rhuMAb 2C4

The observed pertuzumab trough serum concentration (Ctrough) at Cycle 7 was assessed following 3 cycles of pertuzumab IV and trastuzumab IV or the fixed-dose combination (FDC) of pertuzumab and trastuzumab SC. The Per Protocol Pharmacokinetics (PK) analysis population includes all enrolled participants who adhered to the protocol. Exclusions from the Per Protocol PK analysis population were made for the following reasons: participants were missing the Ctrough pre-dose Cycle 8 PK sample, participants with a Ctrough sample collected with at least 2 days deviation from the planned date on Day 21 (i.e., before Day 19 or after Day 23), participants given a dose amount that deviated from the planned dose by \>20% within 3 cycles (from Cycle 5), participants with a dose delay of more than 7 days, a Cycle 7 subcutaneous injection site other than thigh was used, if the Cycle 8 IV pre-dose and post-dose PK samples were switched, and an assay error impacting Ctrough measurement.

The observed trastuzumab trough serum concentration (Ctrough) at Cycle 7 was assessed following 3 cycles of pertuzumab IV and trastuzumab IV or the fixed-dose combination (FDC) of pertuzumab and trastuzumab SC. The Per Protocol Pharmacokinetics (PK) analysis population includes all enrolled participants who adhered to the protocol. Exclusions from the Per Protocol PK analysis population were made for the following reasons: participants were missing the Ctrough pre-dose Cycle 8 PK sample, participants with a Ctrough sample collected with at least 2 days deviation from the planned date on Day 21 (i.e., before Day 19 or after Day 23), participants given a dose amount that deviated from the planned dose by \>20% within 3 cycles (from Cycle 5), participants with a dose delay of more than 7 days, a Cycle 7 subcutaneous injection site other than thigh was used, if the Cycle 8 IV pre-dose and post-dose PK samples were switched, and an assay error impacting Ctrough measurement.

The observed pertuzumab trough serum concentration (Ctrough) at Cycle 7 was assessed following 3 cycles of pertuzumab IV and trastuzumab IV or the fixed-dose combination (FDC) of pertuzumab and trastuzumab SC. The Per Protocol Pharmacokinetics (PK) analysis population includes all enrolled participants who adhered to the protocol. Exclusions from the Per Protocol PK analysis population were made for the following reasons: participants were missing the Ctrough pre-dose Cycle 8 PK sample, participants with a Ctrough sample collected with at least 2 days deviation from the planned date on Day 21 (i.e., before Day 19 or after Day 23), participants given a dose amount that deviated from the planned dose by \>20% within 3 cycles (from Cycle 5), participants with a dose delay of more than 7 days, a subcutaneous injection site other than thigh was used, if the Cycle 8 pre-dose and post-dose samples were switched, and an assay error impacting Ctrough measurement.

Progression-free survival (PFS) was defined as the time from randomization to first occurrence of progressive disease (PD), as determined by the investigator using RECIST v1.1, or death from any cause within 18 weeks after the last tumor assessment, whichever occurred first. As per RECIST v1.1, PD is defined as a 20% increase in the sum of the diameters of target lesions, an increase in size of measurable lesions by at least 5 millimeters (mm), and the appearance of new lesions. The Kaplan-Meier approach was used to estimate median PFS for each treatment arm. Data for participants who did not have a PFS event were censored at the time of the last tumor assessment (if no tumor assessments performed after baseline, at randomization plus 1 day).

Progression-free survival (PFS) was defined as the time from randomization to first occurrence of progressive disease (PD), as determined by the investigator using RECIST v1.1, or death from any cause within 18 weeks after the last tumor assessment, whichever occurred first. As per RECIST v1.1, PD is a 20% increase in the sum of the diameters of target lesions, an increase in size of measurable lesions by at least 5 mm, and the appearance of new lesions. The Kaplan-Meier approach was used to estimate the percentage of participants who were event-free for PFS at 1, 2, and 3 years. Data for participants who did not have a PFS event were censored at the time of the last tumor assessment (if no tumor assessments performed after baseline visit, at randomization plus 1 day). At final analysis, the median \[range\] time on study for Arm A vs. Arm B was 145.29 \[3.3-225.3\] weeks vs. 174.79 \[0.9-226.1\] weeks.

Non-serious AESIs for this study include the following: Cases of potential drug-induced liver injury that include an elevated alanine aminotransferase (ALT) or aspartate aminotransferase (AST) in combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's law; Suspected transmission of an infectious agent by the study drug; or, An asymptomatic decline in left ventricular ejection fraction (LVEF) requiring treatment or leading to discontinuation of human epidermal growth factor receptor 2 (HER2)-targeted therapies.

tpCR was assessed by local pathology review on samples taken at surgery following completion of neoadjuvant therapy. tpCR was defined as the absence of any residual invasive cancer on hematoxylin and eosin evaluation of the resected breast specimen and all sampled ipsilateral lymph nodes ( that is \[i.e.\], ypT0/is, ypN0 in the American Joint Committee on Cancer \[AJCC\] staging system, 7th edition). Percentage of participants with tpCR was reported.

An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Percentage of participants with AEs and SAEs was reported. AEs included both SAEs and non-SAEs. The 95% confidence interval (CI) was computed using Clopper-Pearson method.

An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Intensity of AEs were graded according to NCI CTCAE version 4.0 on a 5-point scale: Grade 1=Mild, intervention not indicated; Grade 2=Moderate, local or noninvasive intervention indicated; Grade 3=Severe or medically significant but not immediately life-threatening; Grade 4= Life-threatening consequences, urgent intervention indicated; and Grade 5=Death related to AE. Percentage of participants with AEs by maximum severity grades was reported.

