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A Study of Trastuzumab Emtansine (T-DM1) in Combination With Docetaxel, and Potentially Pertuzumab, in Participants With Advanced Breast Cancer

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ClinicalTrials.gov Identifier: NCT00934856
Recruitment Status : Completed
First Posted : July 8, 2009
Results First Posted : April 6, 2017
Last Update Posted : April 6, 2017
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

Study Type Interventional
Study Design Allocation: Non-Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Breast Cancer
Interventions Drug: Docetaxel
Drug: Pertuzumab
Drug: Trastuzumab emtansine
Enrollment 98
Recruitment Details  
Pre-assignment Details Overall 152 participants were screened, of which 98 participants were enrolled (25 participants with metastatic breast cancer [MBC] and 73 participants with locally advanced breast cancer [LABC]) and included in the study.
Arm/Group Title MBC: T-DM1 2.4 mg/kg + Doc 75 mg/m^2 (Over 2 Days) MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Over 2 Days) MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Same Day) MBC: T-DM1 3.6 mg/kg + Doc 60 mg/m^2 (Same Day) LABC: T-DM1 + Doc (Doublet Regimen) LABC: T-DM1 + Doc + Pertuzumab (Triplet Regimen)
Hide Arm/Group Description Feasibility part: Participants with human epidermal growth factor receptor 2 (HER2)-positive MBC received docetaxel (Doc) 75 milligrams per square meter (mg/m^2) intravenous (IV) infusion on Day 1 and trastuzumab emtansine (T-DM1) 2.4 milligrams per kilogram (mg/kg) IV infusion on Day 2 of Cycle 1 followed by T-DM1 75 mg/m^2 and docetaxel 2.4 mg/kg IV infusion on Day 1 of each 3-week cycle for a minimum of 6 cycles. After 6 cycles, docetaxel 75 mg/m^2 was stopped and T-DM1 2.4 mg/kg was continued until confirmed evidence of disease progression, unacceptable toxicity, or withdrawal of participant consent. Feasibility part: Participants with HER2-positive MBC received docetaxel 60 mg/m^2 IV infusion on Day 1 and T-DM1 2.4 mg/kg IV infusion on Day 2 of Cycle 1 followed by T-DM1 60 mg/m^2 and docetaxel 2.4 mg/kg IV infusion on Day 1 of each 3-week cycle for a minimum of 6 cycles. After 6 cycles, docetaxel 60 mg/m^2 was stopped and T-DM1 2.4 mg/kg was continued until confirmed evidence of disease progression, unacceptable toxicity, or withdrawal of participant consent. Feasibility part: Participants with HER2-positive MBC received docetaxel 60 mg/m^2 IV infusion and T-DM1 2.4 mg/kg IV infusion on Day 1 of each 3-week cycle for a minimum of 6 cycles. After 6 cycles, docetaxel 60 mg/m^2 was stopped and T-DM1 2.4 mg/kg was continued until confirmed evidence of disease progression, unacceptable toxicity, or withdrawal of participant consent. Feasibility and extension part: Participants with HER2-positive MBC received docetaxel 60 mg/m^2 IV infusion and T-DM1 3.6 mg/kg IV infusion on Day 1 of each 3-week cycle for a minimum of 6 cycles. After 6 cycles, docetaxel 60 mg/m^2 was stopped and T-DM1 3.6 mg/kg was continued until confirmed evidence of disease progression, unacceptable toxicity, or withdrawal of participant consent. Feasibility and extension part: Participants with HER2-positive LABC received T-DM1 3.6 mg/kg IV infusion and docetaxel 60/75/100 mg/m^2 IV infusion on Day 1 of each 3-week cycle, for 6 cycles. Study treatment was administered for up to 6 cycles or until unacceptable toxicity, and prior to surgery. Feasibility and extension part: Participants with HER2-positive LABC received T-DM1 3.6 mg/kg Iv infusion, docetaxel 60/75 mg/m^2 IV infusion, and pertuzumab 840 mg (for Cycle 1) or 420 mg (for remaining cycles) IV infusion on Day 1 of each 3-week cycle, for 6 cycles. Study treatment was administered for up to 6 cycles or until unacceptable toxicity, and prior to surgery.
Period Title: Feasibility Part
Started 6 6 3 6 12 9
Completed 1 1 0 1 12 6
Not Completed 5 5 3 5 0 3
Reason Not Completed
Progressive disease             4             4             2             3             0             0
Physician Decision             0             0             1             0             0             0
Adverse Event             1             1             0             1             0             2
Withdrawal by Subject             0             0             0             1             0             1
Period Title: Extension Part
Started 0 0 0 4 [1] 28 [1] 24 [1]
Completed 0 0 0 2 24 19
Not Completed 0 0 0 2 4 5
Reason Not Completed
Adverse Event             0             0             0             1             4             4
Progressive disease             0             0             0             1             0             0
Non-compliance with drug             0             0             0             0             0             1
[1]
New participants were enrolled in the extension part.
Arm/Group Title MBC: T-DM1 2.4 mg/kg + Doc 75 mg/m^2 (Over 2 Days) MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Over 2 Days) MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Same Day) MBC: T-DM1 3.6 mg/kg + Doc 60 mg/m^2 (Same Day) LABC: T-DM1 + Doc (Doublet Regimen) LABC: T-DM1 + Doc + Pertuzumab (Triplet Regimen) Total
Hide Arm/Group Description Feasibility part: Participants with HER2-positive MBC received docetaxel 75 mg/m^2 IV infusion on Day 1 and T-DM1 2.4 mg/kg IV infusion on Day 2 of Cycle 1 followed by T-DM1 75 mg/m^2 and docetaxel 2.4 mg/kg IV infusion on Day 1 of each 3-week cycle for a minimum of 6 cycles. After 6 cycles, docetaxel 75 mg/m^2 was stopped and T-DM1 2.4 mg/kg was continued until confirmed evidence of disease progression, unacceptable toxicity, or withdrawal of participant consent. Feasibility part: Participants with HER2-positive MBC received docetaxel 60 mg/m^2 IV infusion on Day 1 and T-DM1 2.4 mg/kg IV infusion on Day 2 of Cycle 1 followed by T-DM1 60 mg/m^2 and docetaxel 2.4 mg/kg IV infusion on Day 1 of each 3-week cycle for a minimum of 6 cycles. After 6 cycles, docetaxel 60 mg/m^2 was stopped and T-DM1 2.4 mg/kg was continued until confirmed evidence of disease progression, unacceptable toxicity, or withdrawal of participant consent. Feasibility part: Participants with HER2-positive MBC received docetaxel 60 mg/m^2 IV infusion and T-DM1 2.4 mg/kg IV infusion on Day 1 of each 3-week cycle for a minimum of 6 cycles. After 6 cycles, docetaxel 60 mg/m^2 was stopped and T-DM1 2.4 mg/kg was continued until confirmed evidence of disease progression, unacceptable toxicity, or withdrawal of participant consent. Feasibility and extension part: Participants with HER2-positive MBC received docetaxel 60 mg/m^2 IV infusion and T-DM1 3.6 mg/kg IV infusion on Day 1 of each 3-week cycle for a minimum of 6 cycles. After 6 cycles, docetaxel 60 mg/m^2 was stopped and T-DM1 3.6 mg/kg was continued until confirmed evidence of disease progression, unacceptable toxicity, or withdrawal of participant consent. Feasibility and extension part: Participants with HER2-positive LABC received T-DM1 3.6 mg/kg IV infusion and docetaxel 60/75/100 mg/m^2 IV infusion on Day 1 of each 3-week cycle, for 6 cycles. Study treatment was administered for up to 6 cycles or until unacceptable toxicity, and prior to surgery. Feasibility and extension part: Participants with HER2-positive LABC received T-DM1 3.6 mg/kg Iv infusion, docetaxel 60/75 mg/m^2 IV infusion, and pertuzumab 840 mg (for Cycle 1) or 420 mg (for remaining cycles) IV infusion on Day 1 of each 3-week cycle, for 6 cycles. Study treatment was administered for up to 6 cycles or until unacceptable toxicity, and prior to surgery. Total of all reporting groups
Overall Number of Baseline Participants 6 6 3 10 40 33 98
Hide Baseline Analysis Population Description
All participants who received at least one dose of study medication were included.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 6 participants 6 participants 3 participants 10 participants 40 participants 33 participants 98 participants
43  (7.16) 50.7  (4.84) 57  (12.12) 48  (9.39) 48.6  (9.73) 54.2  (11.43) 50.4  (10.39)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 6 participants 6 participants 3 participants 10 participants 40 participants 33 participants 98 participants
Female
6
 100.0%
6
 100.0%
3
 100.0%
10
 100.0%
40
 100.0%
33
 100.0%
98
 100.0%
Male
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
1.Primary Outcome
Title Number of Participants With Dose Limiting Toxicity (DLT) - MBC and LABC Feasibility Population
Hide Description DLTs included (as per National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] grading): Grade 4 thrombocytopenia, thrombocytopenia of any grade with concurrent hemorrhage or requiring blood platelet transfusion, or thrombocytopenia not recovered by Day 21 to at least 100,000/microliter (mcL); Grade 4 neutropenia lasting for more than 7 days; Febrile neutropenia; Grade greater than or equal to (>/=) 3 neurotoxicity in the form of peripheral neuropathy or peripheral neurotoxicity not improving to baseline or Grade less than or equal to (</=) 1 by Day 21; Any non-hematological toxicity of Grade >/= 3 except for alopecia, fever, and chills, not improving to baseline or Grade </=1 by Day 21, despite adequate toxicity management; Any subjective intolerable toxicity felt by the investigator to be related to either study treatment; Any other treatment-related toxicity prohibiting the start of the Cycle 2 on Day 22; Fulminant skin rash.
