Trial Outcomes & Findings for Neoadjuvant Study With Chemotherapy, Lapatinib And Trastuzumab In Breast Cancer (NCT NCT00429299)

Last Updated: 2016-03-22

Results Overview

Pathological Complete Response (pCR) is defined by the complete absence of infiltrating tumor cells in the breast and in the lymph nodes. The pathological response in the breast was evaluated according to the criteria of Miller and Payne as follows: Grade 1, no change or some alteration to individual malignant cells, but no reduction in overall cellularity; Grade 2, a minor loss in tumor cells (up to 30%); Grade 3, between an estimated 30% and 90% reduction in tumor cells; Grade 4, marked disappearance of tumor cells, with only a small cluster or a dispersed cell remaining (more than 90% loss); Grade 5, no identifiable malignant cells. Ductal carcinoma in situ (DCIS) may be present. Grades were interpreted as follows: Grade 1-2=no response; Grade 3-4=partial response; Grade 5=complete response. pCR was defined by comparing specimens obtained at Baseline (biopsy) to those obtained upon surgery.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

121 participants

Primary outcome timeframe

At Baseline and surgery (within 5 weeks after the last chemotherapy administration) (assessed up to Study Week 29)

Results posted on

2016-03-22

Participant Flow

Participants underwent core biopsy of the primary tumor, for the histological diagnosis and the biological characterization of the tumor. Radiological investigations were performed to rule out the metastatic disease. After diagnostic confirmation of the infiltrating carcinoma, participants were randomized to one of the three treatment arms.

Participant milestones

Participant milestones
Measure	Chemotherapy (CT) Plus Trastuzumab Participants received chemotherapy (CT), which included paclitaxel 80 milligrams per meters squared (mg/m\^2) weekly for 12 weeks, followed by intravenous (IV) fluorouracil 600 mg/m\^2, IV epidoxorubicin 75 mg/m\^2, and IV cyclophosphamide 600 mg/m\^2, once every 21 days for four treatment courses. Trastuzumab was administered throughout the course of the CT and for two weeks after the last CT administration. The first dose of trastuzumab was administered at 4 milligrams per kilogram (mg/kg) IV for 60 minutes on the day of the first paclitaxel course. Subsequent administrations were given weekly at 2 mg/kg IV for 30 minutes. Treatments were administered for 26 weeks prior to surgery.	CT Plus Lapatinib 1500 mg Participants received CT, which included paclitaxel 80 mg/m\^2 weekly for 12 weeks, followed by IV fluorouracil 600 mg/m\^2, IV epidoxorubicin 75 mg/m\^2, and IV cyclophosphamide 600 mg/m\^2, once every 21 days for four treatment courses. Participants received lapatinib 1500 mg/day orally on an empty stomach throughout the course of the CT and for three weeks after the last CT administration. Treatments were administered for 26 weeks prior to surgery. Following Independent Data Monitoring Committee (IDMC) recommendations, lapatinib doses were reduced to 1250 mg/day orally on an empty stomach.	CT Plus Trastuzumab and Lapatinib 1000 mg Participants received CT, which included paclitaxel 80 mg/m\^2 weekly for 12 weeks, followed by IV fluorouracil 600 mg/m\^2, IV epidoxorubicin 75 mg/m\^2, and IV cyclophosphamide 600 mg/m\^2, once every 21 days for four treatment courses. Trastuzumab was administered throughout the course of the CT and for two weeks after the last CT administration. The first dose of trastuzumab was administered at 4 mg/kg IV for 60 minutes on the day of the first paclitaxel course. Subsequent administrations were given weekly at 2 mg/kg IV for 30 minutes. Participants received lapatinib 1000 mg/day orally on an empty stomach throughout the course of the CT and for three weeks after the last CT administration. Treatments were administered for 26 weeks prior to surgery. Following IDMC recommendations, lapatinib doses were reduced to 750 mg/day orally on an empty stomach.
Overall Study STARTED	36	39	46
Overall Study COMPLETED	32	32	42
Overall Study NOT COMPLETED	4	7	4

Reasons for withdrawal

Reasons for withdrawal
Measure	Chemotherapy (CT) Plus Trastuzumab Participants received chemotherapy (CT), which included paclitaxel 80 milligrams per meters squared (mg/m\^2) weekly for 12 weeks, followed by intravenous (IV) fluorouracil 600 mg/m\^2, IV epidoxorubicin 75 mg/m\^2, and IV cyclophosphamide 600 mg/m\^2, once every 21 days for four treatment courses. Trastuzumab was administered throughout the course of the CT and for two weeks after the last CT administration. The first dose of trastuzumab was administered at 4 milligrams per kilogram (mg/kg) IV for 60 minutes on the day of the first paclitaxel course. Subsequent administrations were given weekly at 2 mg/kg IV for 30 minutes. Treatments were administered for 26 weeks prior to surgery.	CT Plus Lapatinib 1500 mg Participants received CT, which included paclitaxel 80 mg/m\^2 weekly for 12 weeks, followed by IV fluorouracil 600 mg/m\^2, IV epidoxorubicin 75 mg/m\^2, and IV cyclophosphamide 600 mg/m\^2, once every 21 days for four treatment courses. Participants received lapatinib 1500 mg/day orally on an empty stomach throughout the course of the CT and for three weeks after the last CT administration. Treatments were administered for 26 weeks prior to surgery. Following Independent Data Monitoring Committee (IDMC) recommendations, lapatinib doses were reduced to 1250 mg/day orally on an empty stomach.	CT Plus Trastuzumab and Lapatinib 1000 mg Participants received CT, which included paclitaxel 80 mg/m\^2 weekly for 12 weeks, followed by IV fluorouracil 600 mg/m\^2, IV epidoxorubicin 75 mg/m\^2, and IV cyclophosphamide 600 mg/m\^2, once every 21 days for four treatment courses. Trastuzumab was administered throughout the course of the CT and for two weeks after the last CT administration. The first dose of trastuzumab was administered at 4 mg/kg IV for 60 minutes on the day of the first paclitaxel course. Subsequent administrations were given weekly at 2 mg/kg IV for 30 minutes. Participants received lapatinib 1000 mg/day orally on an empty stomach throughout the course of the CT and for three weeks after the last CT administration. Treatments were administered for 26 weeks prior to surgery. Following IDMC recommendations, lapatinib doses were reduced to 750 mg/day orally on an empty stomach.
Overall Study Disease Progression	1	1	0
Overall Study Adverse Event	2	5	1
Overall Study Protocol Violation	1	0	0
Overall Study Withdrawal by Subject	0	1	3

