lapatinib

DLTs consisted of only drug-related toxicities (neurologic and non-neurologic DLTs). A neurologic DLT was defined as grade 3/4 clinically significant peripheral motor and/or sensitive neuropathy. Non-neurologic DLTs mainly included the following: grade 3/4 clinically significant non-hematological toxicity (except nausea), grade 4 neutropenia lasting \>=7 days, thrombocytopenia (\<=25000 cells per cubic millimeter), inability to begin next treatment within 2 weeks of scheduled dosing due to unresolved toxicity, treatment delay (due to toxicity) of \>5 days, for Days 8 or 15 of weekly paclitaxel.

OS was defined as the time from randomization until death due to any cause. For participants who did not die, time to death was censored at the time of last contact. For censored participants, time to death was defined as the time from randomization to the time of last contact.

DFS is defined as the time from randomization until the earliest date of disease recurrence (evidence of local, regional, or distant disease progression, second primary tumor) or death due to any cause. Disease recurrence was based on the assessments from the blinded, independent reviewer (radiological and clinical). Participants who initiated alternative anti-cancer therapy prior to disease recurrence or death were treated as censored at the last assessment prior to the time of this initiation. For participants whose disease did not recur or who did not die, DFS was censored at the time of the last independently assessed radiological scan (where initiation of alternative anti-cancer therapy had not commenced). Participants who missed two or more consecutive disease assessments were censored at the last assessment prior to the missed assessments. Participants considered to have malignant disease at Baseline were censored at the time of randomization.

DFS=interval between the date of randomization and the date of the first occurrence of an objective disease recurrence, a second primary cancer, or death from any cause. The date of the event is the earliest date of the occurrence of any of the following: local recurrence (LR) following mastectomy; LR in ipsilateral breast following lumpectomy; regional recurrence; distant recurrence; contralateral breast cancer, including ductal carcinoma in situ; other second primary cancer (excluding squamous or basal cell carcinoma of the skin, melanoma in situ, carcinoma in situ of the cervix, or lobular carcinoma in situ of the breast); death from any cause without a prior event. Par. who started additional anti-cancer adjuvant therapy prior to the recurrence of their disease were to be censored. Par. who did not withdraw from the study and did not experience a specified event or death were to be censored (follow-up ongoing) at the last visit date available at which progression was assessed.

PFS was defined as the time from randomization until the first documented sign of disease progression or death due to any cause.

Benefit is defined as complete response, partial response, or stable disease according to RECIST criteria (vers. 1.1). Efficacy criteria is the number of patients meeting this definition. Patients having stopped before this 4-months time point will be considered as non responders without clinical benefit.

The criteria is the number of patients for whom a toxicity event (according to the NCI-CTC AE vers.4)and/or an impact on functional status (defined by the 8 items IADL assessment scale) has been observed during the first 4 months of treatment.

Pathologic Assessment After 12 weeks of lapatinib and trastuzumab with or without endocrine therapy. Pathologic complete response: no invasive cancer in the residual breast. Near pathologic complete response: residual disease of less than 1 cm in breast.

Investigational treatment was considered tolerable if one or more of the tolerability criteria were met by none or one of the 6 participants in the first cycle of Phase I. If one or more tolerability criteria were met by two or more participants, the issue was referred to the safety committee. Tolerability criteria for toxicities related to investigational treatment included grade 4 neutropenia persisting for 7 or more days, thrombocytopenia with a platelet count of less than or equal to 25,000/millimeter (mm)\^3 , clinically significant Grade 3 or 4 non-haematologic toxicities (excluding nausea) and inability to start cycle 2 within 2 weeks of scheduled dosing due to unresolved toxicity.

Overall survival is defined as the time from the start of treatment until death due to any cause. For participants who survived, time to death was censored at the time of the last confirmation of survival.

Par. with CB are defined as those with complete response (CR), partial response (PR), or stable disease (SD) for \>=12 or 24 weeks. Per Response Evaluation Criteria In Solid Tumors (RECIST), Version 1.1, CR is defined as the disappearance of all target lesions, PR is defined as a \>=30% decrease in the sum of the longest diameter (LD) of target lesions, taking as a reference the baseline sum LD, and SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as a reference the smallest sum LD since the treatment started.

Within 3-4 weeks after last docetaxel dose the surgery was performed to evaluate pathological response. According to the Miller\&Payne Criteria, pCR in node-negative patients is a grade 5-A and in node-positive patients is a grade 5-D.

