A Study of Pertuzumab in Combination With Herceptin and Chemotherapy in Participants With HER2-Positive Breast Cancer

• ClinicalTrials.gov Identifier: NCT00976989
• Recruitment Status: Completed
• First Posted: September 15, 2009
• Results First Posted: June 20, 2016
• Last Update Posted: February 6, 2017
• 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: Pertuzumab; Drug: Trastuzumab; Drug: FEC; Drug: Docetaxel; Drug: TCH
• Enrollment: 225

Participant Flow

Recruitment Details	This study included 3 periods: Neoadjuvant (pre-operative) period and surgery, adjuvant (post-operative) period and post-treatment follow-up period.
Pre-assignment Details

Arm/Group Title	T+P Concomitant Anthracycline-based Chemotherapy	T+P Sequential Anthracycline-based Chemotherapy	T+P Concomitant Non-Anthracycline Chemotherapy
Arm/Group Description	5-Fluorouracil, epirubicin with cyclophosphamide (FEC), trastuzumab and pertuzumab every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.	FEC every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 21 as adjuvant therapy post-surgery.	Trastuzumab, carboplatin, docetaxel (TCH) and pertuzumab every three weeks, for six cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.
Period Title: Overall Study
Started	73	75	77
Completed	60	63	60
Not Completed	13	12	17
Reason Not Completed
Violation of Selection Criteria at Entry	1	0	1
Death	5	7	10
Refused Treatment	4	3	5
Failure to Return	2	1	0
Recurrence of Disease	0	1	0
Other	1	0	1

Baseline Characteristics

Arm/Group Title		T+P Concomitant Anthracycline-based Chemotherapy	T+P Sequential Anthracycline-based Chemotherapy	T+P Concomitant Non-Anthracycline Chemotherapy	Total
Arm/Group Description		5-Fluorouracil, epirubicin with cyclophosphamide (FEC), trastuzumab and pertuzumab every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.	FEC every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 21 as adjuvant therapy post-surgery.	Trastuzumab, carboplatin, docetaxel (TCH) and pertuzumab every three weeks, for six cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.	Total of all reporting groups
Overall Number of Baseline Participants		73	75	77	225
Baseline Analysis Population Description		Safety population included all participants who were randomized and received study drug.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	73 participants	75 participants	77 participants	225 participants
		49.6 (11.41)	50.5 (10.70)	50.6 (10.58)	50.6 (10.86)
Gender; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	73 participants	75 participants	77 participants	225 participants
	Female	73 100.0%	75 100.0%	77 100.0%	225 100.0%
	Male	0 0.0%	0 0.0%	0 0.0%	0 0.0%

Outcome Measures

1. Primary Outcome

Title	Safety: Percentage of Participants With Symptomatic Cardiac Events as Assessed by the Investigator
Description	Left ventricular systolic dysfunction (LVSD) as assessed by the Investigator, including Grade 3, 4 or 5 symptomatic LVSD with symptomatic cardiac events.
Time Frame	From baseline up to approximately 3.5 years

Outcome Measure Data

Analysis Population Description

Safety population included all participants who were randomized and received study drug.

Arm/Group Title	T+P Concomitant Anthracycline-based Chemotherapy	T+P Sequential Anthracycline-based Chemotherapy	T+P Concomitant Non-Anthracycline Chemotherapy
Arm/Group Description:	5-Fluorouracil, epirubicin with cyclophosphamide (FEC), trastuzumab and pertuzumab every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.	FEC every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 21 as adjuvant therapy post-surgery.	Trastuzumab, carboplatin, docetaxel (TCH) and pertuzumab every three weeks, for six cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.
Overall Number of Participants Analyzed	72	75	76
Measure Type: Number; Unit of Measure: percentage of participants
	0	2.7	1.3

2. Primary Outcome

Title	Safety: Percentage of Participants With Left Ventricular Ejection Fraction (LVEF) Decline During Pre-operative (Neoadjuvant) Period
Description	Percentage of participants with LVEF measures decline of ≥ 10% from baseline and to a value of <50% during the pre-operative (neoadjuvant) period.
Time Frame	From baseline up to approximately 18 weeks

Outcome Measure Data

Analysis Population Description

Safety population included all participants who were randomized and received study drug.