Time Frame Cycle 1 (up to 21 days)
Hide Outcome Measure Data
Hide Analysis Population Description
MBC and LABC feasibility population: All participants who received at least one dose of study medication and included in the feasibility part of the study.
Arm/Group Title MBC: T-DM1 2.4 mg/kg + Doc 75 mg/m^2 (Over 2 Days) MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Over 2 Days) MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Same Day) MBC: T-DM1 3.6 mg/kg + Doc 60 mg/m^2 (Same Day) LABC: T-DM1 + Doc (Doublet Regimen) LABC: T-DM1 + Doc + Pertuzumab (Triplet Regimen)
Hide Arm/Group Description:
Participants with HER2-positive MBC received docetaxel 75 mg/m^2 IV infusion on Day 1 and T-DM1 2.4 mg/kg IV infusion on Day 2 of Cycle 1 followed by T-DM1 75 mg/m^2 and docetaxel 2.4 mg/kg IV infusion on Day 1 of each 3-week cycle for a minimum of 6 cycles. After 6 cycles, docetaxel 75 mg/m^2 was stopped and T-DM1 2.4 mg/kg was continued until confirmed evidence of disease progression, unacceptable toxicity, or withdrawal of participant consent.
Participants with HER2-positive MBC received docetaxel 60 mg/m^2 IV infusion on Day 1 and T-DM1 2.4 mg/kg IV infusion on Day 2 of Cycle 1 followed by T-DM1 60 mg/m^2 and docetaxel 2.4 mg/kg IV infusion on Day 1 of each 3-week cycle for a minimum of 6 cycles. After 6 cycles, docetaxel 60 mg/m^2 was stopped and T-DM1 2.4 mg/kg was continued until confirmed evidence of disease progression, unacceptable toxicity, or withdrawal of participant consent.
Participants with HER2-positive MBC received docetaxel 60 mg/m^2 IV infusion and T-DM1 2.4 mg/kg IV infusion on Day 1 of each 3-week cycle for a minimum of 6 cycles. After 6 cycles, docetaxel 60 mg/m^2 was stopped and T-DM1 2.4 mg/kg was continued until confirmed evidence of disease progression, unacceptable toxicity, or withdrawal of participant consent.
Participants with HER2-positive MBC received docetaxel 60 mg/m^2 IV infusion and T-DM1 3.6 mg/kg IV infusion on Day 1 of each 3-week cycle for a minimum of 6 cycles. After 6 cycles, docetaxel 60 mg/m^2 was stopped and T-DM1 3.6 mg/kg was continued until confirmed evidence of disease progression, unacceptable toxicity, or withdrawal of participant consent.
Participants with HER2-positive LABC received T-DM1 3.6 mg/kg IV infusion and docetaxel 60/75/100 mg/m^2 IV infusion on Day 1 of each 3-week cycle, for 6 cycles. Study treatment was administered for up to 6 cycles or until unacceptable toxicity, and prior to surgery.
Participants with HER2-positive LABC received T-DM1 3.6 mg/kg Iv infusion, docetaxel 60/75 mg/m^2 IV infusion, and pertuzumab 840 mg (for Cycle 1) or 420 mg (for remaining cycles) IV infusion on Day 1 of each 3-week cycle, for 6 cycles. Study treatment was administered for up to 6 cycles or until unacceptable toxicity, and prior to surgery.
Overall Number of Participants Analyzed 6 6 3 6 12 9
Measure Type: Number
Unit of Measure: participants
2 1 0 1 2 2
2.Primary Outcome
Title Percentage of Participants With Adverse Events (AEs) or Serious AEs (SAEs) - MBC and LABC Population
Hide Description An AE is any new untoward medical occurrence or worsening of a pre-existing medical condition which does not necessarily have a causal relationship with this treatment. SAE is any untoward medical occurrence that at any dose results in death, is life-threatening, requires in-patient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, results in development of drug dependency or drug abuse, is an important medical event.
Time Frame Baseline up to 28 days after last dose for MBC participants and for LABC participants who could not undergo surgery, and up to 6 weeks post-surgery for LABC participants who underwent surgery (maximum up to approximately 3 years)
Hide Outcome Measure Data
Hide Analysis Population Description
All participants who received at least one dose of study medication were included.
Arm/Group Title MBC: T-DM1 2.4 mg/kg + Doc 75 mg/m^2 (Over 2 Days) MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Over 2 Days) MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Same Day) MBC: T-DM1 3.6 mg/kg + Doc 60 mg/m^2 (Same Day) LABC: T-DM1 + Doc (Doublet Regimen) LABC: T-DM1 + Doc + Pertuzumab (Triplet Regimen)
Hide Arm/Group Description:
Feasibility part: Participants with HER2-positive MBC received docetaxel 75 mg/m^2 IV infusion on Day 1 and T-DM1 2.4 mg/kg IV infusion on Day 2 of Cycle 1 followed by T-DM1 75 mg/m^2 and docetaxel 2.4 mg/kg IV infusion on Day 1 of each 3-week cycle for a minimum of 6 cycles. After 6 cycles, docetaxel 75 mg/m^2 was stopped and T-DM1 2.4 mg/kg was continued until confirmed evidence of disease progression, unacceptable toxicity, or withdrawal of participant consent.
Feasibility part: Participants with HER2-positive MBC received docetaxel 60 mg/m^2 IV infusion on Day 1 and T-DM1 2.4 mg/kg IV infusion on Day 2 of Cycle 1 followed by T-DM1 60 mg/m^2 and docetaxel 2.4 mg/kg IV infusion on Day 1 of each 3-week cycle for a minimum of 6 cycles. After 6 cycles, docetaxel 60 mg/m^2 was stopped and T-DM1 2.4 mg/kg was continued until confirmed evidence of disease progression, unacceptable toxicity, or withdrawal of participant consent.
