A Study of a Combination of Trastuzumab and Capecitabine With or Without Pertuzumab in Patients With HER2-positive Metastatic Breast Cancer (PHEREXA)

• ClinicalTrials.gov Identifier: NCT01026142
• Recruitment Status: Completed
• First Posted: December 4, 2009
• Results First Posted: October 13, 2016
• Last Update Posted: August 14, 2018
• Sponsor: Hoffmann-La Roche
• Information provided by (Responsible Party): Hoffmann-La Roche

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Breast Cancer
• Interventions: Drug: Capecitabine; Drug: Pertuzumab; Drug: Trastuzumab
• Enrollment: 452

Participant Flow

Recruitment Details	452 participants were randomized to one of two treatment arms: trastuzumab and capecitabine (Arm A, 224 participants) or pertuzumab with trastuzumab and capecitabine (Arm B, 228 participants). Of participants randomized to Arm A: trastuzumab and capecitabine, 6 participants did not receive study treatment.
Pre-assignment Details

Arm/Group Title	A: Capecitabine + Trastuzumab	B: Capecitabine + Trastuzumab + Pertuzumab
Arm/Group Description	Capecitabine [Xeloda]: 1250 mg/m2 po twice daily for 14 days every 3 weeks. Trastuzumab [Herceptin]: 8 mg/kg iv loading, then 6 mg/kg iv every 3 weeks.	Capecitabine [Xeloda]: 1000 mg/m2 po twice daily for 14 days every 3 weeks. Pertuzumab [Perjeta]: 840 mg iv loading, then 420 mg iv every 3 weeks. Trastuzumab [Herceptin]: 8 mg/kg iv loading, then 6 mg/kg iv every 3 weeks.
Period Title: Overall Study
Started	224	228
Completed	52	65
Not Completed	172	163
Reason Not Completed
Death	136	134
Withdrew consent or lost to follow-up	36	29

Baseline Characteristics

Arm/Group Title		A: Capecitabine + Trastuzumab	B: Capecitabine + Trastuzumab + Pertuzumab	Total
Arm/Group Description		Capecitabine [Xeloda]: 1250 mg/m2 po twice daily for 14 days every 3 weeks. Trastuzumab [Herceptin]: 8 mg/kg iv loading, then 6 mg/kg iv every 3 weeks.	Capecitabine [Xeloda]: 1000 mg/m2 po twice daily for 14 days every 3 weeks. Pertuzumab [Perjeta]: 840 mg iv loading, then 420 mg iv every 3 weeks. Trastuzumab [Herceptin]: 8 mg/kg iv loading, then 6 mg/kg iv every 3 weeks.	Total of all reporting groups
Overall Number of Baseline Participants		218	228	446
Baseline Analysis Population Description		This is the safety population, which includes all participants who received any amount of study drug; 6 participants randomized to the Capecitabine + Trastuzumab arm withdrew before receiving any study treatment.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	218 participants	228 participants	446 participants
		55.1 (10.10)	53.0 (11.21)	54.0 (10.72)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	218 participants	228 participants	446 participants
	Female	218 100.0%	228 100.0%	446 100.0%
	Male	0 0.0%	0 0.0%	0 0.0%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants	Number Analyzed	218 participants	228 participants	446 participants
Russian Federation		8	3	11
Argentina		3	4	7
Romania		6	8	14
Hungary		13	29	42
Hong Kong		5	11	16
United Kingdom		18	17	35
Thailand		0	5	5
Spain		39	31	70
Canada		3	6	9
Czech Republic		12	10	22
Austria		2	3	5
Netherlands		0	2	2
Belgium		12	11	23
Poland		6	6	12
Brazil		7	6	13
Korea, Republic of		14	24	38
Italy		16	18	34
Mexico		1	0	1
France		19	12	31
Peru		7	8	15
Germany		23	11	34
Croatia		4	3	7

Outcome Measures

1. Primary Outcome

Title	Progression Free Survival (Independent Assessment)
Description	Progression Free Survival (PFS) was defined as the time from randomization to first documented disease progression (PD), as determined by an Independent Review Facility (IRF) using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0, or death from any cause, whichever occurred first. PD was defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions; or the appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. IRF review of tumor assessment ceased after the primary PFS analysis. The primary endpoint was analyzed after approximately 337 IRF-assessed PFS events were observed.
Time Frame	Tumor assessments every 9 weeks from randomization until Week 27, then every 12 weeks thereafter, until IRF-determined PD, initiation of alternative anticancer medication, or death (up to 5.5 years).