An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Percentage of participants with AEs leading to premature discontinuation of IMPs (pertuzumab and trastuzumab) was reported. AEs included both SAEs and non-SAEs. The 95% CI was computed using Clopper-Pearson method.

NYHA functional classification includes: Class I (no limitation in physical activity; ordinary physical activity does not cause fatigue, breathlessness or palpitation), Class II (slight limitation of physical activity; ordinary physical activity results in fatigue, palpitation, breathlessness or angina pectoris), Class III (marked limitation of physical activity; less than ordinary activity will lead to symptomatically 'moderate' heart failure) and Class IV (inability to carry out any physical activity without discomfort; symptoms of congestive cardiac failure are present even at rest). Percentage of participants with AEs suspected to be of cardiac origin by maximum NYHA classification was reported.

LVEF was assessed using echocardiography (ECHO) or multiple-gated acquisition (MUGA) scans. Percentage of participants with LVEF below 50% at any time during the study was reported.

An AE can be any unfavorable and unintended sign (including an abnormality laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.

PFS (IRC-Assessed) was defined as the time from randomization into Part 2 of the trial until progressive disease (PD), MBO or death from any cause, whichever occurred first per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. PD could base on symptom deterioration or was defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since treatment started or the appearance of one or more new lesions and/or the unequivocal progression of existing non-target lesions.

Treatment-emergent adverse events (TEAEs) were adverse events (AEs) that started or worsened in severity on or after the first administration of study drug, up to and including 28 days after the last dose. The investigator graded all AEs for severity per NCI-CTCAE v4.0; if not listed, the AE was assessed as follows: Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening/disabling; Grade 5 = death. The investigator determined whether an AE was related to study drug and independently assessed severity and seriousness of each AE. TEAEs to monitor included anaphylaxis and hypersensitivity, cardiac dysfunction, diarrhoea Grade ≥3, pregnancy-related AEs, interstitial lung disease, infusion-/administration-related reactions, mucositis, (febrile) neutropenia, rash/skin reactions, and suspected transmission of infectious agent. TEAEs of special interest included LVEF decreased, liver enzymes increased, and suspected transmission of infectious agent by the study drug.

All adverse events leading to death, regardless of whether they were classified as treatment emergent, are listed by system organ class (SOC) and preferred term (PT) according to the Medical Dictionary for Regulatory Activities, version 22.1 (MedDRA version 22.1); PTs that are part of a given SOC are listed in the rows directly below each SOC within the results table. Admin. = administration; Mediast. = mediastinal

All adverse events leading to death, regardless of whether they were classified as treatment emergent, are listed by system organ class (SOC) and preferred term (PT) according to the Medical Dictionary for Regulatory Activities, version 22.1 (MedDRA version 22.1); PTs that are part of a given SOC are listed in the rows directly below each SOC within the results table. Admin. = administration; Mediast. = mediastinal

Treatment-emergent adverse events (TEAEs) were adverse events (AEs) that started or worsened in severity on or after the first administration of study drug, up to and including 28 days after the last dose. The investigator graded all AEs for severity per NCI-CTCAE v4.0; if not listed, the AE was assessed as follows: Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening/disabling; Grade 5 = death. The investigator determined whether an AE was related to study drug and independently assessed severity and seriousness of each AE. MedDRA version 22.1 was used to code AEs by system organ class (SOC) and preferred term (PT); PTs that are part of a given SOC are listed in the rows directly below each SOC within the results table. If a participant experienced the same AE at more than one severity grade, only the most severe grade was presented.

Treatment-emergent adverse events (TEAEs) were adverse events (AEs) that started or worsened in severity on or after the first administration of study drug, up to and including 28 days after the last dose. The investigator graded all AEs for severity per NCI-CTCAE v4.0; if not listed, the AE was assessed as follows: Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening/disabling; Grade 5 = death. The investigator determined whether an AE was related to study drug and independently assessed severity and seriousness of each AE. MedDRA version 22.1 was used to code AEs and the system organ classes are presented in descending order according to the total frequency of occurrence. If a participant experienced more than one event in a category, they were counted only once in that category.

Treatment-emergent adverse events (TEAEs) were adverse events (AEs) that started or worsened in severity on or after the first administration of study drug, up to and including 28 days after the last dose. The investigator graded all AEs for severity per NCI-CTCAE v4.0; if not listed, the AE was assessed as follows: Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening/disabling; Grade 5 = death. The investigator determined whether an AE was related to study drug and independently assessed severity and seriousness of each AE. MedDRA version 22.1 was used to code AEs and the preferred terms are presented in descending order according to the total frequency of occurrence. If a participant experienced more than one event in a category, they were counted only once in that category.

Treatment-emergent adverse events (TEAEs) were adverse events (AEs) that started or worsened in severity on or after the first administration of study drug, up to and including 28 days after the last dose. The investigator graded all AEs for severity per NCI-CTCAE v4.0; if not listed, the AE was assessed as follows: Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening/disabling; Grade 5 = death. The investigator determined whether an AE was related to study drug and independently assessed severity and seriousness of each AE. MedDRA version 22.1 was used to code AEs and the preferred terms are presented in descending order according to the total frequency of occurrence. If a participant experienced more than one event in a category, they were counted only once in that category. Discont. = discontinuation; Ptz = pertuzumab; Tax = taxane; Trz = trastuzumab

Treatment-emergent adverse events (TEAEs) were adverse events (AEs) that started or worsened in severity on or after the first administration of study drug, up to and including 28 days after the last dose. The investigator graded all AEs for severity per NCI-CTCAE v4.0; if not listed, the AE was assessed as follows: Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening/disabling; Grade 5 = death. The investigator determined whether an AE was related to study drug and independently assessed severity and seriousness of each AE. MedDRA version 22.1 was used to code AEs and the preferred terms are presented in descending order according to the total frequency of occurrence. If a participant experienced more than one event in a category, they were counted only once in that category. Interrupt. = interruption; Ptz = pertuzumab; Tax = taxane; Trz = trastuzumab