Feasibility part: Participants with HER2-positive MBC received docetaxel 60 mg/m^2 IV infusion and T-DM1 2.4 mg/kg IV infusion on Day 1 of each 3-week cycle for a minimum of 6 cycles. After 6 cycles, docetaxel 60 mg/m^2 was stopped and T-DM1 2.4 mg/kg was continued until confirmed evidence of disease progression, unacceptable toxicity, or withdrawal of participant consent.
Feasibility and extension part: Participants with HER2-positive MBC received docetaxel 60 mg/m^2 IV infusion and T-DM1 3.6 mg/kg IV infusion on Day 1 of each 3-week cycle for a minimum of 6 cycles. After 6 cycles, docetaxel 60 mg/m^2 was stopped and T-DM1 3.6 mg/kg was continued until confirmed evidence of disease progression, unacceptable toxicity, or withdrawal of participant consent.
Feasibility and extension part: Participants with HER2-positive LABC received T-DM1 3.6 mg/kg IV infusion and docetaxel 60/75/100 mg/m^2 IV infusion on Day 1 of each 3-week cycle, for 6 cycles. Study treatment was administered for up to 6 cycles or until unacceptable toxicity, and prior to surgery.
Feasibility and extension part: Participants with HER2-positive LABC received T-DM1 3.6 mg/kg Iv infusion, docetaxel 60/75 mg/m^2 IV infusion, and pertuzumab 840 mg (for Cycle 1) or 420 mg (for remaining cycles) IV infusion on Day 1 of each 3-week cycle, for 6 cycles. Study treatment was administered for up to 6 cycles or until unacceptable toxicity, and prior to surgery.
Overall Number of Participants Analyzed 6 6 3 10 40 33
Measure Type: Number
Unit of Measure: percentage of participants
AEs 100 100 100 100 100 100
SAEs 33.3 33.3 66.7 40.0 22.5 27.3
3.Secondary Outcome
Title Percentage of Participants With Progression-Free Survival (PFS) Event - MBC Population
Hide Description PFS was defined as the time interval between the date of the start of treatment and the date of first documentation of progressive disease (PD) or death from any cause, whichever occurred first. Response was based on Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.0 (v1.0). For target lesions (TLs), PD was at least a 20 percent (%) increase in the sum of longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more lesions. For non-target lesions (NTLs), PD was the appearance of one or more new lesions and/or unequivocal progression of existing NTLs. Data for participants without PD or death was censored at the time of the last response assessment. Percentage of participants with PFS event was calculated as the (number of participants with PFS event [PD or death]) divided by (total number of participants), and then multiplied by 100.
Time Frame Baseline until disease progression or death (up to approximately 3 years)
Hide Outcome Measure Data
Hide Analysis Population Description
MBC population: All participants with MBC who received at least one dose of study medication were included.
Arm/Group Title Overall MBC Participants
Hide Arm/Group Description:
Participants with MBC who were enrolled in the study and who received at least one dose of study medication
Overall Number of Participants Analyzed 25
Measure Type: Number
Unit of Measure: percentage of participants
60.0
4.Secondary Outcome
Title PFS - MBC Population
Hide Description PFS was defined as the time interval between the date of the start of treatment and the date of first documentation of PD or death from any cause, whichever occurred first. Response was based on RECIST v1.0. For TLs, PD was at least a 20 % increase in the sum of LD of TLs, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more lesions. For NTLs, PD was the appearance of one or more new lesions and/or unequivocal progression of existing NTLs. Median PFS time was calculated using Kaplan-Meier estimates. Data for participants without PD or death was censored at the time of the last response assessment.
Time Frame Baseline until disease progression or death (up to approximately 3 years)
Hide Outcome Measure Data
Hide Analysis Population Description
MBC population
Arm/Group Title Overall MBC Participants
Hide Arm/Group Description:
Participants with MBC who were enrolled in the study and who received at least one dose of study medication
Overall Number of Participants Analyzed 25
Median (Full Range)
Unit of Measure: months
13.8
(1.6 to 33.5)
5.Secondary Outcome
Title Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR) - MBC Population
Hide Description BOR was defined as CR or PR recorded from baseline until disease progression/recurrence according to RECIST v1.0 criteria. For TLs, CR was defined as the disappearance of all TLs, and PR was defined as at least a 30% decrease in the sum of LDs of the TLs, taking as a reference the baseline (BL) sum of LDs. For NTLs, CR was defined as the disappearance of all NTLs and normalization of tumor marker levels. Percentage of participants with BOR rate was calculated as the (number of participants with CR or PR) divided by (total number of participants), and then multiplied by 100. The 95% confidence interval (Cl) was determined using the Pearson-Clopper method.
Time Frame Baseline until disease progression or recurrence (up to approximately 3 years)
Hide Outcome Measure Data
Hide Analysis Population Description
MBC population
Arm/Group Title Overall MBC Participants
Hide Arm/Group Description:
Participants with MBC who were enrolled in the study and who received at least one dose of study medication
Overall Number of Participants Analyzed 25
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
80.0
(59.3 to 93.2)
6.Secondary Outcome
Title Percentage of Participants With Treatment Failure - MBC Population
Hide Description Treatment failure was defined as the discontinuation of treatment for any reason, including the following qualifying events: PD, death from any cause, withdrawal from study treatment, or initiation of nonprotocol anti-cancer therapy. Percentage of participants with treatment failure was calculated as the (number of participants with treatment failure) divided by (total number of participants), and then multiplied by 100.
Time Frame Baseline until end of treatment (up to 39.8 months)
Hide Outcome Measure Data
Hide Analysis Population Description
MBC population
Arm/Group Title Overall MBC Participants
Hide Arm/Group Description:
Participants with MBC who were enrolled in the study and who received at least one dose of study medication
Overall Number of Participants Analyzed 25
Measure Type: Number
Unit of Measure: percentage of participants
64.0
7.Secondary Outcome
Title Time to Treatment Failure (TTF) - MBC Population
Hide Description TTF was defined as the time interval between the date of start of treatment and the date of PD, death from any cause, withdrawal from study treatment, or initiation of non-protocol anti-cancer therapy, whichever occurred first. Participants without an event at the time of the analysis were censored at the date of the last follow-up assessment. Median TTF was estimated using the Kaplan-Meier method.
Time Frame Baseline until end of treatment (up to 39.8 months)
Hide Outcome Measure Data
Hide Analysis Population Description
MBC population
Arm/Group Title Overall MBC Participants
Hide Arm/Group Description:
Participants with MBC who were enrolled in the study and who received at least one dose of study medication
Overall Number of Participants Analyzed 25
Median (Full Range)
Unit of Measure: months
13.8
(1.4 to 39.8)
8.Secondary Outcome
Title Percentage of Participants With CR or PR or Stable Disease (SD) for at Least 6 Months [Clinical Benefit Rate (CBR)] - MBC Population
Hide Description CBR was defined as percentage of participants experiencing SD of at least 6 months from the start of treatment plus CR or PR according to the RECIST v1.0 criteria. For TLs: CR- disappearance of all TLs. PR- at least 30% decrease in the sum of LDs of the TLs, taking as a reference the BL sum of LDs. PD- at least 20% increase in the sum of LD of TLs, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more lesions. SD- neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. For NTLs: CR- disappearance of all NTLs and normalization of tumor marker levels. SD- persistence of one or more NTLs and/or maintenance of tumor marker level above the normal limits. Percentage of participants= number of participants with CR/PR/SD divided by total number of participants, and then multiplied by 100. 95% CI was determined using the Pearson-Clopper method.
