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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00951665
Recruitment Status : Completed
First Posted : August 4, 2009
Results First Posted : June 24, 2016
Last Update Posted : June 24, 2016
Sponsor:
Information provided by (Responsible Party):
Genentech, Inc.

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Metastatic Breast Cancer
Interventions Drug: paclitaxel
Drug: pertuzumab [Perjeta]
Drug: trastuzumab emtansine [Kadcyla]
Enrollment 107
Recruitment Details 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  
Arm/Group Title Phase Ib Regimen 1 Phase Ib Regimen 2 Phase Ib Regimen 3 Phase Ib Regimen 4 Phase IIa Group A Phase IIa Group B
Hide Arm/Group Description Participants received trastuzumab emtansine (T-DM1) every three weeks (Q3W) + paclitaxel weekly (QW) intravenously. Participants received T-DM1 Q3W + paclitaxel QW + pertuzumab Q3W intravenously. Participants received T-DM1 QW + paclitaxel QW intravenously. Participants received T-DM1 QW + paclitaxel QW + pertuzumab Q3W intravenously. Participants received maximum tolerated dose (MTD) from Phase 1b i.e. T-DM1 3.6mg/kg Q3W + paclitaxel 80mg/m^2 QW intravenously. Participants received T-DM1 3.6mg/kg Q3W + paclitaxel 80mg/m^2 QW + pertuzumab Q3W intravenously.
Period Title: Phase 1b
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
Reason Not Completed
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 Title: Phase 2a
Started 0 0 0 0 22 22
Completed 0 0 0 0 10 15
Not Completed 0 0 0 0 12 7
Reason Not Completed
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
Arm/Group Title 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
Hide Arm/Group Description Participants received T-DM1 Q3W + paclitaxel QW intravenously. Participants received T-DM1 Q3W + paclitaxel QW + pertuzumab Q3W intravenously. Participants received T-DM1 QW + paclitaxel QW intravenously. Participants received T-DM1 QW + paclitaxel QW + pertuzumab Q3W intravenously. Participants received MTD from Phase 1b i.e. T-DM1 3.6mg/kg Q3W + paclitaxel 80mg/m^2 QW intravenously. Participants received T-DM1 3.6mg/kg Q3W + paclitaxel 80mg/m^2 QW + pertuzumab Q3W intravenously. Total of all reporting groups
Overall Number of Baseline Participants 26 10 21 3 22 22 104
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 26 participants 10 participants 21 participants 3 participants 22 participants 22 participants 104 participants
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)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 26 participants 10 participants 21 participants 3 participants 22 participants 22 participants 104 participants
Female
26
 100.0%
10
 100.0%
19
  90.5%
3
 100.0%
21
  95.5%
22
 100.0%
101
  97.1%
Male
0
   0.0%
0
   0.0%
2
   9.5%
0
   0.0%
1
   4.5%
0
   0.0%
3
   2.9%
1.Primary Outcome
Title Number of Participants With Any Adverse Events (AEs), Serious Adverse Events (SAEs), AEs of Grades 3/4, and Death
Hide Description 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.
Time Frame Up to 30 days after the last dose of study treatment or study discontinuation/termination, whichever is later
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Population: All participants who received at least a single dose of study medication were included.
Arm/Group Title Phase Ib Regimen 1 Phase Ib Regimen 2 Phase Ib Regimen 3 Phase Ib Regimen 4 Phase IIa Group A Phase IIa Group B
Hide Arm/Group Description:
Participants received T-DM1 Q3W + paclitaxel QW intravenously.
Participants received T-DM1 Q3W + paclitaxel QW + pertuzumab Q3W intravenously.
Participants received T-DM1 QW + paclitaxel QW intravenously.
Participants received T-DM1 QW + paclitaxel QW + pertuzumab Q3W intravenously.
Participants received MTD from Phase 1b i.e. T-DM1 3.6mg/kg Q3W and paclitaxel 80mg/m^2 QW intravenously.
Participants received MTD from Phase 1b , i.e. T-DM1 3.6mg/kg Q3W and paclitaxel 80mg/m^2 QW, plus pertuzumab Q3W intravenously.
Overall Number of Participants Analyzed 26 10 21 3 22 22
Measure Type: Number
Unit of Measure: participants
Any AEs 26 10 21 3 22 22
Any SAEs 7 5 7 2 6 6
Death 1 0 2 0 1 1
Any AEs Grade 3 19 5 15 2 13 13
Any AEs Grade 4 0 2 1 1 6 2
AEs leading to T-DM1 discontinuation 3 1 1 1 2 0
AEs leading to paclitaxel discontinuation 20 7 14 3 13 13
AEs leading to pertuzumab discontinuation NA [1]  1 NA [1]  1 NA [1]  0
[1]
NA: Not applicable for this group
2.Primary Outcome
Title 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
Hide Description 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.
Time Frame Up to 23 days
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Population: All participants of the dose finding part of the study (phase 1b) who received at least a single dose of study medication were included. Participants in Phase 1b (Regimen 1, Regimen 2, Regimen 3 and Regimen 4 [60 participants]) were considered for this analysis.
Arm/Group Title Phase Ib Regimen 1 Phase Ib Regimen 2 Phase Ib Regimen 3 Phase Ib Regimen 4
Hide Arm/Group Description:
Participants received T-DM1 Q3W + paclitaxel QW intravenously.
Participants received T-DM1 Q3W + paclitaxel QW + pertuzumab Q3W intravenously.
Participants received T-DM1 QW + paclitaxel QW intravenously.
Participants received T-DM1 QW + paclitaxel QW + pertuzumab Q3W intravenously.
Overall Number of Participants Analyzed 26 10 21 3
Measure Type: Number
Unit of Measure: participants
0 0 0 0
3.Primary Outcome
Title Maximum Tolerated Dose of T-DM1 When T-DM1 (Q3W or QW) and Paclitaxel (QW) Was Administered With and Without Pertuzumab
Hide Description 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.
Time Frame Days 1 to 21
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Population: All participants of the dose finding part of the study (phase 1b) who received at least a single dose of study medication were included.
Arm/Group Title Phase Ib Regimen 1 Phase Ib Regimen 2 Phase Ib Regimen 3 Phase Ib Regimen 4
Hide Arm/Group Description:
Participants received T-DM1 Q3W + paclitaxel QW intravenously.
Participants received T-DM1 Q3W + paclitaxel QW + pertuzumab Q3W intravenously.
Participants received T-DM1 QW + paclitaxel QW intravenously.
Participants received T-DM1 QW + paclitaxel QW + pertuzumab Q3W intravenously.
Overall Number of Participants Analyzed 26 10 21 3
Measure Type: Number
Unit of Measure: mg/kg
3.6 3.6 2.4 2.4
4.Primary Outcome
Title Maximum Tolerated Dose of Paclitaxel When T-DM1 (Q3W or QW) and Paclitaxel (QW) Was Administered With and Without Pertuzumab
Hide Description 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.
Time Frame Days 1 to 21
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Population: All participants of the dose finding part of the study (phase 1b) who received at least a single dose of study medication were included.
Arm/Group Title Phase Ib Regimen 1 Phase Ib Regimen 2 Phase Ib Regimen 3 Phase Ib Regimen 4
Hide Arm/Group Description:
Participants received T-DM1 Q3W + paclitaxel QW intravenously.
Participants received T-DM1 Q3W + paclitaxel QW + pertuzumab Q3W intravenously.
Participants received T-DM1 QW + paclitaxel QW intravenously.
Participants received T-DM1 QW + paclitaxel QW + pertuzumab Q3W intravenously.