Outcome Measure Data

Analysis Population Description

All randomized participants.

Arm/Group Title	A: Capecitabine + Trastuzumab	B: Capecitabine + Trastuzumab + Pertuzumab
Arm/Group Description:	Capecitabine [Xeloda]: 1250 mg/m2 po twice daily for 14 days every 3 weeks. Trastuzumab [Herceptin]: 8 mg/kg iv loading, then 6 mg/kg iv every 3 weeks.	Capecitabine [Xeloda]: 1000 mg/m2 po twice daily for 14 days every 3 weeks. Pertuzumab [Perjeta]: 840 mg iv loading, then 420 mg iv every 3 weeks. Trastuzumab [Herceptin]: 8 mg/kg iv loading, then 6 mg/kg iv every 3 weeks.
Overall Number of Participants Analyzed	224	228
Median (95% Confidence Interval); Unit of Measure: months
	9.0; (8 to 10)	11.1; (9 to 13)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	A: Capecitabine + Trastuzumab, B: Capecitabine + Trastuzumab + Pertuzumab
	Comments	The null hypothesis for the primary endpoint is that the survival distributions of IRF-assessed PFS in the two treatment groups are the same. The alternative hypothesis is that the survival distributions of IRF-assessed PFS in the treatment and the control arms are different: H0: IRF PFS<pertuzumab> = IRF PFS<control> vs. H1: IRF PFS<pertuzumab> ≠ IRF PFS<control>
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0731
	Comments	The primary endpoint, IRF-assessed PFS, is tested at a two-sided 5% significance level.
	Method	Log Rank
	Comments	Two-sided and stratified by: prior CNS disease present/absent, measurable disease at baseline, and response to trastuzumab in 1L metastatic setting.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.82
	Confidence Interval	(2-Sided) 95%; 0.65 to 1.02
	Estimation Comments	The stratified Cox proportional hazard model will be used to estimate the HR between the two treatment arms and its 95% CI.

2. Secondary Outcome

Title	Overall Survival (OS)
Description	Overall Survival (OS) was defined as the time from the date of randomization to the date of death from any cause. The results of the final OS analysis are presented here. Participants who were alive or lost to follow-up at the time of the analysis were censored at the last known alive date. Participants with no postbaseline information were censored at the time of randomization plus 1 day. Prior to the final data analysis cut-off, it was ensured that all participants who were in survival follow-up had been contacted as recently as possible within the last 3 months to confirm current survival status.
Time Frame	From randomization until death from any cause (up to 7.5 years).

Outcome Measure Data

Analysis Population Description

All randomized participants.

Arm/Group Title	A: Capecitabine + Trastuzumab	B: Capecitabine + Trastuzumab + Pertuzumab
Arm/Group Description:	Capecitabine [Xeloda]: 1250 mg/m2 po twice daily for 14 days every 3 weeks. Trastuzumab [Herceptin]: 8 mg/kg iv loading, then 6 mg/kg iv every 3 weeks.	Capecitabine [Xeloda]: 1000 mg/m2 po twice daily for 14 days every 3 weeks. Pertuzumab [Perjeta]: 840 mg iv loading, then 420 mg iv every 3 weeks. Trastuzumab [Herceptin]: 8 mg/kg iv loading, then 6 mg/kg iv every 3 weeks.
Overall Number of Participants Analyzed	224	228
Median (95% Confidence Interval); Unit of Measure: Months
	28.1; (22 to 35)	37.2; (33 to 42)

3. Secondary Outcome

Title	Overall Survival (OS) Rate Based on a 2-year Truncated Analysis
Description	The Overall Survival (OS) 2-year truncated analysis is the Kaplan-Meier estimate of the percentage of participants who were surviving at 2 years. OS is defined as the time from the date of randomization to the date of death from any cause, with censoring of all events and follow-up beyond the end of the second year.
Time Frame	From randomization until death from any cause (up to 2 years)

Outcome Measure Data

Analysis Population Description

All randomized participants.