Arm/Group Title	T+P Concomitant Anthracycline-based Chemotherapy	T+P Sequential Anthracycline-based Chemotherapy	T+P Concomitant Non-Anthracycline Chemotherapy
Arm/Group Description:	5-Fluorouracil, epirubicin with cyclophosphamide (FEC), trastuzumab and pertuzumab every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.	FEC every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 21 as adjuvant therapy post-surgery.	Trastuzumab, carboplatin, docetaxel (TCH) and pertuzumab every three weeks, for six cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.
Overall Number of Participants Analyzed	72	75	76
Measure Type: Number; Unit of Measure: percentage of participants
	5.6	5.3	3.9

3. Secondary Outcome

Title	Efficacy: Percentage of Participants With Complete Pathological Response (pCR)
Description	pCR is defined as the absence of invasive neoplastic cells at microscopic examination of the tumor remnants after surgery following primary systemic therapy. pCR is evaluated after 6 cycles of treatment and surgery or following withdrawal from the study whichever occurs sooner.
Time Frame	At surgery, after 18 weeks (6 cycles) of treatment

Outcome Measure Data

Analysis Population Description

Intent to treat (ITT) population included all participants who were randomized to treatment.

Arm/Group Title	T+P Concomitant Anthracycline-based Chemotherapy	T+P Sequential Anthracycline-based Chemotherapy	T+P Concomitant Non-Anthracycline Chemotherapy
Arm/Group Description:	5-Fluorouracil, epirubicin with cyclophosphamide (FEC), trastuzumab and pertuzumab every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.	FEC every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 21 as adjuvant therapy post-surgery.	Trastuzumab, carboplatin, docetaxel (TCH) and pertuzumab every three weeks, for six cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.
Overall Number of Participants Analyzed	73	75	77
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	61.6; (49.5 to 72.8)	57.3; (45.4 to 68.7)	66.2; (54.6 to 76.6)

4. Secondary Outcome

Title	Efficacy: Clinical Response Rate
Description	Tumor response is defined as complete response (CR), partial response (PR), stable disease (SD) or progressive disease (PD) and is identified as per local practice. Clinical response rate is defined as the percentage of participants who achieve a response of CR or PR at any time pre-surgery. Per Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by mammogram or magnetic resonance imaging (MRI) and clinical breast examination (CBE), CR is disappearance of all target lesions; PR is >=30% decrease in the sum of the longest diameter of target lesions.
Time Frame	During each 3-week cycle of 6 total cycles: up to 18 weeks

Outcome Measure Data

Analysis Population Description

ITT population included all participants who were randomized to treatment.

Arm/Group Title	T+P Concomitant Anthracycline-based Chemotherapy	T+P Sequential Anthracycline-based Chemotherapy	T+P Concomitant Non-Anthracycline Chemotherapy
Arm/Group Description:	5-Fluorouracil, epirubicin with cyclophosphamide (FEC), trastuzumab and pertuzumab every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.	FEC every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 21 as adjuvant therapy post-surgery.	Trastuzumab, carboplatin, docetaxel (TCH) and pertuzumab every three weeks, for six cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.
Overall Number of Participants Analyzed	73	75	77
Measure Type: Number; Unit of Measure: percentage of participants
	91.8	94.7	89.6

5. Secondary Outcome

Title	Efficacy: Time to Clinical Response
Description	Time to clinical response is defined as the time from the date of first dose received to the first date of assessment of clinical response. Clinical response is defined as a response of CR or PR at any time pre-surgery. Per RECIST v1.0 for target lesions and assessed by mammogram or MRI and CBE, CR is disappearance of all target lesions; PR is >=30% decrease in the sum of the longest diameter of target lesions.
Time Frame	Up to 18 weeks

Outcome Measure Data

Analysis Population Description

ITT population included all participants who were randomized to treatment.

Arm/Group Title	T+P Concomitant Anthracycline-based Chemotherapy	T+P Sequential Anthracycline-based Chemotherapy	T+P Concomitant Non-Anthracycline Chemotherapy
Arm/Group Description:	5-Fluorouracil, epirubicin with cyclophosphamide (FEC), trastuzumab and pertuzumab every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.	FEC every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 21 as adjuvant therapy post-surgery.	Trastuzumab, carboplatin, docetaxel (TCH) and pertuzumab every three weeks, for six cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.
Overall Number of Participants Analyzed	73	75	77
Median (95% Confidence Interval); Unit of Measure: weeks
	3.6; (3 to 6)	6.3; (6 to 7)	4.9; (4 to 6)

6. Secondary Outcome

Title	Efficacy: Percentage of Participants Achieving Breast Conserving Surgery
Description	This is the percentage of participants who achieved breast conserving surgery out of the intent-to-treat population without inflammatory breast cancer, as these participants received mastectomy irrespective of their response to neoadjuvant (pre-operative) treatment.
Time Frame	At approximately 18 weeks

Outcome Measure Data

Analysis Population Description

Number of participants analyzed represents the participants with T2-3 tumors for whom mastectomy was planned.