Overall Number of Participants Analyzed 26 10 21 3
Measure Type: Number
Unit of Measure: mg/m^2
80 80 80 80
5.Primary Outcome
Title Number of Participants in Phase IIa of the Study Who Received 12 or More Paclitaxel Doses in Combination With T-DM1 and/or Pertuzumab
Hide Description Participants in Phase IIa received T-DM1 Q3W and paclitaxel in Group A and T-DM1, paclitaxel, and pertuzumab in Group B.
Time Frame From Day 1 to 15 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Population: All participants of the phase IIa part of the study who received at least a single dose of study medication and did not have disease progression in the first 12 weeks of study treatment were included.
Arm/Group Title Phase IIa Group A Phase IIa Group B
Hide Arm/Group Description:
Participants received MTD from Phase Ib i.e. T-DM1 3.6mg/kg Q3W and paclitaxel 80mg/m^2 QW intravenously.
Participants received T-DM1 3.6mg/kg Q3W, paclitaxel 80mg/m^2 QW, and pertuzumab 420 mg Q3W intravenously.
Overall Number of Participants Analyzed 21 22
Measure Type: Number
Unit of Measure: participants
11 11
6.Primary Outcome
Title Number of Participants Who Had Adverse Events That Required Dose Modification of T-DM1 or Paclitaxel
Hide Description 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.
Time Frame Up to 30 days after the last dose of study treatment or study discontinuation/termination, whichever is later
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Population: All participants who received at least a single dose of study medication were included.
Arm/Group Title Phase Ib Regimen 1 Phase Ib Regimen 2 Phase Ib Regimen 3 Phase Ib Regimen 4 Phase IIa Group A Phase IIa Group B
Hide Arm/Group Description:
Participants received T-DM1 Q3W + paclitaxel QW intravenously.
Participants received T-DM1 Q3W + paclitaxel QW + pertuzumab Q3W intravenously.
Participants received T-DM1 QW + paclitaxel QW intravenously.
Participants received T-DM1 QW + paclitaxel QW + pertuzumab Q3W intravenously.
Participants received MTD from Phase 1b i.e. T-DM1 3.6mg/kg Q3W and paclitaxel 80mg/m^2 QW intravenously.
Participants received of T-DM1 3.6mg/kg Q3W, paclitaxel 80mg/m^2 QW, and pertuzumab Q3W intravenously.
Overall Number of Participants Analyzed 26 10 21 3 22 22
Measure Type: Number
Unit of Measure: participants
T-DM1 13 5 19 2 15 12
Paclitaxel 20 7 14 3 18 19
7.Primary Outcome
Title Maximum Serum Concentration (Cmax) of T-DM1 and Total Trastuzumab in Cycle 1 After Q3W Dose Regimen
Hide Description 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.
Time Frame Pre-dose, and 0.25 and 4 hours post-dose on Day 1; Day 8 (before paclitaxel infusion)
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetics (PK) population included all participants from Phase Ib who received at least one dose of T-DM1 or paclitaxel with at least one post-dose concentration data point. Only participants with data available for this parameter were analyzed.
Arm/Group Title Phase Ib Cohort A Phase Ib Cohort B Phase Ib Cohort 1 Phase Ib Cohort J Phase Ib Cohort D Phase Ib Cohort 3B
Hide Arm/Group Description:
Participants received 2 mg/kg T-DM1 Q3W and 65 mg/m^2 paclitaxel QW intravenously.
Participants received 2 mg/kg T-DM1 Q3W and 80 mg/m^2 paclitaxel QW intravenously.
Participants received 2.4 mg/kg T-DM1 Q3W and 65 mg/m^2 paclitaxel QW intravenously.
Participants received 2.4 mg/kg T-DM1 Q3W and 80 mg/m^2 paclitaxel QW intravenously.
Participants received 3.0 mg/kg T-DM1 Q3W and 80 mg/m^2 paclitaxel QW intravenously.
Participants received 3.6 mg/kg T-DM1 Q3W and 80 mg/m^2 paclitaxel QW intravenously.
Overall Number of Participants Analyzed 2 6 8 3 3 3
Mean (Standard Deviation)
Unit of Measure: microgram per millilitre (Mcg /mL)
T-DM1 53.5  (3.1) 44.9  (4.8) 43.6  (16.3) 54.6  (13.6) 62.2  (18.9) 76.1  (31.5)
Total trastuzumab 73.9  (33.4) 61  (23.2) 62  (15.2) 55.2  (12.3) 91  (45.4) 87.4  (39.5)
8.Primary Outcome
Title Maximum Plasma Concentration (Cmax) of DM1 in Cycle 1 After Q3W Dose Regimen
Hide Description Cmax of plasma DM1 in Cycle 1 was estimated by non-compartmental analysis for Phase Ib when T-DM1 was administered Q3W.
Time Frame Pre-dose, and 0.25 and 4 hours post-dose on Day 1; Day 8 (before paclitaxel infusion)
Hide Outcome Measure Data
Hide Analysis Population Description
PK population included all participants from Phase Ib who received at least one dose of T-DM1 or paclitaxel with at least one post-dose concentration data point. Only participants with data available for this parameter were analyzed.
Arm/Group Title Phase Ib Cohort B Phase Ib Cohort 1 Phase Ib Cohort J Phase Ib Cohort D Phase Ib Cohort 3B
Hide Arm/Group Description:
Participants received 2 mg/kg T-DM1 Q3W and 80 mg/m^2 paclitaxel QW intravenously.
Participants received 2.4 mg/kg T-DM1 Q3W and 65 mg/m^2 paclitaxel QW intravenously.
Participants received 2.4 mg/kg T-DM1 Q3W and 80 mg/m^2 paclitaxel QW intravenously.
Participants received 3.0 mg/kg T-DM1 Q3W and 80 mg/m^2 paclitaxel QW intravenously.
Participants received 3.6 mg/kg T-DM1 Q3W and 80 mg/m^2 paclitaxel QW intravenously.
Overall Number of Participants Analyzed 4 8 3 3 3
Mean (Full Range)
Unit of Measure: nano gram per milliliter (ng/mL)
2.4
(2.0 to 2.7)
3.4
(2.0 to 4.9)
2.7
(2.6 to 2.8)
3.2
(2.6 to 4.1)
5.1
(3.2 to 6.3)
9.Primary Outcome
Title 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
Hide Description 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.
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)
Hide Outcome Measure Data
Hide Analysis Population Description
PK population included all participants from Phase Ib who received at least one dose of T-DM1 or paclitaxel with at least one post-dose concentration data point. Only participants with data available for this parameter were analyzed.
Arm/Group Title Phase Ib Cohort A Phase Ib Cohort B Phase Ib Cohort 1 Phase Ib Cohort J Phase Ib Cohort D Phase Ib Cohort 3B
Hide Arm/Group Description:
Participants received 2 mg/kg T-DM1 Q3W and 65 mg/m^2 paclitaxel QW intravenously.
Participants received 2 mg/kg T-DM1 Q3W and 80 mg/m^2 paclitaxel QW intravenously.
Participants received 2.4 mg/kg T-DM1 Q3W and 65 mg/m^2 paclitaxel QW intravenously.
Participants received 2.4 mg/kg T-DM1 Q3W and 80 mg/m^2 paclitaxel QW intravenously.
Participants received 3.0 mg/kg T-DM1 Q3W and 80 mg/m^2 paclitaxel QW intravenously.
Participants received 3.6 mg/kg T-DM1 Q3W and 80 mg/m^2 paclitaxel QW intravenously.
