Trial Outcomes & Findings for Lapatinib +/- Trastuzumab In Addition To Standard Neoadjuvant Breast Cancer Therapy. (NCT NCT00524303)

Last Updated: 2016-11-11

Results Overview

A pCR in the breast was defined as no pathologic evidence of invasive disease (residual ductal carcinoma in situ \[DCIS\] or lobular carcinoma in situ \[LCIS\] was allowed). A pCR in the axillary lymph node(s) was defined as no evidence of breast cancer cells in the lymph node (including subcapsular sinus). Overall pCR was defined as the sum of pCR in the breast and pCR in the lymph nodes. 26 weeks of therapy comprised the 2-week run-in phase, 12 weeks of treatment with FEC, and 12 weeks of treatment with Paclitaxel.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

100 participants

Primary outcome timeframe

Week 26

Results posted on

2016-11-11

Participant Flow

Participant milestones

Participant milestones
Measure	Trastuzumab Participants received trastuzumab alone (a loading dose of 4 milligrams \[mg\]/kilogram \[kg\] on Day 1, followed by a dose of 2 mg/kg on Day 1 of Week 2 and weekly thereafter). Participants were treated with trastuzumab in a 2-week run-in period. On Day 14, a second core needle biopsy was performed, followed by initiation of chemotherapy with 2 combination regimens of 4 cycles each (1 cycle=3 weeks): FEC75 (5-fluorouracil \[5-FU\] 500 mg/meters squared \[m\^2\], epirubicin 75 mg/m\^2, cyclophosphamide 500 mg/m\^2 x 4 cycles on Day 1), then paclitaxel (80 mg/m\^2 x 4 cycles on Day 1, Day 8, and Day 15) in combination with trastuzumab.	Lapatinib Participants received lapatinib alone (1250 mg orally \[PO\] once daily \[QD\]). Participants were treated with lapatinib in a 2-week run-in period. On Day 14, a second core needle biopsy was performed, followed by initiation of chemotherapy with 2 combination regimens of 4 cycles each (1 cycle=3 weeks): FEC75 (5-FU 500 mg/m\^2, epirubicin 75 mg/m\^2, cyclophosphamide 500 mg/m\^2 x 4 cycles on Day 1), then paclitaxel (80 mg/m\^2 x 4 cycles on Day 1, Day 8, and Day 15) in combination with lapatinib.	Trastuzumab+Lapatinib Participants received trastuzumab (given as in Arm 1) and lapatinib (750/1000 mg PO QD). Participants were treated with these medications in a 2-week run-in period. On Day 14, a second core needle biopsy was performed, followed by initiation of chemotherapy with 2 combination regimens of 4 cycles each (1 cycle=3 weeks): FEC75 (5-FU 500 mg/m\^2, epirubicin 75 mg/m\^2, cyclophosphamide 500 mg/m\^2 x 4 cycles on Day 1), then paclitaxel (80 mg/m\^2 x 4 cycles on Day 1, Day 8, and Day 15) in combination with trastuzumab+lapatinib.
Overall Study STARTED	33	34	33
Overall Study COMPLETED	21	24	15
Overall Study NOT COMPLETED	12	10	18

Reasons for withdrawal

Reasons for withdrawal
Measure	Trastuzumab Participants received trastuzumab alone (a loading dose of 4 milligrams \[mg\]/kilogram \[kg\] on Day 1, followed by a dose of 2 mg/kg on Day 1 of Week 2 and weekly thereafter). Participants were treated with trastuzumab in a 2-week run-in period. On Day 14, a second core needle biopsy was performed, followed by initiation of chemotherapy with 2 combination regimens of 4 cycles each (1 cycle=3 weeks): FEC75 (5-fluorouracil \[5-FU\] 500 mg/meters squared \[m\^2\], epirubicin 75 mg/m\^2, cyclophosphamide 500 mg/m\^2 x 4 cycles on Day 1), then paclitaxel (80 mg/m\^2 x 4 cycles on Day 1, Day 8, and Day 15) in combination with trastuzumab.	Lapatinib Participants received lapatinib alone (1250 mg orally \[PO\] once daily \[QD\]). Participants were treated with lapatinib in a 2-week run-in period. On Day 14, a second core needle biopsy was performed, followed by initiation of chemotherapy with 2 combination regimens of 4 cycles each (1 cycle=3 weeks): FEC75 (5-FU 500 mg/m\^2, epirubicin 75 mg/m\^2, cyclophosphamide 500 mg/m\^2 x 4 cycles on Day 1), then paclitaxel (80 mg/m\^2 x 4 cycles on Day 1, Day 8, and Day 15) in combination with lapatinib.	Trastuzumab+Lapatinib Participants received trastuzumab (given as in Arm 1) and lapatinib (750/1000 mg PO QD). Participants were treated with these medications in a 2-week run-in period. On Day 14, a second core needle biopsy was performed, followed by initiation of chemotherapy with 2 combination regimens of 4 cycles each (1 cycle=3 weeks): FEC75 (5-FU 500 mg/m\^2, epirubicin 75 mg/m\^2, cyclophosphamide 500 mg/m\^2 x 4 cycles on Day 1), then paclitaxel (80 mg/m\^2 x 4 cycles on Day 1, Day 8, and Day 15) in combination with trastuzumab+lapatinib.
Overall Study Lost to Follow-up	6	0	3
Overall Study Protocol Violation	0	1	1
Overall Study Withdrawal by Subject	3	0	4
Overall Study Death	0	2	3
Overall Study Adverse Event	1	2	3
Overall Study Did not Complete Study Dosing	1	0	0
Overall Study Worsening Peripheral Neuropathy	1	0	0
Overall Study Disease Progression	0	4	1
Overall Study Disease Recurrence	0	1	0
Overall Study Sponsor Request	0	0	1
Overall Study Physician Decision	0	0	1
Overall Study Completed 5 years	0	0	1