Arm/Group Title	T+P Concomitant Anthracycline-based Chemotherapy	T+P Sequential Anthracycline-based Chemotherapy	T+P Concomitant Non-Anthracycline Chemotherapy
Arm/Group Description:	5-Fluorouracil, epirubicin with cyclophosphamide (FEC), trastuzumab and pertuzumab every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.	FEC every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 21 as adjuvant therapy post-surgery.	Trastuzumab, carboplatin, docetaxel (TCH) and pertuzumab every three weeks, for six cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.
Overall Number of Participants Analyzed	46	36	37
Measure Type: Number; Unit of Measure: percentage of participants
	21.7	16.7	27.0

7. Secondary Outcome

Title	Efficacy: Percentage of Participants Without an Overall Survival (OS) Event
Description	Overall survival (OS) was defined as the time from randomization to the date of death from any cause. Participants who were alive or lost to follow-up were censored at the last known alive date. Participants with no post-baseline information were censored at the date of randomization plus one day.
Time Frame	From baseline to end of study up to 5 years

Outcome Measure Data

Analysis Population Description

ITT population included all participants who were randomized to treatment.

Arm/Group Title	T+P Concomitant Anthracycline-based Chemotherapy	T+P Sequential Anthracycline-based Chemotherapy	T+P Concomitant Non-Anthracycline Chemotherapy
Arm/Group Description:	5-Fluorouracil, epirubicin with cyclophosphamide (FEC), trastuzumab and pertuzumab every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.	FEC every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 21 as adjuvant therapy post-surgery.	Trastuzumab, carboplatin, docetaxel (TCH) and pertuzumab every three weeks, for six cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.
Overall Number of Participants Analyzed	73	75	77
Measure Type: Number; Unit of Measure: percentage of participants
	93.2	90.7	87.0

8. Secondary Outcome

Title	Efficacy: Percentage of Participants Without a Disease-Free Survival (DFS) Event
Description	The DFS was defined as the time from the first date of no disease (i.e., date of surgery) to the first documentation of progressive disease (PD) or death. PD was assessed using RECIST v1.0 and MRI and CBE. It was defined as at least a 20% increase in the sum of diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions. Any evidence of contralateral disease in situ was not considered as PD. Participants who were withdrawn from the study without documented PD were censored at the date of the last assessment when the participant was known to be disease-free.
Time Frame	From baseline to end of study up to 5 years

Outcome Measure Data

Analysis Population Description

ITT population included all participants who were randomized to treatment. Number of participants analyzed is total number of participants evaluable during each period.

Arm/Group Title	T+P Concomitant Anthracycline-based Chemotherapy	T+P Sequential Anthracycline-based Chemotherapy	T+P Concomitant Non-Anthracycline Chemotherapy
Arm/Group Description:	5-Fluorouracil, epirubicin with cyclophosphamide (FEC), trastuzumab and pertuzumab every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.	FEC every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 21 as adjuvant therapy post-surgery.	Trastuzumab, carboplatin, docetaxel (TCH) and pertuzumab every three weeks, for six cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.
Overall Number of Participants Analyzed	69	67	72
Measure Type: Number; Unit of Measure: percentage of participants
	85.5	88.1	84.7

9. Secondary Outcome

Title	Efficacy: Percentage of Participants Without a Progression-Free Survival (PFS) Event
Description	Progression-free survival was defined as the time from the date of randomization to the first documentation of PD or death from any cause, whichever occurred first. PD was assessed using RECIST v1.0 and MRI and CBE. It was defined as at least a 20% increase in the sum of diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions. Participants who were withdrawn from the study without documented PD were censored at the date of the last assessment when the participant was known to be free from PD. Participants without post-baseline assessments but known to be alive were censored at the time of randomization plus one day.
Time Frame	From baseline to end of study up to 5 years

Outcome Measure Data

Analysis Population Description

ITT population included all participants who were randomized to treatment.

Arm/Group Title	T+P Concomitant Anthracycline-based Chemotherapy	T+P Sequential Anthracycline-based Chemotherapy	T+P Concomitant Non-Anthracycline Chemotherapy
Arm/Group Description:	5-Fluorouracil, epirubicin with cyclophosphamide (FEC), trastuzumab and pertuzumab every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.	FEC every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 21 as adjuvant therapy post-surgery.	Trastuzumab, carboplatin, docetaxel (TCH) and pertuzumab every three weeks, for six cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.
Overall Number of Participants Analyzed	73	75	77
Measure Type: Number; Unit of Measure: percentage of participants
	86.3	85.3	81.8

10. Secondary Outcome

Title	Safety: Percentage of Participants With Cardiac Symptoms Associated With Symptomatic Left Ventricular Systolic Dysfunction (LVSD)
Description	Percentage of participants with signs or symptoms of cardiac events.
Time Frame	From Baseline to end of Neoadjuvant Period (up to 18 weeks), Adjuvant Period (up to 1.5 years), Follow-up Period (up to 3.5 years)

Outcome Measure Data

Analysis Population Description

Safety analysis population included all randomized participants who received treatment. Number of participants analyzed is total number of participants evaluable during each period.