Overall Number of Participants Analyzed 2 6 6 3 3 3
Mean (Standard Deviation)
Unit of Measure: day*mcg/mL
T-DM1 241  (57.2) 216  (118) 264  (77.4) 271  (51.2) 382  (140) 523  (288)
Total trastuzumab 633  (496) 518  (359) 460  (308) 401  (249) 959  (609) 764  (372)
10.Primary Outcome
Title Maximum Serum Concentration (Cmax) of T-DM1 and Total Trastuzumab in Cycle 1 After QW Dose Regimen
Hide Description 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.
Time Frame Pre-dose, and 0.25 and 4 hours post-dose on Day 1; Day 8 (before paclitaxel infusion)
Hide Outcome Measure Data
Hide Analysis Population Description
PK population included all participants from Phase Ib who received at least one dose of T-DM1 or paclitaxel with at least one post-dose concentration data point. Only participants with data available for this parameter were analyzed.
Arm/Group Title Phase Ib Cohort 6 Phase Ib Cohort 7 Phase Ib Cohort 8 Phase Ib Cohort F Phase Ib Cohort 4
Hide Arm/Group Description:
Participants received 1.2 mg/kg T-DM1 QW and 65 mg/m^2 paclitaxel QW intravenously.
Participants received 1.6 mg/kg T-DM1 QW and 65 mg/m^2 paclitaxel QW intravenously.
Participants received 2.0 mg/kg T-DM1 QW and 65 mg/m^2 paclitaxel QW intravenously.
Participants received 2.4 mg/kg T-DM1 QW and 65 mg/m^2 paclitaxel QW intravenously.
Participants received 2.4 mg/kg T-DM1 QW and 80 mg/m^2 paclitaxel QW intravenously.
Overall Number of Participants Analyzed 3 9 3 3 3
Mean (Standard Deviation)
Unit of Measure: mcg/mL
T-DM1 24.3  (2.61) 26  (11.2) 39.4  (7.09) 63.7  (8.72) 87.8  (75.3)
Total trastuzumab 57.8  (31.7) 39.9  (24.1) 66.1  (25.2) 97.6  (45.7) 92.1  (69.4)
11.Primary Outcome
Title Maximum Plasma Concentration (Cmax) of DM1 in Cycle 1 After QW Dose Regimen
Hide Description Cmax for plasma DM1 in Cycle 1 was estimated by non-compartmental analysis for Phase Ib when T-DM1 was administered QW
Time Frame Pre-dose, and 0.25 and 4 hours post-dose on Day 1, and Day 8 (before T-DM1 dose)
Hide Outcome Measure Data
Hide Analysis Population Description
PK population included all participants from Phase Ib who received at least one dose of T-DM1 or paclitaxel with at least one post-dose concentration data point. Only participants with data available for this parameter were analyzed.
Arm/Group Title Phase Ib Cohort 6 Phase Ib Cohort 7 Phase Ib Cohort 8 Phase Ib Cohort F Phase Ib Cohort 4
Hide Arm/Group Description:
Participants received 1.2 mg/kg T-DM1 QW and 65 mg/m^2 paclitaxel QW intravenously.
Participants received 1.6 mg/kg T-DM1 QW and 65 mg/m^2 paclitaxel QW intravenously.
Participants received 2.0 mg/kg T-DM1 QW and 65 mg/m^2 paclitaxel QW intravenously.
Participants received 2.4 mg/kg T-DM1 QW and 65 mg/m^2 paclitaxel QW intravenously.
Participants received 2.4 mg/kg T-DM1 QW and 80 mg/m^2 paclitaxel QW intravenously.
Overall Number of Participants Analyzed 3 7 3 3 3
Mean (Full Range)
Unit of Measure: ng/mL
1.0
(0.8 to 1.2)
1.8
(0.8 to 2.7)
3.0
(2.6 to 3.8)
2.7
(2.2 to 3.2)
4.0
(2.4 to 6.9)
12.Primary Outcome
Title Area Under the Serum Concentration-time Curve of Total Exposure (AUClast) of T-DM1 and Total Trastuzumab in Cycle 1 After QW Dose Regimen
Hide Description 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
Time Frame Pre-dose, and 0.25 and 4 hours post-dose on Day 1; Day 8 (before T-DM1 dose)
Hide Outcome Measure Data
Hide Analysis Population Description
PK population included all participants from Phase Ib who received at least one dose of T-DM1 or paclitaxel with at least one post-dose concentration data point. Only participants with data available for this parameter were analyzed.
Arm/Group Title Phase Ib Cohort 6 Phase Ib Cohort 7 Phase Ib Cohort 8 Phase Ib Cohort F Phase Ib Cohort 4
Hide Arm/Group Description:
Participants received 1.2 mg/kg T-DM1 QW and 65 mg/m^2 paclitaxel QW intravenously.
Participants received 1.6 mg/kg T-DM1 QW and 65 mg/m^2 paclitaxel QW intravenously.
Participants received 2.0 mg/kg T-DM1 QW and 65 mg/m^2 paclitaxel QW intravenously.
Participants received 2.4 mg/kg T-DM1 QW and 65 mg/m^2 paclitaxel QW intravenously.
Participants received 2.4 mg/kg T-DM1 QW and 80 mg/m^2 paclitaxel QW intravenously.
Overall Number of Participants Analyzed 3 8 3 3 3
Mean (Standard Deviation)
Unit of Measure: day*µg/mL
T-DM1 84.6  (15.2) 91.9  (41.8) 150  (28.3) 242  (18) 165  (42.4)
Total trastuzumab 275  (170) 149  (94.1) 295  (121) 460  (250) 270  (62.2)
13.Primary Outcome
Title Maximum Plasma Concentration of Paclitaxel in Cycle 1 (in the Absence T-DM1) and Cycle 2 (in the Presence T-DM1)
Hide Description 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.
Time Frame Pre-dose, and 0.25, 1, 2, 4, 6, and 24 hours post-dose for Cycle 1 and Cycle 2
Hide Outcome Measure Data
Hide Analysis Population Description
PK population included all participants from Phase Ib who received at least one dose of T-DM1 or paclitaxel with at least one post-dose concentration data point. "n" denotes number of participants who received the indicated study drug.
Arm/Group Title Phase Ib
Hide Arm/Group Description:
For paclitaxel, plasma concentration-time data were available from 47 patients receiving administration of paclitaxel at QW doses of 65 and 80 mg/m^2.
Overall Number of Participants Analyzed 47
Mean (Standard Deviation)
Unit of Measure: ng/mL
65 mg, Cycle 1 (n = 29) 1430  (53.5)
65 mg, Cycle 2 (n = 24) 1280  (59.8)
80 mg, Cycle 1 (n = 18) 1540  (64.4)
80 mg, Cycle 2 (n = 17) 1590  (56.7)
14.Primary Outcome
Title 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)
Hide Description 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).
Time Frame Pre-dose, and 0.25, 1, 2, 4, 6, and 24 hours post-dose for Cycle 1 and Cycle 2
Hide Outcome Measure Data
Hide Analysis Population Description
PK population included all participants from Phase Ib who received at least one dose of T-DM1 or paclitaxel with at least one post-dose concentration data point. "n" denotes number of participants who received the indicated study drug.
Arm/Group Title Phase Ib
Hide Arm/Group Description:
For paclitaxel, plasma concentration-time data were available from 47 patients receiving administration of paclitaxel at QW doses of 65 and 80 mg/m^2.
Overall Number of Participants Analyzed 47
Mean (Standard Deviation)
Unit of Measure: hr*ng/mL
65 mg, Cycle 1 (n = 29) 3440  (32.3)
65 mg, Cycle 2 (n = 24) 3520  (38)
80 mg, Cycle 1 (n = 18) 3890  (48)
80 mg, Cycle 2 (n = 17) 4220  (49.8)
15.Primary Outcome
Title 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)
Hide Description 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).