Baseline Characteristics

Neoadjuvant Study With Chemotherapy, Lapatinib And Trastuzumab In Breast Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	CT Plus Trastuzumab n=36 Participants Participants received chemotherapy (CT), which included paclitaxel 80 milligrams per meters squared (mg/m\^2) weekly for 12 weeks, followed by intravenous (IV) fluorouracil 600 mg/m\^2, IV epidoxorubicin 75 mg/m\^2, and IV cyclophosphamide 600 mg/m\^2, once every 21 days for four treatment courses. Trastuzumab was administered throughout the course of the CT and for two weeks after the last CT administration. The first dose of trastuzumab was administered at 4 milligrams per kilogram (mg/kg) IV for 60 minutes on the day of the first paclitaxel course. Subsequent administrations were given weekly at 2 mg/kg IV for 30 minutes. Treatments were administered for 26 weeks prior to surgery.	CT Plus Lapatinib 1500 mg n=39 Participants Participants received CT, which included paclitaxel 80 mg/m\^2 weekly for 12 weeks, followed by IV fluorouracil 600 mg/m\^2, IV epidoxorubicin 75 mg/m\^2, and IV cyclophosphamide 600 mg/m\^2, once every 21 days for four treatment courses. Participants received lapatinib 1500 mg/day orally on an empty stomach throughout the course of the CT and for three weeks after the last CT administration. Treatments were administered for 26 weeks prior to surgery. Following Independent Data Monitoring Committee (IDMC) recommendations, lapatinib doses were reduced to 1250 mg/day orally on an empty stomach.	CT Plus Trastuzumab and Lapatinib 1000 mg n=46 Participants Participants received CT, which included paclitaxel 80 mg/m\^2 weekly for 12 weeks, followed by IV fluorouracil 600 mg/m\^2, IV epidoxorubicin 75 mg/m\^2, and IV cyclophosphamide 600 mg/m\^2, once every 21 days for four treatment courses. Trastuzumab was administered throughout the course of the CT and for two weeks after the last CT administration. The first dose of trastuzumab was administered at 4 mg/kg IV for 60 minutes on the day of the first paclitaxel course. Subsequent administrations were given weekly at 2 mg/kg IV for 30 minutes. Participants received lapatinib 1000 mg/day orally on an empty stomach throughout the course of the CT and for three weeks after the last CT administration. Treatments were administered for 26 weeks prior to surgery. Following IDMC recommendations, lapatinib doses were reduced to 750 mg/day orally on an empty stomach.	Total n=121 Participants Total of all reporting groups
Age, Continuous	50 Years n=5 Participants	49 Years n=7 Participants	49 Years n=5 Participants	49.3 Years n=4 Participants
Sex: Female, Male Female	36 Participants n=5 Participants	39 Participants n=7 Participants	46 Participants n=5 Participants	121 Participants n=4 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race/Ethnicity, Customized Caucasian	34 Participants n=5 Participants	37 Participants n=7 Participants	44 Participants n=5 Participants	115 Participants n=4 Participants
Race/Ethnicity, Customized Asian	1 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants	5 Participants n=4 Participants
Race/Ethnicity, Customized Unknown	1 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants

PRIMARY outcome

Timeframe: At Baseline and surgery (within 5 weeks after the last chemotherapy administration) (assessed up to Study Week 29)

Population: Efficacy Analysis Population: all participants in the Intent-to-Treat Population (all participants who were randomized), except for the 2 participants who were excluded because of withdraw of consent and major protocol deviation

Outcome measures

Outcome measures
Measure	CT Plus Trastuzumab n=36 Participants Participants received chemotherapy (CT), which included paclitaxel 80 milligrams per meters squared (mg/m\^2) weekly for 12 weeks, followed by intravenous (IV) fluorouracil 600 mg/m\^2, IV epidoxorubicin 75 mg/m\^2, and IV cyclophosphamide 600 mg/m\^2, once every 21 days for four treatment courses. Trastuzumab was administered throughout the course of the CT and for two weeks after the last CT administration. The first dose of trastuzumab was administered at 4 milligrams per kilogram (mg/kg) IV for 60 minutes on the day of the first paclitaxel course. Subsequent administrations were given weekly at 2 mg/kg IV for 30 minutes. Treatments were administered for 26 weeks prior to surgery.	CT Plus Lapatinib 1500 mg n=38 Participants Participants received CT, which included paclitaxel 80 mg/m\^2 weekly for 12 weeks, followed by IV fluorouracil 600 mg/m\^2, IV epidoxorubicin 75 mg/m\^2, and IV cyclophosphamide 600 mg/m\^2, once every 21 days for four treatment courses. Participants received lapatinib 1500 mg/day orally on an empty stomach throughout the course of the CT and for three weeks after the last CT administration. Treatments were administered for 26 weeks prior to surgery. Following Independent Data Monitoring Committee (IDMC) recommendations, lapatinib doses were reduced to 1250 mg/day orally on an empty stomach.	CT Plus Trastuzumab and Lapatinib 1000 mg n=45 Participants Participants received CT, which included paclitaxel 80 mg/m\^2 weekly for 12 weeks, followed by IV fluorouracil 600 mg/m\^2, IV epidoxorubicin 75 mg/m\^2, and IV cyclophosphamide 600 mg/m\^2, once every 21 days for four treatment courses. Trastuzumab was administered throughout the course of the CT and for two weeks after the last CT administration. The first dose of trastuzumab was administered at 4 mg/kg IV for 60 minutes on the day of the first paclitaxel course. Subsequent administrations were given weekly at 2 mg/kg IV for 30 minutes. Participants received lapatinib 1000 mg/day orally on an empty stomach throughout the course of the CT and for three weeks after the last CT administration. Treatments were administered for 26 weeks prior to surgery. Following IDMC recommendations, lapatinib doses were reduced to 750 mg/day orally on an empty stomach.
Percentage of Participants With Pathological Complete Response (pCR) in the Breast and in the Lymph Nodes	25 Percentage of participants	26.3 Percentage of participants	46.7 Percentage of participants

SECONDARY outcome

Timeframe: At Baseline and after primary treatment (within 2 weeks before surgery; up to Study Week 27)

Population: Efficacy Analysis Population

The clinical response was evaluated by comparing the tumor size (largest tumor diameter) before (at Baseline \[biopsy\]) and after treatment (before surgery), as assessed by ultrasonography examination. The clinical response was scored by Response Evaluation Criteria in Solid Tumors (RECIST) as follows: complete clinical response: the nodule is not detectable and all the ultrasound abnormality detected at diagnosis disappeared (margins circumscribed, round oval shape, parallel orientation, isoechoic echo pattern, no posterior acoustic features, echogenic lesion boundary, and tumor vascularity not present); partial clinical response: the longest diameter of the tumor has been reduced by \>50%, and the ultrasound characteristics of the tumor persist; no response (stable disease): the longest diameter of the tumor has been reduced by \<50% or has increased by no more than 20% from the starting value; progressive disease: tumor longest diameter has increased \>20% from the starting value.