Arm/Group Title	T+P Concomitant Anthracycline-based Chemotherapy	T+P Sequential Anthracycline-based Chemotherapy	T+P Concomitant Non-Anthracycline Chemotherapy
Arm/Group Description:	5-Fluorouracil, epirubicin with cyclophosphamide (FEC), trastuzumab and pertuzumab every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.	FEC every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 21 as adjuvant therapy post-surgery.	Trastuzumab, carboplatin, docetaxel (TCH) and pertuzumab every three weeks, for six cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.
Overall Number of Participants Analyzed	72	75	76
Measure Type: Number; Unit of Measure: percentage of participants
Neoadjuvant Period (n=72, 75, 76)	1.4	2.7	0
Adjuvant Period (n= 68, 65, 67)	0	0	1.5
Follow-up Period (n=70, 75, 74)	0	1.3	0

11. Secondary Outcome

Title	Safety: Percentage of Participants With Asymptomatic Left Ventricular Ejection Fraction (LVEF) Events
Description	Percentage of participants with LVEF events without signs or symptoms of cardiac events.
Time Frame	From baseline to end of Neoadjuvant Period (up to 18 weeks), Adjuvant Period (up to 1.5 years), Follow-up Period (up to 3.5 years)

Outcome Measure Data

Analysis Population Description

Safety analysis population included all randomized participants who received treatment. Number of participants analyzed is total number of participants evaluable during each period.

Arm/Group Title	T+P Concomitant Anthracycline-based Chemotherapy	T+P Sequential Anthracycline-based Chemotherapy	T+P Concomitant Non-Anthracycline Chemotherapy
Arm/Group Description:	5-Fluorouracil, epirubicin with cyclophosphamide (FEC), trastuzumab and pertuzumab every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.	FEC every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 21 as adjuvant therapy post-surgery.	Trastuzumab, carboplatin, docetaxel (TCH) and pertuzumab every three weeks, for six cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.
Overall Number of Participants Analyzed	72	75	76
Measure Type: Number; Unit of Measure: percentage of participants
Neoadjuvant Period (n=72, 75, 76)	5.6	4.0	2.6
Adjuvant Period (n= 66, 64, 63)	3.0	0	4.8
Follow-up Period (n=21, 18, 23)	0	11.1	4.3

12. Secondary Outcome

Title	Safety: Maximum Decrease in Left Ventricular Ejection Fraction (LVEF) Measures
Description	Maximum decrease in LVEF measures is the change from baseline at worst treatment value. LVEF is measured as percentage.
Time Frame	From baseline up to approximately 3.5 years

Outcome Measure Data

Analysis Population Description

Safety analysis population included all randomized participants who received treatment. Number of participants analyzed is total number of participants evaluable.

Arm/Group Title	T+P Concomitant Anthracycline-based Chemotherapy	T+P Sequential Anthracycline-based Chemotherapy	T+P Concomitant Non-Anthracycline Chemotherapy
Arm/Group Description:	5-Fluorouracil, epirubicin with cyclophosphamide (FEC), trastuzumab and pertuzumab every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.	FEC every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 21 as adjuvant therapy post-surgery.	Trastuzumab, carboplatin, docetaxel (TCH) and pertuzumab every three weeks, for six cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.
Overall Number of Participants Analyzed	71	72	73
Mean (Standard Deviation); Unit of Measure: percentage (ejection fraction)
	-6.6 (5.15)	-8.4 (5.66)	-7.0 (6.48)