Arm/Group Title	A: Capecitabine + Trastuzumab	B: Capecitabine + Trastuzumab + Pertuzumab
Arm/Group Description:	Capecitabine [Xeloda]: 1250 mg/m2 po twice daily for 14 days every 3 weeks. Trastuzumab [Herceptin]: 8 mg/kg iv loading, then 6 mg/kg iv every 3 weeks.	Capecitabine [Xeloda]: 1000 mg/m2 po twice daily for 14 days every 3 weeks. Pertuzumab [Perjeta]: 840 mg iv loading, then 420 mg iv every 3 weeks. Trastuzumab [Herceptin]: 8 mg/kg iv loading, then 6 mg/kg iv every 3 weeks.
Overall Number of Participants Analyzed	224	228
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
	55.0; (48.07 to 61.85)	74.9; (69.05 to 80.68)

4. Secondary Outcome

Title	Investigator Assessment Progression-Free Survival (PFS)
Description	Investigator Assessment Progression-Free Survival (PFS) was defined as the time from randomization to the first documented progressive disease, as determined by the investigator using Response Evaluation Criteria in Solid Tumors (RECIST) v1.0, or death from any cause, whichever occurred first. PD is defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions; or the appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions.
Time Frame	Tumor assessments every 9 weeks from randomization until Week 27, then every 12 weeks thereafter, until IRF-determined PD, initiation of alternative anticancer medication, or death (up to 7.5 years).

Outcome Measure Data

Analysis Population Description

All randomized participants.

Arm/Group Title	A: Capecitabine + Trastuzumab	B: Capecitabine + Trastuzumab + Pertuzumab
Arm/Group Description:	Capecitabine [Xeloda]: 1250 mg/m2 po twice daily for 14 days every 3 weeks. Trastuzumab [Herceptin]: 8 mg/kg iv loading, then 6 mg/kg iv every 3 weeks.	Capecitabine [Xeloda]: 1000 mg/m2 po twice daily for 14 days every 3 weeks. Pertuzumab [Perjeta]: 840 mg iv loading, then 420 mg iv every 3 weeks. Trastuzumab [Herceptin]: 8 mg/kg iv loading, then 6 mg/kg iv every 3 weeks.
Overall Number of Participants Analyzed	224	228
Median (95% Confidence Interval); Unit of Measure: Months
	9.0; (8 to 12)	11.8; (9 to 14)

5. Secondary Outcome

Title	Time to Progression (TTP) Based Upon Independent Review Facility (IRF) Assessment
Description	Time to Progression (TTP) was defined as time between randomization and the first occurrence of progressive disease (PD), based on IRF assessment.
Time Frame	Tumor assessments every 9 weeks from randomization until Week 27, then every 12 weeks thereafter, until IRF-determined PD, initiation of alternative anticancer medication, or death (up to 5.5 years).

Outcome Measure Data

Analysis Population Description

All randomized participants.

Arm/Group Title	A: Capecitabine + Trastuzumab	B: Capecitabine + Trastuzumab + Pertuzumab
Arm/Group Description:	Capecitabine [Xeloda]: 1250 mg/m2 po twice daily for 14 days every 3 weeks. Trastuzumab [Herceptin]: 8 mg/kg iv loading, then 6 mg/kg iv every 3 weeks.	Capecitabine [Xeloda]: 1000 mg/m2 po twice daily for 14 days every 3 weeks. Pertuzumab [Perjeta]: 840 mg iv loading, then 420 mg iv every 3 weeks. Trastuzumab [Herceptin]: 8 mg/kg iv loading, then 6 mg/kg iv every 3 weeks.
Overall Number of Participants Analyzed	224	228
Median (95% Confidence Interval); Unit of Measure: Weeks
	39.0; (35 to 44)	50.6; (39 to 62)

6. Secondary Outcome

Title	Time to Treatment Failure (TTF) Based Upon Independent Review Facility (IRF) Assessment
Description	Time to Treatment Failure (TTF) was defined as time between randomization and date of disease progression based on independent review, death, or withdrawal of treatment due to adverse events, withdrawn informed consent, refusal of treatment/failure to cooperate, or failure to return, whichever occurred first.
Time Frame	Tumor assessments every 9 weeks from randomization until Week 27, then every 12 weeks thereafter, until IRF-determined PD, initiation of alternative anticancer medication, or death (up to 5.5 years).

Outcome Measure Data

Analysis Population Description

All randomized participants.