Outcome measures

Outcome measures
Measure	CT Plus Trastuzumab n=36 Participants Participants received chemotherapy (CT), which included paclitaxel 80 milligrams per meters squared (mg/m\^2) weekly for 12 weeks, followed by intravenous (IV) fluorouracil 600 mg/m\^2, IV epidoxorubicin 75 mg/m\^2, and IV cyclophosphamide 600 mg/m\^2, once every 21 days for four treatment courses. Trastuzumab was administered throughout the course of the CT and for two weeks after the last CT administration. The first dose of trastuzumab was administered at 4 milligrams per kilogram (mg/kg) IV for 60 minutes on the day of the first paclitaxel course. Subsequent administrations were given weekly at 2 mg/kg IV for 30 minutes. Treatments were administered for 26 weeks prior to surgery.	CT Plus Lapatinib 1500 mg n=38 Participants Participants received CT, which included paclitaxel 80 mg/m\^2 weekly for 12 weeks, followed by IV fluorouracil 600 mg/m\^2, IV epidoxorubicin 75 mg/m\^2, and IV cyclophosphamide 600 mg/m\^2, once every 21 days for four treatment courses. Participants received lapatinib 1500 mg/day orally on an empty stomach throughout the course of the CT and for three weeks after the last CT administration. Treatments were administered for 26 weeks prior to surgery. Following Independent Data Monitoring Committee (IDMC) recommendations, lapatinib doses were reduced to 1250 mg/day orally on an empty stomach.	CT Plus Trastuzumab and Lapatinib 1000 mg n=45 Participants Participants received CT, which included paclitaxel 80 mg/m\^2 weekly for 12 weeks, followed by IV fluorouracil 600 mg/m\^2, IV epidoxorubicin 75 mg/m\^2, and IV cyclophosphamide 600 mg/m\^2, once every 21 days for four treatment courses. Trastuzumab was administered throughout the course of the CT and for two weeks after the last CT administration. The first dose of trastuzumab was administered at 4 mg/kg IV for 60 minutes on the day of the first paclitaxel course. Subsequent administrations were given weekly at 2 mg/kg IV for 30 minutes. Participants received lapatinib 1000 mg/day orally on an empty stomach throughout the course of the CT and for three weeks after the last CT administration. Treatments were administered for 26 weeks prior to surgery. Following IDMC recommendations, lapatinib doses were reduced to 750 mg/day orally on an empty stomach.
Percentage of Participants With the Indicated Clinical Objective Response (Complete Response and Partial Response), Stable Disease, and Progressive Disease, as Assessed by Ultrasonography Complete Response (CR)	30.5 Percentage of participants	15.8 Percentage of participants	42.2 Percentage of participants
Percentage of Participants With the Indicated Clinical Objective Response (Complete Response and Partial Response), Stable Disease, and Progressive Disease, as Assessed by Ultrasonography Partial Response (PR)	41.7 Percentage of participants	44.7 Percentage of participants	28.9 Percentage of participants
Percentage of Participants With the Indicated Clinical Objective Response (Complete Response and Partial Response), Stable Disease, and Progressive Disease, as Assessed by Ultrasonography Stable Disease	5.5 Percentage of participants	13.1 Percentage of participants	0 Percentage of participants
Percentage of Participants With the Indicated Clinical Objective Response (Complete Response and Partial Response), Stable Disease, and Progressive Disease, as Assessed by Ultrasonography Progressive Disease	2.8 Percentage of participants	2.6 Percentage of participants	0 Percentage of participants
Percentage of Participants With the Indicated Clinical Objective Response (Complete Response and Partial Response), Stable Disease, and Progressive Disease, as Assessed by Ultrasonography Not Evaluable	19.4 Percentage of participants	23.7 Percentage of participants	28.9 Percentage of participants

SECONDARY outcome

Timeframe: At Baseline and at surgery (up to Study Week 29)

Population: Efficacy Analysis Population

The percentage of participants who had BCS and mastectomy and who were initiallycandidates for mastectomy and who actually had BCS was measured. At Baseline, the surgeon stated, within 4 weeks before starting the primary treatment, which type of surgical treatment he would perform in the absence of primary therapy and in the case of primary therapy (if the tumor size was reduced by the primary treatment to less than 3 centimeters), and the reasons for these choices. The rules for choosing the type of surgical treatment are reported in the Consensus Conference on Primary Treatment of Early Breast Cancer. The surgeon was to have re-evaluated the participant after primary treatment. In cases in which the type of surgical procedure was different from that originally programmed, the reason for this chance was to have been reported.

Outcome measures

Outcome measures
Measure	CT Plus Trastuzumab n=36 Participants Participants received chemotherapy (CT), which included paclitaxel 80 milligrams per meters squared (mg/m\^2) weekly for 12 weeks, followed by intravenous (IV) fluorouracil 600 mg/m\^2, IV epidoxorubicin 75 mg/m\^2, and IV cyclophosphamide 600 mg/m\^2, once every 21 days for four treatment courses. Trastuzumab was administered throughout the course of the CT and for two weeks after the last CT administration. The first dose of trastuzumab was administered at 4 milligrams per kilogram (mg/kg) IV for 60 minutes on the day of the first paclitaxel course. Subsequent administrations were given weekly at 2 mg/kg IV for 30 minutes. Treatments were administered for 26 weeks prior to surgery.	CT Plus Lapatinib 1500 mg n=38 Participants Participants received CT, which included paclitaxel 80 mg/m\^2 weekly for 12 weeks, followed by IV fluorouracil 600 mg/m\^2, IV epidoxorubicin 75 mg/m\^2, and IV cyclophosphamide 600 mg/m\^2, once every 21 days for four treatment courses. Participants received lapatinib 1500 mg/day orally on an empty stomach throughout the course of the CT and for three weeks after the last CT administration. Treatments were administered for 26 weeks prior to surgery. Following Independent Data Monitoring Committee (IDMC) recommendations, lapatinib doses were reduced to 1250 mg/day orally on an empty stomach.	CT Plus Trastuzumab and Lapatinib 1000 mg n=45 Participants Participants received CT, which included paclitaxel 80 mg/m\^2 weekly for 12 weeks, followed by IV fluorouracil 600 mg/m\^2, IV epidoxorubicin 75 mg/m\^2, and IV cyclophosphamide 600 mg/m\^2, once every 21 days for four treatment courses. Trastuzumab was administered throughout the course of the CT and for two weeks after the last CT administration. The first dose of trastuzumab was administered at 4 mg/kg IV for 60 minutes on the day of the first paclitaxel course. Subsequent administrations were given weekly at 2 mg/kg IV for 30 minutes. Participants received lapatinib 1000 mg/day orally on an empty stomach throughout the course of the CT and for three weeks after the last CT administration. Treatments were administered for 26 weeks prior to surgery. Following IDMC recommendations, lapatinib doses were reduced to 750 mg/day orally on an empty stomach.
Percentage of Participants Who Had Breast-conserving Surgery (BCS), Mastectomy, and Conversion From Mastectomy to BCS BCS	66.7 Percentage of participants	57.9 Percentage of participants	68.9 Percentage of participants
Percentage of Participants Who Had Breast-conserving Surgery (BCS), Mastectomy, and Conversion From Mastectomy to BCS Mastectomy	33.3 Percentage of participants	39.5 Percentage of participants	31.1 Percentage of participants
Percentage of Participants Who Had Breast-conserving Surgery (BCS), Mastectomy, and Conversion From Mastectomy to BCS Conversion from mastectomy to BCS	61.9 Percentage of participants	42.8 Percentage of participants	60 Percentage of participants

SECONDARY outcome

Timeframe: From randomization up to Study Week 307

Population: ITT Population: all participants who were randomized

Time to treatment failure (TTF) is defined as the interval of time between the date of randomization and the earliest date of disease progression, premature treatment discontinuation and death due to any cause. The overall disease progression date is the earlier of the two disease progression dates from ultrasonography and mammography assessments. For ultrasonography, disease progression is defined as at least 20% increase in the longest diameter of the primary lesion at pre-surgery comparing to Baseline. For mammography, disease progression is defined as at least 20% increase in the larger nodule dimension at pre-surgery comparing to Baseline. For participants who has neither progressed, pre-maturely withdrawn or died, time to treatment failure will be censored at the latest date of ultrasonography and mammography tumor assessments.