Time Frame Baseline until disease progression, recurrence or death (up to approximately 3 years)
Hide Outcome Measure Data
Hide Analysis Population Description
MBC population
Arm/Group Title Overall MBC Participants
Hide Arm/Group Description:
Participants with MBC who were enrolled in the study and who received at least one dose of study medication
Overall Number of Participants Analyzed 25
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
92.0
(74.0 to 99.0)
9.Secondary Outcome
Title Duration of Response - MBC Population
Hide Description Duration of response was calculated for participants with CR or PR based on the RECIST v1.0 criteria. Duration of response was defined as the time interval between the date the CR or PR was first recorded and the date on which PD was first noted or date of death, whichever occurred first. Participants with no documented PD after CR or PR were censored at the last date at which they were known to have had the CR or PR, respectively. Median duration of response was estimated using the Kaplan-Meier method.
Time Frame Baseline until disease progression, recurrence or death (up to approximately 3 years)
Hide Outcome Measure Data
Hide Analysis Population Description
MBC population
Arm/Group Title Overall MBC Participants
Hide Arm/Group Description:
Participants with MBC who were enrolled in the study and who received at least one dose of study medication
Overall Number of Participants Analyzed 25
Median (Full Range)
Unit of Measure: months
12.4
(3.9 to 32.7)
10.Secondary Outcome
Title Percentage of Participants With Pathological CR (pCR) - LABC Population
Hide Description The pCR was defined as the absence of invasive neoplastic cells at microscopic examination of the tumor remnants and lymph nodes after surgery following primary systemic therapy.
Time Frame Within 6 weeks of post-surgery (up to approximately 3 years)
Hide Outcome Measure Data
Hide Analysis Population Description
LABC population: All participants with LABC who received at least one dose of study medication.
Arm/Group Title LABC: T-DM1 + Doc (Doublet Regimen) LABC: T-DM1 + Doc + Pertuzumab (Triplet Regimen)
Hide Arm/Group Description:
Feasibility and extension part: Participants with HER2-positive LABC received T-DM1 3.6 mg/kg IV infusion and docetaxel 60/75/100 mg/m^2 IV infusion on Day 1 of each 3-week cycle, for 6 cycles. Study treatment was administered for up to 6 cycles or until unacceptable toxicity, and prior to surgery.
Feasibility and extension part: Participants with HER2-positive LABC received T-DM1 3.6 mg/kg Iv infusion, docetaxel 60/75 mg/m^2 IV infusion, and pertuzumab 840 mg (for Cycle 1) or 420 mg (for remaining cycles) IV infusion on Day 1 of each 3-week cycle, for 6 cycles. Study treatment was administered for up to 6 cycles or until unacceptable toxicity, and prior to surgery.
Overall Number of Participants Analyzed 40 33
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
60.0
(43.3 to 75.1)
60.6
(42.1 to 77.1)
11.Secondary Outcome
Title Percentage of Participants With a BOR of CR or PR - LABC Population
Hide Description BOR was defined as CR or PR recorded from baseline until disease progression/recurrence according to RECIST v1.0 criteria. For TLs, CR was defined as the disappearance of all TLs, and PR was defined as at least a 30% decrease in the sum of LDs of the TLs, taking as a reference the baseline (BL) sum of LDs. For NTLs, CR was defined as the disappearance of all NTLs and normalization of tumor marker levels. Percentage of participants with BOR rate was calculated as the (number of participants with CR or PR) divided by (total number of participants), and then multiplied by 100. The 95% Cl was determined using the Pearson-Clopper method.
Time Frame Baseline until disease progression, recurrence or death (up to approximately 3 years)
Hide Outcome Measure Data
Hide Analysis Population Description
LABC population
Arm/Group Title LABC: T-DM1 + Doc (Doublet Regimen) LABC: T-DM1 + Doc + Pertuzumab (Triplet Regimen)
Hide Arm/Group Description:
Feasibility and extension part: Participants with HER2-positive LABC received T-DM1 3.6 mg/kg IV infusion and docetaxel 60/75/100 mg/m^2 IV infusion on Day 1 of each 3-week cycle, for 6 cycles. Study treatment was administered for up to 6 cycles or until unacceptable toxicity, and prior to surgery.
Feasibility and extension part: Participants with HER2-positive LABC received T-DM1 3.6 mg/kg Iv infusion, docetaxel 60/75 mg/m^2 IV infusion, and pertuzumab 840 mg (for Cycle 1) or 420 mg (for remaining cycles) IV infusion on Day 1 of each 3-week cycle, for 6 cycles. Study treatment was administered for up to 6 cycles or until unacceptable toxicity, and prior to surgery.
Overall Number of Participants Analyzed 40 33
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
70.0
(53.5 to 83.4)
51.5
(33.5 to 69.2)
12.Secondary Outcome
Title Number of Participants With Anti-Therapeutic Antibody (ATA) Response to Trastuzumab - MBC and LABC Population
Hide Description Number of participants with ATA response was reported. Data for this outcome measure was planned to be reported for overall MBC and LABC participants and not by individual treatment arms.
Time Frame Baseline (Day 1 of Cycle 1), Post baseline (at first follow-up visit [28 days after last dose of study drug][up to approximately 145 weeks])
Hide Outcome Measure Data
Hide Analysis Population Description
All participants who received at least one dose of study medication were included. Here, number analyzed=participants evaluable for ATA at specified time-point.
Arm/Group Title Overall MBC and LABC Participants
Hide Arm/Group Description:
All enrolled participants who received at least one dose of study medication
Overall Number of Participants Analyzed 98
Measure Type: Number
Unit of Measure: participants
Baseline Number Analyzed 89 participants
3
Post-baseline Number Analyzed 79 participants
3
13.Secondary Outcome
Title Maximum Observed Concentration (Cmax) of Serum Trastuzumab Emtansine
Hide Description [Not Specified]
Time Frame Cycle 1: pre-dose (Hour [Hr] 0), 0.25, 4 hrs post end of infusion (EOI) of T-DM1 on Day 2; on Days 3 and 8. Cycle 2: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 1; on Day 8 (1 cycle = 21 days) (T-DM1 infusion duration = 1.5 hrs)
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic (PK) analysis population: PK-evaluable participants were defined as participants who received at least one dose of T-DM1 or docetaxel with at least one post-dose concentration data point. Number analyzed = participants evaluable for specified cycle for each arm.
Arm/Group Title MBC: T-DM1 2.4 mg/kg MBC: T-DM1 3.6 mg/kg LABC: T-DM1 3.6 mg/kg
Hide Arm/Group Description:
All MBC participants who received T-DM1 2.4 mg/kg IV infusion.
All MBC participants who received T-DM1 3.6 mg/kg IV infusion.
All LABC participants who received T-DM1 3.6 mg/kg IV infusion.
Overall Number of Participants Analyzed 15 10 73
Mean (Standard Deviation)
Unit of Measure: micrograms per milliliter (mcg/mL)
Cycle 1 Number Analyzed 15 participants 10 participants 73 participants
78.6  (16.6) 76.2  (36.4) 85.7  (15.3)
Cycle 2 Number Analyzed 14 participants 9 participants 67 participants
78.7  (16.7) 93.7  (27.6) 80.2  (18.4)
14.Secondary Outcome
Title Apparent Terminal Half-Life (t1/2) of Serum Trastuzumab Emtansine
Hide Description [Not Specified]
Time Frame Cycle 1: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 2; on Days 3 and 8. Cycle 2: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 1; on Day 8 (1 cycle = 21 days) (T-DM1 infusion duration = 1.5 hrs)
Hide Outcome Measure Data
Hide Analysis Population Description
PK analysis population. Overall number of participants analyzed = participants evaluable for this outcome measure. Number analyzed = participants evaluable for specified cycle for each arm.