Baseline Characteristics

Lapatinib +/- Trastuzumab In Addition To Standard Neoadjuvant Breast Cancer Therapy.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Trastuzumab n=33 Participants Participants received trastuzumab alone (a loading dose of 4 milligrams \[mg\]/kilogram \[kg\] on Day 1, followed by a dose of 2 mg/kg on Day 1 of Week 2 and weekly thereafter). Participants were treated with trastuzumab in a 2-week run-in period. On Day 14, a second core needle biopsy was performed, followed by initiation of chemotherapy with 2 combination regimens of 4 cycles each (1 cycle=3 weeks): FEC75 (5-fluorouracil \[5-FU\] 500 mg/meters squared \[m\^2\], epirubicin 75 mg/m\^2, cyclophosphamide 500 mg/m\^2 x 4 cycles on Day 1), then paclitaxel (80 mg/m\^2 x 4 cycles on Day 1, Day 8, and Day 15) in combination with trastuzumab.	Lapatinib n=34 Participants Participants received lapatinib alone (1250 mg orally \[PO\] once daily \[QD\]). Participants were treated with lapatinib in a 2-week run-in period. On Day 14, a second core needle biopsy was performed, followed by initiation of chemotherapy with 2 combination regimens of 4 cycles each (1 cycle=3 weeks): FEC75 (5-FU 500 mg/m\^2, epirubicin 75 mg/m\^2, cyclophosphamide 500 mg/m\^2 x 4 cycles on Day 1), then paclitaxel (80 mg/m\^2 x 4 cycles on Day 1, Day 8, and Day 15) in combination with lapatinib.	Trastuzumab+Lapatinib n=33 Participants Participants received trastuzumab (given as in Arm 1) and lapatinib (750/1000 mg PO QD). Participants were treated with these medications in a 2-week run-in period. On Day 14, a second core needle biopsy was performed, followed by initiation of chemotherapy with 2 combination regimens of 4 cycles each (1 cycle=3 weeks): FEC75 (5-FU 500 mg/m\^2, epirubicin 75 mg/m\^2, cyclophosphamide 500 mg/m\^2 x 4 cycles on Day 1), then paclitaxel (80 mg/m\^2 x 4 cycles on Day 1, Day 8, and Day 15) in combination with trastuzumab+lapatinib.	Total n=100 Participants Total of all reporting groups
Age, Continuous	51.1 Years STANDARD_DEVIATION 10.90 • n=93 Participants	50.8 Years STANDARD_DEVIATION 8.76 • n=4 Participants	49.2 Years STANDARD_DEVIATION 10.47 • n=27 Participants	50.4 Years STANDARD_DEVIATION 10.01 • n=483 Participants
Sex: Female, Male Female	33 Participants n=93 Participants	34 Participants n=4 Participants	33 Participants n=27 Participants	100 Participants n=483 Participants
Sex: Female, Male Male	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants
Race/Ethnicity, Customized African American/African heritage	8 participants n=93 Participants	1 participants n=4 Participants	2 participants n=27 Participants	11 participants n=483 Participants
Race/Ethnicity, Customized American Indian or Alaska native	0 participants n=93 Participants	0 participants n=4 Participants	1 participants n=27 Participants	1 participants n=483 Participants
Race/Ethnicity, Customized Asian - Central/South Asian heritage	0 participants n=93 Participants	1 participants n=4 Participants	0 participants n=27 Participants	1 participants n=483 Participants
Race/Ethnicity, Customized Asian - East Asian heritage	0 participants n=93 Participants	1 participants n=4 Participants	0 participants n=27 Participants	1 participants n=483 Participants
Race/Ethnicity, Customized Asian - South East Asian heritage	0 participants n=93 Participants	2 participants n=4 Participants	1 participants n=27 Participants	3 participants n=483 Participants
Race/Ethnicity, Customized White - Arabic/North African heritage	0 participants n=93 Participants	1 participants n=4 Participants	0 participants n=27 Participants	1 participants n=483 Participants
Race/Ethnicity, Customized White - White/Caucasian/European heritage	25 participants n=93 Participants	27 participants n=4 Participants	29 participants n=27 Participants	81 participants n=483 Participants
Race/Ethnicity, Customized Mixed race	0 participants n=93 Participants	1 participants n=4 Participants	0 participants n=27 Participants	1 participants n=483 Participants

PRIMARY outcome

Timeframe: Week 26

Population: Intent-to-Treat-Evaluable (ITT-E) Population: ITT participants with evaluable tumor responses who had been \>=75% compliant to 5-fluorouracil (5-FU) 500 mg/m\^2, epirubicin 75 mg/m\^2, cyclophosphamide 500 mg/m\^2 (FEC75) and paclitaxel 80 mg/m\^2 and had undergone surgery.

Outcome measures

Outcome measures
Measure	Trastuzumab n=26 Participants Participants received trastuzumab alone (a loading dose of 4 milligrams \[mg\]/kilogram \[kg\] on Day 1, followed by a dose of 2 mg/kg on Day 1 of Week 2 and weekly thereafter). Participants were treated with trastuzumab in a 2-week run-in period. On Day 14, a second core needle biopsy was performed, followed by initiation of chemotherapy with 2 combination regimens of 4 cycles each (1 cycle=3 weeks): FEC75 (5-fluorouracil \[5-FU\] 500 mg/meters squared \[m\^2\], epirubicin 75 mg/m\^2, cyclophosphamide 500 mg/m\^2 x 4 cycles on Day 1), then paclitaxel (80 mg/m\^2 x 4 cycles on Day 1, Day 8, and Day 15) in combination with trastuzumab.	Lapatinib n=29 Participants Participants received lapatinib alone (1250 mg orally \[PO\] once daily \[QD\]). Participants were treated with lapatinib in a 2-week run-in period. On Day 14, a second core needle biopsy was performed, followed by initiation of chemotherapy with 2 combination regimens of 4 cycles each (1 cycle=3 weeks): FEC75 (5-FU 500 mg/m\^2, epirubicin 75 mg/m\^2, cyclophosphamide 500 mg/m\^2 x 4 cycles on Day 1), then paclitaxel (80 mg/m\^2 x 4 cycles on Day 1, Day 8, and Day 15) in combination with lapatinib.	Trastuzumab+Lapatinib n=23 Participants Participants received trastuzumab (given as in Arm 1) and lapatinib (750/1000 mg PO QD). Participants were treated with these medications in a 2-week run-in period. On Day 14, a second core needle biopsy was performed, followed by initiation of chemotherapy with 2 combination regimens of 4 cycles each (1 cycle=3 weeks): FEC75 (5-FU 500 mg/m\^2, epirubicin 75 mg/m\^2, cyclophosphamide 500 mg/m\^2 x 4 cycles on Day 1), then paclitaxel (80 mg/m\^2 x 4 cycles on Day 1, Day 8, and Day 15) in combination with trastuzumab+lapatinib.
Percentage of Participants With Overall Pathological Complete Response (pCR) After 26 Weeks of Therapy	54.0 percentage of participants	45.0 percentage of participants	74.0 percentage of participants

SECONDARY outcome

Timeframe: Week 26 or EOT or Early withdrawal

Population: ITT Population: all randomized participants regardless of whether they had received any treatment.

cCR was defined as the percentage of participants achieving either a Complete Response (CR) or a Partial Response (PR) using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. CR was defined as the disappearance of all target lesions, and 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.