Outcome measures

Outcome measures
Measure	CT Plus Trastuzumab n=36 Participants Participants received chemotherapy (CT), which included paclitaxel 80 milligrams per meters squared (mg/m\^2) weekly for 12 weeks, followed by intravenous (IV) fluorouracil 600 mg/m\^2, IV epidoxorubicin 75 mg/m\^2, and IV cyclophosphamide 600 mg/m\^2, once every 21 days for four treatment courses. Trastuzumab was administered throughout the course of the CT and for two weeks after the last CT administration. The first dose of trastuzumab was administered at 4 milligrams per kilogram (mg/kg) IV for 60 minutes on the day of the first paclitaxel course. Subsequent administrations were given weekly at 2 mg/kg IV for 30 minutes. Treatments were administered for 26 weeks prior to surgery.	CT Plus Lapatinib 1500 mg n=39 Participants Participants received CT, which included paclitaxel 80 mg/m\^2 weekly for 12 weeks, followed by IV fluorouracil 600 mg/m\^2, IV epidoxorubicin 75 mg/m\^2, and IV cyclophosphamide 600 mg/m\^2, once every 21 days for four treatment courses. Participants received lapatinib 1500 mg/day orally on an empty stomach throughout the course of the CT and for three weeks after the last CT administration. Treatments were administered for 26 weeks prior to surgery. Following Independent Data Monitoring Committee (IDMC) recommendations, lapatinib doses were reduced to 1250 mg/day orally on an empty stomach.	CT Plus Trastuzumab and Lapatinib 1000 mg n=46 Participants Participants received CT, which included paclitaxel 80 mg/m\^2 weekly for 12 weeks, followed by IV fluorouracil 600 mg/m\^2, IV epidoxorubicin 75 mg/m\^2, and IV cyclophosphamide 600 mg/m\^2, once every 21 days for four treatment courses. Trastuzumab was administered throughout the course of the CT and for two weeks after the last CT administration. The first dose of trastuzumab was administered at 4 mg/kg IV for 60 minutes on the day of the first paclitaxel course. Subsequent administrations were given weekly at 2 mg/kg IV for 30 minutes. Participants received lapatinib 1000 mg/day orally on an empty stomach throughout the course of the CT and for three weeks after the last CT administration. Treatments were administered for 26 weeks prior to surgery. Following IDMC recommendations, lapatinib doses were reduced to 750 mg/day orally on an empty stomach.
Time to Treatment Failure From the Start of Primary Therapy	28.2 Months Interval 28.2 to 59.8	39.6 Months The confidence limits for the median value are not estimable because there are no time points that satisfy the condition using the method of Klein and Moeschberger (1997).	39.6 Months Interval 6.3 to 39.6

SECONDARY outcome

Timeframe: From randomization up to 29 weeks

Population: ITT Population

Treatment failure is defined as the occurrence of local tumor progression (including ipsilateral and controlateral breast), distant tumor progression, permanent treatment discontinuation (either for the experimental or conventional arm), or death due to any cause.

Outcome measures

Outcome measures
Measure	CT Plus Trastuzumab n=36 Participants Participants received chemotherapy (CT), which included paclitaxel 80 milligrams per meters squared (mg/m\^2) weekly for 12 weeks, followed by intravenous (IV) fluorouracil 600 mg/m\^2, IV epidoxorubicin 75 mg/m\^2, and IV cyclophosphamide 600 mg/m\^2, once every 21 days for four treatment courses. Trastuzumab was administered throughout the course of the CT and for two weeks after the last CT administration. The first dose of trastuzumab was administered at 4 milligrams per kilogram (mg/kg) IV for 60 minutes on the day of the first paclitaxel course. Subsequent administrations were given weekly at 2 mg/kg IV for 30 minutes. Treatments were administered for 26 weeks prior to surgery.	CT Plus Lapatinib 1500 mg n=39 Participants Participants received CT, which included paclitaxel 80 mg/m\^2 weekly for 12 weeks, followed by IV fluorouracil 600 mg/m\^2, IV epidoxorubicin 75 mg/m\^2, and IV cyclophosphamide 600 mg/m\^2, once every 21 days for four treatment courses. Participants received lapatinib 1500 mg/day orally on an empty stomach throughout the course of the CT and for three weeks after the last CT administration. Treatments were administered for 26 weeks prior to surgery. Following Independent Data Monitoring Committee (IDMC) recommendations, lapatinib doses were reduced to 1250 mg/day orally on an empty stomach.	CT Plus Trastuzumab and Lapatinib 1000 mg n=46 Participants Participants received CT, which included paclitaxel 80 mg/m\^2 weekly for 12 weeks, followed by IV fluorouracil 600 mg/m\^2, IV epidoxorubicin 75 mg/m\^2, and IV cyclophosphamide 600 mg/m\^2, once every 21 days for four treatment courses. Trastuzumab was administered throughout the course of the CT and for two weeks after the last CT administration. The first dose of trastuzumab was administered at 4 mg/kg IV for 60 minutes on the day of the first paclitaxel course. Subsequent administrations were given weekly at 2 mg/kg IV for 30 minutes. Participants received lapatinib 1000 mg/day orally on an empty stomach throughout the course of the CT and for three weeks after the last CT administration. Treatments were administered for 26 weeks prior to surgery. Following IDMC recommendations, lapatinib doses were reduced to 750 mg/day orally on an empty stomach.
Number of Participants With Treatment Failure	7 Participants	9 Participants	7 Participants

SECONDARY outcome

Timeframe: At Baseline and Withdrawal (assessed up to Study Week 29)

Population: ITT Population. Only those participants contributing data to the indicated time points were analyzed.

The percentage of inhibition of intermediate (EGFR, HER2, pMAPK, pAKT, PTEN, and PI3KCA) and final (TUNEL and Ki67) biomarkers of the proliferation and apoptosis pathways was calculated as the difference between the staining scores before (Baseline \[biopsy\]) and after treatment (withdrawal).