Time Frame Pre-dose, and 0.25, 1, 2, 4, 6, and 24 hours post-dose for Cycle 1 and Cycle 2
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PK population included all participants from Phase Ib who received at least one dose of T-DM1 or paclitaxel with at least one post-dose concentration data point. "n" denotes number of participants who received the indicated study drug.
Arm/Group Title Phase Ib
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For paclitaxel, plasma concentration-time data were available from 47 patients receiving administration of paclitaxel at QW doses of 65 and 80 mg/m^2.
Overall Number of Participants Analyzed 47
Mean (Standard Deviation)
Unit of Measure: hr
65 mg, Cycle 1 (n = 29) 9.89  (17.1)
65 mg, Cycle 2 (n = 24) 11.7  (25.1)
80 mg, Cycle 1 (n = 18) 8.94  (20)
80 mg, Cycle 2 (n = 17) 10.8  (30.8)
16.Primary Outcome
Title 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)
Hide Description 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).
Time Frame Pre-dose, and 0.25, 1, 2, 4, 6, and 24 hours post-dose for Cycle 1 and Cycle 2
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PK population included all participants from Phase Ib who received at least one dose of T-DM1 or paclitaxel with at least one post-dose concentration data point. "n" denotes number of participants who received the indicated study drug.
Arm/Group Title Phase Ib
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For paclitaxel, plasma concentration-time data were available from 47 patients receiving administration of paclitaxel at QW doses of 65 and 80 mg/m^2.
Overall Number of Participants Analyzed 47
Mean (Standard Deviation)
Unit of Measure: L/hr/m^2
65 mg, Cycle 1 (n = 29) 20.7  (31.1)
65 mg, Cycle 2 (n = 24) 21  (36.4)
80 mg, Cycle 1 (n = 18) 22.8  (51.1)
80 mg, Cycle 2 (n = 17) 23  (44.1)
17.Primary Outcome
Title 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)
Hide Description 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).
Time Frame Pre-dose, and 0.25, 1, 2, 4, 6, and 24 hours post-dose for Cycle 1 and Cycle 2
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PK population included all participants from Phase Ib who received at least one dose of T-DM1 or paclitaxel with at least one post-dose concentration data point. "n" denotes number of participants who received the indicated study drug.
Arm/Group Title Phase Ib
Hide Arm/Group Description:
For paclitaxel, plasma concentration-time data were available from 47 patients receiving administration of paclitaxel at QW doses of 65 and 80 mg/m^2.
Overall Number of Participants Analyzed 47
Mean (Standard Deviation)
Unit of Measure: L/m^2
65 mg, Cycle 1 (n = 29) 167  (56.3)
65 mg, Cycle 2 (n = 24) 220  (57.3)
80 mg, Cycle 1 (n = 18) 166  (78.9)
80 mg, Cycle 2 (n = 17) 196  (56.5)
18.Primary Outcome
Title Number of Participants With Change From Baseline in Cardiac Function
Hide Description 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.
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
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Safety Population: All participants who received at least a single dose of study medication were included.
Arm/Group Title Phase Ib Regimen 1 Phase Ib Regimen 2 Phase Ib Regimen 3 Phase Ib Regimen 4 Phase IIa Group A Phase IIa Group B
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Participants received T-DM1 Q3W + paclitaxel QW intravenously.
Participants received T-DM1 Q3W + paclitaxel QW + pertuzumab Q3W intravenously.
Participants received T-DM1 QW + paclitaxel QW intravenously.
Participants received T-DM1 QW + paclitaxel QW + pertuzumab Q3W intravenously.
Participants received MTD from Phase 1b i.e. T-DM1 3.6mg/kg Q3W and paclitaxel 80mg/m^2 QW intravenously.
Participants received MTD from Phase 1b , i.e. T-DM1 3.6mg/kg Q3W and paclitaxel 80mg/m^2 QW, plus pertuzumab Q3W intravenously.
Overall Number of Participants Analyzed 26 10 21 3 22 22
Measure Type: Number
Unit of Measure: participants
LVEF, increase 8 3 5 0 5 4
LVEF, 0 to <15% 17 7 14 3 15 18
LVEF, >=15 to <25% 0 0 2 0 0 0
LVEF, missing 1 0 0 0 2 0
New segmental wall abnormality 0 1 0 0 3 1
19.Secondary Outcome
Title Percentage of Participants With Objective Response Rate (ORR)
Hide Description Participants with measurable disease (at least one lesion 2 centimeters [cm] or more on computed tomography (CT) scan or 1 cm or more on spiral CT scan) were considered for OR. ORR is defined as the percentage of patients with a complete response (CR)/partial response (PR) determined on two consecutive tumor assessments at least 4 weeks apart based on modified Response Evaluation Criteria in Solid Tumors, Version 1.0 (RECIST). CR defined as disappearance of all target and non-target lesions and normalization of tumor marker level. PR defined as at least 30 percent decrease in sum of the longest diameters of the target lesions taking as reference the baseline sum longest diameters.
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
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An efficacy population: All participants who received at least a single dose of study medication were included. Participants with measurable disease were considered for OR.
Arm/Group Title Phase Ib Regimen 1 Phase Ib Regimen 2 Phase Ib Regimen 3 Phase Ib Regimen 4 Phase IIa Group A Phase IIa Group B
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Participants received T-DM1 Q3W + paclitaxel QW intravenously.
Participants received T-DM1 Q3W + paclitaxel QW + pertuzumab Q3W intravenously.
Participants received T-DM1 QW + paclitaxel QW intravenously.
Participants received T-DM1 QW + paclitaxel QW + pertuzumab Q3W intravenously.
Participants received MTD from Phase 1b i.e. T-DM1 3.6mg/kg Q3W and paclitaxel 80mg/m^2 QW intravenously.
Participants received MTD from Phase 1b , i.e. T-DM1 3.6mg/kg Q3W and paclitaxel 80mg/m^2 QW, plus pertuzumab Q3W intravenously.
Overall Number of Participants Analyzed 24 10 18 3 21 21
Measure Type: Number
Unit of Measure: percentage of participants
50.0 70.0 50.0 66.7 47.6 52.4
20.Secondary Outcome
Title Duration of Objective Response
Hide Description Duration of OR is only calculated for participants with OR and is defined as the time from the first tumor assessment that supports the participant's OR to disease progression or death.
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
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An efficacy population: All participants who received at least a single dose of study medication were included. Participants with OR were considered for this outcome measure.
Arm/Group Title Phase Ib Regimen 1 Phase Ib Regimen 2 Phase Ib Regimen 3 Phase Ib Regimen 4 Phase IIa Group A Phase IIa Group B
Hide Arm/Group Description:
Participants received T-DM1 Q3W + paclitaxel QW intravenously.
Participants received T-DM1 Q3W + paclitaxel QW + pertuzumab Q3W intravenously.
Participants received T-DM1 QW + paclitaxel QW intravenously.
Participants received T-DM1 QW + paclitaxel QW + pertuzumab Q3W intravenously.
Participants received MTD from Phase 1b i.e. T-DM1 3.6mg/kg Q3W and paclitaxel 80mg/m^2 QW intravenously.
Participants received MTD from Phase 1b , i.e. T-DM1 3.6mg/kg Q3W and paclitaxel 80mg/m^2 QW, plus pertuzumab Q3W intravenously.
Overall Number of Participants Analyzed 12 7 9 2 10 11
Median (95% Confidence Interval)
Unit of Measure: months
7.1 [1] 
(4.2 to NA)
NA [1] 
(5.8 to NA)
7.0 [1] 
(4.8 to NA)
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
[1]
Not estimable due to limited follow-up.