Arm/Group Title	A: Capecitabine + Trastuzumab	B: Capecitabine + Trastuzumab + Pertuzumab
Arm/Group Description:	Capecitabine [Xeloda]: 1250 mg/m2 po twice daily for 14 days every 3 weeks. Trastuzumab [Herceptin]: 8 mg/kg iv loading, then 6 mg/kg iv every 3 weeks.	Capecitabine [Xeloda]: 1000 mg/m2 po twice daily for 14 days every 3 weeks. Pertuzumab [Perjeta]: 840 mg iv loading, then 420 mg iv every 3 weeks. Trastuzumab [Herceptin]: 8 mg/kg iv loading, then 6 mg/kg iv every 3 weeks.
Overall Number of Participants Analyzed	224	228
Median (95% Confidence Interval); Unit of Measure: Weeks
	39.0; (34 to 44)	50.9; (39 to 62)

7. Secondary Outcome

Title	Overall Objective Response Rate (ORR)
Description	Overall Objective Response Rate is based upon investigator and IRF assessments. Objective Response Rate (ORR) was defined as the percentage of participants with a confirmed complete response (CR) or partial response (PR) among those who had measurable disease at baseline. CR was defined as the disappearance of all target lesions. PR was defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD.
Time Frame	Tumor assessments every 9 weeks from randomization until Week 27, then every 12 weeks thereafter, until IRF-determined PD, initiation of alternative anticancer medication, or death (up to 5.5 years).

Outcome Measure Data

Analysis Population Description

Participants without a post-baseline tumor assessment were considered to be non-responders and were not included in this outcome measure.

Arm/Group Title	A: Capecitabine + Trastuzumab	B: Capecitabine + Trastuzumab + Pertuzumab
Arm/Group Description:	Capecitabine [Xeloda]: 1250 mg/m2 po twice daily for 14 days every 3 weeks. Trastuzumab [Herceptin]: 8 mg/kg iv loading, then 6 mg/kg iv every 3 weeks.	Capecitabine [Xeloda]: 1000 mg/m2 po twice daily for 14 days every 3 weeks. Pertuzumab [Perjeta]: 840 mg iv loading, then 420 mg iv every 3 weeks. Trastuzumab [Herceptin]: 8 mg/kg iv loading, then 6 mg/kg iv every 3 weeks.
Overall Number of Participants Analyzed	164	163
Measure Type: Number; Unit of Measure: Percentage of participants
Complete Response (CR) - IRF Assessment	0	1.8
Partial Response (PR) - IRF assessment	32.9	38.7
Complete Response (CR) - Investigator Assessed	1.2	6.7
Partial Response (PR) - Investigator Assessed	36.0	38.0

8. Secondary Outcome

Title	Clinical Benefit Rate (CBR)
Description	Clinical Benefit Rate is based upon Independent Review Facility (IRF) assessments; defined as the percentage of participants a complete response (CR), partial response (PR), or stable disease for at least 8 cycles or 6 months.
Time Frame	Tumor assessments every 9 weeks from randomization until Week 27, then every 12 weeks thereafter, until IRF-determined PD, initiation of alternative anticancer medication, or death (up to 5.5 years).

Outcome Measure Data

Analysis Population Description

Participants without a post-baseline tumor assessment were considered to be non-responders and were not included in this outcome measure.

Arm/Group Title	A: Capecitabine + Trastuzumab	B: Capecitabine + Trastuzumab + Pertuzumab
Arm/Group Description:	Capecitabine [Xeloda]: 1250 mg/m2 po twice daily for 14 days every 3 weeks. Trastuzumab [Herceptin]: 8 mg/kg iv loading, then 6 mg/kg iv every 3 weeks.	Capecitabine [Xeloda]: 1000 mg/m2 po twice daily for 14 days every 3 weeks. Pertuzumab [Perjeta]: 840 mg iv loading, then 420 mg iv every 3 weeks. Trastuzumab [Herceptin]: 8 mg/kg iv loading, then 6 mg/kg iv every 3 weeks.
Overall Number of Participants Analyzed	224	228
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
	54.0; (47.3 to 60.7)	63.6; (57.0 to 69.8)

9. Secondary Outcome

Title	Duration of Objective Response
Description	Duration of Objective Response was defined for the subpopulation of responders as time from first Independent Review Facility (IRF)-assessed complete response (CR) or partial response (PR) to subsequent first documented, IRF-confirmed evidence of disease progression. Only participants with an objective response were included in the analysis of duration of objective response.
Time Frame	Tumor assessments every 9 weeks from randomization until Week 27, then every 12 weeks thereafter, until IRF-determined PD, initiation of alternative anticancer medication, or death (up to 5.5 years).