Treatment-emergent adverse events (TEAEs) were adverse events (AEs) that started or worsened in severity on or after the first dose of study drug, up to and including 28 days after the last dose. The investigator graded all AEs for severity per NCI-CTCAE v4.0; if not listed, it was assessed as follows: Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening/disabling; Grade 5 = death. If a participant had more than one event in a category, they were counted only once in that category. TEAEs to monitor included anaphylaxis and hypersensitivity, cardiac dysfunction, diarrhoea Grade ≥3, pregnancy-related AEs, interstitial lung disease, infusion-/administration-related reactions, mucositis, (febrile) neutropenia, rash/skin reactions, and suspected transmission of infectious agent. MedDRA version 22.1 was used to code AEs; AEs may fall within multiple categories.

Treatment-emergent adverse events (TEAEs) were adverse events (AEs) that started or worsened in severity on or after the first dose of study drug, up to and including 28 days after the last dose. The investigator graded all AEs for severity per NCI-CTCAE v4.0; if not listed, it was assessed as follows: Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening/disabling; Grade 5 = death. If a participant had more than one event in a category, they were counted only once in that category. TEAEs to monitor included anaphylaxis and hypersensitivity, cardiac dysfunction, diarrhoea Grade ≥3, pregnancy-related AEs, interstitial lung disease, infusion-/administration-related reactions, mucositis, (febrile) neutropenia, rash/skin reactions, and suspected transmission of infectious agent. MedDRA version 22.1 was used to code AEs; preferred terms (PT) that are part of a given category are listed in the rows directly below each category within the results table.

Treatment-emergent adverse events (TEAEs) were adverse events (AEs) that started or worsened in severity on or after the first administration of study drug, up to and including 28 days after the last dose. The investigator graded all AEs for severity per NCI-CTCAE v4.0; if not listed, the AE was assessed as follows: Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening/disabling; Grade 5 = death. The investigator determined whether an AE was related to study drug and independently assessed severity and seriousness of each AE. TEAEs of special interest included LVEF decreased, liver enzymes (ALT or AST) increased, and suspected transmission of infectious agent by the study drug. MedDRA version 22.1 was used to code AEs; preferred terms (PT) that are part of a given category are listed in the rows directly below each category within the results table. If a participant experienced more than one event in a category, they were counted only once in that category.

Treatment-emergent adverse events (TEAEs) were adverse events (AEs) that started or worsened in severity on or after the first administration of study drug, up to and including 28 days after the last dose. The investigator graded all AEs for severity per NCI-CTCAE v4.0; if not listed, the AE was assessed as follows: Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening/disabling; Grade 5 = death. The investigator determined whether an AE was related to study drug and independently assessed severity and seriousness of each AE.

Treatment-emergent adverse events (TEAEs) were adverse events (AEs) that started or worsened in severity on or after the first administration of study drug, up to and including 28 days after the last dose. The investigator graded all AEs for severity per NCI-CTCAE v4.0; if not listed, the AE was assessed as follows: Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening/disabling; Grade 5 = death. The investigator determined whether an AE was related to study drug and independently assessed severity and seriousness of each AE. TEAEs to monitor included anaphylaxis and hypersensitivity, cardiac dysfunction, diarrhoea Grade ≥3, pregnancy-related AEs, interstitial lung disease, infusion-/administration-related reactions, mucositis, (febrile) neutropenia, rash/skin reactions, and suspected transmission of infectious agent.

Treatment-emergent adverse events (TEAEs) were adverse events (AEs) that started or worsened in severity on or after the first administration of study drug, up to and including 28 days after the last dose. The investigator graded all AEs for severity per NCI-CTCAE v4.0; if not listed, the AE was assessed as follows: Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening/disabling; Grade 5 = death. The investigator determined whether an AE was related to study drug and independently assessed severity and seriousness of each AE. TEAEs to monitor included anaphylaxis and hypersensitivity, cardiac dysfunction, diarrhoea Grade ≥3, pregnancy-related AEs, interstitial lung disease, infusion-/administration-related reactions, mucositis, (febrile) neutropenia, rash/skin reactions, and suspected transmission of infectious agent.

Treatment-emergent adverse events (TEAEs) were adverse events (AEs) that started or worsened in severity on or after the first administration of study drug, up to and including 28 days after the last dose. The investigator graded all AEs for severity per NCI-CTCAE v4.0; if not listed, the AE was assessed as follows: Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening/disabling; Grade 5 = death. The investigator determined whether an AE was related to study drug and independently assessed severity and seriousness of each AE.

Treatment-emergent adverse events (TEAEs) were adverse events (AEs) that started or worsened in severity on or after the first administration of study drug, up to and including 28 days after the last dose. The investigator graded all AEs for severity per NCI-CTCAE v4.0; if not listed, the AE was assessed as follows: Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening/disabling; Grade 5 = death. The investigator determined whether an AE was related to study drug and independently assessed severity and seriousness of each AE.

Treatment-emergent adverse events (TEAEs) were adverse events (AEs) that started or worsened in severity on or after the first administration of study drug, up to and including 28 days after the last dose. The investigator graded all AEs for severity per NCI-CTCAE v4.0; if not listed, the AE was assessed as follows: Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening/disabling; Grade 5 = death. The investigator determined whether an AE was related to study drug and independently assessed severity and seriousness of each AE.

Treatment-emergent adverse events (TEAEs) were adverse events (AEs) that started or worsened in severity on or after the first administration of study drug, up to and including 28 days after the last dose. The investigator graded all AEs for severity per NCI-CTCAE v4.0; if not listed, the AE was assessed as follows: Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening/disabling; Grade 5 = death. The investigator determined whether an AE was related to study drug and independently assessed severity and seriousness of each AE.