21.Secondary Outcome
Title Percentage of Participants With Clinical Benefit
Hide Description Clinical benefit is defined as CR, PR, or stable disease (SD) of 6 months or more duration as assessed by the investigator. CR and PR are identified in previous outcome measure. SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum longest diameter since the treatment started. PD is 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 the treatment started or the appearance of one or more new lesions.
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
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An efficacy population: All participants who received at least a single dose of study medication were included.
Arm/Group Title Phase Ib Regimen 1 Phase Ib Regimen 2 Phase Ib Regimen 3 Phase Ib Regimen 4 Phase IIa Group A Phase IIa Group B
Hide Arm/Group Description:
Participants received T-DM1 Q3W + paclitaxel QW intravenously.
Participants received T-DM1 Q3W + paclitaxel QW + pertuzumab Q3W intravenously.
Participants received T-DM1 QW + paclitaxel QW intravenously.
Participants received T-DM1 QW + paclitaxel QW + pertuzumab Q3W intravenously.
Participants received MTD from Phase 1b i.e. T-DM1 3.6mg/kg Q3W and paclitaxel 80mg/m^2 QW intravenously.
Participants received MTD from Phase 1b , i.e. T-DM1 3.6mg/kg Q3W and paclitaxel 80mg/m^2 QW, plus pertuzumab Q3W intravenously.
Overall Number of Participants Analyzed 26 10 21 3 22 22
Measure Type: Number
Unit of Measure: percentage of participants
65.4 80.0 61.9 66.7 54.5 59.1
22.Secondary Outcome
Title Progression-free Survival (PFS)
Hide Description PFS is defined as the time from the first day of study treatment to documented disease progression or death on study i.e., death due to any cause within 30-days of last dose of study treatment, whichever occurs first.
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
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Hide Analysis Population Description
An efficacy population: All participants who received at least a single dose of study medication were included.
Arm/Group Title Phase Ib Regimen 1 Phase Ib Regimen 2 Phase Ib Regimen 3 Phase Ib Regimen 4 Phase IIa Group A Phase IIa Group B
Hide Arm/Group Description:
Participants received T-DM1 Q3W + paclitaxel QW intravenously.
Participants received T-DM1 Q3W + paclitaxel QW + pertuzumab Q3W intravenously.
Participants received T-DM1 QW + paclitaxel QW intravenously.
Participants received T-DM1 QW + paclitaxel QW + pertuzumab Q3W intravenously.
Participants received MTD from Phase 1b i.e. T-DM1 3.6mg/kg Q3W and paclitaxel 80mg/m^2 QW intravenously.
Participants received MTD from Phase 1b , i.e. T-DM1 3.6mg/kg Q3W and paclitaxel 80mg/m^2 QW, plus pertuzumab Q3W intravenously.
Overall Number of Participants Analyzed 26 10 21 3 22 22
Median (Full Range)
Unit of Measure: months
11.7
(1.3 to 13)
11.9
(4.3 to 12.3)
11.3
(1.7 to 12.0)
11.0
(1.3 to 12.2)
6.0
(0.1 to 10.0)
6.6
(2.6 to 8.4)
Time Frame Up to 30 days after the last dose of study treatment or study discontinuation/termination, whichever is later (Approximately 4 years)
Adverse Event Reporting Description SAEs and other AEs were collected in the safety population, which was defined as all participants who received at least a single dose of study medication. There was one SAE that lead to death and the preferred term was not captured for it. The same SAE was captured as 'Death - unknown cause' in the below SAE table.
 
Arm/Group Title Phase Ib Regimen 1 Phase Ib Regimen 2 Phase Ib Regimen 3 Phase Ib Regimen 4 Phase IIa Group A Phase IIa Group B
Hide Arm/Group Description Participants received T-DM1 Q3W + paclitaxel QW intravenously. Participants received T-DM1 Q3W + paclitaxel QW + pertuzumab Q3W intravenously. Participants received T-DM1 QW + paclitaxel QW intravenously. Participants received T-DM1 QW + paclitaxel QW + pertuzumab Q3W intravenously. Participants received MTD from Phase 1b i.e. T-DM1 3.6mg/kg Q3W and paclitaxel 80mg/m^2 QW intravenously. Participants received MTD from Phase 1b , i.e. T-DM1 3.6mg/kg Q3W and paclitaxel 80mg/m^2 QW, plus pertuzumab Q3W intravenously.
All-Cause Mortality
Phase Ib Regimen 1 Phase Ib Regimen 2 Phase Ib Regimen 3 Phase Ib Regimen 4 Phase IIa Group A Phase IIa Group B
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/--   --/--   --/--   --/-- 
Hide Serious Adverse Events
Phase Ib Regimen 1 Phase Ib Regimen 2 Phase Ib Regimen 3 Phase Ib Regimen 4 Phase IIa Group A Phase IIa Group B
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   7/26 (26.92%)   5/10 (50.00%)   7/21 (33.33%)   2/3 (66.67%)   6/22 (27.27%)   6/22 (27.27%) 
Blood and lymphatic system disorders             
Febrile neutropenia † 1  1/26 (3.85%)  0/10 (0.00%)  0/21 (0.00%)  0/3 (0.00%)  0/22 (0.00%)  0/22 (0.00%) 
Neutropenia † 1  0/26 (0.00%)  0/10 (0.00%)  0/21 (0.00%)  1/3 (33.33%)  0/22 (0.00%)  0/22 (0.00%) 
Thrombocytopenia † 1  0/26 (0.00%)  1/10 (10.00%)  0/21 (0.00%)  0/3 (0.00%)  1/22 (4.55%)  0/22 (0.00%) 