Arm/Group Title MBC: T-DM1 2.4 mg/kg MBC: T-DM1 3.6 mg/kg LABC: T-DM1 3.6 mg/kg
Hide Arm/Group Description:
All MBC participants who received T-DM1 2.4 mg/kg IV infusion.
All MBC participants who received T-DM1 3.6 mg/kg IV infusion.
All LABC participants who received T-DM1 3.6 mg/kg IV infusion.
Overall Number of Participants Analyzed 15 8 72
Mean (Standard Deviation)
Unit of Measure: days
Cycle 1 Number Analyzed 15 participants 7 participants 72 participants
2.79  (0.637) 3.45  (0.779) 3.46  (0.558)
Cycle 2 Number Analyzed 14 participants 8 participants 63 participants
3.14  (0.574) 3.85  (0.568) 3.62  (0.516)
15.Secondary Outcome
Title Area Under the Concentration-Time Curve From Time 0 to Infinity (AUCinf) of Serum Trastuzumab Emtansine
Hide Description [Not Specified]
Time Frame Cycle 1: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 2; on Days 3 and 8. Cycle 2: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 1; on Day 8 (1 cycle = 21 days) (T-DM1 infusion duration = 1.5 hrs)
Hide Outcome Measure Data
Hide Analysis Population Description
PK analysis population. Overall number of participants analyzed = participants evaluable for this outcome measure. Number analyzed = participants evaluable for specified cycle for each arm.
Arm/Group Title MBC: T-DM1 2.4 mg/kg MBC: T-DM1 3.6 mg/kg LABC: T-DM1 3.6 mg/kg
Hide Arm/Group Description:
All MBC participants who received T-DM1 2.4 mg/kg IV infusion.
All MBC participants who received T-DM1 3.6 mg/kg IV infusion.
All LABC participants who received T-DM1 3.6 mg/kg IV infusion.
Overall Number of Participants Analyzed 15 8 72
Mean (Standard Deviation)
Unit of Measure: day*mcg/mL
Cycle 1 Number Analyzed 15 participants 7 participants 72 participants
396  (124) 447  (144) 442  (90.7)
Cycle 2 Number Analyzed 14 participants 8 participants 63 participants
471  (94.5) 556  (223) 488  (123)
16.Secondary Outcome
Title Clearance (CL) of Serum Trastuzumab Emtansine
Hide Description [Not Specified]
Time Frame Cycle 1: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 2; on Days 3 and 8. Cycle 2: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 1; on Day 8 (1 cycle = 21 days) (T-DM1 infusion duration = 1.5 hrs)
Hide Outcome Measure Data
Hide Analysis Population Description
PK analysis population. Overall number of participants analyzed = participants evaluable for this outcome measure. Number analyzed = participants evaluable for specified cycle for each arm.
Arm/Group Title MBC: T-DM1 2.4 mg/kg MBC: T-DM1 3.6 mg/kg LABC: T-DM1 3.6 mg/kg
Hide Arm/Group Description:
All MBC participants who received T-DM1 2.4 mg/kg IV infusion.
All MBC participants who received T-DM1 3.6 mg/kg IV infusion.
All LABC participants who received T-DM1 3.6 mg/kg IV infusion.
Overall Number of Participants Analyzed 15 8 72
Mean (Standard Deviation)
Unit of Measure: milliliters/day/kilogram (mL/day/kg)
Cycle 1 Number Analyzed 15 participants 7 participants 72 participants
8.94  (12) 8.87  (2.96) 8.48  (1.86)
Cycle 2 Number Analyzed 14 participants 8 participants 63 participants
5.21  (1.27) 7.16  (2.95) 7.68  (2.73)
17.Secondary Outcome
Title Volume of Distribution at Steady State (Vss) of Serum Trastuzumab Emtansine
Hide Description [Not Specified]
Time Frame Cycle 1: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 2; on Days 3 and 8. Cycle 2: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 1; on Day 8 (1 cycle = 21 days) (T-DM1 infusion duration = 1.5 hrs)
Hide Outcome Measure Data
Hide Analysis Population Description
PK analysis population. Overall number of participants analyzed = participants evaluable for this outcome measure. Number analyzed = participants evaluable for specified cycle for each arm.
Arm/Group Title MBC: T-DM1 2.4 mg/kg MBC: T-DM1 3.6 mg/kg LABC: T-DM1 3.6 mg/kg
Hide Arm/Group Description:
All MBC participants who received T-DM1 2.4 mg/kg IV infusion.
All MBC participants who received T-DM1 3.6 mg/kg IV infusion.
All LABC participants who received T-DM1 3.6 mg/kg IV infusion.
Overall Number of Participants Analyzed 15 8 72
Mean (Standard Deviation)
Unit of Measure: mL/kg
Cycle 1 Number Analyzed 15 participants 7 participants 72 participants
22.1  (6.74) 33.2  (9.13) 33.2  (8.36)
Cycle 2 Number Analyzed 14 participants 8 participants 63 participants
17.7  (4.73) 31.4  (16.9) 28.8  (9.32)
18.Secondary Outcome
Title Cmax of Total Serum Trastuzumab
Hide Description [Not Specified]
Time Frame Cycle 1: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 2; on Days 3 and 8. Cycle 2: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 1; on Day 8 (1 cycle = 21 days) (T-DM1 infusion duration = 1.5 hrs)
Hide Outcome Measure Data
Hide Analysis Population Description
PK analysis population. Overall number of participants analyzed = participants evaluable for this outcome measure. Number analyzed = participants evaluable for specified cycle for each arm.
Arm/Group Title MBC: T-DM1 2.4 mg/kg MBC: T-DM1 3.6 mg/kg LABC: T-DM1 3.6 mg/kg
Hide Arm/Group Description:
All MBC participants who received T-DM1 2.4 mg/kg IV infusion.
All MBC participants who received T-DM1 3.6 mg/kg IV infusion.
All LABC participants who received T-DM1 3.6 mg/kg IV infusion.
Overall Number of Participants Analyzed 15 10 73
Mean (Standard Deviation)
Unit of Measure: mcg/mL
Cycle 1 Number Analyzed 15 participants 10 participants 73 participants
88.7  (22.6) 89.2  (47.4) 120  (46.6)
Cycle 2 Number Analyzed 14 participants 9 participants 67 participants
85.8  (17.5) 97.7  (29.4) 113  (43.8)
19.Secondary Outcome
Title t1/2 of Total Serum Trastuzumab
Hide Description [Not Specified]
Time Frame Cycle 1: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 2; on Days 3 and 8. Cycle 2: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 1; on Day 8 (1 cycle = 21 days) (T-DM1 infusion duration = 1.5 hrs)
Hide Outcome Measure Data
Hide Analysis Population Description
PK analysis population. Overall number of participants analyzed = participants evaluable for this outcome measure. Number analyzed = participants evaluable for specified cycle for each arm.
Arm/Group Title MBC: T-DM1 2.4 mg/kg MBC: T-DM1 3.6 mg/kg LABC: T-DM1 3.6 mg/kg
Hide Arm/Group Description:
All MBC participants who received T-DM1 2.4 mg/kg IV infusion.
All MBC participants who received T-DM1 3.6 mg/kg IV infusion.
All LABC participants who received T-DM1 3.6 mg/kg IV infusion.