Adverse Events

Time Frame	Up to approximately 5 years
Adverse Event Reporting Description	Safety population included all participants who were randomized and received study drug.
Arm/Group Title	T+P Concomitant Anthracycline-based Chemotherapy	T+P Sequential Anthracycline-based Chemotherapy	T+P Concomitant Non-Anthracycline Chemotherapy
Arm/Group Description	5-Fluorouracil, epirubicin with cyclophosphamide (FEC), trastuzumab and pertuzumab every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.	FEC every three weeks for three cycles, followed by docetaxel, trastuzumab and pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 21 as adjuvant therapy post-surgery.	Trastuzumab, carboplatin, docetaxel (TCH) and pertuzumab every three weeks, for six cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery.
All-Cause Mortality
	T+P Concomitant Anthracycline-based Chemotherapy	T+P Sequential Anthracycline-based Chemotherapy	T+P Concomitant Non-Anthracycline Chemotherapy
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--	--/--
Serious Adverse Events
	T+P Concomitant Anthracycline-based Chemotherapy	T+P Sequential Anthracycline-based Chemotherapy	T+P Concomitant Non-Anthracycline Chemotherapy
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	23/72 (31.94%)	18/75 (24.00%)	31/76 (40.79%)
Blood and lymphatic system disorders
Febrile Neutropenia † 1	10/72 (13.89%)	4/75 (5.33%)	11/76 (14.47%)
Neutropenia † 1	2/72 (2.78%)	3/75 (4.00%)	1/76 (1.32%)
Leukopenia † 1	2/72 (2.78%)	0/75 (0.00%)	0/76 (0.00%)
Thrombocytopenia † 1	0/72 (0.00%)	0/75 (0.00%)	2/76 (2.63%)
Cardiac disorders
Left ventricular dysfunction † 1	1/72 (1.39%)	3/75 (4.00%)	1/76 (1.32%)
Cardiovascular disorder † 1	0/72 (0.00%)	0/75 (0.00%)	1/76 (1.32%)
Conduction disorder † 1	0/72 (0.00%)	0/75 (0.00%)	1/76 (1.32%)
Gastrointestinal disorders
Diarrhoea † 1	1/72 (1.39%)	3/75 (4.00%)	4/76 (5.26%)
Vomiting † 1	0/72 (0.00%)	2/75 (2.67%)	0/76 (0.00%)
Nausea † 1	0/72 (0.00%)	1/75 (1.33%)	0/76 (0.00%)
Small intestinal obstruction † 1	0/72 (0.00%)	0/75 (0.00%)	1/76 (1.32%)
General disorders
Mucosal inflammation † 1	0/72 (0.00%)	0/75 (0.00%)	2/76 (2.63%)
Chest pain † 1	0/72 (0.00%)	0/75 (0.00%)	1/76 (1.32%)
General physical health deterioration † 1	0/72 (0.00%)	0/75 (0.00%)	1/76 (1.32%)
Pyrexia † 1	1/72 (1.39%)	0/75 (0.00%)	0/76 (0.00%)
Immune system disorders
Drug hypersensitivity † 1	1/72 (1.39%)	0/75 (0.00%)	2/76 (2.63%)
Anaphylactic reaction † 1	0/72 (0.00%)	0/75 (0.00%)	1/76 (1.32%)
Infections and infestations
Pneumonia † 1	2/72 (2.78%)	0/75 (0.00%)	2/76 (2.63%)
Neutropenic infection † 1	0/72 (0.00%)	2/75 (2.67%)	1/76 (1.32%)
Wound infection † 1	0/72 (0.00%)	1/75 (1.33%)	1/76 (1.32%)
Anal abscess † 1	1/72 (1.39%)	0/75 (0.00%)	0/76 (0.00%)
Appendicitis † 1	0/72 (0.00%)	1/75 (1.33%)	0/76 (0.00%)
Catheter site infection † 1	0/72 (0.00%)	0/75 (0.00%)	1/76 (1.32%)
Clostridium difficile colitis † 1	0/72 (0.00%)	0/75 (0.00%)	1/76 (1.32%)
Clostridium difficile infection † 1	1/72 (1.39%)	0/75 (0.00%)	0/76 (0.00%)
Cystitis † 1	1/72 (1.39%)	0/75 (0.00%)	0/76 (0.00%)
Device related infection † 1	0/72 (0.00%)	1/75 (1.33%)	0/76 (0.00%)
Device related sepsis † 1	0/72 (0.00%)	1/75 (1.33%)	0/76 (0.00%)
Gastroenteritis † 1	0/72 (0.00%)	1/75 (1.33%)	0/76 (0.00%)
Infection † 1	0/72 (0.00%)	1/75 (1.33%)	0/76 (0.00%)
Lung Abscess † 1	1/72 (1.39%)	0/75 (0.00%)	0/76 (0.00%)
Neutropenic sepsis † 1	0/72 (0.00%)	0/75 (0.00%)	1/76 (1.32%)
Pseudomembranous colitis † 1	1/72 (1.39%)	0/75 (0.00%)	0/76 (0.00%)
Pyelonephritis † 1	0/72 (0.00%)	0/75 (0.00%)	1/76 (1.32%)
Urinary tract infection † 1	1/72 (1.39%)	0/75 (0.00%)	0/76 (0.00%)
Injury, poisoning and procedural complications
Post procedural haematoma † 1	0/72 (0.00%)	0/75 (0.00%)	1/76 (1.32%)
Seroma † 1	0/72 (0.00%)	1/75 (1.33%)	0/76 (0.00%)
