects affected / exposed	0 / 385 (0.00%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Atrial septal defect acquired
subjects affected / exposed	1 / 385 (0.26%)	0 / 388 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Atrioventricular block complete
subjects affected / exposed	0 / 385 (0.00%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	1 / 385 (0.26%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 1	0 / 0
Cardiac failure
subjects affected / exposed	3 / 385 (0.78%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	2 / 3	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac ventricular thrombosis
subjects affected / exposed	1 / 385 (0.26%)	0 / 388 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Intracardiac thrombus
subjects affected / exposed	1 / 385 (0.26%)	0 / 388 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	2 / 385 (0.52%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0
Myocarditis
subjects affected / exposed	0 / 385 (0.00%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Prinzmetal angina
subjects affected / exposed	1 / 385 (0.26%)	0 / 388 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Acute coronary syndrome
subjects affected / exposed	1 / 385 (0.26%)	0 / 388 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Anticholinergic syndrome
subjects affected / exposed	1 / 385 (0.26%)	0 / 388 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebral haemorrhage
subjects affected / exposed	0 / 385 (0.00%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Cerebral infarction
subjects affected / exposed	0 / 385 (0.00%)	2 / 388 (0.52%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebral ischaemia
subjects affected / exposed	1 / 385 (0.26%)	0 / 388 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	0 / 385 (0.00%)	3 / 388 (0.77%)
occurrences causally related to treatment / all	0 / 0	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 1
Dizziness
subjects affected / exposed	1 / 385 (0.26%)	0 / 388 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hydrocephalus
subjects affected / exposed	0 / 385 (0.00%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ischaemic cerebral infarction
subjects affected / exposed	0 / 385 (0.00%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ischaemic stroke
subjects affected / exposed	1 / 385 (0.26%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Loss of consciousness
subjects affected / exposed	1 / 385 (0.26%)	0 / 388 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Neuropathy peripheral
subjects affected / exposed	1 / 385 (0.26%)	0 / 388 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Presyncope
subjects affected / exposed	1 / 385 (0.26%)	0 / 388 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Seizure
subjects affected / exposed	1 / 385 (0.26%)	0 / 388 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Syncope
subjects affected / exposed	2 / 385 (0.52%)	0 / 388 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Subarachnoid haemorrhage
subjects affected / exposed	0 / 385 (0.00%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Epilepsy
subjects affected / exposed	0 / 385 (0.00%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	8 / 385 (2.08%)	16 / 388 (4.12%)
occurrences causally related to treatment / all	6 / 11	13 / 19
deaths causally related to treatment / all	0 / 0	0 / 1
Disseminated intravascular coagulation
subjects affected / exposed	0 / 385 (0.00%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	6 / 385 (1.56%)	9 / 388 (2.32%)
occurrences causally related to treatment / all	6 / 6	7 / 9
deaths causally related to treatment / all	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	3 / 385 (0.78%)	3 / 388 (0.77%)
occurrences causally related to treatment / all	4 / 4	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Pancytopenia
subjects affected / exposed	0 / 385 (0.00%)	3 / 388 (0.77%)
occurrences causally related to treatment / all	0 / 0	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	2 / 385 (0.52%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	2 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ear and labyrinth disorders
Tinnitus
subjects affected / exposed	0 / 385 (0.00%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	3 / 385 (0.78%)	2 / 388 (0.52%)
occurrences causally related to treatment / all	1 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	0 / 385 (0.00%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Colitis