Outcome measures

Outcome measures
Measure	Trastuzumab n=33 Participants Participants received trastuzumab alone (a loading dose of 4 milligrams \[mg\]/kilogram \[kg\] on Day 1, followed by a dose of 2 mg/kg on Day 1 of Week 2 and weekly thereafter). Participants were treated with trastuzumab in a 2-week run-in period. On Day 14, a second core needle biopsy was performed, followed by initiation of chemotherapy with 2 combination regimens of 4 cycles each (1 cycle=3 weeks): FEC75 (5-fluorouracil \[5-FU\] 500 mg/meters squared \[m\^2\], epirubicin 75 mg/m\^2, cyclophosphamide 500 mg/m\^2 x 4 cycles on Day 1), then paclitaxel (80 mg/m\^2 x 4 cycles on Day 1, Day 8, and Day 15) in combination with trastuzumab.	Lapatinib n=34 Participants Participants received lapatinib alone (1250 mg orally \[PO\] once daily \[QD\]). Participants were treated with lapatinib in a 2-week run-in period. On Day 14, a second core needle biopsy was performed, followed by initiation of chemotherapy with 2 combination regimens of 4 cycles each (1 cycle=3 weeks): FEC75 (5-FU 500 mg/m\^2, epirubicin 75 mg/m\^2, cyclophosphamide 500 mg/m\^2 x 4 cycles on Day 1), then paclitaxel (80 mg/m\^2 x 4 cycles on Day 1, Day 8, and Day 15) in combination with lapatinib.	Trastuzumab+Lapatinib n=33 Participants Participants received trastuzumab (given as in Arm 1) and lapatinib (750/1000 mg PO QD). Participants were treated with these medications in a 2-week run-in period. On Day 14, a second core needle biopsy was performed, followed by initiation of chemotherapy with 2 combination regimens of 4 cycles each (1 cycle=3 weeks): FEC75 (5-FU 500 mg/m\^2, epirubicin 75 mg/m\^2, cyclophosphamide 500 mg/m\^2 x 4 cycles on Day 1), then paclitaxel (80 mg/m\^2 x 4 cycles on Day 1, Day 8, and Day 15) in combination with trastuzumab+lapatinib.
Percentage of Participants With Clinical Complete Response (cCR) at 26 Weeks or at End of Treatment (EOT) or Early Withdrawal	61.0 percentage of participants	68.0 percentage of participants	61.0 percentage of participants

SECONDARY outcome

Timeframe: From first dose date until disease progression, assessed up to a maximum of 5 years

Population: ITT Population

Percentage is the Kaplan Meier estimate of DFS. DFS is time from randomization until disease recurrence (contralateral breast cancer; second primary cancer; progression during neo-adjuvant treatment; or death from any cause). Par. who experienced progression during treatment and were withdrawn were considered to have a DFS event at withdrawal.

Outcome measures

Outcome measures
Measure	Trastuzumab n=33 Participants Participants received trastuzumab alone (a loading dose of 4 milligrams \[mg\]/kilogram \[kg\] on Day 1, followed by a dose of 2 mg/kg on Day 1 of Week 2 and weekly thereafter). Participants were treated with trastuzumab in a 2-week run-in period. On Day 14, a second core needle biopsy was performed, followed by initiation of chemotherapy with 2 combination regimens of 4 cycles each (1 cycle=3 weeks): FEC75 (5-fluorouracil \[5-FU\] 500 mg/meters squared \[m\^2\], epirubicin 75 mg/m\^2, cyclophosphamide 500 mg/m\^2 x 4 cycles on Day 1), then paclitaxel (80 mg/m\^2 x 4 cycles on Day 1, Day 8, and Day 15) in combination with trastuzumab.	Lapatinib n=34 Participants Participants received lapatinib alone (1250 mg orally \[PO\] once daily \[QD\]). Participants were treated with lapatinib in a 2-week run-in period. On Day 14, a second core needle biopsy was performed, followed by initiation of chemotherapy with 2 combination regimens of 4 cycles each (1 cycle=3 weeks): FEC75 (5-FU 500 mg/m\^2, epirubicin 75 mg/m\^2, cyclophosphamide 500 mg/m\^2 x 4 cycles on Day 1), then paclitaxel (80 mg/m\^2 x 4 cycles on Day 1, Day 8, and Day 15) in combination with lapatinib.	Trastuzumab+Lapatinib n=33 Participants Participants received trastuzumab (given as in Arm 1) and lapatinib (750/1000 mg PO QD). Participants were treated with these medications in a 2-week run-in period. On Day 14, a second core needle biopsy was performed, followed by initiation of chemotherapy with 2 combination regimens of 4 cycles each (1 cycle=3 weeks): FEC75 (5-FU 500 mg/m\^2, epirubicin 75 mg/m\^2, cyclophosphamide 500 mg/m\^2 x 4 cycles on Day 1), then paclitaxel (80 mg/m\^2 x 4 cycles on Day 1, Day 8, and Day 15) in combination with trastuzumab+lapatinib.
Percentage of Participants (Par.) With Disease-free Survival (DFS) at the End of 5 Years From Randomization	90 Percentage Interval 72.0 to 97.0	67 Percentage Interval 47.0 to 80.0	66 Percentage Interval 44.0 to 82.0

SECONDARY outcome

Timeframe: Baseline and EOT (up to Week 26) or Early withdrawal

Population: Safety Population: all randomized participants (par) who received at least one dose of investigational product, based on actual treatment received if this differed from that to which par was randomized. Not all par were analyzed: some par were randomized to an arm they did not want or par were randomized in error (eligibility criteria weren't met).

12-lead ECGs were performed, and participants were classified as having normal ECG, abnormal- not clinically significant (NCS) ECG, and abnormal-clinically significant (CS) ECG per investigator opinion and reported result.