Metabolism and nutrition disorders
Dehydration † 1	0/72 (0.00%)	1/75 (1.33%)	1/76 (1.32%)
Electrolyte imbalance † 1	0/72 (0.00%)	0/75 (0.00%)	1/76 (1.32%)
Hypokalaemia † 1	0/72 (0.00%)	0/75 (0.00%)	1/76 (1.32%)
Hypomagnesaemia † 1	0/72 (0.00%)	0/75 (0.00%)	1/76 (1.32%)
Hyponatraemia † 1	0/72 (0.00%)	1/75 (1.33%)	0/76 (0.00%)
Musculoskeletal and connective tissue disorders
Musculoskeletal pain † 1	1/72 (1.39%)	0/75 (0.00%)	0/76 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Metastatic neoplasm † 1	1/72 (1.39%)	0/75 (0.00%)	0/76 (0.00%)
Nervous system disorders
Cerebrovascular accident † 1	0/72 (0.00%)	0/75 (0.00%)	1/76 (1.32%)
Epilepsy † 1	0/72 (0.00%)	0/75 (0.00%)	1/76 (1.32%)
Psychiatric disorders
Panic attack † 1	0/72 (0.00%)	1/75 (1.33%)	0/76 (0.00%)
Reproductive system and breast disorders
Breast mass † 1	0/72 (0.00%)	1/75 (1.33%)	0/76 (0.00%)
Breast necrosis † 1	1/72 (1.39%)	0/75 (0.00%)	0/76 (0.00%)
Ovarian cyst † 1	0/72 (0.00%)	1/75 (1.33%)	0/76 (0.00%)
Vaginal haemorrhage † 1	1/72 (1.39%)	0/75 (0.00%)	0/76 (0.00%)
Respiratory, thoracic and mediastinal disorders
Epistaxis † 1	0/72 (0.00%)	0/75 (0.00%)	1/76 (1.32%)
Pneumonitis † 1	0/72 (0.00%)	1/75 (1.33%)	0/76 (0.00%)
Pulmonary embolism † 1	1/72 (1.39%)	0/75 (0.00%)	0/76 (0.00%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA (18.1)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	T+P Concomitant Anthracycline-based Chemotherapy	T+P Sequential Anthracycline-based Chemotherapy	T+P Concomitant Non-Anthracycline Chemotherapy
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	72/72 (100.00%)	73/75 (97.33%)	76/76 (100.00%)
Blood and lymphatic system disorders
Neutropenia † 1	36/72 (50.00%)	33/75 (44.00%)	37/76 (48.68%)
Anaemia † 1	14/72 (19.44%)	8/75 (10.67%)	29/76 (38.16%)
Leukopenia † 1	16/72 (22.22%)	12/75 (16.00%)	13/76 (17.11%)
Thrombocytopenia † 1	5/72 (6.94%)	1/75 (1.33%)	23/76 (30.26%)
Febrile neutropenia † 1	4/72 (5.56%)	3/75 (4.00%)	2/76 (2.63%)
Cardiac disorders
Left ventricular dysfunction † 1	7/72 (9.72%)	8/75 (10.67%)	7/76 (9.21%)
Palpitations † 1	3/72 (4.17%)	1/75 (1.33%)	4/76 (5.26%)
Eye disorders
Lacrimation increased † 1	9/72 (12.50%)	4/75 (5.33%)	6/76 (7.89%)
Eyelid oedema † 1	1/72 (1.39%)	1/75 (1.33%)	4/76 (5.26%)
Gastrointestinal disorders
Diarrhoea † 1	46/72 (63.89%)	44/75 (58.67%)	55/76 (72.37%)
Nausea † 1	38/72 (52.78%)	41/75 (54.67%)	34/76 (44.74%)
Vomiting † 1	29/72 (40.28%)	27/75 (36.00%)	30/76 (39.47%)
Dyspepsia † 1	19/72 (26.39%)	9/75 (12.00%)	17/76 (22.37%)
Constipation † 1	14/72 (19.44%)	18/75 (24.00%)	13/76 (17.11%)
Stomatitis † 1	10/72 (13.89%)	13/75 (17.33%)	9/76 (11.84%)
Abdominal pain upper † 1	7/72 (9.72%)	6/75 (8.00%)	5/76 (6.58%)
Abdominal pain † 1	3/72 (4.17%)	7/75 (9.33%)	6/76 (7.89%)
Dry mouth † 1	4/72 (5.56%)	2/75 (2.67%)	8/76 (10.53%)
Haemorrhoids † 1	5/72 (6.94%)	1/75 (1.33%)	4/76 (5.26%)
Abdominal distension † 1	2/72 (2.78%)	2/75 (2.67%)	4/76 (5.26%)
Oral pain † 1	1/72 (1.39%)	4/75 (5.33%)	2/76 (2.63%)
General disorders
Fatigue † 1	30/72 (41.67%)	28/75 (37.33%)	33/76 (43.42%)
Mucosal inflammation † 1	17/72 (23.61%)	15/75 (20.00%)	12/76 (15.79%)
Pyrexia † 1	11/72 (15.28%)	9/75 (12.00%)	15/76 (19.74%)
Asthenia † 1	9/72 (12.50%)	14/75 (18.67%)	10/76 (13.16%)
Oedema peripheral † 1	10/72 (13.89%)	5/75 (6.67%)	9/76 (11.84%)
Pain † 1	3/72 (4.17%)	7/75 (9.33%)	4/76 (5.26%)
Chills † 1	4/72 (5.56%)	1/75 (1.33%)	7/76 (9.21%)
Chest pain † 1	2/72 (2.78%)	4/75 (5.33%)	5/76 (6.58%)
Influenza like illness † 1	2/72 (2.78%)	5/75 (6.67%)	2/76 (2.63%)
Oedema † 1	1/72 (1.39%)	3/75 (4.00%)	5/76 (6.58%)
Malaise † 1	0/72 (0.00%)	2/75 (2.67%)	5/76 (6.58%)
Axillary pain † 1	0/72 (0.00%)	0/75 (0.00%)	5/76 (6.58%)
Chest discomfort † 1	4/72 (5.56%)	3/75 (4.00%)	3/76 (3.95%)
Immune system disorders
Drug hypersensitivity † 1	6/72 (8.33%)	2/75 (2.67%)	7/76 (9.21%)