Participants were analyzed for intratumoral expression levels of genes involved in the 5-fluorouracil (FU) pathway and lapatinib-targeted genes. Change in biomarker expression levels was calculated as the levels measured after the lapatinib Run-in Period (Baseline) of the study minus the levels measured at the start of monotherapy (Day -7). EGFR, epidermal growth factor receptor; HER, human epidermal growth factor receptor. Data are presented as ratios of the normalized gene expression of the target gene to that of beta actin.

Response is defined as documented evidence of complete response (CR) or partial response (PR). The investigator evaluated response based on Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Complete response is defined as the disappearance of all target lesions (TLs) and non-TLs and the appearance of no new lesions (NLs). Partial response for TLs is defined as \>= a 30% decrease in the sum of the longest diameter (LD) of TLs, taking as a reference the Baseline sum LD. For non-TLs it is defined as the persistence of 1 or more non-TL and no new TLs or non-TLs.

5-month (mo.) PFS was defined as the percentage of par. who were alive/progression free for 5 months from the time of initial treatment. PFS is defined as the time from the initial treatment until the first observation of disease progression (DP)/death due to any cause; the percentage of par. whose follow-up ended or was ongoing was reported. DP is defined as symptomatic progression or the appearance of \>=1 NL and/or unequivocal progression of existing non-TLs, and a \>=20% increase in the sum of the LD of TLs, taking as a reference the smallest sum LD recorded since treatment started.

RECIST-based response assessment was done at Weeks (Wks) 4 and 8 and every 8 weeks thereafter. Cutaneous disease assessment was done at Wk 4 and every 4 weeks thereafter. OR was evaluated when the skin and RECIST assessments coincided. Per RECIST, CR is the disappearance of all target and non-target lesions; PR is at least a 30 percent (%) decrease in the sum of the longest diameter (LD) of target lesions, taking as a reference the baseline sum LD. Cutaneous disease contained non-measurable and measurable skin disease, which was assessed by skin assessment tools.

Paired core samples taken at baseline and time of main surgery analysed for Ki67, TUNEL, HER2, EGFR, ER, PgR, pAkt,pERK \& stathmin

CBR is defined as the percentage of participants receiving at least one dose of study medication who achieved a best overall response classified as a complete or partial (confirmed) tumor response or stable disease for at least 6 months (24 weeks). A "complete response" is defined as the disappearance of all target or non-target lesions, "partial response" and "disease progression" as at least a 30% decrease and at least a 20% increase, respectively, in the sum of the longest diameter of target lesions, and "stable disease" as neither "partial response" nor "disease progression."

cOR is defined as the documented evidence of complete response (CR) and partial response (PR) as assessed by ultrasound examination using Response Evaluation Criteria In Solid Tumors (RECIST). CR is defined as the disappearance of all target lesions (TLs) and non-TLs and the appearance of no new lesions (NLs). PR for TLs is defined as a \>=30% decrease in the sum of the longest diameter (LD) of TLs, taking as a reference the Baseline sum LD. For non-TLs, it is defined as the persistence of \>=1 non-TL and no new TLs or non-TLs.

Complete clinical response=nodule not detectable; all ultrasound abnormalities detected at diagnosis have disappeared. Partial clinical response=the tumor's longest diameter (LD) is reduced by 50% or more; ultrasound characteristics of the tumor persist. Minimal response=the tumor's LD is reduced by 25%-49%. Stable disease=the tumor's LD is decreased by less than 25% and is increased by no more than 25% from the starting value. Progressive disease=the tumor's LD is increased by more than 25% from the starting value. Participants who were not evaluable did not have data available.

Each on-study and follow-up laboratory parameter and vital sign was compared to the participant's baseline (BL) values to investigate what changes occurred. mmHg, millimeters of mercury.

Each on-study and follow-up laboratory parameter and vital sign was compared to the participant's baseline (BL) values to investigate what changes occurred. mmHg, millimeters of mercury.

Each on-study and follow-up laboratory parameter and vital sign was compared to the participant's baseline (BL) values to investigate what changes occurred. bpm, beats per minute.

Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline.

Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline.

Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline.

Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline.

Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline.

Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline.

Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline.

Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline.

Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline.

Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline. The hematocrit is the proportion of blood volume that is occupied by red blood cells.

Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline.

Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline. Prothrombin time is a measure of the extrinsic pathway of coagulation that is used to determine the clotting tendency of blood. The International Normalized Ratio is the ratio of a patient's prothrombin time to a normal (control) sample.

Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline. Partial thromboplastin time is a performance indicator detecting abnormalities in blood clotting.

Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline.

Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline.

Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline.

Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline.

Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline.

Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline.

Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline.

Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline.

Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline.

Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline.

Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline. The hematocrit is the proportion of blood volume that is occupied by red blood cells.

Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline.

Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline. Prothrombin time is a measure of the extrinsic pathway of coagulation that is used to determine the clotting tendency of blood. The International Normalized Ratio is the ratio of a patient's prothrombin time to a normal (control) sample.

Change from baseline is calculated as the maximum changed value in the study minus the value at Baseline. Partial thromboplastin time is a performance indicator detecting abnormalities in blood clotting.

A dose-limiting toxicity (DLT) is defined as predefined adverse events or events that prevented participants from receiving 75% of their scheduled doses or from starting their next treatment period. The dose at which no more than 1 out of 6 participants experiences a DLT is defined as the optimally tolerated regimen. The OTR is important because it determines the highest dose combination that can be given without significant toxicity.

OR is the number of participants whose response was classified as a complete response or partial response (disappearance of enhancing tumor (ET) or reduction of ET by \>=50%, respectively, on consecutive scans \[CS\] \>=1 month (m) apart, off steroids, and neurologically stable/improved), progressive disease (increase of ET of \>=25% on CS \>=1 m apart or neurologically worse, and steroids stable/increased), or stable disease (all other situations) per MacDonald criteria. Participants were evaluated with magnetic resonance imaging. Baseline and the 4- and 8-w assessments are categorized as \<8 w.

OR is the number of participants whose response was classified as a complete response or partial response (disappearance of enhancing tumor (ET) or reduction of ET by \>=50%, respectively, on consecutive scans \[CS\] \>=1 month (m) apart, off steroids, and neurologically stable/improved), progressive disease (increase of ET of \>=25% on CS \>=1 m apart or neurologically worse, and steroids stable/increased), or stable disease (all other situations) per MacDonald criteria. Participants were evaluated with magnetic resonance imaging. Baseline and the 4- and 8-w assessments are categorized as \<8 w.

OR is the number of participants whose response was classified as a complete response or partial response (disappearance of enhancing tumor (ET) or reduction of ET by \>=50%, respectively, on consecutive scans \[CS\] \>=1 month (m) apart, off steroids, and neurologically stable/improved), progressive disease (increase of ET of \>=25% on CS \>=1 m apart or neurologically worse, and steroids stable/increased), or stable disease (all other situations) per MacDonald criteria. Participants were evaluated with magnetic resonance imaging. Baseline and the 4- and 8-w assessments are categorized as \<8 w.

Progression-free survival (PFS) analysis was performed on all participants. PFS is presented as the number of participants experiencing disease progression or death due to any cause. Participants who are alive and have not progressed at the time of analysis are considered censored, and the date associated with the last visit with disease assessment will be used. The participants who are still alive and whose follow-up extends to at least 6 months are considered At Risk.

Participants with CR are defined as those who achieved a complete tumor response at 6 months after the completion of the chemoradiation treatment (CRT), as assessed by independent radiological review. Tumor response was assessed using modified Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Per RECIST, CR is defined as the disappearance of all target and non-target lesions. Data are based on Week 24 scans from participants receiving study treatment at that time and on those in follow-up.

PFS is defined as the interval between the date of randomization and the date of disease progression or death due to any cause. The study was designed to test Combination vs. Lapatinib first. The result indicated that Combination would not show improvement over Lapatinib even if followed until the final analysis and the Combination arm was terminated. The monotherapy arms continued to the final analysis. Data shown here are from this interim analysis.

PFS is defined as the interval between the date of randomization and the date of disease progression or death due to any cause. This study began as a 3-arm study. The combination arm was terminated at the interim analysis. The monotherapy arms continued to final analysis. Data shown here are from the final analysis.

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.

The percentage of participants with progressive disease (PD) 12 weeks after randomization was measured. Per Response Evaluation Criteria In Solid Tumors (RECIST), a response of PD is defined as a \>=20% increase in target lesions. Participants were also classified as having PD if their response at Week 12 was unknown or missing. Response was determined by an independent radiologist and by an investigator.