Outcome measures

Outcome measures
Measure	Trastuzumab n=28 Participants Participants received trastuzumab alone (a loading dose of 4 milligrams \[mg\]/kilogram \[kg\] on Day 1, followed by a dose of 2 mg/kg on Day 1 of Week 2 and weekly thereafter). Participants were treated with trastuzumab in a 2-week run-in period. On Day 14, a second core needle biopsy was performed, followed by initiation of chemotherapy with 2 combination regimens of 4 cycles each (1 cycle=3 weeks): FEC75 (5-fluorouracil \[5-FU\] 500 mg/meters squared \[m\^2\], epirubicin 75 mg/m\^2, cyclophosphamide 500 mg/m\^2 x 4 cycles on Day 1), then paclitaxel (80 mg/m\^2 x 4 cycles on Day 1, Day 8, and Day 15) in combination with trastuzumab.	Lapatinib n=32 Participants Participants received lapatinib alone (1250 mg orally \[PO\] once daily \[QD\]). Participants were treated with lapatinib in a 2-week run-in period. On Day 14, a second core needle biopsy was performed, followed by initiation of chemotherapy with 2 combination regimens of 4 cycles each (1 cycle=3 weeks): FEC75 (5-FU 500 mg/m\^2, epirubicin 75 mg/m\^2, cyclophosphamide 500 mg/m\^2 x 4 cycles on Day 1), then paclitaxel (80 mg/m\^2 x 4 cycles on Day 1, Day 8, and Day 15) in combination with lapatinib.	Trastuzumab+Lapatinib n=30 Participants Participants received trastuzumab (given as in Arm 1) and lapatinib (750/1000 mg PO QD). Participants were treated with these medications in a 2-week run-in period. On Day 14, a second core needle biopsy was performed, followed by initiation of chemotherapy with 2 combination regimens of 4 cycles each (1 cycle=3 weeks): FEC75 (5-FU 500 mg/m\^2, epirubicin 75 mg/m\^2, cyclophosphamide 500 mg/m\^2 x 4 cycles on Day 1), then paclitaxel (80 mg/m\^2 x 4 cycles on Day 1, Day 8, and Day 15) in combination with trastuzumab+lapatinib.
Number of Participants With the Indicated Electrocardiogram (ECG) Status at Baseline and at EOT or Early Withdrawal Baseline, Abnormal-CS, n= 28, 32, 30	0 participants	1 participants	0 participants
Number of Participants With the Indicated Electrocardiogram (ECG) Status at Baseline and at EOT or Early Withdrawal EOT/early withdrawal, Normal, n= 16, 21, 16	10 participants	12 participants	12 participants
Number of Participants With the Indicated Electrocardiogram (ECG) Status at Baseline and at EOT or Early Withdrawal EOT/early withdrawal, Abnormal-NCS, n= 16, 21, 16	6 participants	8 participants	4 participants
Number of Participants With the Indicated Electrocardiogram (ECG) Status at Baseline and at EOT or Early Withdrawal EOT/early withdrawal, Abnormal-CS, n= 16, 21, 16	0 participants	1 participants	0 participants
Number of Participants With the Indicated Electrocardiogram (ECG) Status at Baseline and at EOT or Early Withdrawal Baseline, Normal, n= 28, 32, 30	18 participants	23 participants	23 participants
Number of Participants With the Indicated Electrocardiogram (ECG) Status at Baseline and at EOT or Early Withdrawal Baseline, Abnormal-NCS, n= 28, 32, 30	10 participants	8 participants	7 participants

SECONDARY outcome

Timeframe: Weeks 3, 9, and 15; EOT or early withdrawal; and 3- and 6-month survival follow-up after last chemotherapy course

Population: Safety Population. Not all participants in the Safety Population were analyzed: some participants were randomized to an arm they did not want or participants were randomized in error (eligibility criteria weren't met).

LVEF is the measurement of how much blood is being pumped out of the left ventricle of the heart (the main pumping chamber) with each contraction and is used to determine cardiac function. LVEF was measured by performing echocardiogram (ECHO). If ECHO could not be performed or if the investigator believed that it was not conclusive to evaluate LVEF, then a multigated acquisition (MUGA) scan was performed.

Outcome measures

Outcome measures
Measure	Trastuzumab n=32 Participants Participants received trastuzumab alone (a loading dose of 4 milligrams \[mg\]/kilogram \[kg\] on Day 1, followed by a dose of 2 mg/kg on Day 1 of Week 2 and weekly thereafter). Participants were treated with trastuzumab in a 2-week run-in period. On Day 14, a second core needle biopsy was performed, followed by initiation of chemotherapy with 2 combination regimens of 4 cycles each (1 cycle=3 weeks): FEC75 (5-fluorouracil \[5-FU\] 500 mg/meters squared \[m\^2\], epirubicin 75 mg/m\^2, cyclophosphamide 500 mg/m\^2 x 4 cycles on Day 1), then paclitaxel (80 mg/m\^2 x 4 cycles on Day 1, Day 8, and Day 15) in combination with trastuzumab.	Lapatinib n=34 Participants Participants received lapatinib alone (1250 mg orally \[PO\] once daily \[QD\]). Participants were treated with lapatinib in a 2-week run-in period. On Day 14, a second core needle biopsy was performed, followed by initiation of chemotherapy with 2 combination regimens of 4 cycles each (1 cycle=3 weeks): FEC75 (5-FU 500 mg/m\^2, epirubicin 75 mg/m\^2, cyclophosphamide 500 mg/m\^2 x 4 cycles on Day 1), then paclitaxel (80 mg/m\^2 x 4 cycles on Day 1, Day 8, and Day 15) in combination with lapatinib.	Trastuzumab+Lapatinib n=31 Participants Participants received trastuzumab (given as in Arm 1) and lapatinib (750/1000 mg PO QD). Participants were treated with these medications in a 2-week run-in period. On Day 14, a second core needle biopsy was performed, followed by initiation of chemotherapy with 2 combination regimens of 4 cycles each (1 cycle=3 weeks): FEC75 (5-FU 500 mg/m\^2, epirubicin 75 mg/m\^2, cyclophosphamide 500 mg/m\^2 x 4 cycles on Day 1), then paclitaxel (80 mg/m\^2 x 4 cycles on Day 1, Day 8, and Day 15) in combination with trastuzumab+lapatinib.
Cumulative Number of Participants With at Least One Decrease of More Than or Equal to 20% in Left Ventricular Ejection Fraction (LVEF) at the Indicated Time Points Compared to LVEF at Baseline Week 3, n= 30, 31, 26	1 participants	0 participants	1 participants
Cumulative Number of Participants With at Least One Decrease of More Than or Equal to 20% in Left Ventricular Ejection Fraction (LVEF) at the Indicated Time Points Compared to LVEF at Baseline Week 9, n= 30, 32, 27	1 participants	0 participants	1 participants
Cumulative Number of Participants With at Least One Decrease of More Than or Equal to 20% in Left Ventricular Ejection Fraction (LVEF) at the Indicated Time Points Compared to LVEF at Baseline Week 15, n= 31, 34, 28	1 participants	2 participants	2 participants
Cumulative Number of Participants With at Least One Decrease of More Than or Equal to 20% in Left Ventricular Ejection Fraction (LVEF) at the Indicated Time Points Compared to LVEF at Baseline Early withdrawal/EOT, n= 31, 34, 28	1 participants	4 participants	2 participants
Cumulative Number of Participants With at Least One Decrease of More Than or Equal to 20% in Left Ventricular Ejection Fraction (LVEF) at the Indicated Time Points Compared to LVEF at Baseline 3-month survival follow-up, n= 31, 34, 28	2 participants	4 participants	3 participants
Cumulative Number of Participants With at Least One Decrease of More Than or Equal to 20% in Left Ventricular Ejection Fraction (LVEF) at the Indicated Time Points Compared to LVEF at Baseline 6-month survival follow-up, n= 31, 34, 28	4 participants	4 participants	4 participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Tumor core biopsy taken at Baseline and Treatment Day 14