Cardiac disorders             
Cardiac failure congestive † 1  0/26 (0.00%)  0/10 (0.00%)  0/21 (0.00%)  0/3 (0.00%)  1/22 (4.55%)  0/22 (0.00%) 
Extrasystoles † 1  0/26 (0.00%)  0/10 (0.00%)  0/21 (0.00%)  0/3 (0.00%)  1/22 (4.55%)  0/22 (0.00%) 
Gastrointestinal disorders             
Nausea † 1  1/26 (3.85%)  0/10 (0.00%)  0/21 (0.00%)  0/3 (0.00%)  1/22 (4.55%)  1/22 (4.55%) 
Abdominal pain † 1  0/26 (0.00%)  0/10 (0.00%)  0/21 (0.00%)  0/3 (0.00%)  1/22 (4.55%)  0/22 (0.00%) 
Constipation † 1  0/26 (0.00%)  0/10 (0.00%)  0/21 (0.00%)  0/3 (0.00%)  1/22 (4.55%)  0/22 (0.00%) 
Gastrointestinal haemorrhage † 1  0/26 (0.00%)  0/10 (0.00%)  0/21 (0.00%)  0/3 (0.00%)  1/22 (4.55%)  0/22 (0.00%) 
General disorders             
Death - unknown cause † 1  1/26 (3.85%)  0/10 (0.00%)  0/21 (0.00%)  0/3 (0.00%)  0/22 (0.00%)  0/22 (0.00%) 
Thrombosis in device † 1  0/26 (0.00%)  0/10 (0.00%)  0/21 (0.00%)  1/3 (33.33%)  0/22 (0.00%)  0/22 (0.00%) 
Ulcer † 1  0/26 (0.00%)  0/10 (0.00%)  1/21 (4.76%)  0/3 (0.00%)  0/22 (0.00%)  0/22 (0.00%) 
Fatigue † 1  0/26 (0.00%)  0/10 (0.00%)  0/21 (0.00%)  0/3 (0.00%)  1/22 (4.55%)  1/22 (4.55%) 
Chills † 1  0/26 (0.00%)  0/10 (0.00%)  0/21 (0.00%)  0/3 (0.00%)  0/22 (0.00%)  1/22 (4.55%) 
Device occlusion † 1  0/26 (0.00%)  0/10 (0.00%)  0/21 (0.00%)  0/3 (0.00%)  0/22 (0.00%)  1/22 (4.55%) 
Immune system disorders             
Hypersensitivity † 1  1/26 (3.85%)  0/10 (0.00%)  0/21 (0.00%)  0/3 (0.00%)  0/22 (0.00%)  0/22 (0.00%) 
Infections and infestations             
Cellulitis † 1  2/26 (7.69%)  0/10 (0.00%)  1/21 (4.76%)  0/3 (0.00%)  0/22 (0.00%)  0/22 (0.00%) 
Gastroenteritis † 1  1/26 (3.85%)  1/10 (10.00%)  0/21 (0.00%)  0/3 (0.00%)  1/22 (4.55%)  0/22 (0.00%) 
Pneumonia † 1  0/26 (0.00%)  2/10 (20.00%)  2/21 (9.52%)  0/3 (0.00%)  0/22 (0.00%)  0/22 (0.00%) 
Sepsis † 1  0/26 (0.00%)  0/10 (0.00%)  2/21 (9.52%)  0/3 (0.00%)  0/22 (0.00%)  0/22 (0.00%) 
Device related infection † 1  0/26 (0.00%)  0/10 (0.00%)  1/21 (4.76%)  0/3 (0.00%)  0/22 (0.00%)  0/22 (0.00%) 
Campylobacter infection † 1  0/26 (0.00%)  0/10 (0.00%)  0/21 (0.00%)  0/3 (0.00%)  0/22 (0.00%)  1/22 (4.55%) 
Influenza † 1  0/26 (0.00%)  0/10 (0.00%)  0/21 (0.00%)  0/3 (0.00%)  0/22 (0.00%)  1/22 (4.55%) 
Streptococcal sepsis † 1  0/26 (0.00%)  0/10 (0.00%)  0/21 (0.00%)  0/3 (0.00%)  0/22 (0.00%)  1/22 (4.55%) 
Injury, poisoning and procedural complications             
Subdural Haematoma † 1  0/26 (0.00%)  0/10 (0.00%)  1/21 (4.76%)  0/3 (0.00%)  0/22 (0.00%)  0/22 (0.00%) 
Investigations             
Haemoglobin Decreased † 1  0/26 (0.00%)  0/10 (0.00%)  0/21 (0.00%)  0/3 (0.00%)  1/22 (4.55%)  0/22 (0.00%) 
Metabolism and nutrition disorders             
Dehydration † 1  1/26 (3.85%)  0/10 (0.00%)  0/21 (0.00%)  0/3 (0.00%)  0/22 (0.00%)  0/22 (0.00%) 
Musculoskeletal and connective tissue disorders             
Intervertebral disc protrusion † 1  1/26 (3.85%)  0/10 (0.00%)  0/21 (0.00%)  0/3 (0.00%)  0/22 (0.00%)  0/22 (0.00%) 
Muscular weakness † 1  1/26 (3.85%)  0/10 (0.00%)  0/21 (0.00%)  0/3 (0.00%)  0/22 (0.00%)  1/22 (4.55%) 
Groin pain † 1  0/26 (0.00%)  1/10 (10.00%)  0/21 (0.00%)  0/3 (0.00%)  0/22 (0.00%)  0/22 (0.00%) 
Arthralgia † 1  0/26 (0.00%)  0/10 (0.00%)  0/21 (0.00%)  0/3 (0.00%)  0/22 (0.00%)  1/22 (4.55%) 
Pain in extremity † 1  0/26 (0.00%)  0/10 (0.00%)  0/21 (0.00%)  0/3 (0.00%)  0/22 (0.00%)  1/22 (4.55%) 
Pathological fracture † 1  0/26 (0.00%)  0/10 (0.00%)  0/21 (0.00%)  0/3 (0.00%)  1/22 (4.55%)  0/22 (0.00%) 
Nervous system disorders             
Akathisia † 1  1/26 (3.85%)  0/10 (0.00%)  0/21 (0.00%)  0/3 (0.00%)  0/22 (0.00%)  0/22 (0.00%) 
Dizziness † 1  0/26 (0.00%)  0/10 (0.00%)  0/21 (0.00%)  0/3 (0.00%)  1/22 (4.55%)  0/22 (0.00%) 
Psychiatric disorders             
Mental Status Changes † 1  1/26 (3.85%)  0/10 (0.00%)  0/21 (0.00%)  0/3 (0.00%)  0/22 (0.00%)  0/22 (0.00%) 
Respiratory, thoracic and mediastinal disorders             
Epistaxis † 1  0/26 (0.00%)  0/10 (0.00%)  0/21 (0.00%)  1/3 (33.33%)  0/22 (0.00%)  0/22 (0.00%) 
Pneumonitis † 1  0/26 (0.00%)  0/10 (0.00%)  1/21 (4.76%)  0/3 (0.00%)  0/22 (0.00%)  0/22 (0.00%) 
Dyspnoea † 1  0/26 (0.00%)  0/10 (0.00%)  0/21 (0.00%)  0/3 (0.00%)  1/22 (4.55%)  0/22 (0.00%) 
Pneumothorax † 1  0/26 (0.00%)  0/10 (0.00%)  0/21 (0.00%)  0/3 (0.00%)  0/22 (0.00%)  1/22 (4.55%) 
Skin and subcutaneous tissue disorders             
Rash † 1  0/26 (0.00%)  0/10 (0.00%)  0/21 (0.00%)  0/3 (0.00%)  1/22 (4.55%)  0/22 (0.00%) 
Vascular disorders             
Deep vein thrombosis † 1  0/26 (0.00%)  1/10 (10.00%)  0/21 (0.00%)  0/3 (0.00%)  0/22 (0.00%)  0/22 (0.00%) 
Haemorrhage † 1  0/26 (0.00%)  1/10 (10.00%)  0/21 (0.00%)  0/3 (0.00%)  0/22 (0.00%)  0/22 (0.00%) 
†
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA (16.0)
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Phase Ib Regimen 1 Phase Ib Regimen 2 Phase Ib Regimen 3 Phase Ib Regimen 4 Phase IIa Group A Phase IIa Group B