Outcome measures

Outcome measures
Measure	CT Plus Trastuzumab n=34 Participants Participants received chemotherapy (CT), which included paclitaxel 80 milligrams per meters squared (mg/m\^2) weekly for 12 weeks, followed by intravenous (IV) fluorouracil 600 mg/m\^2, IV epidoxorubicin 75 mg/m\^2, and IV cyclophosphamide 600 mg/m\^2, once every 21 days for four treatment courses. Trastuzumab was administered throughout the course of the CT and for two weeks after the last CT administration. The first dose of trastuzumab was administered at 4 milligrams per kilogram (mg/kg) IV for 60 minutes on the day of the first paclitaxel course. Subsequent administrations were given weekly at 2 mg/kg IV for 30 minutes. Treatments were administered for 26 weeks prior to surgery.	CT Plus Lapatinib 1500 mg n=37 Participants Participants received CT, which included paclitaxel 80 mg/m\^2 weekly for 12 weeks, followed by IV fluorouracil 600 mg/m\^2, IV epidoxorubicin 75 mg/m\^2, and IV cyclophosphamide 600 mg/m\^2, once every 21 days for four treatment courses. Participants received lapatinib 1500 mg/day orally on an empty stomach throughout the course of the CT and for three weeks after the last CT administration. Treatments were administered for 26 weeks prior to surgery. Following Independent Data Monitoring Committee (IDMC) recommendations, lapatinib doses were reduced to 1250 mg/day orally on an empty stomach.	CT Plus Trastuzumab and Lapatinib 1000 mg n=42 Participants Participants received CT, which included paclitaxel 80 mg/m\^2 weekly for 12 weeks, followed by IV fluorouracil 600 mg/m\^2, IV epidoxorubicin 75 mg/m\^2, and IV cyclophosphamide 600 mg/m\^2, once every 21 days for four treatment courses. Trastuzumab was administered throughout the course of the CT and for two weeks after the last CT administration. The first dose of trastuzumab was administered at 4 mg/kg IV for 60 minutes on the day of the first paclitaxel course. Subsequent administrations were given weekly at 2 mg/kg IV for 30 minutes. Participants received lapatinib 1000 mg/day orally on an empty stomach throughout the course of the CT and for three weeks after the last CT administration. Treatments were administered for 26 weeks prior to surgery. Following IDMC recommendations, lapatinib doses were reduced to 750 mg/day orally on an empty stomach.
Percentage of Inhibition of Biomarkers Ki67, pAKT, pMAPK, Tunel Test, PTEN, and pEGFR After Treatment Ki67, Baseline, n=34, 37, 42	25 Percentage of inhibition Interval 10.0 to 60.0	25 Percentage of inhibition Interval 4.0 to 70.0	30 Percentage of inhibition Interval 4.0 to 90.0
Percentage of Inhibition of Biomarkers Ki67, pAKT, pMAPK, Tunel Test, PTEN, and pEGFR After Treatment Ki67, Post-treatment, n=22, 21, 18	19 Percentage of inhibition Interval 1.0 to 50.0	15 Percentage of inhibition Interval 3.0 to 40.0	10 Percentage of inhibition Interval 1.0 to 30.0
Percentage of Inhibition of Biomarkers Ki67, pAKT, pMAPK, Tunel Test, PTEN, and pEGFR After Treatment pAKT, Baseline, n=34, 37, 42	2.5 Percentage of inhibition Interval 1.0 to 100.0	10 Percentage of inhibition Interval 0.0 to 90.0	0 Percentage of inhibition Interval 0.0 to 90.0
Percentage of Inhibition of Biomarkers Ki67, pAKT, pMAPK, Tunel Test, PTEN, and pEGFR After Treatment pAKT, Post-treatment, 18, 20, 17	0 Percentage of inhibition Interval 0.0 to 10.0	0 Percentage of inhibition Interval 0.0 to 90.0	0 Percentage of inhibition Interval 0.0 to 90.0
Percentage of Inhibition of Biomarkers Ki67, pAKT, pMAPK, Tunel Test, PTEN, and pEGFR After Treatment pMAPK, Baseline, n=9, 5, 7	0 Percentage of inhibition Interval 0.0 to 10.0	10 Percentage of inhibition Interval 0.0 to 80.0	0 Percentage of inhibition Interval 0.0 to 20.0
Percentage of Inhibition of Biomarkers Ki67, pAKT, pMAPK, Tunel Test, PTEN, and pEGFR After Treatment pMAPK, Post-treatment, n=0, 1, 2	NA Percentage of inhibition No participants were analyzed for pMAPK at this time point.	70 Percentage of inhibition Interval 70.0 to 70.0	5 Percentage of inhibition Interval 0.0 to 10.0
Percentage of Inhibition of Biomarkers Ki67, pAKT, pMAPK, Tunel Test, PTEN, and pEGFR After Treatment Tunel test, Baseline, n=25, 27, 31	0.4 Percentage of inhibition Interval 0.05 to 2.6	0.58 Percentage of inhibition Interval 0.05 to 1.5	0.8 Percentage of inhibition Interval 0.05 to 2.5
Percentage of Inhibition of Biomarkers Ki67, pAKT, pMAPK, Tunel Test, PTEN, and pEGFR After Treatment Tunel test, Post-treatment, n=7, 12, 11	0.1 Percentage of inhibition Interval 0.05 to 1.1	0.1 Percentage of inhibition Interval 0.05 to 0.55	0.05 Percentage of inhibition Interval 0.05 to 0.4
Percentage of Inhibition of Biomarkers Ki67, pAKT, pMAPK, Tunel Test, PTEN, and pEGFR After Treatment PTEN, Baseline, n=27, 35, 37	80 Percentage of inhibition Interval 0.0 to 100.0	80 Percentage of inhibition Interval 0.0 to 100.0	90 Percentage of inhibition Interval 0.0 to 100.0
Percentage of Inhibition of Biomarkers Ki67, pAKT, pMAPK, Tunel Test, PTEN, and pEGFR After Treatment PTEN, Post-treatment, n=14, 17, 15	100 Percentage of inhibition Interval 10.0 to 100.0	80 Percentage of inhibition Interval 0.0 to 100.0	80 Percentage of inhibition Interval 0.0 to 100.0
Percentage of Inhibition of Biomarkers Ki67, pAKT, pMAPK, Tunel Test, PTEN, and pEGFR After Treatment pEGFR, Baseline, n=21, 24, 28	0 Percentage of inhibition Interval 0.0 to 80.0	0 Percentage of inhibition Interval 0.0 to 60.0	0 Percentage of inhibition Interval 0.0 to 70.0
Percentage of Inhibition of Biomarkers Ki67, pAKT, pMAPK, Tunel Test, PTEN, and pEGFR After Treatment pEGFR, Post-treatment, n=5, 10, 11	0 Percentage of inhibition Interval 0.0 to 90.0	0 Percentage of inhibition Interval 0.0 to 0.0	0 Percentage of inhibition Interval 0.0 to 5.0

SECONDARY outcome

Timeframe: From the first dose of randomized therapy to 30 days after the last dose of randomized therapy (assessed up to Study Week 29)

Population: Safety Population: all randomized participants

An AE is defined as any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect. Medical or scientific judgment had been exercised in deciding whether reporting was appropriate in other situations.

Outcome measures

Outcome measures
Measure	CT Plus Trastuzumab n=36 Participants Participants received chemotherapy (CT), which included paclitaxel 80 milligrams per meters squared (mg/m\^2) weekly for 12 weeks, followed by intravenous (IV) fluorouracil 600 mg/m\^2, IV epidoxorubicin 75 mg/m\^2, and IV cyclophosphamide 600 mg/m\^2, once every 21 days for four treatment courses. Trastuzumab was administered throughout the course of the CT and for two weeks after the last CT administration. The first dose of trastuzumab was administered at 4 milligrams per kilogram (mg/kg) IV for 60 minutes on the day of the first paclitaxel course. Subsequent administrations were given weekly at 2 mg/kg IV for 30 minutes. Treatments were administered for 26 weeks prior to surgery.	CT Plus Lapatinib 1500 mg n=39 Participants Participants received CT, which included paclitaxel 80 mg/m\^2 weekly for 12 weeks, followed by IV fluorouracil 600 mg/m\^2, IV epidoxorubicin 75 mg/m\^2, and IV cyclophosphamide 600 mg/m\^2, once every 21 days for four treatment courses. Participants received lapatinib 1500 mg/day orally on an empty stomach throughout the course of the CT and for three weeks after the last CT administration. Treatments were administered for 26 weeks prior to surgery. Following Independent Data Monitoring Committee (IDMC) recommendations, lapatinib doses were reduced to 1250 mg/day orally on an empty stomach.	CT Plus Trastuzumab and Lapatinib 1000 mg n=46 Participants Participants received CT, which included paclitaxel 80 mg/m\^2 weekly for 12 weeks, followed by IV fluorouracil 600 mg/m\^2, IV epidoxorubicin 75 mg/m\^2, and IV cyclophosphamide 600 mg/m\^2, once every 21 days for four treatment courses. Trastuzumab was administered throughout the course of the CT and for two weeks after the last CT administration. The first dose of trastuzumab was administered at 4 mg/kg IV for 60 minutes on the day of the first paclitaxel course. Subsequent administrations were given weekly at 2 mg/kg IV for 30 minutes. Participants received lapatinib 1000 mg/day orally on an empty stomach throughout the course of the CT and for three weeks after the last CT administration. Treatments were administered for 26 weeks prior to surgery. Following IDMC recommendations, lapatinib doses were reduced to 750 mg/day orally on an empty stomach.
Number of Participants With Any Adverse Event (AE), Including Serious Adverse Events (SAEs), Occurring in >=5% of Participants	35 Participants	38 Participants	46 Participants

SECONDARY outcome

Timeframe: Baseline

Population: ITT Population. Only those participants for which high-quality tumor tissue samples were available were analyzed.