Treatment-emergent adverse events (TEAEs) were adverse events (AEs) that started or worsened in severity on or after the first administration of study drug, up to and including 28 days after the last dose. The investigator graded all AEs for severity per NCI-CTCAE v4.0; if not listed, the AE was assessed as follows: Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening/disabling; Grade 5 = death. The investigator determined whether an AE was related to study drug and independently assessed severity and seriousness of each AE.

Congestive heart failure was defined as the Standardised MedDRA Query (SMQ) 'Cardiac failure (wide)' from the Medical Dictionary for Regulatory Activities, version 22.1 (MedDRA version 22.1).

Congestive heart failure was defined as SMQ 'Cardiac failure (wide)' from the MedDRA version 22.1. Time to onset of the first episode of congestive heart failure was analyzed using a Kaplan-Meier approach. Participants who did not experience any congestive heart failure at the time of data-cut were censored at the date of the last attended visit whilst on-treatment (including visits up to and including 28 days after last dose of study treatment). Only treatment emergent congestive heart failure events are included.

All participants must have had a baseline LVEF ≥50% to enroll in the study; patients with significant cardiac disease or baseline LVEF below 50% were not eligible for this study. The change from baseline LVEF values were reported at every 3 cycles over the course of the study and at the final treatment, worst treatment, and maximum decrease values. The final treatment value was defined as the last LVEF value observed before all study treatment discontinuation. The worst treatment value was defined as the lowest LVEF value observed before all study treatment discontinuation. The maximum decrease value was defined as the largest decrease of LVEF value from baseline, or minimum increase if a participant's post-baseline LVEF measures were all larger than the baseline value.

All participants must have had a baseline LVEF greater than or equal to (≥)50% to enroll in the study; patients with significant cardiac disease or baseline LVEF below 50% were not eligible for this study. The number of participants are reported according to four change from baseline in LVEF value categories over the course of the study: 1) an increase or decrease from baseline LVEF less than (\<)10% points or no change in LVEF; 2) an absolute LVEF value \<45% points and a decrease from baseline LVEF ≥10% points to \<15% points; 3) an absolute LVEF value \<45% points and a decrease from baseline LVEF ≥15% points; or 4) an absolute LVEF value ≥45% points and a decrease from baseline LVEF ≥10% points. BL = baseline; Decr. = decrease; Incr. = increase

Clinical laboratory tests for hematology and coagulation parameters were performed at local laboratories. Laboratory toxicities were defined based on NCI-CTC v4.0 from Grades 1 (least severe) to 4 (most severe). Some laboratory parameters are bi-dimensional (i.e. can be graded in both the low and high direction). These parameters were split and presented in both directions. Baseline was defined as the last non-missing measurement taken prior to the first dose of study treatment (including unscheduled assessments). Values from all visits, including unscheduled visits, were included in the derivation of the worst post-baseline grade. Not every abnormal laboratory value qualified as an adverse event, only if it met any of the following criteria: was clinically significant (per investigator); was accompanied by clinical symptoms; resulted in a change in study treatment; or resulted in a medical intervention or a change in concomitant therapy.

Clinical laboratory tests for hematology and coagulation parameters were performed at local laboratories. Laboratory toxicities were defined based on local laboratory normal ranges (for parameters with NCI-CTC grade not defined). Some laboratory parameters are bi-dimensional (i.e. can be graded in both the low and high direction). These parameters were split and presented in both directions. Baseline was defined as the last non-missing measurement taken prior to the first dose of study treatment (including unscheduled assessments). Values from all visits, including unscheduled visits, were included in the derivation of the worst post-baseline grade. Not every abnormal laboratory value qualified as an adverse event, only if it met any of the following criteria: was clinically significant (per investigator); was accompanied by clinical symptoms; resulted in a change in study treatment; or resulted in a medical intervention or a change in concomitant therapy.

Clinical laboratory tests for biochemistry parameters were performed at local laboratories. Laboratory toxicities were defined based on NCI-CTC v4.0 from Grades 1 (least severe) to 4 (most severe). Some laboratory parameters are bi-dimensional (i.e. can be graded in both the low and high direction). These parameters were split and presented in both directions. Baseline was defined as the last non-missing measurement taken prior to the first dose of study treatment (including unscheduled assessments). Values from all visits, including unscheduled visits, were included in the derivation of the worst post-baseline grade. Not every abnormal laboratory value qualified as an adverse event, only if it met any of the following criteria: was clinically significant (per investigator); was accompanied by clinical symptoms; resulted in a change in study treatment; or resulted in a medical intervention or a change in concomitant therapy.

Clinical laboratory tests for biochemistry parameters were performed at local laboratories. Laboratory toxicities were defined based on local laboratory normal ranges (for parameters with NCI-CTC grade not defined). Some laboratory parameters are bi-dimensional (i.e. can be graded in both the low and high direction). These parameters were split and presented in both directions. Baseline was defined as the last non-missing measurement taken prior to the first dose of study treatment (including unscheduled assessments). Values from all visits, including unscheduled visits, were included in the derivation of the worst post-baseline grade. Not every abnormal laboratory value qualified as an adverse event, only if it met any of the following criteria: was clinically significant (per investigator); was accompanied by clinical symptoms; resulted in a change in study treatment; or resulted in a medical intervention or a change in concomitant therapy.