Overall Number of Participants Analyzed 15 8 73
Mean (Standard Deviation)
Unit of Measure: days
Cycle 1 Number Analyzed 15 participants 7 participants 73 participants
6.44  (2.6) 6.38  (1.41) 8.12  (4.2)
Cycle 2 Number Analyzed 13 participants 8 participants 62 participants
6.67  (1.92) 7.83  (1.68) 9.91  (5.01)
20.Secondary Outcome
Title AUCinf of Total Serum Trastuzumab
Hide Description [Not Specified]
Time Frame Cycle 1: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 2; on Days 3 and 8. Cycle 2: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 1; on Day 8 (1 cycle = 21 days) (T-DM1 infusion duration = 1.5 hrs)
Hide Outcome Measure Data
Hide Analysis Population Description
PK analysis population. Overall number of participants analyzed = participants evaluable for this outcome measure. Number analyzed = participants evaluable for specified cycle for each arm.
Arm/Group Title MBC: T-DM1 2.4 mg/kg MBC: T-DM1 3.6 mg/kg LABC: T-DM1 3.6 mg/kg
Hide Arm/Group Description:
All MBC participants who received T-DM1 2.4 mg/kg IV infusion.
All MBC participants who received T-DM1 3.6 mg/kg IV infusion.
All LABC participants who received T-DM1 3.6 mg/kg IV infusion.
Overall Number of Participants Analyzed 15 8 73
Mean (Standard Deviation)
Unit of Measure: day*mcg/mL
Cycle 1 Number Analyzed 15 participants 7 participants 73 participants
785  (429) 707  (201) 1210  (856)
Cycle 2 Number Analyzed 13 participants 8 participants 62 participants
809  (308) 1040  (359) 1570  (1180)
21.Secondary Outcome
Title CL of Total Serum Trastuzumab
Hide Description [Not Specified]
Time Frame Cycle 1: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 2; on Days 3 and 8. Cycle 2: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 1; on Day 8 (1 cycle = 21 days) (T-DM1 infusion duration = 1.5 hrs)
Hide Outcome Measure Data
Hide Analysis Population Description
PK analysis population. Overall number of participants analyzed = participants evaluable for this outcome measure. Number analyzed = participants evaluable for specified cycle for each arm.
Arm/Group Title MBC: T-DM1 2.4 mg/kg MBC: T-DM1 3.6 mg/kg LABC: T-DM1 3.6 mg/kg
Hide Arm/Group Description:
All MBC participants who received T-DM1 2.4 mg/kg IV infusion.
All MBC participants who received T-DM1 3.6 mg/kg IV infusion.
All LABC participants who received T-DM1 3.6 mg/kg IV infusion.
Overall Number of Participants Analyzed 15 8 73
Mean (Standard Deviation)
Unit of Measure: mL/day/kg
Cycle 1 Number Analyzed 15 participants 7 participants 73 participants
6.78  (13.3) 5.45  (1.46) 4.22  (2.13)
Cycle 2 Number Analyzed 13 participants 8 participants 62 participants
3.32  (1.53) 3.71  (1.23) 3.38  (2.11)
22.Secondary Outcome
Title Vss of Total Serum Trastuzumab
Hide Description [Not Specified]
Time Frame Cycle 1: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 2; on Days 3 and 8. Cycle 2: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 1; on Day 8 (1 cycle = 21 days) (T-DM1 infusion duration = 1.5 hrs)
Hide Outcome Measure Data
Hide Analysis Population Description
PK analysis population. Overall number of participants analyzed = participants evaluable for this outcome measure. Number analyzed = participants evaluable for specified cycle for each arm.
Arm/Group Title MBC: T-DM1 2.4 mg/kg MBC: T-DM1 3.6 mg/kg LABC: T-DM1 3.6 mg/kg
Hide Arm/Group Description:
All MBC participants who received T-DM1 2.4 mg/kg IV infusion.
All MBC participants who received T-DM1 3.6 mg/kg IV infusion.
All LABC participants who received T-DM1 3.6 mg/kg IV infusion.
Overall Number of Participants Analyzed 15 8 73
Mean (Standard Deviation)
Unit of Measure: mL/kg
Cycle 1 Number Analyzed 15 participants 7 participants 73 participants
27  (7.16) 41.3  (9.24) 36.5  (12.7)
Cycle 2 Number Analyzed 13 participants 8 participants 62 participants
24.6  (5.05) 36.4  (11.3) 35.2  (12)
23.Secondary Outcome
Title Cmax of Plasma N2’-Deacetyl-N2’-(3-mercapto-1-oxopropyl)-Maytansine (DM1)
Hide Description DM1 is the metabolite of trastuzumab emtansine.
Time Frame Cycle 1: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 2; on Days 3 and 8. Cycle 2: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 1; on Day 8 (1 cycle = 21 days) (T-DM1 infusion duration = 1.5 hrs)
Hide Outcome Measure Data
Hide Analysis Population Description
PK analysis population. Overall number of participants analyzed = participants evaluable for this outcome measure. Number analyzed = participants evaluable for specified cycle for each arm.
Arm/Group Title MBC: T-DM1 2.4 mg/kg MBC: T-DM1 3.6 mg/kg LABC: T-DM1 3.6 mg/kg
Hide Arm/Group Description:
All MBC participants who received T-DM1 2.4 mg/kg IV infusion.
All MBC participants who received T-DM1 3.6 mg/kg IV infusion.
All LABC participants who received T-DM1 3.6 mg/kg IV infusion.
Overall Number of Participants Analyzed 13 9 73
Mean (Standard Deviation)
Unit of Measure: nanograms per milliliter (ng/mL)
Cycle 1 Number Analyzed 13 participants 9 participants 73 participants
3.55  (1.6) 3.42  (0.944) 4.51  (1.38)
Cycle 2 Number Analyzed 13 participants 9 participants 67 participants
3.34  (0.815) 3.9  (1.19) 4.65  (1.57)
24.Secondary Outcome
Title t1/2 of Plasma DM1
Hide Description [Not Specified]
Time Frame Cycle 1: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 2; on Days 3 and 8. Cycle 2: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 1; on Day 8 (1 cycle = 21 days) (T-DM1 infusion duration = 1.5 hrs)
Hide Outcome Measure Data
Hide Analysis Population Description
PK analysis population. Overall number of participants analyzed = participants evaluable for this outcome measure. Number analyzed = participants evaluable for specified cycle for each arm.
Arm/Group Title MBC: T-DM1 2.4 mg/kg MBC: T-DM1 3.6 mg/kg LABC: T-DM1 3.6 mg/kg
Hide Arm/Group Description:
All MBC participants who received T-DM1 2.4 mg/kg IV infusion.
All MBC participants who received T-DM1 3.6 mg/kg IV infusion.
All LABC participants who received T-DM1 3.6 mg/kg IV infusion.
Overall Number of Participants Analyzed 12 7 68
Mean (Standard Deviation)
Unit of Measure: days
Cycle 1 Number Analyzed 12 participants 7 participants 68 participants
1.12  (0.702) 1.2  (0.985) 1.87  (1.63)
Cycle 2 Number Analyzed 2 participants 1 participants 31 participants
3.75  (0.912) 2.91 3.32  (0.7)
25.Secondary Outcome
Title AUCinf of Plasma DM1
Hide Description [Not Specified]
Time Frame Cycle 1: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 2; on Days 3 and 8. Cycle 2: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 1; on Day 8 (1 cycle = 21 days) (T-DM1 infusion duration = 1.5 hrs)
Hide Outcome Measure Data
Hide Analysis Population Description
PK analysis population. Overall number of participants analyzed = participants evaluable for this outcome measure. Number analyzed = participants evaluable for specified cycle for each arm.
Arm/Group Title MBC: T-DM1 2.4 mg/kg MBC: T-DM1 3.6 mg/kg LABC: T-DM1 3.6 mg/kg
Hide Arm/Group Description:
All MBC participants who received T-DM1 2.4 mg/kg IV infusion.
All MBC participants who received T-DM1 3.6 mg/kg IV infusion.
All LABC participants who received T-DM1 3.6 mg/kg IV infusion.