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   26/60 (43.33%)   10/10 (100.00%)   21/21 (100.00%)   3/3 (100.00%)   22/22 (100.00%)   22/22 (100.00%) 
Blood and lymphatic system disorders             
Anaemia † 1  6/60 (10.00%)  2/10 (20.00%)  5/21 (23.81%)  1/3 (33.33%)  4/22 (18.18%)  5/22 (22.73%) 
Neutropenia † 1  3/60 (5.00%)  3/10 (30.00%)  7/21 (33.33%)  1/3 (33.33%)  8/22 (36.36%)  4/22 (18.18%) 
Thrombocytopenia † 1  4/60 (6.67%)  2/10 (20.00%)  4/21 (19.05%)  1/3 (33.33%)  8/22 (36.36%)  5/22 (22.73%) 
Leukopenia † 1  3/60 (5.00%)  1/10 (10.00%)  1/21 (4.76%)  0/3 (0.00%)  1/22 (4.55%)  0/22 (0.00%) 
Eye disorders             
Dry eye † 1  8/60 (13.33%)  3/10 (30.00%)  9/21 (42.86%)  2/3 (66.67%)  6/22 (27.27%)  12/22 (54.55%) 
Vision blurred † 1  5/60 (8.33%)  3/10 (30.00%)  6/21 (28.57%)  1/3 (33.33%)  6/22 (27.27%)  6/22 (27.27%) 
Lacrimation increased † 1  6/60 (10.00%)  2/10 (20.00%)  1/21 (4.76%)  0/3 (0.00%)  1/22 (4.55%)  2/22 (9.09%) 
Conjunctivitis † 1  2/60 (3.33%)  1/10 (10.00%)  0/21 (0.00%)  0/3 (0.00%)  0/22 (0.00%)  1/22 (4.55%) 
Photophobia † 1  1/60 (1.67%)  1/10 (10.00%)  1/21 (4.76%)  0/3 (0.00%)  0/22 (0.00%)  1/22 (4.55%) 
Visual impairment † 1  1/60 (1.67%)  1/10 (10.00%)  1/21 (4.76%)  0/3 (0.00%)  0/22 (0.00%)  2/22 (9.09%) 
Gastrointestinal disorders             
Diarrhoea † 1  8/60 (13.33%)  5/10 (50.00%)  8/21 (38.10%)  2/3 (66.67%)  4/22 (18.18%)  11/22 (50.00%) 
Nausea † 1  7/60 (11.67%)  3/10 (30.00%)  10/21 (47.62%)  0/3 (0.00%)  9/22 (40.91%)  9/22 (40.91%) 
Constipation † 1  8/60 (13.33%)  3/10 (30.00%)  3/21 (14.29%)  1/3 (33.33%)  4/22 (18.18%)  4/22 (18.18%) 
Dry mouth † 1  5/60 (8.33%)  1/10 (10.00%)  6/21 (28.57%)  1/3 (33.33%)  3/22 (13.64%)  1/22 (4.55%) 
Vomiting † 1  4/60 (6.67%)  2/10 (20.00%)  4/21 (19.05%)  0/3 (0.00%)  5/22 (22.73%)  3/22 (13.64%) 
Abdominal pain † 1  4/60 (6.67%)  0/10 (0.00%)  2/21 (9.52%)  0/3 (0.00%)  1/22 (4.55%)  1/22 (4.55%) 
Dyspepsia † 1  3/60 (5.00%)  2/10 (20.00%)  2/21 (9.52%)  0/3 (0.00%)  1/22 (4.55%)  3/22 (13.64%) 
Abdominal pain upper † 1  2/60 (3.33%)  0/10 (0.00%)  2/21 (9.52%)  0/3 (0.00%)  1/22 (4.55%)  0/22 (0.00%) 
Stomatitis † 1  1/60 (1.67%)  1/10 (10.00%)  2/21 (9.52%)  0/3 (0.00%)  0/22 (0.00%)  0/22 (0.00%) 
Gastrooesophageal reflux disease † 1  1/60 (1.67%)  1/10 (10.00%)  0/21 (0.00%)  0/3 (0.00%)  0/22 (0.00%)  3/22 (13.64%) 
General disorders             
Fatigue † 1  23/60 (38.33%)  8/10 (80.00%)  18/21 (85.71%)  2/3 (66.67%)  16/22 (72.73%)  19/22 (86.36%) 
Mucosal Inflammation † 1  4/60 (6.67%)  3/10 (30.00%)  3/21 (14.29%)  0/3 (0.00%)  2/22 (9.09%)  5/22 (22.73%) 
Oedema Peripheral † 1  4/60 (6.67%)  2/10 (20.00%)  3/21 (14.29%)  0/3 (0.00%)  4/22 (18.18%)  0/22 (0.00%) 
Pyrexia † 1  2/60 (3.33%)  1/10 (10.00%)  7/21 (33.33%)  0/3 (0.00%)  2/22 (9.09%)  3/22 (13.64%) 
Chills † 1  0/60 (0.00%)  1/10 (10.00%)  1/21 (4.76%)  0/3 (0.00%)  1/22 (4.55%)  4/22 (18.18%) 
Chest pain † 1  0/60 (0.00%)  1/10 (10.00%)  1/21 (4.76%)  0/3 (0.00%)  1/22 (4.55%)  2/22 (9.09%) 
Gait disturbance † 1  2/60 (3.33%)  0/10 (0.00%)  0/21 (0.00%)  0/3 (0.00%)  1/22 (4.55%)  3/22 (13.64%) 
Hepatobiliary disorders             
Hypertransaminasaemia † 1  0/60 (0.00%)  1/10 (10.00%)  1/21 (4.76%)  1/3 (33.33%)  0/22 (0.00%)  0/22 (0.00%) 
Infections and infestations             
Upper respiratory tract infection † 1  8/60 (13.33%)  2/10 (20.00%)  4/21 (19.05%)  1/3 (33.33%)  2/22 (9.09%)  3/22 (13.64%) 
Urinary tract infection † 1  3/60 (5.00%)  1/10 (10.00%)  3/21 (14.29%)  0/3 (0.00%)  2/22 (9.09%)  5/22 (22.73%) 
Cellulitis † 1  2/60 (3.33%)  2/10 (20.00%)  2/21 (9.52%)  0/3 (0.00%)  0/22 (0.00%)  1/22 (4.55%) 
Herpes zoster † 1  3/60 (5.00%)  0/10 (0.00%)  0/21 (0.00%)  0/3 (0.00%)  1/22 (4.55%)  0/22 (0.00%) 
Eye infection † 1  2/60 (3.33%)  0/10 (0.00%)  1/21 (4.76%)  0/3 (0.00%)  0/22 (0.00%)  0/22 (0.00%) 
Injury, poisoning and procedural complications             
Infusion related reaction † 1  2/60 (3.33%)  0/10 (0.00%)  1/21 (4.76%)  0/3 (0.00%)  2/22 (9.09%)  0/22 (0.00%) 
Investigations             
Aspartate aminotransferase increased † 1  4/60 (6.67%)  2/10 (20.00%)  4/21 (19.05%)  0/3 (0.00%)  0/22 (0.00%)  2/22 (9.09%) 
Alanine aminotransferase increased † 1  2/60 (3.33%)  1/10 (10.00%)  2/21 (9.52%)  0/3 (0.00%)  0/22 (0.00%)  0/22 (0.00%) 
Haemoglobin decreased † 1  2/60 (3.33%)  0/10 (0.00%)  1/21 (4.76%)  0/3 (0.00%)  1/22 (4.55%)  1/22 (4.55%) 
Weight increased † 1  2/60 (3.33%)  0/10 (0.00%)  1/21 (4.76%)  0/3 (0.00%)  0/22 (0.00%)  0/22 (0.00%) 
Weight decreased † 1  0/60 (0.00%)  1/10 (10.00%)  2/21 (9.52%)  0/3 (0.00%)  1/22 (4.55%)  0/22 (0.00%) 
Metabolism and nutrition disorders             
Decreased appetite † 1  7/60 (11.67%)  1/10 (10.00%)  8/21 (38.10%)  0/3 (0.00%)  5/22 (22.73%)  7/22 (31.82%) 
Hypokalaemia † 1  5/60 (8.33%)  3/10 (30.00%)  7/21 (33.33%)  1/3 (33.33%)  3/22 (13.64%)  2/22 (9.09%) 
Hyponatraemia † 1  2/60 (3.33%)  0/10 (0.00%)  2/21 (9.52%)  0/3 (0.00%)  2/22 (9.09%)  2/22 (9.09%) 
