A Study of Trastuzumab Emtansine, Paclitaxel, and Pertuzumab in Patients With HER2-Positive, Locally Advanced or Metastatic Breast Cancer

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
This study was conducted from 21 Jul 2009 to 04 Jun 2013 at 5 centers (4 centers for Phase Ib and 5 centers for Phase IIa) in the United States.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

Reporting Groups

	Description
Phase Ib Regimen 1	Participants received trastuzumab emtansine (T-DM1) every three weeks (Q3W) + paclitaxel weekly (QW) intravenously.
Phase Ib Regimen 2	Participants received T-DM1 Q3W + paclitaxel QW + pertuzumab Q3W intravenously.
Phase Ib Regimen 3	Participants received T-DM1 QW + paclitaxel QW intravenously.
Phase Ib Regimen 4	Participants received T-DM1 QW + paclitaxel QW + pertuzumab Q3W intravenously.
Phase IIa Group A	Participants received maximum tolerated dose (MTD) from Phase 1b i.e. T-DM1 3.6mg/kg Q3W + paclitaxel 80mg/m^2 QW intravenously.
Phase IIa Group B	Participants received T-DM1 3.6mg/kg Q3W + paclitaxel 80mg/m^2 QW + pertuzumab Q3W intravenously.

Participant Flow for 2 periods

Period 1:   Phase 1b

	Phase Ib Regimen 1	Phase Ib Regimen 2	Phase Ib Regimen 3	Phase Ib Regimen 4	Phase IIa Group A	Phase IIa Group B
STARTED	29	10	21	3	0	0
Started Treatment	26	10	21	3	0	0
COMPLETED	7	6	4	2	0	0
NOT COMPLETED	22	4	17	1	0	0
Adverse Event	2	1	0	1	0	0
Death	1	0	2	0	0	0
Physician Decision	4	0	1	0	0	0
Withdrawal by Subject	0	1	0	0	0	0
Disease Progression	13	2	14	0	0	0
Protocol Violation	2	0	0	0	0	0

Period 2:   Phase 2a

	Phase Ib Regimen 1	Phase Ib Regimen 2	Phase Ib Regimen 3	Phase Ib Regimen 4	Phase IIa Group A	Phase IIa Group B
STARTED	0	0	0	0	22	22
COMPLETED	0	0	0	0	10	15
NOT COMPLETED	0	0	0	0	12	7
Adverse Event	0	0	0	0	2	0
Death	0	0	0	0	1	1
Lost to Follow-up	0	0	0	0	1	0
Physician Decision	0	0	0	0	0	1
Withdrawal by Subject	0	0	0	0	2	0
Disease Progression	0	0	0	0	6	5

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups

	Description
Phase Ib Regimen 1	Participants received T-DM1 Q3W + paclitaxel QW intravenously.
Phase Ib Regimen 2	Participants received T-DM1 Q3W + paclitaxel QW + pertuzumab Q3W intravenously.
Phase Ib Regimen 3	Participants received T-DM1 QW + paclitaxel QW intravenously.
Phase Ib Regimen 4	Participants received T-DM1 QW + paclitaxel QW + pertuzumab Q3W intravenously.
Phase IIa Group A	Participants received MTD from Phase 1b i.e. T-DM1 3.6mg/kg Q3W + paclitaxel 80mg/m^2 QW intravenously.
Phase IIa Group B	Participants received T-DM1 3.6mg/kg Q3W + paclitaxel 80mg/m^2 QW + pertuzumab Q3W intravenously.
Total	Total of all reporting groups

Baseline Measures

	Phase Ib Regimen 1	Phase Ib Regimen 2	Phase Ib Regimen 3	Phase Ib Regimen 4	Phase IIa Group A	Phase IIa Group B	Total
Overall Participants Analyzed  [Units: Participants]	26	10	21	3	22	22	104
Age  [Units: Years] Mean (Standard Deviation)	53.3  (12.3)	51.3  (11.9)	54.1  (8.5)	49.3  (4.0)	51.7  (11.8)	55.1  (7.7)	53.2  (10.3)
Gender  [Units: Participants]
Female	26	10	19	3	21	22	101
Male	0	0	2	0	1	0	3

1.  Primary:

Number of Participants With Any Adverse Events (AEs), Serious Adverse Events (SAEs), AEs of Grades 3/4, and Death   [ Time Frame: Up to 30 days after the last dose of study treatment or study discontinuation/termination, whichever is later ]

2.  Primary:

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   [ Time Frame: Up to 23 days ]

3.  Primary:

Maximum Tolerated Dose of T-DM1 When T-DM1 (Q3W or QW) and Paclitaxel (QW) Was Administered With and Without Pertuzumab   [ Time Frame: Days 1 to 21 ]