Percentage of participants with IDFS events (excluding SPNBC) is reported. IDFS event was defined as the first occurrence of one of the following events: Ipsilateral invasive breast tumor recurrence (that is \[i.e.\], an invasive breast cancer involving the same breast parenchyma as the original primary lesion); ipsilateral local-regional invasive breast cancer recurrence (i.e., an invasive breast cancer in the axilla, regional lymph nodes, chest wall, and/or skin of the ipsilateral breast); distant recurrence (i.e., evidence of breast cancer in any anatomic site - other than the two above mentioned sites); death attributable to any cause; contralateral invasive breast cancer. All SPNBCs and in situ carcinomas (including ductal carcinoma in situ \[DCIS\] and lobular carcinoma in situ \[LCIS\]) and non-melanoma skin cancer were excluded as an event.

Kaplan-Meier estimate of the percentage of participants who were IDFS event-free (excluding SPNBC) at 3 years is reported. IDFS event was defined as the first occurrence of one of the following events: Ipsilateral invasive breast tumor recurrence (i.e., an invasive breast cancer involving the same breast parenchyma as the original primary lesion); ipsilateral local-regional invasive breast cancer recurrence (i.e., an invasive breast cancer in the axilla, regional lymph nodes, chest wall, and/or skin of the ipsilateral breast); distant recurrence (i.e., evidence of breast cancer in any anatomic site - other than the two above mentioned sites); death attributable to any cause; contralateral invasive breast cancer. All SPNBCs and in situ carcinomas (including DCIS and LCIS) and non-melanoma skin cancer were excluded as an event.

Tumor assessments were performed according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. Disease progression was defined as a greater than or equal to (≥) 20 percent (%) and 5-millimeter (mm) increase in sum of diameters of target lesions, taking as reference the smallest sum obtained during the study, or appearance of new lesion(s). The percentage of participants with death or disease progression was calculated as \[number of participants with event divided by the number analyzed\] multiplied by 100.

Tumor assessments were performed according to RECIST version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. PFS was defined as the time from randomization to first documented disease progression or death from any cause. Disease progression was defined as a ≥20% and 5-mm increase in sum of diameters of target lesions, taking as reference the smallest sum obtained during the study, or appearance of new lesion(s). Median duration of PFS was estimated using Kaplan-Meier analysis, and corresponding confidence intervals (CIs) were computed using the Brookmeyer-Crowley method.

Progression Free Survival (PFS) was defined as the time from randomization to first documented disease progression (PD), as determined by an Independent Review Facility (IRF) using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0, or death from any cause, whichever occurred first. PD was defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions; or the appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. IRF review of tumor assessment ceased after the primary PFS analysis. The primary endpoint was analyzed after approximately 337 IRF-assessed PFS events were observed.

PFS was defined as the time from randomization to first documented radiographical progressive disease (PD), as determined by an independent review facility (IRF) using RECIST version 1.0, or death from any cause (within 18 weeks of last tumor assessment), whichever occurred first (Kaplan-Meier method). For target lesions, PD was defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum of the LD recorded since treatment started or the appearance of ≥1 new lesion. For non-target lesions, PD was defined as the appearance of ≥1 new lesion or unequivocal progression of existing lesions. Participants without IRF-determined PD or who had not died within 18 weeks of their last IRF-determined, progression-free tumor assessment were censored at the date of the last IRF-reviewed, evaluable tumor assessment; those with no post-baseline tumor assessment and who had not died within 18 weeks of baseline were censored at 1 day.

Kaplan-Meier estimates of iDFS will be estimated and plotted with the corresponding 95% confidence intervals. from the time of randomization until the occurrence of the first of the following events: invasive local/regional recurrence, Contralateral invasive breast cancer, Distant recurrence, Death from any cause

Question 1 of the Patient Preference Questionnaire (PPQ) asked participants the following question: "All things considered, which method of administration did you prefer?" The three available options for a participant's response were: IV, SC, or No preference. A point estimate with associated exact Clopper-Pearson binomial 95% confidence interval was calculated only for the percentage of participants who preferred PH FDC SC.

Responses were assessed by the investigator, based on magnetic resonance imaging (MRI) of the brain, physical examinations, routine neurological examinations, and corticosteroid dosing. An objective response in the central nervous system (CNS) was a complete response (CR) or partial response (PR) confirmed by repeat assessment, according to RANO-BM criteria. A CR was defined as the disappearance of all CNS target lesions sustained for at least 4 weeks; no new lesions; no corticosteroids; and stable or improved clinically; for non-target lesions, a CR was the disappearance of all enhancing CNS non-target lesions and no new CNS lesions. A PR was defined as at least a 30% decrease in the sum longest diameter (LD) of CNS target lesions, taking as reference the baseline sum LD sustained for at least 4 weeks; no new lesions; stable to decreased corticosteroid dose; and stable or improved clinically. The 95% Clopper-Pearson exact confidence intervals were calculated for responses.

The rate of pCR is the percentage of participants with Residual Cancer Burden (RCB)=0 as defined by established guidelines (Symmans et al. JCO 2007; M.D Anderson http://www.mdanderson.org/breastcancer\_RCB). Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

Symptomatic left ventricular systolic dysfunction (otherwise referred to as heart failure) is a serious adverse event. The NYHA Functional Classification System for Heart Failure considers the patient's symptoms: Class III: Marked limitation of physical activity; Comfortable at rest, but less than ordinary activity causes fatigue, palpitation, or dyspnea. Class IV: Unable to carry on any physical activity without discomfort; Symptoms of heart failure at rest; If any physical activity is undertaken, discomfort increases. The 95% CIs were calculated with the Clopper-Pearson method. Results included events with onset from first dose of pertuzumab/trastuzumab prior to surgery through the day before the first dose of any study drug after surgery. If participant withdrew without entering adjuvant period, results included all events with onset from first dose of pertuzumab/trastuzumab through 42 days after last dose of any study drug or on the day of target surgery whichever was later.