Analysis of mutations in the PI3KCA gene was performed from RNA extracted from frozen tumor tissue samples (sections). A gene is either a wild-type (no mutation) or mutated (presence of a mutation). Exons 9 and 20 of the PI3KCA gene were accessed (high frequency mutation at these two spots).

Outcome measures

Outcome measures
Measure	CT Plus Trastuzumab n=30 Participants Participants received chemotherapy (CT), which included paclitaxel 80 milligrams per meters squared (mg/m\^2) weekly for 12 weeks, followed by intravenous (IV) fluorouracil 600 mg/m\^2, IV epidoxorubicin 75 mg/m\^2, and IV cyclophosphamide 600 mg/m\^2, once every 21 days for four treatment courses. Trastuzumab was administered throughout the course of the CT and for two weeks after the last CT administration. The first dose of trastuzumab was administered at 4 milligrams per kilogram (mg/kg) IV for 60 minutes on the day of the first paclitaxel course. Subsequent administrations were given weekly at 2 mg/kg IV for 30 minutes. Treatments were administered for 26 weeks prior to surgery.	CT Plus Lapatinib 1500 mg n=37 Participants Participants received CT, which included paclitaxel 80 mg/m\^2 weekly for 12 weeks, followed by IV fluorouracil 600 mg/m\^2, IV epidoxorubicin 75 mg/m\^2, and IV cyclophosphamide 600 mg/m\^2, once every 21 days for four treatment courses. Participants received lapatinib 1500 mg/day orally on an empty stomach throughout the course of the CT and for three weeks after the last CT administration. Treatments were administered for 26 weeks prior to surgery. Following Independent Data Monitoring Committee (IDMC) recommendations, lapatinib doses were reduced to 1250 mg/day orally on an empty stomach.	CT Plus Trastuzumab and Lapatinib 1000 mg n=42 Participants Participants received CT, which included paclitaxel 80 mg/m\^2 weekly for 12 weeks, followed by IV fluorouracil 600 mg/m\^2, IV epidoxorubicin 75 mg/m\^2, and IV cyclophosphamide 600 mg/m\^2, once every 21 days for four treatment courses. Trastuzumab was administered throughout the course of the CT and for two weeks after the last CT administration. The first dose of trastuzumab was administered at 4 mg/kg IV for 60 minutes on the day of the first paclitaxel course. Subsequent administrations were given weekly at 2 mg/kg IV for 30 minutes. Participants received lapatinib 1000 mg/day orally on an empty stomach throughout the course of the CT and for three weeks after the last CT administration. Treatments were administered for 26 weeks prior to surgery. Following IDMC recommendations, lapatinib doses were reduced to 750 mg/day orally on an empty stomach.
Number of Variations/Somatic Mutation in PI3KCA at Baseline PIK3CA Exon 9 Wild-Type	29 Variations/Somatic mutations	35 Variations/Somatic mutations	39 Variations/Somatic mutations
Number of Variations/Somatic Mutation in PI3KCA at Baseline PIK3CA Exon 9 Mutation	1 Variations/Somatic mutations	2 Variations/Somatic mutations	3 Variations/Somatic mutations
Number of Variations/Somatic Mutation in PI3KCA at Baseline PIK3CA Exon 20 Wild-type	25 Variations/Somatic mutations	31 Variations/Somatic mutations	37 Variations/Somatic mutations
Number of Variations/Somatic Mutation in PI3KCA at Baseline PIK3CA Exon 20 Mutation	5 Variations/Somatic mutations	6 Variations/Somatic mutations	5 Variations/Somatic mutations