4.  Primary:

Maximum Tolerated Dose of Paclitaxel When T-DM1 (Q3W or QW) and Paclitaxel (QW) Was Administered With and Without Pertuzumab   [ Time Frame: Days 1 to 21 ]

5.  Primary:

Number of Participants in Phase IIa of the Study Who Received 12 or More Paclitaxel Doses in Combination With T-DM1 and/or Pertuzumab   [ Time Frame: From Day 1 to 15 weeks ]

6.  Primary:

Number of Participants Who Had Adverse Events That Required Dose Modification of T-DM1 or Paclitaxel   [ Time Frame: Up to 30 days after the last dose of study treatment or study discontinuation/termination, whichever is later ]

7.  Primary:

Maximum Serum Concentration (Cmax) of T-DM1 and Total Trastuzumab in Cycle 1 After Q3W Dose Regimen   [ Time Frame: Pre-dose, and 0.25 and 4 hours post-dose on Day 1; Day 8 (before paclitaxel infusion) ]

8.  Primary:

Maximum Plasma Concentration (Cmax) of DM1 in Cycle 1 After Q3W Dose Regimen   [ Time Frame: Pre-dose, and 0.25 and 4 hours post-dose on Day 1; Day 8 (before paclitaxel infusion) ]

9.  Primary:

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   [ Time Frame: 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) ]

10.  Primary:

Maximum Serum Concentration (Cmax) of T-DM1 and Total Trastuzumab in Cycle 1 After QW Dose Regimen   [ Time Frame: Pre-dose, and 0.25 and 4 hours post-dose on Day 1; Day 8 (before paclitaxel infusion) ]

11.  Primary:

Maximum Plasma Concentration (Cmax) of DM1 in Cycle 1 After QW Dose Regimen   [ Time Frame: Pre-dose, and 0.25 and 4 hours post-dose on Day 1, and Day 8 (before T-DM1 dose) ]

12.  Primary:

Area Under the Serum Concentration-time Curve of Total Exposure (AUClast) of T-DM1 and Total Trastuzumab in Cycle 1 After QW Dose Regimen   [ Time Frame: Pre-dose, and 0.25 and 4 hours post-dose on Day 1; Day 8 (before T-DM1 dose) ]

13.  Primary:

Maximum Plasma Concentration of Paclitaxel in Cycle 1 (in the Absence T-DM1) and Cycle 2 (in the Presence T-DM1)   [ Time Frame: Pre-dose, and 0.25, 1, 2, 4, 6, and 24 hours post-dose for Cycle 1 and Cycle 2 ]

14.  Primary:

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)   [ Time Frame: Pre-dose, and 0.25, 1, 2, 4, 6, and 24 hours post-dose for Cycle 1 and Cycle 2 ]

15.  Primary:

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)   [ Time Frame: Pre-dose, and 0.25, 1, 2, 4, 6, and 24 hours post-dose for Cycle 1 and Cycle 2 ]

16.  Primary:

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)   [ Time Frame: Pre-dose, and 0.25, 1, 2, 4, 6, and 24 hours post-dose for Cycle 1 and Cycle 2 ]

17.  Primary:

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)   [ Time Frame: Pre-dose, and 0.25, 1, 2, 4, 6, and 24 hours post-dose for Cycle 1 and Cycle 2 ]

18.  Primary:

Number of Participants With Change From Baseline in Cardiac Function   [ Time Frame: 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 ]

19.  Secondary:

Percentage of Participants With Objective Response Rate (ORR)   [ Time Frame: Tumor assessments performed at the end of Cycle 2 and then every 2 cycles (i.e., Cycles 4, 6, 8, 10, etc. [each cycle of 21 days]) throughout the duration of the study (12 months) until disease progression or study discontinuation, whichever occurs first ]

20.  Secondary:

Duration of Objective Response   [ Time Frame: Tumor assessments performed at the end of Cycle 2 and then every 2 cycles (i.e., Cycles 4, 6, 8, 10, etc. [each cycle of 21 days]) throughout the duration of the study (12 months) until disease progression or study discontinuation, whichever occurs first ]

21.  Secondary:

Percentage of Participants With Clinical Benefit   [ Time Frame: Tumor assessments performed at the end of Cycle 2 and then every 2 cycles (i.e., Cycles 4, 6, 8, 10, etc. [each cycle of 21 days]) throughout the duration of the study (12 months) until disease progression or study discontinuation, whichever occurs first ]

22.  Secondary:

Progression-free Survival (PFS)   [ Time Frame: Tumor assessments performed at the end of Cycle 2 and then every 2 cycles (i.e., Cycles 4, 6, 8, 10, etc. [each cycle of 21 days]) throughout the duration of the study (12 months) until disease progression or study discontinuation, whichever occurs first ]

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
Given the small sample size in the different patient subsets, no formal hypothesis testing was performed, and all statistical analyses should be considered descriptive and hypothesis-generating only.