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	A: Capecitabine + Trastuzumab	B: Capecitabine + Trastuzumab + Pertuzumab
Arm/Group Description:	Capecitabine [Xeloda]: 1250 mg/m2 po twice daily for 14 days every 3 weeks. Trastuzumab [Herceptin]: 8 mg/kg iv loading, then 6 mg/kg iv every 3 weeks.	Capecitabine [Xeloda]: 1000 mg/m2 po twice daily for 14 days every 3 weeks. Pertuzumab [Perjeta]: 840 mg iv loading, then 420 mg iv every 3 weeks. Trastuzumab [Herceptin]: 8 mg/kg iv loading, then 6 mg/kg iv every 3 weeks.
Overall Number of Participants Analyzed	54	66
Median (95% Confidence Interval); Unit of Measure: Weeks
	30.0; (21 to 42)	51.6; (42 to 57)

Adverse Events

Time Frame	Adverse events were recorded and reported during the study and up to two years after the last dose of the study drug was received.
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	A: Capecitabine + Trastuzumab		B: Capecitabine + Trastuzumab + Pertuzumab
Arm/Group Description	Capecitabine [Xeloda]: 1250 mg/m2 po twice daily for 14 days every 3 weeks. Trastuzumab [Herceptin]: 8 mg/kg iv loading, then 6 mg/kg iv every 3 weeks.		Capecitabine [Xeloda]: 1000 mg/m2 po twice daily for 14 days every 3 weeks. Pertuzumab [Perjeta]: 840 mg iv loading, then 420 mg iv every 3 weeks. Trastuzumab [Herceptin]: 8 mg/kg iv loading, then 6 mg/kg iv every 3 weeks.
All-Cause Mortality
	A: Capecitabine + Trastuzumab		B: Capecitabine + Trastuzumab + Pertuzumab
	Affected / at Risk (%)		Affected / at Risk (%)
Total	136/218 (62.39%)		134/228 (58.77%)
Serious Adverse Events
	A: Capecitabine + Trastuzumab		B: Capecitabine + Trastuzumab + Pertuzumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	53/218 (24.31%)		58/228 (25.44%)
Blood and lymphatic system disorders
Febrile Neutropenia † 1	2/218 (0.92%)	2	1/228 (0.44%)	1
Neutropenia † 1	2/218 (0.92%)	2	1/228 (0.44%)	1
Anaemia † 1	1/218 (0.46%)	2	0/228 (0.00%)	0
Thrombocytopenia † 1	1/218 (0.46%)	1	1/228 (0.44%)	1
Pancytopenia † 1	0/218 (0.00%)	0	1/228 (0.44%)	1
Cardiac disorders
Left Ventricular Dysfunction † 1	4/218 (1.83%)	4	13/228 (5.70%)	13
Atrial Fibrillation † 1	0/218 (0.00%)	0	2/228 (0.88%)	2
Angina Unstable † 1	0/218 (0.00%)	0	1/228 (0.44%)	1
Arteriospasm Coronary † 1	1/218 (0.46%)	1	0/228 (0.00%)	0
Cardiac Arrest † 1	1/218 (0.46%)	1	0/228 (0.00%)	0
Supraventricular Extrasystoles † 1	0/218 (0.00%)	0	1/228 (0.44%)	1
Ventricular Fibrillation † 1	0/218 (0.00%)	0	1/228 (0.44%)	1
Eye disorders
Retinal Detachment † 1	0/218 (0.00%)	0	1/228 (0.44%)	1
Gastrointestinal disorders
Diarrhoea † 1	6/218 (2.75%)	6	8/228 (3.51%)	8
Nausea † 1	2/218 (0.92%)	2	1/228 (0.44%)	1
Vomiting † 1	2/218 (0.92%)	2	1/228 (0.44%)	1
Abdominal Hernia † 1	0/218 (0.00%)	0	1/228 (0.44%)	1
Colitis † 1	0/218 (0.00%)	0	1/228 (0.44%)	1
Diverticulum † 1	1/218 (0.46%)	1	0/228 (0.00%)	0