LVEF significant decline was defined as the decline in LVEF of \>/= 10%-points from baseline to an LVEF of \< 50%. A Confirmed LVEF Significant Decline was defined as at least two consecutive readings of significant declines in LVEF. A Single LVEF Significant Decline was defined as only one reading of a significant decline (no consecutive readings) in LVEF. The category of 'At Least one LVEF Significant Decline Event' was defined as the total of confirmed and single LVEF significant declines. The 95% confidence intervals (CIs) were calculated using the Clopper-Pearson method. Results include events with onset from the first dose of pertuzumab or trastuzumab prior to surgery through the day before the first dose of any study drug after surgery. If participant withdrew without entering adjuvant period, results included all events with onset from first dose of pertuzumab or trastuzumab through 42 days after last dose of any study drug or on the day of target surgery whichever is later.

Tumor response was assessed by investigator according to RECIST v1.1. BOR was defined as percentage of participants with a confirmed complete response (CR) or partial response (PR). All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total or pathological nodes (with short axis \[SA\] of at least (\>/=) 15 millimeter \[mm\]) were identified as target lesions (TLs) and measured and recorded at baseline. A sum of diameters (longest for non-nodal lesions, SA for nodal lesions) for all TLs was calculated and reported as baseline sum of diameters (SD). All other lesions (or sites of disease) were identified as non-TLs. CR: disappearance of all TLs and SA reduction to less than (\<) 10 mm for nodal TLs/ non-TLs. PR: \>/=30 percent (%) decrease in SD of TLs, taking as reference baseline SD. Confirmation of response at 2 consecutive tumor assessments \>/=4 weeks apart was required. The 95% confidence interval (CI) was computed using Clopper-Pearson approach.

Progression-free survival (PFS) was defined as the time from randomization until the first radiographically documented progression of disease or death from any cause, whichever occurred first (either during study treatment or during follow-up). Progression of disease was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1 and is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The sum of target lesion diameters must also demonstrate an absolute increase of at least 5 mm (Note: the appearance of one or more new lesions is also considered progression). Participants with no PFS events were censored at the time of the last evaluable tumor assessment. The primary analysis of PFS was planned to be performed when a total of 165 PFS events had occurred, and the final analysis after at least 60 months follow-up.

An adverse event (AE) was defined as any untoward medical occurrence in a participant administered the investigational product which does not necessarily have a causal relationship with this treatment.

Left ventricular systolic dysfunction (LVSD) as assessed by the Investigator, including Grade 3, 4 or 5 symptomatic LVSD with symptomatic cardiac events.

Percentage of participants with LVEF measures decline of ≥ 10% from baseline and to a value of \<50% during the pre-operative (neoadjuvant) period.

The QT interval is a measure of time between the start of the Q wave and the end of the T wave in the heart's electrical cycle. The corrected QT interval was calculated using Fridericia's correction (QTcF) from electrocardiogram (ECG) data. Each participant had triplicate QTcF intervals measured at each timepoint and the average was calculated for each patient at each timepoint. For each timepoint, a participant's corresponding baseline QTcF interval was subtracted from the average QTcF intervals to create a baseline-adjusted average QTcF interval.

The assessment of FDG-PET response was performed by a central reading site. PET response was based on the maximum standard uptake value (SUVmax) of up to 5 regions of interest (ROI). The tumor ROIs were identified for each patient on pretreatment FDG-PET scans and corresponded to a subset of the target lesions identified for Response Evaluation Criteria for Solid Tumors (RECIST) analysis. Specifically, the SUVmax of each ROI on the on-treatment scans was compared with the SUVmax on the corresponding pretreatment scan and the percent change was calculated. When there was more than 1 ROI, the overall percent change in SUVmax was the arithmetic mean of the percent changes in SUVmax for each of the ROIs (mSUVmax). An PET response is defined as a decrease of ≥ 20% in mSUVmax. EGFR mutation status was assessed in tumor tissue samples taken from each patient.

Tumor response was assessed using RECIST version 1.0 to determine the objective response (OR) rate, or the percentage of participants with either confirmed CR or PR. CR was defined as the disappearance of all target lesions, and PR was defined as at least a 30 percent (%) decrease in the sum of the longest diameter compared to Baseline. Response was to be confirmed a minimum of 4 weeks after the initial response was documented. The OR rate was calculated as \[number of participants meeting the above criteria divided by the number analyzed\] multiplied by 100.

Tumor response was assessed using RECIST version 1.0 to determine the clinical benefit response (CBR) rate, or the percentage of participants with either confirmed CR or PR, or SD lasting at least 6 months. 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 compared to Baseline. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient (20%) increase to qualify for disease progression, in addition to no new target lesions. Response was to be confirmed a minimum of 4 weeks after the initial response was documented. The CBR rate was calculated as \[number of participants meeting the above criteria divided by the number analyzed\] multiplied by 100.

Disease progression was assessed according to RECIST (Response Evaluation Criteria In Solid Tumors), for participants with measurable disease, or by changes in CA 125 (Cancer Antigen 125) according to GCIG (Gynecologic Cancer Inter Group) for all participants. Participants who did not progress or died while being followed were censored at the time of the last valid tumor assessment or valid CA 125 assessment.

The probability of being event free (no disease progression or death events) at 1 year in participants remaining at risk.

A best overall response could occur at any time during the study and was determined by Response Evaluation Criteria in Solid Tumors (RECIST). A CR was defined as the disappearance of all target lesions (TL) or the disappearance of all non-TLs and normalization of tumor marker level. A PR was defined as at least a 30% decrease in the sum of the longest diameter (SLD) of TLs, taking as reference the baseline SLD. SD was defined as neither sufficient shrinkage to qualify for a PR nor sufficient increase to qualify for PD, taking as reference the smallest SLD since the treatment started for TLs and the persistence of 1 or more non-TL(s) and/or the maintenance of tumor marker level above normal limits. PD was defined as at least a 20% increase in the SLD of TLs, taking as reference the smallest SLD recorded since the treatment started or the appearance of one or more new lesions or the appearance of 1 or more new lesions and/or unequivocal progression of existing non-TLs.