Adverse Events

CT Plus Trastuzumab

Serious events: 14 serious events

Other events: 35 other events

Deaths: 0 deaths

CT Plus Lapatinib 1500 mg

Serious events: 13 serious events

Other events: 38 other events

Deaths: 0 deaths

CT Plus Trastuzumab and Lapatinib 1000 mg

Serious events: 21 serious events

Other events: 46 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	CT Plus Trastuzumab n=36 participants at risk Participants received chemotherapy (CT), which included paclitaxel 80 milligrams per meters squared (mg/m\^2) weekly for 12 weeks, followed by intravenous (IV) fluorouracil 600 mg/m\^2, IV epidoxorubicin 75 mg/m\^2, and IV cyclophosphamide 600 mg/m\^2, once every 21 days for four treatment courses. Trastuzumab was administered throughout the course of the CT and for two weeks after the last CT administration. The first dose of trastuzumab was administered at 4 milligrams per kilogram (mg/kg) IV for 60 minutes on the day of the first paclitaxel course. Subsequent administrations were given weekly at 2 mg/kg IV for 30 minutes. Treatments were administered for 26 weeks prior to surgery.	CT Plus Lapatinib 1500 mg n=39 participants at risk Participants received CT, which included paclitaxel 80 mg/m\^2 weekly for 12 weeks, followed by IV fluorouracil 600 mg/m\^2, IV epidoxorubicin 75 mg/m\^2, and IV cyclophosphamide 600 mg/m\^2, once every 21 days for four treatment courses. Participants received lapatinib 1500 mg/day orally on an empty stomach throughout the course of the CT and for three weeks after the last CT administration. Treatments were administered for 26 weeks prior to surgery. Following Independent Data Monitoring Committee (IDMC) recommendations, lapatinib doses were reduced to 1250 mg/day orally on an empty stomach.	CT Plus Trastuzumab and Lapatinib 1000 mg n=46 participants at risk Participants received CT, which included paclitaxel 80 mg/m\^2 weekly for 12 weeks, followed by IV fluorouracil 600 mg/m\^2, IV epidoxorubicin 75 mg/m\^2, and IV cyclophosphamide 600 mg/m\^2, once every 21 days for four treatment courses. Trastuzumab was administered throughout the course of the CT and for two weeks after the last CT administration. The first dose of trastuzumab was administered at 4 mg/kg IV for 60 minutes on the day of the first paclitaxel course. Subsequent administrations were given weekly at 2 mg/kg IV for 30 minutes. Participants received lapatinib 1000 mg/day orally on an empty stomach throughout the course of the CT and for three weeks after the last CT administration. Treatments were administered for 26 weeks prior to surgery. Following IDMC recommendations, lapatinib doses were reduced to 750 mg/day orally on an empty stomach.
Blood and lymphatic system disorders Neutropenia	27.8% 10/36 • Serious adverse events (SAEs) and non-serious AEs were collected from the first dose of randomized therapy to 30 days after the last dose of randomized therapy (up to Study Week 29). SAEs and non-serious AEs were collected for all participants who received at least one dose of study medication.	17.9% 7/39 • Serious adverse events (SAEs) and non-serious AEs were collected from the first dose of randomized therapy to 30 days after the last dose of randomized therapy (up to Study Week 29). SAEs and non-serious AEs were collected for all participants who received at least one dose of study medication.	34.8% 16/46 • Serious adverse events (SAEs) and non-serious AEs were collected from the first dose of randomized therapy to 30 days after the last dose of randomized therapy (up to Study Week 29). SAEs and non-serious AEs were collected for all participants who received at least one dose of study medication.
Blood and lymphatic system disorders Febrile neutropenia	2.8% 1/36 • Serious adverse events (SAEs) and non-serious AEs were collected from the first dose of randomized therapy to 30 days after the last dose of randomized therapy (up to Study Week 29). SAEs and non-serious AEs were collected for all participants who received at least one dose of study medication.	5.1% 2/39 • Serious adverse events (SAEs) and non-serious AEs were collected from the first dose of randomized therapy to 30 days after the last dose of randomized therapy (up to Study Week 29). SAEs and non-serious AEs were collected for all participants who received at least one dose of study medication.	2.2% 1/46 • Serious adverse events (SAEs) and non-serious AEs were collected from the first dose of randomized therapy to 30 days after the last dose of randomized therapy (up to Study Week 29). SAEs and non-serious AEs were collected for all participants who received at least one dose of study medication.
Gastrointestinal disorders Diarrhoea	0.00% 0/36 • Serious adverse events (SAEs) and non-serious AEs were collected from the first dose of randomized therapy to 30 days after the last dose of randomized therapy (up to Study Week 29). SAEs and non-serious AEs were collected for all participants who received at least one dose of study medication.	7.7% 3/39 • Serious adverse events (SAEs) and non-serious AEs were collected from the first dose of randomized therapy to 30 days after the last dose of randomized therapy (up to Study Week 29). SAEs and non-serious AEs were collected for all participants who received at least one dose of study medication.	2.2% 1/46 • Serious adverse events (SAEs) and non-serious AEs were collected from the first dose of randomized therapy to 30 days after the last dose of randomized therapy (up to Study Week 29). SAEs and non-serious AEs were collected for all participants who received at least one dose of study medication.
Gastrointestinal disorders Vomiting	2.8% 1/36 • Serious adverse events (SAEs) and non-serious AEs were collected from the first dose of randomized therapy to 30 days after the last dose of randomized therapy (up to Study Week 29). SAEs and non-serious AEs were collected for all participants who received at least one dose of study medication.	7.7% 3/39 • Serious adverse events (SAEs) and non-serious AEs were collected from the first dose of randomized therapy to 30 days after the last dose of randomized therapy (up to Study Week 29). SAEs and non-serious AEs were collected for all participants who received at least one dose of study medication.	0.00% 0/46 • Serious adverse events (SAEs) and non-serious AEs were collected from the first dose of randomized therapy to 30 days after the last dose of randomized therapy (up to Study Week 29). SAEs and non-serious AEs were collected for all participants who received at least one dose of study medication.
Gastrointestinal disorders Abdominal pain	0.00% 0/36 • Serious adverse events (SAEs) and non-serious AEs were collected from the first dose of randomized therapy to 30 days after the last dose of randomized therapy (up to Study Week 29). SAEs and non-serious AEs were collected for all participants who received at least one dose of study medication.	2.6% 1/39 • Serious adverse events (SAEs) and non-serious AEs were collected from the first dose of randomized therapy to 30 days after the last dose of randomized therapy (up to Study Week 29). SAEs and non-serious AEs were collected for all participants who received at least one dose of study medication.	0.00% 0/46 • Serious adverse events (SAEs) and non-serious AEs were collected from the first dose of randomized therapy to 30 days after the last dose of randomized therapy (up to Study Week 29). SAEs and non-serious AEs were collected for all participants who received at least one dose of study medication.
Gastrointestinal disorders Rectal haemorrhage	2.8% 1/36 • Serious adverse events (SAEs) and non-serious AEs were collected from the first dose of randomized therapy to 30 days after the last dose of randomized therapy (up to Study Week 29). SAEs and non-serious AEs were collected for all participants who received at least one dose of study medication.	0.00% 0/39 • Serious adverse events (SAEs) and non-serious AEs were collected from the first dose of randomized therapy to 30 days after the last dose of randomized therapy (up to Study Week 29). SAEs and non-serious AEs were collected for all participants who received at least one dose of study medication.	0.00% 0/46 • Serious adverse events (SAEs) and non-serious AEs were collected from the first dose of randomized therapy to 30 days after the last dose of randomized therapy (up to Study Week 29). SAEs and non-serious AEs were collected for all participants who received at least one dose of study medication.
Gastrointestinal disorders Stomatitis	2.8% 1/36 • Serious adverse events (SAEs) and non-serious AEs were collected from the first dose of randomized therapy to 30 days after the last dose of randomized therapy (up to Study Week 29). SAEs and non-serious AEs were collected for all participants who received at least one dose of study medication.	0.00% 0/39 • Serious adverse events (SAEs) and non-serious AEs were collected from the first dose of randomized therapy to 30 days after the last dose of randomized therapy (up to Study Week 29). SAEs and non-serious AEs were collected for all participants who received at least one dose of study medication.	0.00% 0/46 • Serious adverse events (SAEs) and non-serious AEs were collected from the first dose of randomized therapy to 30 days after the last dose of randomized therapy (up to Study Week 29). SAEs and non-serious AEs were collected for all participants who received at least one dose of study medication.
Investigations Alanine aminotransferase increased	2.8% 1/36 • Serious adverse events (SAEs) and non-serious AEs were collected from the first dose of randomized therapy to 30 days after the last dose of randomized therapy (up to Study Week 29). SAEs and non-serious AEs were collected for all participants who received at least one dose of study medication.	0.00% 0/39 • Serious adverse events (SAEs) and non-serious AEs were collected from the first dose of randomized therapy to 30 days after the last dose of randomized therapy (up to Study Week 29). SAEs and non-serious AEs were collected for all participants who received at least one dose of study medication.	6.5% 3/46 • Serious adverse events (SAEs) and non-serious AEs were collected from the first dose of randomized therapy to 30 days after the last dose of randomized therapy (up to Study Week 29). SAEs and non-serious AEs were collected for all participants who received at least one dose of study medication.
Investigations Blood bilirubin increased	0.00% 0/36 • Serious adverse events (SAEs) and non-serious AEs were collected from the first dose of randomized therapy to 30 days after the last dose of randomized therapy (up to Study Week 29). SAEs and non-serious AEs were collected for all participants who received at least one dose of study medication.	2.6% 1/39 • Serious adverse events (SAEs) and non-serious AEs were collected from the first dose of randomized therapy to 30 days after the last dose of randomized therapy (up to Study Week 29). SAEs and non-serious AEs were collected for all participants who received at least one dose of study medication.	2.2% 1/46 • Serious adverse events (SAEs) and non-serious AEs were collected from the first dose of randomized therapy to 30 days after the last dose of randomized therapy (up to Study Week 29). SAEs and non-serious AEs were collected for all participants who received at least one dose of study medication.
