A Phase Ib-IIa, Open-label, Dose-Escalation Study of the Safety, Tolerability and Pharmacokinetics of Trastuzumab Emtansine, Paclitaxel and Pertuzumab Administered Intravenously to Patients With Her2-positive, Locally Advanced or Metastatic Breast Cancer

Number of Participants With Any Adverse Events (AEs), Serious Adverse Events (SAEs), AEs of Grades 3/4, and Death

时间窗: Up to 30 days after the last dose of study treatment or study discontinuation/termination, whichever is later

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.

Maximum Serum Concentration (Cmax) of T-DM1 and Total Trastuzumab in Cycle 1 After Q3W Dose Regimen

时间窗: Pre-dose, and 0.25 and 4 hours post-dose on Day 1; Day 8 (before paclitaxel infusion)

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.

Maximum Plasma Concentration of Paclitaxel in Cycle 1 (in the Absence T-DM1) and Cycle 2 (in the Presence T-DM1)

时间窗: Pre-dose, and 0.25, 1, 2, 4, 6, and 24 hours post-dose for Cycle 1 and Cycle 2

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 Clearance (CL) of Concentration of Paclitaxel in Cycle 1 (in the Absence of T-DM1) and Cycle 2 (in the Presence of T-DM1)

时间窗: Pre-dose, and 0.25, 1, 2, 4, 6, and 24 hours post-dose for Cycle 1 and Cycle 2

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).

Area Under Plasma Concentration - Time Curve of Paclitaxel From Time 0 to Infinity (AUC0-inf) in Cycle 1 (in the Absence of T-DM1) and Cycle 2 (in the Presence of T-DM1)

时间窗: Pre-dose, and 0.25, 1, 2, 4, 6, and 24 hours post-dose for Cycle 1 and Cycle 2

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).

Number of Participants With Dose Limiting Toxicity (DLT) of the Combination of T-DM1 and Paclitaxel When T-DM1 Was Administered on Either an Q3W or QW Schedule for Both With and Without Pertuzumab Treatment

时间窗: Up to 23 days

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.

Maximum Tolerated Dose of T-DM1 When T-DM1 (Q3W or QW) and Paclitaxel (QW) Was Administered With and Without Pertuzumab

时间窗: Days 1 to 21

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.

Number of Participants Who Had Adverse Events That Required Dose Modification of T-DM1 or Paclitaxel

时间窗: Up to 30 days after the last dose of study treatment or study discontinuation/termination, whichever is later

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.

Area Under the Serum Concentration-time Curve of Total Exposure (AUClast) of T-DM1 and Total Trastuzumab in Cycle 1 After QW Dose Regimen

时间窗: Pre-dose, and 0.25 and 4 hours post-dose on Day 1; Day 8 (before T-DM1 dose)

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

Maximum Tolerated Dose of Paclitaxel When T-DM1 (Q3W or QW) and Paclitaxel (QW) Was Administered With and Without Pertuzumab

时间窗: Days 1 to 21

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.

Number of Participants in Phase IIa of the Study Who Received 12 or More Paclitaxel Doses in Combination With T-DM1 and/or Pertuzumab

时间窗: From Day 1 to 15 weeks

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

Maximum Plasma Concentration (Cmax) of DM1 in Cycle 1 After Q3W Dose Regimen

时间窗: Pre-dose, and 0.25 and 4 hours post-dose on Day 1; Day 8 (before paclitaxel infusion)

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

Area Under the Serum Concentration-time Curve of Total Exposure (AUC0-Day 21) of T-DM1 and Total Trastuzumab in Cycle 1 After Q3W Dose Regimen

时间窗: Pre- and post-dose (0.25 and 4 hours and Day 8 [before paclitaxel infusion) for Cycle 1 and pre- and post-dose (0.25 and 4 hours) for Cycle 2 (each cycle of 21 days)

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.

Maximum Serum Concentration (Cmax) of T-DM1 and Total Trastuzumab in Cycle 1 After QW Dose Regimen

时间窗: Pre-dose, and 0.25 and 4 hours post-dose on Day 1; Day 8 (before paclitaxel infusion)

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.

Maximum Plasma Concentration (Cmax) of DM1 in Cycle 1 After QW Dose Regimen

时间窗: Pre-dose, and 0.25 and 4 hours post-dose on Day 1, and Day 8 (before T-DM1 dose)

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

An Elimination Half-life (t1/2) of Plasma Concentration of Paclitaxel in Cycle 1 (in the Absence of T-DM1) and Cycle 2 (in the Presence of T-DM1)

时间窗: Pre-dose, and 0.25, 1, 2, 4, 6, and 24 hours post-dose for Cycle 1 and Cycle 2

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).

An Apparent Volume of Distribution at Steady-state (Vss) of Plasma Concentration of Paclitaxel in Cycle 1 (in the Absence of T-DM1) and Cycle 2 (in the Presence of T-DM1)

时间窗: Pre-dose, and 0.25, 1, 2, 4, 6, and 24 hours post-dose for Cycle 1 and Cycle 2

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).

Number of Participants With Change From Baseline in Cardiac Function

时间窗: Baseline (30 days prior to study dose), end of Cycle 2, and then every three cycles in Phase Ib and every four cycles in Phase IIa throughout the duration of the study (12 months) until disease progression or study discontinuation, whichever occurs first

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.