Dysphagia † 1	0/218 (0.00%)	0	1/228 (0.44%)	1
Gastric Perforation † 1	1/218 (0.46%)	1	0/228 (0.00%)	0
Gastric Ulcer † 1	1/218 (0.46%)	1	0/228 (0.00%)	0
Ileus † 1	1/218 (0.46%)	1	0/228 (0.00%)	0
Subileus † 1	0/218 (0.00%)	0	1/228 (0.44%)	1
General disorders
General Physical Health Deterioration † 1	2/218 (0.92%)	2	2/228 (0.88%)	2
Pyrexia † 1	2/218 (0.92%)	2	2/228 (0.88%)	2
Chest Pain † 1	0/218 (0.00%)	0	1/228 (0.44%)	1
Device Related Thrombosis † 1	0/218 (0.00%)	0	1/228 (0.44%)	1
Hepatobiliary disorders
Cholecystitis † 1	1/218 (0.46%)	1	1/228 (0.44%)	1
Hyperbilirubinaemia † 1	1/218 (0.46%)	1	0/228 (0.00%)	0
Immune system disorders
Anaphylactic Shock † 1	0/218 (0.00%)	0	1/228 (0.44%)	1
Infections and infestations
Sepsis † 1	2/218 (0.92%)	2	0/228 (0.00%)	0
Appendicitis † 1	1/218 (0.46%)	1	0/228 (0.00%)	0
Bacteraemia † 1	1/218 (0.46%)	1	0/228 (0.00%)	0
Catheter Site Infection † 1	1/218 (0.46%)	1	0/228 (0.00%)	0
Cellulitis † 1	0/218 (0.00%)	0	1/228 (0.44%)	1
Clostridium Difficile Colitis † 1	0/218 (0.00%)	0	1/228 (0.44%)	1
Device Related Infection † 1	1/218 (0.46%)	1	0/228 (0.00%)	0
Gastroenteritis † 1	1/218 (0.46%)	1	0/228 (0.00%)	0
Phlebitis Infective † 1	1/218 (0.46%)	1	0/228 (0.00%)	0
Pneumonia † 1	1/218 (0.46%)	1	1/228 (0.44%)	1
Pulmonary Tuberculosis † 1	0/218 (0.00%)	0	1/228 (0.44%)	1
Respiratory Tract Infection † 1	1/218 (0.46%)	1	0/228 (0.00%)	0
Urinary Tract Infection † 1	0/218 (0.00%)	0	1/228 (0.44%)	1
Injury, poisoning and procedural complications
Femur Fracture † 1	2/218 (0.92%)	2	2/228 (0.88%)	2
Infusion Related Reaction † 1	0/218 (0.00%)	0	2/228 (0.88%)	2
Acetabulum Fracture † 1	0/218 (0.00%)	0	1/228 (0.44%)	1
Bone Fissure † 1	0/218 (0.00%)	0	1/228 (0.44%)	1
Craniocerebral Injury † 1	0/218 (0.00%)	0	1/228 (0.44%)	1
Facial Bones Fracture † 1	1/218 (0.46%)	1	0/228 (0.00%)	0
Fracture † 1	0/218 (0.00%)	0	1/228 (0.44%)	1
Hip Fracture † 1	1/218 (0.46%)	1	0/228 (0.00%)	0
Joint Dislocation † 1	1/218 (0.46%)	1	0/228 (0.00%)	0
Lumbar Vertebral Fracture † 1	1/218 (0.46%)	1	0/228 (0.00%)	0
Meniscus Injury † 1	1/218 (0.46%)	1	0/228 (0.00%)	0
Subdural Haematoma † 1	1/218 (0.46%)	1	0/228 (0.00%)	0
Synovial Rupture † 1	0/218 (0.00%)	0	1/228 (0.44%)	1
Wrist Fracture † 1	1/218 (0.46%)	1	0/228 (0.00%)	0
Subarachnoid Haemorrhage † 1	1/218 (0.46%)	1	0/228 (0.00%)	0
Investigations
Blood Sodium Decreased † 1	1/218 (0.46%)	1	0/228 (0.00%)	0
Metabolism and nutrition disorders
Hypokalaemia † 1	0/218 (0.00%)	0	1/228 (0.44%)	1
Musculoskeletal and connective tissue disorders
Back Pain † 1	1/218 (0.46%)	1	2/228 (0.88%)	2
Bone Pain † 1	0/218 (0.00%)	0	1/228 (0.44%)	1
Joint Swelling † 1	1/218 (0.46%)	1	0/228 (0.00%)	0
Osteitis † 1	0/218 (0.00%)	0	1/228 (0.44%)	1
Osteonecrosis † 1	0/218 (0.00%)	0	1/228 (0.44%)	1