subjects affected / exposed	0 / 385 (0.00%)	2 / 388 (0.52%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Constipation
subjects affected / exposed	0 / 385 (0.00%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	17 / 385 (4.42%)	20 / 388 (5.15%)
occurrences causally related to treatment / all	20 / 20	19 / 22
deaths causally related to treatment / all	0 / 0	1 / 1
Duodenal stenosis
subjects affected / exposed	1 / 385 (0.26%)	0 / 388 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Dysphagia
subjects affected / exposed	4 / 385 (1.04%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	0 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Enteritis
subjects affected / exposed	1 / 385 (0.26%)	0 / 388 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Enterocolitis
subjects affected / exposed	0 / 385 (0.00%)	4 / 388 (1.03%)
occurrences causally related to treatment / all	0 / 0	3 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric haemorrhage
subjects affected / exposed	6 / 385 (1.56%)	2 / 388 (0.52%)
occurrences causally related to treatment / all	1 / 7	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric perforation
subjects affected / exposed	2 / 385 (0.52%)	2 / 388 (0.52%)
occurrences causally related to treatment / all	0 / 2	2 / 2
deaths causally related to treatment / all	0 / 1	0 / 0
Gastric stenosis
subjects affected / exposed	1 / 385 (0.26%)	0 / 388 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric ulcer
subjects affected / exposed	1 / 385 (0.26%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorder
subjects affected / exposed	0 / 385 (0.00%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Gastrointestinal haemorrhage
subjects affected / exposed	0 / 385 (0.00%)	3 / 388 (0.77%)
occurrences causally related to treatment / all	0 / 0	1 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal inflammation
subjects affected / exposed	1 / 385 (0.26%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal obstruction
subjects affected / exposed	0 / 385 (0.00%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal perforation
subjects affected / exposed	0 / 385 (0.00%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal ulcer
subjects affected / exposed	0 / 385 (0.00%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 385 (0.00%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Haematemesis
subjects affected / exposed	0 / 385 (0.00%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhoids
subjects affected / exposed	1 / 385 (0.26%)	0 / 388 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ileus
subjects affected / exposed	2 / 385 (0.52%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	1 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Ileus paralytic
subjects affected / exposed	1 / 385 (0.26%)	0 / 388 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Intestinal mass
subjects affected / exposed	0 / 385 (0.00%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	0 / 385 (0.00%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lower gastrointestinal haemorrhage
subjects affected / exposed	0 / 385 (0.00%)	2 / 388 (0.52%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Melaena
subjects affected / exposed	2 / 385 (0.52%)	0 / 388 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nausea
subjects affected / exposed	7 / 385 (1.82%)	7 / 388 (1.80%)
occurrences causally related to treatment / all	7 / 7	7 / 9
deaths causally related to treatment / all	0 / 0	0 / 0
Obstruction gastric
subjects affected / exposed	2 / 385 (0.52%)	5 / 388 (1.29%)
occurrences causally related to treatment / all	1 / 2	1 / 7
deaths causally related to treatment / all	0 / 0	0 / 0
Oesophageal haemorrhage
subjects affected / exposed	1 / 385 (0.26%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Stomatitis
subjects affected / exposed	2 / 385 (0.52%)	2 / 388 (0.52%)
occurrences causally related to treatment / all	2 / 2	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Upper gastrointestinal haemorrhage
subjects affected / exposed	3 / 385 (0.78%)	5 / 388 (1.29%)
occurrences causally related to treatment / all	1 / 3	2 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Vomiting
subjects affected / exposed	7 / 385 (1.82%)	13 / 388 (3.35%)
occurrences causally related to treatment / all	5 / 8	12 / 17
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric pneumatosis
subjects affected / exposed	1 / 385 (0.26%)	0 / 388 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Mechanical ileus