Infections and infestations
Nasopharyngitis † 1	6/72 (8.33%)	9/75 (12.00%)	9/76 (11.84%)
Upper respiratory tract infection † 1	7/72 (9.72%)	10/75 (13.33%)	3/76 (3.95%)
Urinary tract infection † 1	5/72 (6.94%)	7/75 (9.33%)	7/76 (9.21%)
Rhinitis † 1	6/72 (8.33%)	1/75 (1.33%)	4/76 (5.26%)
Cystitis † 1	0/72 (0.00%)	4/75 (5.33%)	6/76 (7.89%)
Conjunctivitis † 1	3/72 (4.17%)	2/75 (2.67%)	4/76 (5.26%)
Influenza † 1	5/72 (6.94%)	4/75 (5.33%)	2/76 (2.63%)
Injury, poisoning and procedural complications
Radiation skin injury † 1	11/72 (15.28%)	14/75 (18.67%)	7/76 (9.21%)
Seroma † 1	4/72 (5.56%)	4/75 (5.33%)	1/76 (1.32%)
Investigations
Haemoglobin decreased † 1	6/72 (8.33%)	4/75 (5.33%)	7/76 (9.21%)
Alanine aminotransferase increased † 1	5/72 (6.94%)	3/75 (4.00%)	8/76 (10.53%)
Aspartate aminotransferase increased † 1	4/72 (5.56%)	3/75 (4.00%)	5/76 (6.58%)
Weight decreased † 1	3/72 (4.17%)	4/75 (5.33%)	5/76 (6.58%)
Metabolism and nutrition disorders
Decreased appetite † 1	15/72 (20.83%)	8/75 (10.67%)	16/76 (21.05%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	18/72 (25.00%)	18/75 (24.00%)	11/76 (14.47%)
Myalgia † 1	14/72 (19.44%)	16/75 (21.33%)	8/76 (10.53%)
Back pain † 1	11/72 (15.28%)	9/75 (12.00%)	7/76 (9.21%)
Musculoskeletal pain † 1	11/72 (15.28%)	8/75 (10.67%)	5/76 (6.58%)
Pain in extremity † 1	7/72 (9.72%)	7/75 (9.33%)	7/76 (9.21%)
Muscle spasms † 1	4/72 (5.56%)	4/75 (5.33%)	6/76 (7.89%)
Musculoskeletal chest pain † 1	5/72 (6.94%)	3/75 (4.00%)	5/76 (6.58%)
Bone pain † 1	4/72 (5.56%)	4/75 (5.33%)	2/76 (2.63%)
Nervous system disorders
Headache † 1	20/72 (27.78%)	15/75 (20.00%)	16/76 (21.05%)
Dysgeusia † 1	8/72 (11.11%)	10/75 (13.33%)	16/76 (21.05%)
Dizziness † 1	7/72 (9.72%)	9/75 (12.00%)	15/76 (19.74%)
Neuropathy peripheral † 1	5/72 (6.94%)	4/75 (5.33%)	8/76 (10.53%)
Peripheral sensory neuropathy † 1	4/72 (5.56%)	8/75 (10.67%)	5/76 (6.58%)
Paraesthesia † 1	3/72 (4.17%)	4/75 (5.33%)	9/76 (11.84%)
Polyneuropathy † 1	4/72 (5.56%)	1/75 (1.33%)	4/76 (5.26%)
Psychiatric disorders
Insomnia † 1	12/72 (16.67%)	13/75 (17.33%)	17/76 (22.37%)
Depression † 1	3/72 (4.17%)	3/75 (4.00%)	4/76 (5.26%)
Anxiety † 1	1/72 (1.39%)	4/75 (5.33%)	4/76 (5.26%)
Renal and urinary disorders
Dysuria † 1	2/72 (2.78%)	0/75 (0.00%)	7/76 (9.21%)
Reproductive system and breast disorders
Breast pain † 1	2/72 (2.78%)	3/75 (4.00%)	6/76 (7.89%)
Vulvovaginal dryness † 1	0/72 (0.00%)	1/75 (1.33%)	4/76 (5.26%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea † 1	13/72 (18.06%)	8/75 (10.67%)	10/76 (13.16%)
Epistaxis † 1	8/72 (11.11%)	10/75 (13.33%)	11/76 (14.47%)
Cough † 1	10/72 (13.89%)	8/75 (10.67%)	10/76 (13.16%)
Oropharyngeal pain † 1	7/72 (9.72%)	6/75 (8.00%)	9/76 (11.84%)
Rhinorrhoea † 1	3/72 (4.17%)	5/75 (6.67%)	7/76 (9.21%)
Skin and subcutaneous tissue disorders
Alopecia † 1	35/72 (48.61%)	39/75 (52.00%)	42/76 (55.26%)
Rash † 1	17/72 (23.61%)	8/75 (10.67%)	20/76 (26.32%)
Nail disorder † 1	9/72 (12.50%)	8/75 (10.67%)	10/76 (13.16%)
Erythema † 1	10/72 (13.89%)	5/75 (6.67%)	11/76 (14.47%)
Dry skin † 1	5/72 (6.94%)	7/75 (9.33%)	8/76 (10.53%)
Palmar -plantar erythrodysaesthesia syndrome † 1	5/72 (6.94%)	9/75 (12.00%)	6/76 (7.89%)
Pruritus † 1	3/72 (4.17%)	7/75 (9.33%)	4/76 (5.26%)
Skin reaction † 1	2/72 (2.78%)	5/75 (6.67%)	3/76 (3.95%)
Dermatitis † 1	1/72 (1.39%)	5/75 (6.67%)	0/76 (0.00%)
Hyperhidrosis † 1	1/72 (1.39%)	0/75 (0.00%)	5/76 (6.58%)
Night sweats † 1	1/72 (1.39%)	0/75 (0.00%)	5/76 (6.58%)
Skin hyperpigmentation † 1	2/72 (2.78%)	4/75 (5.33%)	0/76 (0.00%)
Skin exfoliation † 1	0/72 (0.00%)	4/75 (5.33%)	0/76 (0.00%)
Vascular disorders
Hot Flush † 1	11/72 (15.28%)	9/75 (12.00%)	10/76 (13.16%)
Hypertension † 1	5/72 (6.94%)	2/75 (2.67%)	5/76 (6.58%)
Lymphoedema † 1	2/72 (2.78%)	5/75 (6.67%)	4/76 (5.26%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA (18.1)