Population: ITT-E Population. Only those participants with matched pairs of biopsy samples for analysis at Baseline and on Day 14 were analyzed.

Expression (exp) of biomarker proteins (prot) were analyzed to determine if individual prot levels either in the Baseline or Day 14 breast tumor biopsy specimen correlated with breast pCR. A biomarker indicates a change in exp or state of a prot that correlates with the risk or disease progression, or with the susceptibility of the disease to a given treatment. Biomarkers are characteristic biological properties that can be detected and measured in parts of the body like blood or tissue. pCR=yes: participants (par.) had breast pCR. pCR=no: par. did not have breast pCR. Prot exp values are represented as normalized, scaled values; the unit of measurement is unit-less. Raw exp values were processed as follows: background subtraction of the raw exp value, then that value divided by beta-acting exp to normalize the exp value. A Standard Z score was calculated to scale the exp value.

Outcome measures

Outcome measures
Measure	Trastuzumab n=11 Participants Participants received trastuzumab alone (a loading dose of 4 milligrams \[mg\]/kilogram \[kg\] on Day 1, followed by a dose of 2 mg/kg on Day 1 of Week 2 and weekly thereafter). Participants were treated with trastuzumab in a 2-week run-in period. On Day 14, a second core needle biopsy was performed, followed by initiation of chemotherapy with 2 combination regimens of 4 cycles each (1 cycle=3 weeks): FEC75 (5-fluorouracil \[5-FU\] 500 mg/meters squared \[m\^2\], epirubicin 75 mg/m\^2, cyclophosphamide 500 mg/m\^2 x 4 cycles on Day 1), then paclitaxel (80 mg/m\^2 x 4 cycles on Day 1, Day 8, and Day 15) in combination with trastuzumab.	Lapatinib n=9 Participants Participants received lapatinib alone (1250 mg orally \[PO\] once daily \[QD\]). Participants were treated with lapatinib in a 2-week run-in period. On Day 14, a second core needle biopsy was performed, followed by initiation of chemotherapy with 2 combination regimens of 4 cycles each (1 cycle=3 weeks): FEC75 (5-FU 500 mg/m\^2, epirubicin 75 mg/m\^2, cyclophosphamide 500 mg/m\^2 x 4 cycles on Day 1), then paclitaxel (80 mg/m\^2 x 4 cycles on Day 1, Day 8, and Day 15) in combination with lapatinib.	Trastuzumab+Lapatinib Participants received trastuzumab (given as in Arm 1) and lapatinib (750/1000 mg PO QD). Participants were treated with these medications in a 2-week run-in period. On Day 14, a second core needle biopsy was performed, followed by initiation of chemotherapy with 2 combination regimens of 4 cycles each (1 cycle=3 weeks): FEC75 (5-FU 500 mg/m\^2, epirubicin 75 mg/m\^2, cyclophosphamide 500 mg/m\^2 x 4 cycles on Day 1), then paclitaxel (80 mg/m\^2 x 4 cycles on Day 1, Day 8, and Day 15) in combination with trastuzumab+lapatinib.
Mean Intra-tumoral Expression of the Indicated Proteins at Baseline and Day 14 Baseline, EGFR_Tyr1068; pCR=yes, n=0, 4	NA : normalized relative expression level Standard Deviation NA This protein was not significantly expressed at this time point in this treatment arm.	-0.70 : normalized relative expression level Standard Deviation 0.47	—
Mean Intra-tumoral Expression of the Indicated Proteins at Baseline and Day 14 Baseline, Baseline, EGFR_Tyr1068; pCR=no, n=0, 11	NA : normalized relative expression level Standard Deviation NA This protein was not significantly expressed at this time point in this treatment arm.	0.05 : normalized relative expression level Standard Deviation 0.55	—
Mean Intra-tumoral Expression of the Indicated Proteins at Baseline and Day 14 Post Baseline, EGFR_Tyr1068; pCR=yes, n=9, 0	0.65 : normalized relative expression level Standard Deviation 1.02	NA : normalized relative expression level Standard Deviation NA This protein was not significantly expressed at this time point in this treatment arm.	—
Mean Intra-tumoral Expression of the Indicated Proteins at Baseline and Day 14 Post Baseline, EGFR_Tyr1068; pCR=no, n=6, 0	-0.26 : normalized relative expression level Standard Deviation 0.56	NA : normalized relative expression level Standard Deviation NA This protein was not significantly expressed at this time point in this treatment arm.	—
Mean Intra-tumoral Expression of the Indicated Proteins at Baseline and Day 14 Day 14, pSTAT5; pCR=yes, n=11, 6	NA : normalized relative expression level Standard Deviation NA This protein was not significantly expressed at this time point in this treatment arm.	NA : normalized relative expression level Standard Deviation NA This protein was not significantly expressed at this time point in this treatment arm.	—
Mean Intra-tumoral Expression of the Indicated Proteins at Baseline and Day 14 Day 14, pSTAT5; pCR=no, n=9, 11	NA : normalized relative expression level Standard Deviation NA This protein was not significantly expressed at this time point in this treatment arm.	NA : normalized relative expression level Standard Deviation NA This protein was not significantly expressed at this time point in this treatment arm.	—
Mean Intra-tumoral Expression of the Indicated Proteins at Baseline and Day 14 Post Baseline, PI3K; pCR=yes, n=0, 5	NA : normalized relative expression level Standard Deviation NA This protein was not significantly expressed at this time point in this treatment arm.	0.46 : normalized relative expression level Standard Deviation 0.73	—
Mean Intra-tumoral Expression of the Indicated Proteins at Baseline and Day 14 Post Baseline, PI3K; pCR=no, n=0, 10	NA : normalized relative expression level Standard Deviation NA This protein was not significantly expressed at this time point in this treatment arm.	-0.53 : normalized relative expression level Standard Deviation 0.67	—
Mean Intra-tumoral Expression of the Indicated Proteins at Baseline and Day 14 Post Baseline, LC3B; pCR=yes, n=0, 5	NA : normalized relative expression level Standard Deviation NA This protein was not significantly expressed at this time point in this treatment arm.	0.68 : normalized relative expression level Standard Deviation 0.81	—
Mean Intra-tumoral Expression of the Indicated Proteins at Baseline and Day 14 Post Baseline, LC3B; pCR=no, n=0, 10	NA : normalized relative expression level Standard Deviation NA This protein was not significantly expressed at this time point in this treatment arm.	-0.43 : normalized relative expression level Standard Deviation 0.75	—
Mean Intra-tumoral Expression of the Indicated Proteins at Baseline and Day 14 Post Baseline, MMP9; pCR=yes, n=0, 5	NA : normalized relative expression level Standard Deviation NA This protein was not significantly expressed at this time point in this treatment arm.	0.71 : normalized relative expression level Standard Deviation 0.34	—
Mean Intra-tumoral Expression of the Indicated Proteins at Baseline and Day 14 Post Baseline, MMP9; pCR=no, n=0, 5	NA : normalized relative expression level Standard Deviation NA This protein was not significantly expressed at this time point in this treatment arm.	-0.48 : normalized relative expression level Standard Deviation 0.48	—
Mean Intra-tumoral Expression of the Indicated Proteins at Baseline and Day 14 Post Baseline, GSK3_a_b_Tyr279_216; pCR=yes, n=8,0	0.26 : normalized relative expression level Standard Deviation 0.82	NA : normalized relative expression level Standard Deviation NA This protein was not significantly expressed at this time point in this treatment arm.	—
Mean Intra-tumoral Expression of the Indicated Proteins at Baseline and Day 14 Post Baseline, GSK3_a_b_Tyr279_216; pCR=no, n=5,0	-0.86 : normalized relative expression level Standard Deviation 0.67	NA : normalized relative expression level Standard Deviation NA This protein was not significantly expressed at this time point in this treatment arm.	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Tumor core biopsy taken at Baseline and Treatment Day 14