subjects affected / exposed	0 / 385 (0.00%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis
subjects affected / exposed	1 / 385 (0.26%)	0 / 388 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cholecystitis acute
subjects affected / exposed	1 / 385 (0.26%)	3 / 388 (0.77%)
occurrences causally related to treatment / all	0 / 1	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatic function abnormal
subjects affected / exposed	0 / 385 (0.00%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Actinic keratosis
subjects affected / exposed	1 / 385 (0.26%)	0 / 388 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	7 / 385 (1.82%)	4 / 388 (1.03%)
occurrences causally related to treatment / all	6 / 7	4 / 4
deaths causally related to treatment / all	1 / 2	0 / 0
Hydronephrosis
subjects affected / exposed	0 / 385 (0.00%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal failure
subjects affected / exposed	2 / 385 (0.52%)	3 / 388 (0.77%)
occurrences causally related to treatment / all	2 / 2	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Renal impairment
subjects affected / exposed	1 / 385 (0.26%)	2 / 388 (0.52%)
occurrences causally related to treatment / all	0 / 1	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Endocrine disorders
Autoimmune thyroiditis
subjects affected / exposed	1 / 385 (0.26%)	0 / 388 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Inappropriate antidiuretic hormone secretion
subjects affected / exposed	1 / 385 (0.26%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pseudoaldosteronism
subjects affected / exposed	1 / 385 (0.26%)	0 / 388 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	0 / 385 (0.00%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gouty arthritis
subjects affected / exposed	0 / 385 (0.00%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Muscular weakness
subjects affected / exposed	1 / 385 (0.26%)	0 / 388 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Abdominal infection
subjects affected / exposed	0 / 385 (0.00%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Arthritis bacterial
subjects affected / exposed	1 / 385 (0.26%)	0 / 388 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bacteraemia
subjects affected / exposed	2 / 385 (0.52%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Biliary sepsis
subjects affected / exposed	0 / 385 (0.00%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	1 / 385 (0.26%)	0 / 388 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	1 / 385 (0.26%)	0 / 388 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Device related infection
subjects affected / exposed	2 / 385 (0.52%)	0 / 388 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Device related sepsis
subjects affected / exposed	1 / 385 (0.26%)	0 / 388 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diarrhoea infectious
subjects affected / exposed	1 / 385 (0.26%)	0 / 388 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 385 (0.00%)	2 / 388 (0.52%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatitis B
subjects affected / exposed	0 / 385 (0.00%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infection
subjects affected / exposed	0 / 385 (0.00%)	3 / 388 (0.77%)
occurrences causally related to treatment / all	0 / 0	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Liver abscess
subjects affected / exposed	1 / 385 (0.26%)	2 / 388 (0.52%)
occurrences causally related to treatment / all	0 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Parotitis
subjects affected / exposed	0 / 385 (0.00%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Peritonitis
subjects affected / exposed	1 / 385 (0.26%)	0 / 388 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	14 / 385 (3.64%)	14 / 388 (3.61%)
occurrences causally related to treatment / all	6 / 15	5 / 14
deaths causally related to treatment / all	0 / 3	0 / 2
Pneumonia Klebsiella
subjects affected / exposed	0 / 385 (0.00%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	0 / 385 (0.00%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Sepsis
subjects affected / exposed	8 / 385 (2.08%)	2 / 388 (0.52%)
occurrences causally related to treatment / all	5 / 8	2 / 2
deaths causally related to treatment / all	3 / 4	1 / 1
Septic shock
subjects affected / exposed	3 / 385 (0.78%)	4 / 388 (1.03%)
occurrences causally related to treatment / all	1 / 3	3 / 4
deaths causally related to treatment / all	0 / 0	3 / 3
Upper respiratory tract infection