Response by tumor measurement occurred if there was documented and confirmed CR or PR determined by 2 consecutive investigator assessments that were at least 28 days apart. Response was assessed by either the RECIST v 1.1 or by CA-125 changes, based on measurable or non-measurable disease at baseline. Per RECIST v 1.1 (for measurable disease), CR: disappearance of all target and non-target lesions and normalization of tumor marker level; PR: at least a 30 percent (%) decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter. Per CA-125 changes (for non-measurable disease), CR: decrease in the CA-125 to within the normal limits and less than (\<) 40 international units per milliliter (IU/mL) and no clinical or radiological evidence of disease, PR: a greater than (\>) 50 percent (%) decrease in CA-125 values from baseline, and no clinical or radiological evidence of new lesions.

Response by tumor measurement occurred if there was documented and confirmed CR or PR. Response was assessed by both the RECIST and by PSA levels measurement, based on measurable or non-measurable disease at baseline. Per RECIST, CR: disappearance of all target and non-target lesions and normalization of tumor marker level; PR: at least a 30 percent (%) decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of longest diameter. A PSA response was defined as a PSA decline of greater than or equal to (≥) 50%, which had to be confirmed by a second PSA value at least 4 weeks later.

Per RECIST, disease progression was defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum of longest diameter recorded since the treatment started or the appearance of 1 or more new lesions, and/or unequivocal progression of existing non-target lesions.

Objective tumor response was assessed using Response Evaluation Criteria in Solid Tumors (RECIST). Confirmed CR was defined as the disappearance of all target lesions, and confirmed PR was defined as at least at 30 percent (%) decrease in the sum of the longest diameters of target lesions. Response was to be confirmed at follow-up assessment completed within 4 weeks of the first documented response. The percentage of participants achieving a best overall response of CR or PR was calculated as \[number of participants meeting the above criteria divided by the number analyzed\] multiplied by 100.

See title

An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered to be related to the medicinal product. An SAE is 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 results in a congenital anomaly/birth defect.

DLT is defined as one of the following toxicities related to study drug during Cycle 1, according to the NCI CTCAE, Version 3: Grade 3 or higher non-hematologic AEs; Grade 3 or higher elevation of serum bilirubin, hepatic transaminases, or alkaline phosphatase; Grade 4 or higher thrombocytopenia; Grade 4 or higher neutropenia; any subjectively intolerable toxicity related to T-DM1, paclitaxel, or pertuzumab; any treatment-related toxicity prohibiting the start of the second cycle of treatment and/or prompting to a dose delay or modification during the DLT observation period, such as prompting a dose reduction at Cycle 2 Day1.

The MTD was defined as the highest dose of T-DM1 and paclitaxel at which 0 of 3 participants or 1 of 6 experienced a DLT, when T-DM1 (Q3W or QW) and paclitaxel (QW) was administered with and without pertuzumab treatment.

The MTD was defined as the highest dose of paclitaxel at which 0 of 3 participants or 1 of 6 experienced a DLT, when paclitaxel (QW) and T-DM1 (Q3W or QW) was administered with and without pertuzumab treatment.

Participants in Phase IIa received T-DM1 Q3W and paclitaxel in Group A and T-DM1, paclitaxel, and pertuzumab in Group B.

Participants were assessed for toxicity prior to each dose of T-DM1 and paclitaxel; dosing occurred only if the clinical assessment and laboratory test values were acceptable. Dose modifications included dose delayed or any dose reduction. Participants in whom significant toxicities had not recovered to the treatment range defined by the dose modification guidelines at the time of their next scheduled dose, had their dose of T-DM1 and/or paclitaxel delayed or reduced for up to 21 days.

Cmax of serum T-DM1 and total trastuzumab (sum of conjugated and unconjugated trastuzumab) in Cycle 1 was estimated by non-compartmental analysis for Phase Ib when T-DM1 was administered Q3W.

Cmax of plasma DM1 in Cycle 1 was estimated by non-compartmental analysis for Phase Ib when T-DM1 was administered Q3W.

AUC0-21 for serum T-DM1 and total trastuzumab (sum of conjugated and unconjugated trastuzumab) in Cycle 1 was estimated by non-compartmental analysis for Phase Ib when T-DM1 was administered Q3W.

Cmax for serum T-DM1 and total trastuzumab (sum of conjugated and unconjugated trastuzumab) in Cycle 1 was estimated by non-compartmental analysis when T-DM1 was administered QW.

Cmax for plasma DM1 in Cycle 1 was estimated by non-compartmental analysis for Phase Ib when T-DM1 was administered QW

AUClast for serum T-DM1 and serum total trastuzumab (sum of conjugated and unconjugated trastuzumab) in Cycle 1 was estimated by non-compartmental analysis for Phase Ib when T-DM1 was administered QW

Plasma Cmax of paclitaxel (65 mg/m\^2 and 80 mg/m\^2) for Cycle 1 (in the absence T-DM1) and Cycle 2 (in the presence T-DM1) was estimated by non-compartmental analysis.

Plasma AUC0-inf of paclitaxel (65 mg/m\^2 and 80 mg/m\^2) was estimated by non-compartmental analysis in Cycle 1 (in the absence T-DM1) and Cycle 2 (in the presence T-DM1).

Plasma t1/2 of paclitaxel (65 mg/m\^2 and 80 mg/m\^2) was estimated by non-compartmental analysis in Cycle 1 (in the absence T-DM1) and Cycle 2 (in the presence T-DM1).

Plasma CL of paclitaxel (65 mg/m\^2 and 80 mg/m\^2) was estimated by non-compartmental analysis for in Cycle 1 (in the absence T-DM1) and Cycle 2 (in the presence T-DM1).

Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Vss is the apparent volume of distribution at steady-state which is estimated by (D/AUC\[0-inf\]) X (AUMC\[0-inf\])/AUC\[0-inf\]) where D is the dose of study drug, AUMC(0-inf) is the area under the first moment curve extrapolated to infinity and AUC(0-inf) is the area under the plasma concentration-time curve from time zero to infinite time. The Vss of paclitaxel (65 mg/m2 and 80 mg/m2) is observed in Cycle 1 (in the absence of T-DM1) and Cycle 2 (in the presence of T-DM1).

Change in cardiac functions i.e., left ventricular ejection fraction (LVEF) and segmental wall abnormalities were assessed by echocardiogram or multigated acquisition scans. LVEF was assessed as change from baseline as 0 to \<15%, \>=15 to \<25%, \>=25%, and missing values.

DLTs included (as per National Cancer Institute Common Terminology Criteria for Adverse Events \[NCI CTCAE\] grading): Grade 4 thrombocytopenia, thrombocytopenia of any grade with concurrent hemorrhage or requiring blood platelet transfusion, or thrombocytopenia not recovered by Day 21 to at least 100,000/microliter (mcL); Grade 4 neutropenia lasting for more than 7 days; Febrile neutropenia; Grade greater than or equal to (\>/=) 3 neurotoxicity in the form of peripheral neuropathy or peripheral neurotoxicity not improving to baseline or Grade less than or equal to (\</=) 1 by Day 21; Any non-hematological toxicity of Grade \>/= 3 except for alopecia, fever, and chills, not improving to baseline or Grade \</=1 by Day 21, despite adequate toxicity management; Any subjective intolerable toxicity felt by the investigator to be related to either study treatment; Any other treatment-related toxicity prohibiting the start of the Cycle 2 on Day 22; Fulminant skin rash.

An AE is any new untoward medical occurrence or worsening of a pre-existing medical condition which does not necessarily have a causal relationship with this treatment. SAE is any untoward medical occurrence that at any dose results in death, is life-threatening, requires in-patient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, results in development of drug dependency or drug abuse, is an important medical event.

A DLT was defined as: Any non-hematological toxicity ≥ Grade 3 according to the Common Terminology Criteria for Adverse Events, version 3.0, except for fever, chills, and flu-like symptoms, which occurred despite adequate participant management. The following Grade 1-3 toxicities were exempt: Grade 1-3 skin and/or epithelial toxicities consistent with erlotinib single agent therapy, unless they did not respond to treatment or dose reduction or interruption (Grade 4 skin and/or epithelial toxicities were considered to be a DLT); Grade 4 neutropenia occurring for \> 7 days; febrile neutropenia which occurred despite adequate participant management; Grade 4 thrombocytopenia or any thrombocytopenia requiring platelet transfusion; and any subjectively intolerable toxicity felt by the investigator to be related to either one of the compounds.

A prior dose level was defined as an MTD if at a certain dose level, there were greater than or equal to (≥) 2 out of 6 participants who had Dose Limiting Toxicities (DLTs). If there were no DLTs or DLTs were seen in less than (\<) 2 participants in the highest dose level, that was considered as MTD. Participants received escalating doses of docetaxel and pertuzumab until DLTs were observed. DLTs were defined as any of the following: 1) Any non-hematological toxicity ≥ Grade 3 according to Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 except for fever, chills and flu-like symptoms, in spite of adequate toxicity management, 2) Grade 4 neutropenia lasting greater than (\>) 7 days, 3) Febrile neutropenia, 4) Thrombocytopenia Grade 4 or any thrombocytopenia requiring platelet transfusion or 5) Any subjectively intolerable toxicity felt by the investigator to be related to either one of the compounds.

MTD was defined as the highest tolerated dose combination of capecitabine (825 mg, 1000 mg or 1250 mg) and pertuzumab, without causing Dose Limiting Toxicities (DLTs). DLTs were defined as follows: 1) Any non-hematological toxicity greater than or equal to (≥) Grade 3 according to Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 except for fever, chills and flu-like symptoms, in spite of adequate toxicity management; 2) Grade 4 neutropenia lasting \> 7 days; 3) Febrile neutropenia; 4) Thrombocytopenia Grade 4 or any thrombocytopenia requiring platelet transfusion; 5) Any subjectively intolerable toxicity felt by the investigator to be related to either one of the compounds. Participants who withdrew from the study without completing the first treatment cycle for reasons other than DLT were not considered evaluable for DLT. MTD was measured in mg/m\^2.

For this protocol, an AE is defined any untoward medical occurrence (e.g., sign, symptom, disease, syndrome, intercurrent illness, abnormal laboratory finding) that emerges or worsens relative to pretreatment baseline during the treatment or post-treatment periods, regardless of the suspected cause. For this protocol an SAE was defined as any AE that occurred at any dose if: * It resulted in death (i.e., the AE caused or led to death), * It was life threatening, * It required or prolonged inpatient hospitalization, * It was disabling, * It resulted in a congenital anomaly/birth defect, * It may have jeopardized the participant or may have required medical or surgical intervention to prevent one of the outcomes listed above. The primary cause of death for all reported cases was disease progression, and all of the deaths occurred following study discontinuation, with one death occurring within 4 weeks of the last treatment day.

Incidence of DLTs defined as any Grade 3 or 4 major organ toxicity according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC) Version 2 or any subjectively intolerable toxicity felt by the investigator to be related to rhuMAb 2C4. One participant in the 15.0 mg/kg dose group experienced a gastrointestinal hemorrhage on Day 16. This event was judged by the investigator to be related to study drug. The participant recovered in 3 days and continued to receive rhuMAb 2C4 beyond Cycle 2.This was the only DLT reported during the first two treatment cycles.