Pain in Extremity † 1	1/218 (0.46%)	1	0/228 (0.00%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute Myeloid Leukaemia † 1	1/218 (0.46%)	1	0/228 (0.00%)	0
Acute Promyelocytic Leukaemia † 1	0/218 (0.00%)	0	1/228 (0.44%)	1
Cervix Carcinoma † 1	1/218 (0.46%)	1	0/228 (0.00%)	0
Breast Cancer † 1	1/218 (0.46%)	1	0/228 (0.00%)	0
Nervous system disorders
Syncope † 1	2/218 (0.92%)	2	1/228 (0.44%)	1
Dizziness † 1	1/218 (0.46%)	1	1/228 (0.44%)	1
Hemiparesis † 1	1/218 (0.46%)	1	0/228 (0.00%)	0
Ischaemic Stroke † 1	1/218 (0.46%)	1	0/228 (0.00%)	0
Sciatica † 1	0/218 (0.00%)	0	1/228 (0.44%)	1
Secondary Cerebellar Degeneration † 1	1/218 (0.46%)	1	0/228 (0.00%)	0
Status Epilepticus † 1	0/218 (0.00%)	0	1/228 (0.44%)	1
Psychiatric disorders
Delirium † 1	1/218 (0.46%)	1	0/228 (0.00%)	0
Depression † 1	0/218 (0.00%)	0	1/228 (0.44%)	1
Renal and urinary disorders
Ureteric Stenosis † 1	1/218 (0.46%)	1	0/228 (0.00%)	0
Reproductive system and breast disorders
Endometrial Hyperplasia † 1	0/218 (0.00%)	0	1/228 (0.44%)	1
Respiratory, thoracic and mediastinal disorders
Pulmonary Embolism † 1	4/218 (1.83%)	4	3/228 (1.32%)	4
Pulmonary Thrombosis † 1	0/218 (0.00%)	0	2/228 (0.88%)	2
Dyspnoea † 1	1/218 (0.46%)	1	0/228 (0.00%)	0
Skin and subcutaneous tissue disorders
Palmar-Plantar Erythrodysaesthesia Syndrome † 1	1/218 (0.46%)	1	1/228 (0.44%)	1
Rash † 1	0/218 (0.00%)	0	1/228 (0.44%)	1
Vascular disorders
Vena Cava Thrombosis † 1	1/218 (0.46%)	1	2/228 (0.88%)	2
Hypertension † 1	1/218 (0.46%)	1	0/228 (0.00%)	0
Thrombophlebitis Superficial † 1	1/218 (0.46%)	1	0/228 (0.00%)	0
Venous Thrombosis † 1	1/218 (0.46%)	1	0/228 (0.00%)	0
1 Term from vocabulary, MedDRA (20.0); † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	A: Capecitabine + Trastuzumab		B: Capecitabine + Trastuzumab + Pertuzumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	209/218 (95.87%)		216/228 (94.74%)
Blood and lymphatic system disorders
Neutropenia † 1	38/218 (17.43%)	89	29/228 (12.72%)	74
Anaemia † 1	17/218 (7.80%)	23	21/228 (9.21%)	28
Cardiac disorders
Left Ventricular Dysfunction † 1	5/218 (2.29%)	5	13/228 (5.70%)	15
Eye disorders
Lacrimation Increased † 1	13/218 (5.96%)	17	6/228 (2.63%)	8
Gastrointestinal disorders
Diarrhoea † 1	128/218 (58.72%)	275	157/228 (68.86%)	436
Nausea † 1	97/218 (44.50%)	152	88/228 (38.60%)	129
Vomiting † 1	45/218 (20.64%)	56	37/228 (16.23%)	58
Stomatitis † 1	32/218 (14.68%)	39	41/228 (17.98%)	60
Abdominal Pain † 1	30/218 (13.76%)	36	28/228 (12.28%)	50
Abdominal Pain Upper † 1	24/218 (11.01%)	31	29/228 (12.72%)	45
Dyspepsia † 1	22/218 (10.09%)	23	24/228 (10.53%)	33
Constipation † 1	21/218 (9.63%)	27	18/228 (7.89%)	22
General disorders
Asthenia † 1	51/218 (23.39%)	87	47/228 (20.61%)	77
Fatigue † 1	39/218 (17.89%)	59	44/228 (19.30%)	62
Mucosal Inflammation † 1	27/218 (12.39%)	36	32/228 (14.04%)	45
Pyrexia † 1	20/218 (9.17%)	24	29/228 (12.72%)	41