subjects affected / exposed	3 / 385 (0.78%)	2 / 388 (0.52%)
occurrences causally related to treatment / all	1 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	1 / 385 (0.26%)	0 / 388 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	0 / 385 (0.00%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Appendicitis
subjects affected / exposed	1 / 385 (0.26%)	0 / 388 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular device infection
subjects affected / exposed	1 / 385 (0.26%)	0 / 388 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Cachexia
subjects affected / exposed	1 / 385 (0.26%)	0 / 388 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Decreased appetite
subjects affected / exposed	17 / 385 (4.42%)	9 / 388 (2.32%)
occurrences causally related to treatment / all	15 / 18	9 / 9
deaths causally related to treatment / all	0 / 0	0 / 0
Dehydration
subjects affected / exposed	9 / 385 (2.34%)	9 / 388 (2.32%)
occurrences causally related to treatment / all	9 / 10	7 / 9
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetes mellitus
subjects affected / exposed	0 / 385 (0.00%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetes mellitus inadequate control
subjects affected / exposed	0 / 385 (0.00%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Failure to thrive
subjects affected / exposed	0 / 385 (0.00%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	0 / 385 (0.00%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypernatraemia
subjects affected / exposed	1 / 385 (0.26%)	0 / 388 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypocalcaemia
subjects affected / exposed	2 / 385 (0.52%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	2 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	7 / 385 (1.82%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	6 / 8	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypomagnesaemia
subjects affected / exposed	2 / 385 (0.52%)	2 / 388 (0.52%)
occurrences causally related to treatment / all	2 / 2	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	2 / 385 (0.52%)	2 / 388 (0.52%)
occurrences causally related to treatment / all	2 / 2	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Malnutrition
subjects affected / exposed	1 / 385 (0.26%)	1 / 388 (0.26%)
occurrences causally related to treatment / all	1 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0

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

Non-serious adverse events	Pertuzumab + Trastuzumab + Chemotherapy	Placebo + Trastuzumab + Chemotherapy
Total subjects affected by non serious adverse events
subjects affected / exposed	373 / 385 (96.88%)	376 / 388 (96.91%)
Investigations
Blood creatinine increased
subjects affected / exposed	29 / 385 (7.53%)	22 / 388 (5.67%)
occurrences all number	36	31
Creatinine renal clearance decreased
subjects affected / exposed	71 / 385 (18.44%)	50 / 388 (12.89%)
occurrences all number	97	65
Weight decreased
subjects affected / exposed	78 / 385 (20.26%)	49 / 388 (12.63%)
occurrences all number	80	51
Ejection fraction decreased
subjects affected / exposed	20 / 385 (5.19%)	18 / 388 (4.64%)
occurrences all number	24	20
Injury, poisoning and procedural complications
Infusion related reaction
subjects affected / exposed	45 / 385 (11.69%)	23 / 388 (5.93%)
occurrences all number	52	26
Vascular disorders
Hypertension
subjects affected / exposed	20 / 385 (5.19%)	21 / 388 (5.41%)
occurrences all number	24	21
Nervous system disorders
Dizziness
subjects affected / exposed	31 / 385 (8.05%)	30 / 388 (7.73%)
occurrences all number	35	38
Dysgeusia
subjects affected / exposed	31 / 385 (8.05%)	27 / 388 (6.96%)
occurrences all number	40	27
Neuropathy peripheral
subjects affected / exposed	34 / 385 (8.83%)	29 / 388 (7.47%)
occurrences all number	38	30
Peripheral sensory neuropathy
subjects affected / exposed	29 / 385 (7.53%)	34 / 388 (8.76%)
occurrences all number	37	35
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	159 / 385 (41.30%)	142 / 388 (36.60%)
occurrences all number	208	189
Leukopenia
subjects affected / exposed	80 / 385 (20.78%)	69 / 388 (17.78%)
occurrences all number	148	113
Neutropenia
subjects affected / exposed	200 / 385 (51.95%)	202 / 388 (52.06%)
occurrences all number	340	298
Thrombocytopenia
subjects affected / exposed	61 / 385 (15.84%)	73 / 388 (18.81%)
occurrences all number	105	100
General disorders and administration site conditions
Asthenia
subjects affected / exposed	59 / 385 (15.32%)	60 / 388 (15.46%)