Stem cell data were of poor quality and thus could not be analyzed. Increases or decreases in cancer stem cells and how the changes correlated with response/non-response to treatment were to have been assessed.

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: Tumor core biopsy taken at Baseline and Treatment Day 14

Transcriptional data were of poor quality and thus could not be analyzed. Gene pathways that correlate with response/non-response to treatment were to have been evaluated. The unit of measure is unit less; however, the processed values would be considered normalized relative expression level.

Outcome measures

Outcome data not reported

Adverse Events

Trastuzumab

Serious events: 7 serious events

Other events: 31 other events

Deaths: 0 deaths

Lapatinib

Serious events: 7 serious events

Other events: 34 other events

Deaths: 0 deaths

Trastuzumab+Lapatinib

Serious events: 8 serious events

Other events: 31 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

GSK Response Center

GlaxoSmithKline

Phone: 866-435-7343

Results disclosure agreements

Principal investigator is a sponsor employee GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.
Publication restrictions are in place

Restriction type: OTHER

Measure	Trastuzumab n=32 participants at risk Participants received trastuzumab alone (a loading dose of 4 milligrams \[mg\]/kilogram \[kg\] on Day 1, followed by a dose of 2 mg/kg on Day 1 of Week 2 and weekly thereafter). Participants were treated with trastuzumab in a 2-week run-in period. On Day 14, a second core needle biopsy was performed, followed by initiation of chemotherapy with 2 combination regimens of 4 cycles each (1 cycle=3 weeks): FEC75 (5-fluorouracil \[5-FU\] 500 mg/meters squared \[m\^2\], epirubicin 75 mg/m\^2, cyclophosphamide 500 mg/m\^2 x 4 cycles on Day 1), then paclitaxel (80 mg/m\^2 x 4 cycles on Day 1, Day 8, and Day 15) in combination with trastuzumab.	Lapatinib n=34 participants at risk Participants received lapatinib alone (1250 mg orally \[PO\] once daily \[QD\]). Participants were treated with lapatinib in a 2-week run-in period. On Day 14, a second core needle biopsy was performed, followed by initiation of chemotherapy with 2 combination regimens of 4 cycles each (1 cycle=3 weeks): FEC75 (5-FU 500 mg/m\^2, epirubicin 75 mg/m\^2, cyclophosphamide 500 mg/m\^2 x 4 cycles on Day 1), then paclitaxel (80 mg/m\^2 x 4 cycles on Day 1, Day 8, and Day 15) in combination with lapatinib.	Trastuzumab+Lapatinib n=31 participants at risk Participants received trastuzumab (given as in Arm 1) and lapatinib (750/1000 mg PO QD). Participants were treated with these medications in a 2-week run-in period. On Day 14, a second core needle biopsy was performed, followed by initiation of chemotherapy with 2 combination regimens of 4 cycles each (1 cycle=3 weeks): FEC75 (5-FU 500 mg/m\^2, epirubicin 75 mg/m\^2, cyclophosphamide 500 mg/m\^2 x 4 cycles on Day 1), then paclitaxel (80 mg/m\^2 x 4 cycles on Day 1, Day 8, and Day 15) in combination with trastuzumab+lapatinib.
Blood and lymphatic system disorders Febrile nuetropenia	9.4% 3/32 In the Safety Population, serious and non-serious adverse events were collected from all randomized participants who received at least one dose of investigational product and was based on the actual treatment received if this differed from that to which the participant was randomized.	0.00% 0/34 In the Safety Population, serious and non-serious adverse events were collected from all randomized participants who received at least one dose of investigational product and was based on the actual treatment received if this differed from that to which the participant was randomized.	6.5% 2/31 In the Safety Population, serious and non-serious adverse events were collected from all randomized participants who received at least one dose of investigational product and was based on the actual treatment received if this differed from that to which the participant was randomized.
Blood and lymphatic system disorders Neutropenia	9.4% 3/32 In the Safety Population, serious and non-serious adverse events were collected from all randomized participants who received at least one dose of investigational product and was based on the actual treatment received if this differed from that to which the participant was randomized.	0.00% 0/34 In the Safety Population, serious and non-serious adverse events were collected from all randomized participants who received at least one dose of investigational product and was based on the actual treatment received if this differed from that to which the participant was randomized.	3.2% 1/31 In the Safety Population, serious and non-serious adverse events were collected from all randomized participants who received at least one dose of investigational product and was based on the actual treatment received if this differed from that to which the participant was randomized.
Blood and lymphatic system disorders Anaemia	3.1% 1/32 In the Safety Population, serious and non-serious adverse events were collected from all randomized participants who received at least one dose of investigational product and was based on the actual treatment received if this differed from that to which the participant was randomized.	0.00% 0/34 In the Safety Population, serious and non-serious adverse events were collected from all randomized participants who received at least one dose of investigational product and was based on the actual treatment received if this differed from that to which the participant was randomized.	0.00% 0/31 In the Safety Population, serious and non-serious adverse events were collected from all randomized participants who received at least one dose of investigational product and was based on the actual treatment received if this differed from that to which the participant was randomized.
Infections and infestations Cellilitis	0.00% 0/32 In the Safety Population, serious and non-serious adverse events were collected from all randomized participants who received at least one dose of investigational product and was based on the actual treatment received if this differed from that to which the participant was randomized.	2.9% 1/34 In the Safety Population, serious and non-serious adverse events were collected from all randomized participants who received at least one dose of investigational product and was based on the actual treatment received if this differed from that to which the participant was randomized.	0.00% 0/31 In the Safety Population, serious and non-serious adverse events were collected from all randomized participants who received at least one dose of investigational product and was based on the actual treatment received if this differed from that to which the participant was randomized.
Infections and infestations Diverticulitis	0.00% 0/32 In the Safety Population, serious and non-serious adverse events were collected from all randomized participants who received at least one dose of investigational product and was based on the actual treatment received if this differed from that to which the participant was randomized.	2.9% 1/34 In the Safety Population, serious and non-serious adverse events were collected from all randomized participants who received at least one dose of investigational product and was based on the actual treatment received if this differed from that to which the participant was randomized.	0.00% 0/31 In the Safety Population, serious and non-serious adverse events were collected from all randomized participants who received at least one dose of investigational product and was based on the actual treatment received if this differed from that to which the participant was randomized.