Overall Number of Participants Analyzed 12 7 68
Mean (Standard Deviation)
Unit of Measure: day*ng/mL
Cycle 1 Number Analyzed 12 participants 7 participants 68 participants
5.72  (5.16) 5.01  (2.54) 9.38  (9.33)
Cycle 2 Number Analyzed 2 participants 1 participants 31 participants
17.8  (4.6) 20 18.5  (4.28)
26.Secondary Outcome
Title Cmax of Plasma Docetaxel
Hide Description Docetaxel infusion duration = 1 hr (as per summary of product characteristics [SmPC])
Time Frame Cycle 1: pre-dose (Hr 0), 0.25, 0.5, 1, 2, 4, 8, 23 hrs post EOI of docetaxel on Day 1. Cycle 2: pre-dose (Hr 0), 0.5 hr and 59 min after start of infusion, 0.25, 0.5, 1, 2, 4, 8, 23 hrs post EOI of docetaxel on Day 1 (1 cycle = 21 days)
Hide Outcome Measure Data
Hide Analysis Population Description
PK analysis population. Overall number of participants analyzed = participants evaluable for this outcome measure. Number analyzed = participants evaluable for specified cycle for each arm.
Arm/Group Title MBC: Docetaxel 75 mg/m^2 MBC: Docetaxel 60 mg/m^2 LABC: Docetaxel 60 mg/m^2 LABC: Docetaxel 75 mg/m^2 LABC: Docetaxel 100 mg/m^2
Hide Arm/Group Description:
All MBC participants who received docetaxel 75 mg/m^2 IV infusion.
All MBC participants who received docetaxel 60 mg/m^2 IV infusion.
All LABC participants who received docetaxel 60 mg/m^2 IV infusion.
All LABC participants who received docetaxel 75 mg/m^2 IV infusion.
All LABC participants who received docetaxel 100 mg/m^2 IV infusion.
Overall Number of Participants Analyzed 6 19 14 36 22
Mean (Standard Deviation)
Unit of Measure: ng/mL
Cycle 1 Number Analyzed 6 participants 19 participants 14 participants 36 participants 22 participants
500  (216) 1300  (829) 1470  (551) 1710  (426) 2950  (1540)
Cycle 2 Number Analyzed 6 participants 17 participants 12 participants 35 participants 19 participants
791  (637) 1320  (826) 1590  (441) 1960  (552) 2790  (979)
27.Secondary Outcome
Title t1/2 of Plasma Docetaxel
Hide Description Docetaxel infusion duration = 1 hr (as per SmPC)
Time Frame Cycle 1: pre-dose (Hr 0), 0.25, 0.5, 1, 2, 4, 8, 23 hrs post EOI of docetaxel on Day 1. Cycle 2: pre-dose (Hr 0), 0.5 hr and 59 min after start of infusion, 0.25, 0.5, 1, 2, 4, 8, 23 hrs post EOI of docetaxel on Day 1 (1 cycle = 21 days)
Hide Outcome Measure Data
Hide Analysis Population Description
PK analysis population. Overall number of participants analyzed = participants evaluable for this outcome measure. Number analyzed = participants evaluable for specified cycle for each arm.
Arm/Group Title MBC: Docetaxel 75 mg/m^2 MBC: Docetaxel 60 mg/m^2 LABC: Docetaxel 60 mg/m^2 LABC: Docetaxel 75 mg/m^2 LABC: Docetaxel 100 mg/m^2
Hide Arm/Group Description:
All MBC participants who received docetaxel 75 mg/m^2 IV infusion.
All MBC participants who received docetaxel 60 mg/m^2 IV infusion.
All LABC participants who received docetaxel 60 mg/m^2 IV infusion.
All LABC participants who received docetaxel 75 mg/m^2 IV infusion.
All LABC participants who received docetaxel 100 mg/m^2 IV infusion.
Overall Number of Participants Analyzed 6 19 14 36 22
Mean (Standard Deviation)
Unit of Measure: hours (hr)
Cycle 1 Number Analyzed 6 participants 19 participants 14 participants 36 participants 22 participants
6.83  (4.22) 5.17  (4.02) 4.25  (5.61) 8.29  (5.75) 8.76  (3.82)
Cycle 2 Number Analyzed 6 participants 17 participants 12 participants 35 participants 19 participants
7.7  (4.15) 7.88  (6.18) 5.9  (3.83) 6.69  (5.55) 7.24  (3.58)
28.Secondary Outcome
Title AUCinf of Plasma Docetaxel
Hide Description Docetaxel infusion duration = 1 hr (as per SmPC)
Time Frame Cycle 1: pre-dose (Hr 0), 0.25, 0.5, 1, 2, 4, 8, 23 hrs post EOI of docetaxel on Day 1. Cycle 2: pre-dose (Hr 0), 0.5 hr and 59 min after start of infusion, 0.25, 0.5, 1, 2, 4, 8, 23 hrs post EOI of docetaxel on Day 1 (1 cycle = 21 days)
Hide Outcome Measure Data
Hide Analysis Population Description
PK analysis population. Overall number of participants analyzed = participants evaluable for this outcome measure. Number analyzed = participants evaluable for specified cycle for each arm.
Arm/Group Title MBC: Docetaxel 75 mg/m^2 MBC: Docetaxel 60 mg/m^2 LABC: Docetaxel 60 mg/m^2 LABC: Docetaxel 75 mg/m^2 LABC: Docetaxel 100 mg/m^2
Hide Arm/Group Description:
All MBC participants who received docetaxel 75 mg/m^2 IV infusion.
All MBC participants who received docetaxel 60 mg/m^2 IV infusion.
All LABC participants who received docetaxel 60 mg/m^2 IV infusion.
All LABC participants who received docetaxel 75 mg/m^2 IV infusion.
All LABC participants who received docetaxel 100 mg/m^2 IV infusion.
Overall Number of Participants Analyzed 6 19 14 36 22
Mean (Standard Deviation)
Unit of Measure: hr*ng/mL
Cycle 1 Number Analyzed 6 participants 19 participants 14 participants 36 participants 22 participants
1050  (475) 1560  (874) 1540  (421) 2140  (669) 4020  (2120)
Cycle 2 Number Analyzed 6 participants 17 participants 12 participants 35 participants 19 participants
1700  (1190) 1710  (875) 3260  (5100) 2420  (887) 3840  (1930)
29.Secondary Outcome
Title CL of Plasma Docetaxel
Hide Description Docetaxel infusion duration = 1 hr (as per SmPC)
Time Frame Cycle 1: pre-dose (Hr 0), 0.25, 0.5, 1, 2, 4, 8, 23 hrs post EOI of docetaxel on Day 1. Cycle 2: pre-dose (Hr 0), 0.5 hr and 59 min after start of infusion, 0.25, 0.5, 1, 2, 4, 8, 23 hrs post EOI of docetaxel on Day 1 (1 cycle = 21 days)
Hide Outcome Measure Data
Hide Analysis Population Description
PK analysis population. Overall number of participants analyzed = participants evaluable for this outcome measure. Number analyzed = participants evaluable for specified cycle for each arm.
Arm/Group Title MBC: Docetaxel 75 mg/m^2 MBC: Docetaxel 60 mg/m^2 LABC: Docetaxel 60 mg/m^2 LABC: Docetaxel 75 mg/m^2 LABC: Docetaxel 100 mg/m^2
Hide Arm/Group Description:
All MBC participants who received docetaxel 75 mg/m^2 IV infusion.
All MBC participants who received docetaxel 60 mg/m^2 IV infusion.
All LABC participants who received docetaxel 60 mg/m^2 IV infusion.
All LABC participants who received docetaxel 75 mg/m^2 IV infusion.