occurrences all number	83	78
Chills
subjects affected / exposed	37 / 385 (9.61%)	17 / 388 (4.38%)
occurrences all number	37	19
Fatigue
subjects affected / exposed	144 / 385 (37.40%)	123 / 388 (31.70%)
occurrences all number	182	166
Mucosal inflammation
subjects affected / exposed	43 / 385 (11.17%)	34 / 388 (8.76%)
occurrences all number	60	40
Oedema
subjects affected / exposed	20 / 385 (5.19%)	19 / 388 (4.90%)
occurrences all number	33	32
Oedema peripheral
subjects affected / exposed	27 / 385 (7.01%)	33 / 388 (8.51%)
occurrences all number	31	36
Pyrexia
subjects affected / exposed	55 / 385 (14.29%)	60 / 388 (15.46%)
occurrences all number	81	69
Gastrointestinal disorders
Abdominal distension
subjects affected / exposed	25 / 385 (6.49%)	19 / 388 (4.90%)
occurrences all number	36	24
Abdominal pain
subjects affected / exposed	44 / 385 (11.43%)	51 / 388 (13.14%)
occurrences all number	60	59
Abdominal pain upper
subjects affected / exposed	28 / 385 (7.27%)	23 / 388 (5.93%)
occurrences all number	33	25
Constipation
subjects affected / exposed	56 / 385 (14.55%)	84 / 388 (21.65%)
occurrences all number	64	107
Diarrhoea
subjects affected / exposed	230 / 385 (59.74%)	125 / 388 (32.22%)
occurrences all number	351	173
Dyspepsia
subjects affected / exposed	24 / 385 (6.23%)	30 / 388 (7.73%)
occurrences all number	27	40
Dysphagia
subjects affected / exposed	28 / 385 (7.27%)	32 / 388 (8.25%)
occurrences all number	34	38
Nausea
subjects affected / exposed	224 / 385 (58.18%)	218 / 388 (56.19%)
occurrences all number	314	311
Stomatitis
subjects affected / exposed	81 / 385 (21.04%)	69 / 388 (17.78%)
occurrences all number	102	86
Vomiting
subjects affected / exposed	147 / 385 (38.18%)	122 / 388 (31.44%)
occurrences all number	200	167
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	25 / 385 (6.49%)	21 / 388 (5.41%)
occurrences all number	30	32
Dyspnoea
subjects affected / exposed	22 / 385 (5.71%)	14 / 388 (3.61%)
occurrences all number	25	18
Hiccups
subjects affected / exposed	33 / 385 (8.57%)	37 / 388 (9.54%)
occurrences all number	37	45
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	21 / 385 (5.45%)	25 / 388 (6.44%)
occurrences all number	25	26
Dry skin
subjects affected / exposed	32 / 385 (8.31%)	18 / 388 (4.64%)
occurrences all number	39	21
Palmar-plantar erythrodysaesthesia syndrome
subjects affected / exposed	86 / 385 (22.34%)	100 / 388 (25.77%)
occurrences all number	91	112
Pruritus
subjects affected / exposed	38 / 385 (9.87%)	16 / 388 (4.12%)
occurrences all number	51	25
Rash
subjects affected / exposed	27 / 385 (7.01%)	13 / 388 (3.35%)
occurrences all number	30	15
Skin hyperpigmentation
subjects affected / exposed	17 / 385 (4.42%)	21 / 388 (5.41%)
occurrences all number	17	21
Psychiatric disorders
Insomnia
subjects affected / exposed	34 / 385 (8.83%)	46 / 388 (11.86%)
occurrences all number	45	48
Infections and infestations
Upper respiratory tract infection
subjects affected / exposed	24 / 385 (6.23%)	13 / 388 (3.35%)
occurrences all number	37	18
Nasopharyngitis
subjects affected / exposed	21 / 385 (5.45%)	18 / 388 (4.64%)
occurrences all number	22	24
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	172 / 385 (44.68%)	158 / 388 (40.72%)
occurrences all number	243	218
Hypoalbuminaemia
subjects affected / exposed	20 / 385 (5.19%)	21 / 388 (5.41%)
occurrences all number	24	23
Hypocalcaemia
subjects affected / exposed	24 / 385 (6.23%)	23 / 388 (5.93%)
occurrences all number	32	26
Hypokalaemia
subjects affected / exposed	74 / 385 (19.22%)	46 / 388 (11.86%)
occurrences all number	98	57
Hypomagnesaemia
subjects affected / exposed	30 / 385 (7.79%)	21 / 388 (5.41%)
occurrences all number	38	22
Hyponatraemia
subjects affected / exposed	17 / 385 (4.42%)	29 / 388 (7.47%)
occurrences all number	19	29

More information

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Were there any global substantial amendments to the protocol? Yes

04 Mar 2014

The protocol was amended to provide clarity and consistency around protocol procedures, assessments, and analyses (i.e., safety reporting, chemotherapy dose adjustment, study assessments timing, contraception use, etc.). The period for contraception use was extended from 6 to 7 months following the last dose of study treatment. The safety reporting period for pregnancy (occurring during/after trastuzumab treatment) was updated from 6 to 7 months.

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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