Infections and infestations Gastroenteritis	0.00% 0/32 In the Safety Population, serious and non-serious adverse events were collected from all randomized participants who received at least one dose of investigational product and was based on the actual treatment received if this differed from that to which the participant was randomized.	0.00% 0/34 In the Safety Population, serious and non-serious adverse events were collected from all randomized participants who received at least one dose of investigational product and was based on the actual treatment received if this differed from that to which the participant was randomized.	3.2% 1/31 In the Safety Population, serious and non-serious adverse events were collected from all randomized participants who received at least one dose of investigational product and was based on the actual treatment received if this differed from that to which the participant was randomized.
Infections and infestations Upper respiratory tract infection	3.1% 1/32 In the Safety Population, serious and non-serious adverse events were collected from all randomized participants who received at least one dose of investigational product and was based on the actual treatment received if this differed from that to which the participant was randomized.	0.00% 0/34 In the Safety Population, serious and non-serious adverse events were collected from all randomized participants who received at least one dose of investigational product and was based on the actual treatment received if this differed from that to which the participant was randomized.	0.00% 0/31 In the Safety Population, serious and non-serious adverse events were collected from all randomized participants who received at least one dose of investigational product and was based on the actual treatment received if this differed from that to which the participant was randomized.
Infections and infestations Urinary tract infection	0.00% 0/32 In the Safety Population, serious and non-serious adverse events were collected from all randomized participants who received at least one dose of investigational product and was based on the actual treatment received if this differed from that to which the participant was randomized.	0.00% 0/34 In the Safety Population, serious and non-serious adverse events were collected from all randomized participants who received at least one dose of investigational product and was based on the actual treatment received if this differed from that to which the participant was randomized.	3.2% 1/31 In the Safety Population, serious and non-serious adverse events were collected from all randomized participants who received at least one dose of investigational product and was based on the actual treatment received if this differed from that to which the participant was randomized.
Gastrointestinal disorders Diarrhoea	0.00% 0/32 In the Safety Population, serious and non-serious adverse events were collected from all randomized participants who received at least one dose of investigational product and was based on the actual treatment received if this differed from that to which the participant was randomized.	5.9% 2/34 In the Safety Population, serious and non-serious adverse events were collected from all randomized participants who received at least one dose of investigational product and was based on the actual treatment received if this differed from that to which the participant was randomized.	6.5% 2/31 In the Safety Population, serious and non-serious adverse events were collected from all randomized participants who received at least one dose of investigational product and was based on the actual treatment received if this differed from that to which the participant was randomized.
Gastrointestinal disorders Vomiting	0.00% 0/32 In the Safety Population, serious and non-serious adverse events were collected from all randomized participants who received at least one dose of investigational product and was based on the actual treatment received if this differed from that to which the participant was randomized.	2.9% 1/34 In the Safety Population, serious and non-serious adverse events were collected from all randomized participants who received at least one dose of investigational product and was based on the actual treatment received if this differed from that to which the participant was randomized.	3.2% 1/31 In the Safety Population, serious and non-serious adverse events were collected from all randomized participants who received at least one dose of investigational product and was based on the actual treatment received if this differed from that to which the participant was randomized.
Gastrointestinal disorders Nausea	0.00% 0/32 In the Safety Population, serious and non-serious adverse events were collected from all randomized participants who received at least one dose of investigational product and was based on the actual treatment received if this differed from that to which the participant was randomized.	0.00% 0/34 In the Safety Population, serious and non-serious adverse events were collected from all randomized participants who received at least one dose of investigational product and was based on the actual treatment received if this differed from that to which the participant was randomized.	3.2% 1/31 In the Safety Population, serious and non-serious adverse events were collected from all randomized participants who received at least one dose of investigational product and was based on the actual treatment received if this differed from that to which the participant was randomized.
Gastrointestinal disorders Stomatitis	0.00% 0/32 In the Safety Population, serious and non-serious adverse events were collected from all randomized participants who received at least one dose of investigational product and was based on the actual treatment received if this differed from that to which the participant was randomized.	0.00% 0/34 In the Safety Population, serious and non-serious adverse events were collected from all randomized participants who received at least one dose of investigational product and was based on the actual treatment received if this differed from that to which the participant was randomized.	3.2% 1/31 In the Safety Population, serious and non-serious adverse events were collected from all randomized participants who received at least one dose of investigational product and was based on the actual treatment received if this differed from that to which the participant was randomized.
General disorders Pyrexia	0.00% 0/32 In the Safety Population, serious and non-serious adverse events were collected from all randomized participants who received at least one dose of investigational product and was based on the actual treatment received if this differed from that to which the participant was randomized.	8.8% 3/34 In the Safety Population, serious and non-serious adverse events were collected from all randomized participants who received at least one dose of investigational product and was based on the actual treatment received if this differed from that to which the participant was randomized.	0.00% 0/31 In the Safety Population, serious and non-serious adverse events were collected from all randomized participants who received at least one dose of investigational product and was based on the actual treatment received if this differed from that to which the participant was randomized.