Investigations Aspartate aminotransferase increased	0.00% 0/36 • Serious adverse events (SAEs) and non-serious AEs were collected from the first dose of randomized therapy to 30 days after the last dose of randomized therapy (up to Study Week 29). SAEs and non-serious AEs were collected for all participants who received at least one dose of study medication.	0.00% 0/39 • Serious adverse events (SAEs) and non-serious AEs were collected from the first dose of randomized therapy to 30 days after the last dose of randomized therapy (up to Study Week 29). SAEs and non-serious AEs were collected for all participants who received at least one dose of study medication.	2.2% 1/46 • Serious adverse events (SAEs) and non-serious AEs were collected from the first dose of randomized therapy to 30 days after the last dose of randomized therapy (up to Study Week 29). SAEs and non-serious AEs were collected for all participants who received at least one dose of study medication.
Investigations Neutrophil count	0.00% 0/36 • Serious adverse events (SAEs) and non-serious AEs were collected from the first dose of randomized therapy to 30 days after the last dose of randomized therapy (up to Study Week 29). SAEs and non-serious AEs were collected for all participants who received at least one dose of study medication.	2.6% 1/39 • Serious adverse events (SAEs) and non-serious AEs were collected from the first dose of randomized therapy to 30 days after the last dose of randomized therapy (up to Study Week 29). SAEs and non-serious AEs were collected for all participants who received at least one dose of study medication.	0.00% 0/46 • Serious adverse events (SAEs) and non-serious AEs were collected from the first dose of randomized therapy to 30 days after the last dose of randomized therapy (up to Study Week 29). SAEs and non-serious AEs were collected for all participants who received at least one dose of study medication.
General disorders Pyrexia	2.8% 1/36 • Serious adverse events (SAEs) and non-serious AEs were collected from the first dose of randomized therapy to 30 days after the last dose of randomized therapy (up to Study Week 29). SAEs and non-serious AEs were collected for all participants who received at least one dose of study medication.	2.6% 1/39 • Serious adverse events (SAEs) and non-serious AEs were collected from the first dose of randomized therapy to 30 days after the last dose of randomized therapy (up to Study Week 29). SAEs and non-serious AEs were collected for all participants who received at least one dose of study medication.	0.00% 0/46 • Serious adverse events (SAEs) and non-serious AEs were collected from the first dose of randomized therapy to 30 days after the last dose of randomized therapy (up to Study Week 29). SAEs and non-serious AEs were collected for all participants who received at least one dose of study medication.
General disorders Hyperpyrexia	0.00% 0/36 • Serious adverse events (SAEs) and non-serious AEs were collected from the first dose of randomized therapy to 30 days after the last dose of randomized therapy (up to Study Week 29). SAEs and non-serious AEs were collected for all participants who received at least one dose of study medication.	2.6% 1/39 • Serious adverse events (SAEs) and non-serious AEs were collected from the first dose of randomized therapy to 30 days after the last dose of randomized therapy (up to Study Week 29). SAEs and non-serious AEs were collected for all participants who received at least one dose of study medication.	0.00% 0/46 • Serious adverse events (SAEs) and non-serious AEs were collected from the first dose of randomized therapy to 30 days after the last dose of randomized therapy (up to Study Week 29). SAEs and non-serious AEs were collected for all participants who received at least one dose of study medication.
Infections and infestations Device related infection	0.00% 0/36 • Serious adverse events (SAEs) and non-serious AEs were collected from the first dose of randomized therapy to 30 days after the last dose of randomized therapy (up to Study Week 29). SAEs and non-serious AEs were collected for all participants who received at least one dose of study medication.	0.00% 0/39 • Serious adverse events (SAEs) and non-serious AEs were collected from the first dose of randomized therapy to 30 days after the last dose of randomized therapy (up to Study Week 29). SAEs and non-serious AEs were collected for all participants who received at least one dose of study medication.	2.2% 1/46 • Serious adverse events (SAEs) and non-serious AEs were collected from the first dose of randomized therapy to 30 days after the last dose of randomized therapy (up to Study Week 29). SAEs and non-serious AEs were collected for all participants who received at least one dose of study medication.
Infections and infestations Fungal skin infection	2.8% 1/36 • Serious adverse events (SAEs) and non-serious AEs were collected from the first dose of randomized therapy to 30 days after the last dose of randomized therapy (up to Study Week 29). SAEs and non-serious AEs were collected for all participants who received at least one dose of study medication.	0.00% 0/39 • Serious adverse events (SAEs) and non-serious AEs were collected from the first dose of randomized therapy to 30 days after the last dose of randomized therapy (up to Study Week 29). SAEs and non-serious AEs were collected for all participants who received at least one dose of study medication.	0.00% 0/46 • Serious adverse events (SAEs) and non-serious AEs were collected from the first dose of randomized therapy to 30 days after the last dose of randomized therapy (up to Study Week 29). SAEs and non-serious AEs were collected for all participants who received at least one dose of study medication.
Skin and subcutaneous tissue disorders Nail disorder	0.00% 0/36 • Serious adverse events (SAEs) and non-serious AEs were collected from the first dose of randomized therapy to 30 days after the last dose of randomized therapy (up to Study Week 29). SAEs and non-serious AEs were collected for all participants who received at least one dose of study medication.	0.00% 0/39 • Serious adverse events (SAEs) and non-serious AEs were collected from the first dose of randomized therapy to 30 days after the last dose of randomized therapy (up to Study Week 29). SAEs and non-serious AEs were collected for all participants who received at least one dose of study medication.	2.2% 1/46 • Serious adverse events (SAEs) and non-serious AEs were collected from the first dose of randomized therapy to 30 days after the last dose of randomized therapy (up to Study Week 29). SAEs and non-serious AEs were collected for all participants who received at least one dose of study medication.
Skin and subcutaneous tissue disorders Rash	0.00% 0/36 • Serious adverse events (SAEs) and non-serious AEs were collected from the first dose of randomized therapy to 30 days after the last dose of randomized therapy (up to Study Week 29). SAEs and non-serious AEs were collected for all participants who received at least one dose of study medication.	2.6% 1/39 • Serious adverse events (SAEs) and non-serious AEs were collected from the first dose of randomized therapy to 30 days after the last dose of randomized therapy (up to Study Week 29). SAEs and non-serious AEs were collected for all participants who received at least one dose of study medication.	0.00% 0/46 • Serious adverse events (SAEs) and non-serious AEs were collected from the first dose of randomized therapy to 30 days after the last dose of randomized therapy (up to Study Week 29). SAEs and non-serious AEs were collected for all participants who received at least one dose of study medication.
Immune system disorders Drug hypersensitivity	0.00% 0/36 • Serious adverse events (SAEs) and non-serious AEs were collected from the first dose of randomized therapy to 30 days after the last dose of randomized therapy (up to Study Week 29). SAEs and non-serious AEs were collected for all participants who received at least one dose of study medication.	0.00% 0/39 • Serious adverse events (SAEs) and non-serious AEs were collected from the first dose of randomized therapy to 30 days after the last dose of randomized therapy (up to Study Week 29). SAEs and non-serious AEs were collected for all participants who received at least one dose of study medication.	2.2% 1/46 • Serious adverse events (SAEs) and non-serious AEs were collected from the first dose of randomized therapy to 30 days after the last dose of randomized therapy (up to Study Week 29). SAEs and non-serious AEs were collected for all participants who received at least one dose of study medication.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Clear cell renal cell carcinoma	0.00% 0/36 • Serious adverse events (SAEs) and non-serious AEs were collected from the first dose of randomized therapy to 30 days after the last dose of randomized therapy (up to Study Week 29). SAEs and non-serious AEs were collected for all participants who received at least one dose of study medication.	0.00% 0/39 • Serious adverse events (SAEs) and non-serious AEs were collected from the first dose of randomized therapy to 30 days after the last dose of randomized therapy (up to Study Week 29). SAEs and non-serious AEs were collected for all participants who received at least one dose of study medication.	2.2% 1/46 • Serious adverse events (SAEs) and non-serious AEs were collected from the first dose of randomized therapy to 30 days after the last dose of randomized therapy (up to Study Week 29). SAEs and non-serious AEs were collected for all participants who received at least one dose of study medication.
Nervous system disorders Syncope	0.00% 0/36 • Serious adverse events (SAEs) and non-serious AEs were collected from the first dose of randomized therapy to 30 days after the last dose of randomized therapy (up to Study Week 29). SAEs and non-serious AEs were collected for all participants who received at least one dose of study medication.	0.00% 0/39 • Serious adverse events (SAEs) and non-serious AEs were collected from the first dose of randomized therapy to 30 days after the last dose of randomized therapy (up to Study Week 29). SAEs and non-serious AEs were collected for all participants who received at least one dose of study medication.	2.2% 1/46 • Serious adverse events (SAEs) and non-serious AEs were collected from the first dose of randomized therapy to 30 days after the last dose of randomized therapy (up to Study Week 29). SAEs and non-serious AEs were collected for all participants who received at least one dose of study medication.