OR is defined as the number of participants achieving either a CR or PR, per Response Evaulation Criteria in Solid Tumors (RECIST). The best OR is defined as the best response recorded from the start of treatment until progressive disease (PD)/recurrence. CR is defined as the disappearance of all target lesions (TLs) and non-TLs. PR is defined as at least a 30% decrease in the sum of the longest diameters (LD) of TLs, taking as a reference the Baseline sum LD and no PD, or complete resolution of TLs and the persistence of one or more non-TL(s), as assessed by the IRC. PD is defined as at least a 20% increase in the sum of the LD of TLs, taking as a reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions or unequivocal progression of existing non-TLs. Responses were confirmed at subsequent assessments made \>=28 days after the original response. Participants with an unknown or missing response are treated as non-responders.

Apoptotic Index-TUNEL Assay is a method which counts a total of at least 1000 neoplastic nuclei(Cells with morphological changes defining cell death) subdivided in 10 fields chosen randomly at 400x magnification. A 'responder' was defined as having 20% cell death.

Tumor response was measured as the number of participants achieving either a complete response (CR; disappearance of all target lesions) or partial response (PR; 30% decrease in the sum of the longest diameter of target lesions) among all participants who received study treatment. Tumor response was evaluated as the best response in accordance with response evaluation criteria in solid tumors (RECIST). Progressive disease: a 20% increase in the sum of the longest diameter of target lesions. Stable disease: small changes that do not meet the above-mentioned criteria.

pCR was defined as the percentage of participants who achieved an assessment of complete response (CR) following pathologic review of resected tissue. CR was the disappearance of all target lesions. Participants in each cohort with unknown or missing response (i.e., those that did not undergo surgery) were included in the denominator when calculating the percentage. From an efficacy standpoint, the HER2+ population response was considered to be of special interest.

OR is defined as the number of participants achieving either a confirmed CR or PR, per Response Evaluation Criteria in Solid Tumors (RECIST, v 1.0). Best OR is defined as the best response recorded from the start of treatment until progressive disease (PD)/recurrence. CR is defined as the disappearance of all target lesions (TLs) and non-TLs. PR is defined as at least a 30% decrease in the sum of the longest diameters (LD) of TLs, taking as a reference the Baseline sum LD and no PD, or complete resolution of TLs and the persistence of one or more non-TL(s), as assessed by the IRC. PD is defined as at least a 20% increase in the sum of the LD of TLs, taking as a reference the smallest sum LD recorded since the treatment started or the appearance of \>= 1 new lesions or unequivocal progression of existing non-TLs. Responses were confirmed at subsequent assessments made \>=28 days after the original response. Participants with an unknown or missing response are treated as non-responders.

The overall response is defined as the number of participants whose tumor response was classified as a complete response (CR; disappearance of all target lesions) or partial response (PR; 30% decrease in the sum of the longest diameter of target lesions) per Response Evaluation Criteria in Solid Tumors. Response was measured for participants in Phase II only. To determine response, radiographic images were taken at baseline, 8 weeks, and every 8 weeks thereafter until the participant withdrew from the study.

The safety and tolerability endpoints will consist of the evaluation of adverse events (AEs), and changes in vital signs and laboratory values.

Blood samples will be collected at indicated time points for the determination of midazolam concentration. AUC of midazolam in the presence and absence of lapatinib will be determined.

Blood samples will be collected at indicated time points for the determination of midazolam concentration. Cmax of midazolam in the presence and absence of lapatinib will be determined.

Blood samples will be collected at indicated time points for the determination of midazolam concentration. CL of midazolam in the presence and absence of lapatinib will be determined.

Blood samples will be collected at indicated time points for the determination of midazolam concentration. t1/2 of midazolam in the presence and absence of lapatinib will be determined.

Blood samples will be collected at indicated time points for the determination of midazolam concentration. Absolute bioavailability of midazolam in the presence and absence of lapatinib will be determined.

biomarker analysis of tumor biopsies pre/post dose

An AE is any untoward medical occurrence in a subject or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect, any other situation according to medical or scientific judgment that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the subject or may require medical or surgical intervention will be categorized as SAE.

Blood sample will be collected to evaluate laboratory parameters.

Optimally Tolerated regimen is a dose regimen where 1 out of 6 subjects experiences a dose-limiting toxicity (DLT).