General disorders Chest discomfort	0.00% 0/32 In the Safety Population, serious and non-serious adverse events were collected from all randomized participants who received at least one dose of investigational product and was based on the actual treatment received if this differed from that to which the participant was randomized.	0.00% 0/34 In the Safety Population, serious and non-serious adverse events were collected from all randomized participants who received at least one dose of investigational product and was based on the actual treatment received if this differed from that to which the participant was randomized.	3.2% 1/31 In the Safety Population, serious and non-serious adverse events were collected from all randomized participants who received at least one dose of investigational product and was based on the actual treatment received if this differed from that to which the participant was randomized.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	9.4% 3/32 In the Safety Population, serious and non-serious adverse events were collected from all randomized participants who received at least one dose of investigational product and was based on the actual treatment received if this differed from that to which the participant was randomized.	0.00% 0/34 In the Safety Population, serious and non-serious adverse events were collected from all randomized participants who received at least one dose of investigational product and was based on the actual treatment received if this differed from that to which the participant was randomized.	3.2% 1/31 In the Safety Population, serious and non-serious adverse events were collected from all randomized participants who received at least one dose of investigational product and was based on the actual treatment received if this differed from that to which the participant was randomized.
Respiratory, thoracic and mediastinal disorders Dysponea	0.00% 0/32 In the Safety Population, serious and non-serious adverse events were collected from all randomized participants who received at least one dose of investigational product and was based on the actual treatment received if this differed from that to which the participant was randomized.	0.00% 0/34 In the Safety Population, serious and non-serious adverse events were collected from all randomized participants who received at least one dose of investigational product and was based on the actual treatment received if this differed from that to which the participant was randomized.	3.2% 1/31 In the Safety Population, serious and non-serious adverse events were collected from all randomized participants who received at least one dose of investigational product and was based on the actual treatment received if this differed from that to which the participant was randomized.
Metabolism and nutrition disorders Dehydration	0.00% 0/32 In the Safety Population, serious and non-serious adverse events were collected from all randomized participants who received at least one dose of investigational product and was based on the actual treatment received if this differed from that to which the participant was randomized.	2.9% 1/34 In the Safety Population, serious and non-serious adverse events were collected from all randomized participants who received at least one dose of investigational product and was based on the actual treatment received if this differed from that to which the participant was randomized.	3.2% 1/31 In the Safety Population, serious and non-serious adverse events were collected from all randomized participants who received at least one dose of investigational product and was based on the actual treatment received if this differed from that to which the participant was randomized.
Metabolism and nutrition disorders Hyponatraemia	0.00% 0/32 In the Safety Population, serious and non-serious adverse events were collected from all randomized participants who received at least one dose of investigational product and was based on the actual treatment received if this differed from that to which the participant was randomized.	2.9% 1/34 In the Safety Population, serious and non-serious adverse events were collected from all randomized participants who received at least one dose of investigational product and was based on the actual treatment received if this differed from that to which the participant was randomized.	0.00% 0/31 In the Safety Population, serious and non-serious adverse events were collected from all randomized participants who received at least one dose of investigational product and was based on the actual treatment received if this differed from that to which the participant was randomized.
Investigations Liver function test abnormal	0.00% 0/32 In the Safety Population, serious and non-serious adverse events were collected from all randomized participants who received at least one dose of investigational product and was based on the actual treatment received if this differed from that to which the participant was randomized.	0.00% 0/34 In the Safety Population, serious and non-serious adverse events were collected from all randomized participants who received at least one dose of investigational product and was based on the actual treatment received if this differed from that to which the participant was randomized.	3.2% 1/31 In the Safety Population, serious and non-serious adverse events were collected from all randomized participants who received at least one dose of investigational product and was based on the actual treatment received if this differed from that to which the participant was randomized.
Skin and subcutaneous tissue disorders Swelling face	0.00% 0/32 In the Safety Population, serious and non-serious adverse events were collected from all randomized participants who received at least one dose of investigational product and was based on the actual treatment received if this differed from that to which the participant was randomized.	2.9% 1/34 In the Safety Population, serious and non-serious adverse events were collected from all randomized participants who received at least one dose of investigational product and was based on the actual treatment received if this differed from that to which the participant was randomized.	0.00% 0/31 In the Safety Population, serious and non-serious adverse events were collected from all randomized participants who received at least one dose of investigational product and was based on the actual treatment received if this differed from that to which the participant was randomized.
Vascular disorders Deep vein thrombosis	0.00% 0/32 In the Safety Population, serious and non-serious adverse events were collected from all randomized participants who received at least one dose of investigational product and was based on the actual treatment received if this differed from that to which the participant was randomized.	0.00% 0/34 In the Safety Population, serious and non-serious adverse events were collected from all randomized participants who received at least one dose of investigational product and was based on the actual treatment received if this differed from that to which the participant was randomized.	3.2% 1/31 In the Safety Population, serious and non-serious adverse events were collected from all randomized participants who received at least one dose of investigational product and was based on the actual treatment received if this differed from that to which the participant was randomized.