Hypomagnesaemia † 1  1/60 (1.67%)  0/10 (0.00%)  0/21 (0.00%)  0/3 (0.00%)  3/22 (13.64%)  0/22 (0.00%) 
Musculoskeletal and connective tissue disorders             
Arthralgia † 1  8/60 (13.33%)  3/10 (30.00%)  7/21 (33.33%)  2/3 (66.67%)  9/22 (40.91%)  7/22 (31.82%) 
Back pain † 1  7/60 (11.67%)  1/10 (10.00%)  2/21 (9.52%)  0/3 (0.00%)  1/22 (4.55%)  1/22 (4.55%) 
Myalgia † 1  4/60 (6.67%)  1/10 (10.00%)  3/21 (14.29%)  0/3 (0.00%)  5/22 (22.73%)  6/22 (27.27%) 
Joint stiffness † 1  4/60 (6.67%)  0/10 (0.00%)  1/21 (4.76%)  1/3 (33.33%)  0/22 (0.00%)  1/22 (4.55%) 
Pain in extremity † 1  4/60 (6.67%)  0/10 (0.00%)  2/21 (9.52%)  0/3 (0.00%)  3/22 (13.64%)  1/22 (4.55%) 
Bone pain † 1  2/60 (3.33%)  0/10 (0.00%)  2/21 (9.52%)  0/3 (0.00%)  2/22 (9.09%)  2/22 (9.09%) 
Muscular weakness † 1  2/60 (3.33%)  0/10 (0.00%)  1/21 (4.76%)  0/3 (0.00%)  1/22 (4.55%)  1/22 (4.55%) 
Musculoskeletal pain † 1  2/60 (3.33%)  0/10 (0.00%)  1/21 (4.76%)  0/3 (0.00%)  1/22 (4.55%)  0/22 (0.00%) 
Neck pain † 1  2/60 (3.33%)  0/10 (0.00%)  1/21 (4.76%)  0/3 (0.00%)  0/22 (0.00%)  0/22 (0.00%) 
Muscle spasms † 1  1/60 (1.67%)  1/10 (10.00%)  1/21 (4.76%)  1/3 (33.33%)  2/22 (9.09%)  2/22 (9.09%) 
Nervous system disorders             
Neuropathy peripheral † 1  22/60 (36.67%)  8/10 (80.00%)  18/21 (85.71%)  3/3 (100.00%)  20/22 (90.91%)  19/22 (86.36%) 
Dysgeusia † 1  4/60 (6.67%)  0/10 (0.00%)  3/21 (14.29%)  0/3 (0.00%)  1/22 (4.55%)  2/22 (9.09%) 
Headache † 1  3/60 (5.00%)  3/10 (30.00%)  4/21 (19.05%)  0/3 (0.00%)  4/22 (18.18%)  4/22 (18.18%) 
Dizziness † 1  2/60 (3.33%)  2/10 (20.00%)  5/21 (23.81%)  0/3 (0.00%)  3/22 (13.64%)  3/22 (13.64%) 
Paraesthesia † 1  2/60 (3.33%)  1/10 (10.00%)  0/21 (0.00%)  0/3 (0.00%)  0/22 (0.00%)  0/22 (0.00%) 
Peripheral sensory neuropathy † 1  1/60 (1.67%)  0/10 (0.00%)  2/21 (9.52%)  0/3 (0.00%)  0/22 (0.00%)  1/22 (4.55%) 
Psychiatric disorders             
Depression † 1  7/60 (11.67%)  0/10 (0.00%)  0/21 (0.00%)  0/3 (0.00%)  1/22 (4.55%)  0/22 (0.00%) 
Insomnia † 1  4/60 (6.67%)  2/10 (20.00%)  2/21 (9.52%)  0/3 (0.00%)  3/22 (13.64%)  2/22 (9.09%) 
Anxiety † 1  2/60 (3.33%)  2/10 (20.00%)  1/21 (4.76%)  0/3 (0.00%)  0/22 (0.00%)  0/22 (0.00%) 
Renal and urinary disorders             
Urinary incontinence † 1  2/60 (3.33%)  0/10 (0.00%)  1/21 (4.76%)  0/3 (0.00%)  0/22 (0.00%)  0/22 (0.00%) 
Pollakiuria † 1  1/60 (1.67%)  1/10 (10.00%)  1/21 (4.76%)  0/3 (0.00%)  1/22 (4.55%)  1/22 (4.55%) 
Respiratory, thoracic and mediastinal disorders             
Cough † 1  8/60 (13.33%)  2/10 (20.00%)  4/21 (19.05%)  1/3 (33.33%)  4/22 (18.18%)  5/22 (22.73%) 
Dyspnoea † 1  6/60 (10.00%)  1/10 (10.00%)  6/21 (28.57%)  1/3 (33.33%)  2/22 (9.09%)  7/22 (31.82%) 
Rhinorrhoea † 1  4/60 (6.67%)  2/10 (20.00%)  2/21 (9.52%)  1/3 (33.33%)  3/22 (13.64%)  1/22 (4.55%) 
Oropharyngeal pain † 1  1/60 (1.67%)  1/10 (10.00%)  1/21 (4.76%)  0/3 (0.00%)  0/22 (0.00%)  1/22 (4.55%) 
Epistaxis † 1  9/60 (15.00%)  6/10 (60.00%)  9/21 (42.86%)  2/3 (66.67%)  5/22 (22.73%)  11/22 (50.00%) 
Skin and subcutaneous tissue disorders             
Alopecia † 1  10/60 (16.67%)  6/10 (60.00%)  8/21 (38.10%)  1/3 (33.33%)  6/22 (27.27%)  11/22 (50.00%) 
Rash † 1  5/60 (8.33%)  7/10 (70.00%)  6/21 (28.57%)  2/3 (66.67%)  3/22 (13.64%)  9/22 (40.91%) 
Dry skin † 1  2/60 (3.33%)  1/10 (10.00%)  1/21 (4.76%)  0/3 (0.00%)  2/22 (9.09%)  3/22 (13.64%) 
Nail disorder † 1  2/60 (3.33%)  1/10 (10.00%)  1/21 (4.76%)  0/3 (0.00%)  4/22 (18.18%)  2/22 (9.09%) 
Dermatitis acneiform † 1  2/60 (3.33%)  1/10 (10.00%)  0/21 (0.00%)  0/3 (0.00%)  1/22 (4.55%)  0/22 (0.00%) 
Onycholysis † 1  2/60 (3.33%)  1/10 (10.00%)  0/21 (0.00%)  0/3 (0.00%)  0/22 (0.00%)  0/22 (0.00%) 
Erythema † 1  1/60 (1.67%)  1/10 (10.00%)  2/21 (9.52%)  0/3 (0.00%)  0/22 (0.00%)  0/22 (0.00%) 
Pruritus † 1  2/60 (3.33%)  1/10 (10.00%)  0/21 (0.00%)  0/3 (0.00%)  1/22 (4.55%)  0/22 (0.00%) 
Photosensitivity reaction † 1  1/60 (1.67%)  1/10 (10.00%)  0/21 (0.00%)  0/3 (0.00%)  1/22 (4.55%)  2/22 (9.09%) 
Vascular disorders             
Hypertension † 1  1/60 (1.67%)  0/10 (0.00%)  3/21 (14.29%)  0/3 (0.00%)  2/22 (9.09%)  0/22 (0.00%) 
Hot flush † 1  1/60 (1.67%)  1/10 (10.00%)  0/21 (0.00%)  1/3 (33.33%)  0/22 (0.00%)  0/22 (0.00%) 
Lymphoedema † 1  0/60 (0.00%)  0/10 (0.00%)  3/21 (14.29%)  0/3 (0.00%)  1/22 (4.55%)  1/22 (4.55%) 
†
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA (16.0)
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.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Roche Trial Information Hotline
Organization: F. Hoffmann-La Roche AG
Phone: +41 61 6878333
EMail: global.trial_information@roche.com
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: Genentech, Inc.
ClinicalTrials.gov Identifier: NCT00951665    
Other Study ID Numbers: TDM4652g
GO01355 ( Other Identifier: Hoffmann-La Roche )
First Submitted: August 3, 2009
First Posted: August 4, 2009
Results First Submitted: January 4, 2016
Results First Posted: June 24, 2016
Last Update Posted: June 24, 2016