Oedema Peripheral † 1	13/218 (5.96%)	13	18/228 (7.89%)	19
Chest Pain † 1	12/218 (5.50%)	15	9/228 (3.95%)	11
Infections and infestations
Viral Upper Respiratory Tract Infection † 1	12/218 (5.50%)	15	25/228 (10.96%)	37
Urinary Tract Infection † 1	17/218 (7.80%)	20	21/228 (9.21%)	28
Upper Respiratory Tract Infection † 1	9/218 (4.13%)	12	19/228 (8.33%)	46
Paronychia † 1	11/218 (5.05%)	15	15/228 (6.58%)	16
Influenza † 1	4/218 (1.83%)	5	12/228 (5.26%)	12
Investigations
Weight Decreased † 1	13/218 (5.96%)	14	19/228 (8.33%)	20
Aspartate Aminotransferase Increased † 1	11/218 (5.05%)	15	17/228 (7.46%)	26
Alanine Aminotransferase Increased † 1	8/218 (3.67%)	11	17/228 (7.46%)	24
Metabolism and nutrition disorders
Decreased Appetite † 1	28/218 (12.84%)	43	36/228 (15.79%)	43
Hypokalaemia † 1	13/218 (5.96%)	19	28/228 (12.28%)	40
Musculoskeletal and connective tissue disorders
Pain in Extremity † 1	15/218 (6.88%)	24	27/228 (11.84%)	32
Arthralgia † 1	17/218 (7.80%)	19	21/228 (9.21%)	27
Back Pain † 1	18/218 (8.26%)	23	20/228 (8.77%)	23
Muscle Spasms † 1	12/218 (5.50%)	20	17/228 (7.46%)	21
Bone Pain † 1	12/218 (5.50%)	16	8/228 (3.51%)	9
Myalgia † 1	6/218 (2.75%)	8	12/228 (5.26%)	19
Musculoskeletal Chest Pain † 1	5/218 (2.29%)	7	12/228 (5.26%)	13
Nervous system disorders
Headache † 1	39/218 (17.89%)	68	40/228 (17.54%)	52
Dizziness † 1	21/218 (9.63%)	28	24/228 (10.53%)	26
Neuropathy Peripheral † 1	14/218 (6.42%)	17	16/228 (7.02%)	17
Paraesthesia † 1	13/218 (5.96%)	15	9/228 (3.95%)	9
Psychiatric disorders
Insomnia † 1	12/218 (5.50%)	17	23/228 (10.09%)	27
Respiratory, thoracic and mediastinal disorders
Cough † 1	22/218 (10.09%)	27	30/228 (13.16%)	38
Dyspnoea † 1	24/218 (11.01%)	28	21/228 (9.21%)	25
Epistaxis † 1	9/218 (4.13%)	9	12/228 (5.26%)	14
Skin and subcutaneous tissue disorders
Palmar-Plantar Erythrodysaesthesia Syndrome † 1	159/218 (72.94%)	242	129/228 (56.58%)	179
Rash † 1	11/218 (5.05%)	12	35/228 (15.35%)	45
Pruritus † 1	7/218 (3.21%)	7	21/228 (9.21%)	29
Dry Skin † 1	9/218 (4.13%)	10	16/228 (7.02%)	17
Nail Disorder † 1	8/218 (3.67%)	8	14/228 (6.14%)	15
Alopecia † 1	11/218 (5.05%)	12	6/228 (2.63%)	6
Vascular disorders
Hypertension † 1	14/218 (6.42%)	18	19/228 (8.33%)	19
1 Term from vocabulary, MedDRA (20.0); † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.

Results Point of Contact

• Name/Title: Medical Communications
• Organization: Hoffmann-La Roche
• Phone: 800 821-8590
• EMail: genentech@druginfo.com

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT01026142 History of Changes
• Other Study ID Numbers: MO22324; 2008-006801-17 ( EudraCT Number )
• First Submitted: November 27, 2009
• First Posted: December 4, 2009
• Results First Submitted: August 17, 2016
• Results First Posted: October 13, 2016
• Last Update Posted: August 14, 2018