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

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Schneeweiss A, Chia S, Hickish T, Harvey V, Eniu A, Waldron-Lynch M, Eng-Wong J, Kirk S, Cortes J. Long-term efficacy analysis of the randomised, phase II TRYPHAENA cardiac safety study: Evaluating pertuzumab and trastuzumab plus standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer. Eur J Cancer. 2018 Jan;89:27-35. doi: 10.1016/j.ejca.2017.10.021. Epub 2017 Dec 8.

Swain SM, Schneeweiss A, Gianni L, Gao JJ, Stein A, Waldron-Lynch M, Heeson S, Beattie MS, Yoo B, Cortes J, Baselga J. Incidence and management of diarrhea in patients with HER2-positive breast cancer treated with pertuzumab. Ann Oncol. 2017 Apr 1;28(4):761-768. doi: 10.1093/annonc/mdw695. Erratum In: Ann Oncol. 2018 Apr 1;29(4):1075. Ann Oncol. 2018 Jul 1;29(7):1607. Ann Oncol. 2019 Aug 1;30(8):1404.

Schneeweiss A, Chia S, Hegg R, Tausch C, Deb R, Ratnayake J, McNally V, Ross G, Kiermaier A, Cortes J. Evaluating the predictive value of biomarkers for efficacy outcomes in response to pertuzumab- and trastuzumab-based therapy: an exploratory analysis of the TRYPHAENA study. Breast Cancer Res. 2014 Jul 8;16(4):R73. doi: 10.1186/bcr3690.

Schneeweiss A, Chia S, Hickish T, Harvey V, Eniu A, Hegg R, Tausch C, Seo JH, Tsai YF, Ratnayake J, McNally V, Ross G, Cortes J. Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol. 2013 Sep;24(9):2278-84. doi: 10.1093/annonc/mdt182. Epub 2013 May 22.

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT00976989
• Other Study ID Numbers: BO22280; 2009-012019-17 ( EudraCT Number )
• First Submitted: September 14, 2009
• First Posted: September 15, 2009
• Results First Submitted: March 28, 2016
• Results First Posted: June 20, 2016
• Last Update Posted: February 6, 2017