All LABC participants who received docetaxel 100 mg/m^2 IV infusion.
Overall Number of Participants Analyzed 6 19 14 36 22
Mean (Standard Deviation)
Unit of Measure: liters/hour/square meter (L/hr/m^2)
Cycle 1 Number Analyzed 6 participants 19 participants 14 participants 36 participants 22 participants
82.2  (32.6) 58.3  (40.9) 42.8  (16.4) 39.5  (16.8) 30.5  (14.5)
Cycle 2 Number Analyzed 6 participants 17 participants 12 participants 35 participants 19 participants
59  (29.9) 51.2  (38.5) 32.6  (13.1) 33.6  (11.9) 27.9  (9.13)
30.Secondary Outcome
Title Vss of Plasma Docetaxel
Hide Description Docetaxel infusion duration = 1 hr (as per SmPC)
Time Frame Cycle 1: pre-dose (Hr 0), 0.25, 0.5, 1, 2, 4, 8, 23 hrs post EOI of docetaxel on Day 1. Cycle 2: pre-dose (Hr 0), 0.5 hr and 59 min after start of infusion, 0.25, 0.5, 1, 2, 4, 8, 23 hrs post EOI of docetaxel on Day 1 (1 cycle = 21 days)
Hide Outcome Measure Data
Hide Analysis Population Description
PK analysis population. Overall number of participants analyzed = participants evaluable for this outcome measure. Number analyzed = participants evaluable for specified cycle for each arm.
Arm/Group Title MBC: Docetaxel 75 mg/m^2 MBC: Docetaxel 60 mg/m^2 LABC: Docetaxel 60 mg/m^2 LABC: Docetaxel 75 mg/m^2 LABC: Docetaxel 100 mg/m^2
Hide Arm/Group Description:
All MBC participants who received docetaxel 75 mg/m^2 IV infusion.
All MBC participants who received docetaxel 60 mg/m^2 IV infusion.
All LABC participants who received docetaxel 60 mg/m^2 IV infusion.
All LABC participants who received docetaxel 75 mg/m^2 IV infusion.
All LABC participants who received docetaxel 100 mg/m^2 IV infusion.
Overall Number of Participants Analyzed 6 19 14 36 22
Mean (Standard Deviation)
Unit of Measure: liters per square meter (L/m^2)
Cycle 1 Number Analyzed 6 participants 19 participants 14 participants 36 participants 22 participants
530  (398) 203  (275) 75  (113) 126  (86.7) 116  (73.3)
Cycle 2 Number Analyzed 6 participants 17 participants 12 participants 35 participants 19 participants
380  (257) 253  (234) 93.2  (64.7) 79  (53.6) 84.8  (39.1)
Time Frame Baseline up to 28 days after last dose for MBC participants and for LABC participants who could not undergo surgery, and up to 6 weeks post-surgery for LABC participants who underwent surgery (maximum up to approximately 3 years)
Adverse Event Reporting Description All participants who received at least one dose of study medication were included.
 
Arm/Group Title MBC: T-DM1 2.4 mg/kg + Doc 75 mg/m^2 (Over 2 Days) MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Over 2 Days) MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Same Day) MBC: T-DM1 3.6 mg/kg + Doc 60 mg/m^2 (Same Day) LABC: T-DM1 + Doc (Doublet Regimen) LABC: T-DM1 + Doc + Pertuzumab (Triplet Regimen)
Hide Arm/Group Description Feasibility part: Participants with HER2-positive MBC received docetaxel 75 mg/m^2 IV infusion on Day 1 and T-DM1 2.4 mg/kg IV infusion on Day 2 of Cycle 1 followed by T-DM1 75 mg/m^2 and docetaxel 2.4 mg/kg IV infusion on Day 1 of each 3-week cycle for a minimum of 6 cycles. After 6 cycles, docetaxel 75 mg/m^2 was stopped and T-DM1 2.4 mg/kg was continued until confirmed evidence of disease progression, unacceptable toxicity, or withdrawal of participant consent. Feasibility part: Participants with HER2-positive MBC received docetaxel 60 mg/m^2 IV infusion on Day 1 and T-DM1 2.4 mg/kg IV infusion on Day 2 of Cycle 1 followed by T-DM1 60 mg/m^2 and docetaxel 2.4 mg/kg IV infusion on Day 1 of each 3-week cycle for a minimum of 6 cycles. After 6 cycles, docetaxel 60 mg/m^2 was stopped and T-DM1 2.4 mg/kg was continued until confirmed evidence of disease progression, unacceptable toxicity, or withdrawal of participant consent. Feasibility part: Participants with HER2-positive MBC received docetaxel 60 mg/m^2 IV infusion and T-DM1 2.4 mg/kg IV infusion on Day 1 of each 3-week cycle for a minimum of 6 cycles. After 6 cycles, docetaxel 60 mg/m^2 was stopped and T-DM1 2.4 mg/kg was continued until confirmed evidence of disease progression, unacceptable toxicity, or withdrawal of participant consent. Feasibility and extension part: Participants with HER2-positive MBC received docetaxel 60 mg/m^2 IV infusion and T-DM1 3.6 mg/kg IV infusion on Day 1 of each 3-week cycle for a minimum of 6 cycles. After 6 cycles, docetaxel 60 mg/m^2 was stopped and T-DM1 3.6 mg/kg was continued until confirmed evidence of disease progression, unacceptable toxicity, or withdrawal of participant consent. Feasibility and extension part: Participants with HER2-positive LABC received T-DM1 3.6 mg/kg IV infusion and docetaxel 60/75/100 mg/m^2 IV infusion on Day 1 of each 3-week cycle, for 6 cycles. Study treatment was administered for up to 6 cycles or until unacceptable toxicity, and prior to surgery. Feasibility and extension part: Participants with HER2-positive LABC received T-DM1 3.6 mg/kg Iv infusion, docetaxel 60/75 mg/m^2 IV infusion, and pertuzumab 840 mg (for Cycle 1) or 420 mg (for remaining cycles) IV infusion on Day 1 of each 3-week cycle, for 6 cycles. Study treatment was administered for up to 6 cycles or until unacceptable toxicity, and prior to surgery.
All-Cause Mortality
MBC: T-DM1 2.4 mg/kg + Doc 75 mg/m^2 (Over 2 Days) MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Over 2 Days) MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Same Day) MBC: T-DM1 3.6 mg/kg + Doc 60 mg/m^2 (Same Day) LABC: T-DM1 + Doc (Doublet Regimen) LABC: T-DM1 + Doc + Pertuzumab (Triplet Regimen)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/--   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
MBC: T-DM1 2.4 mg/kg + Doc 75 mg/m^2 (Over 2 Days) MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Over 2 Days) MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Same Day) MBC: T-DM1 3.6 mg/kg + Doc 60 mg/m^2 (Same Day) LABC: T-DM1 + Doc (Doublet Regimen) LABC: T-DM1 + Doc + Pertuzumab (Triplet Regimen)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   2/6 (33.33%)   2/6 (33.33%)   2/3 (66.67%)   4/10 (40.00%)   9/40 (22.50%)   9/33 (27.27%) 
Blood and lymphatic system disorders             
Febrile neutropenia * 1  1/6 (16.67%)  1/6 (16.67%)  1/3 (33.33%)  0/10 (0.00%)  1/40 (2.50%)  1/33 (3.03%) 
Neutropenia * 1  0/6 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/10 (0.00%)  1/40 (2.50%)  2/33 (6.06%) 
Thrombocytopenia * 1  1/6 (16.67%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  1/40 (2.50%)  1/33 (3.03%) 
Gastrointestinal disorders             
Diarrhoea * 1  0/6 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  0/40 (0.00%)  1/33 (3.03%) 
General disorders             
Pyrexia * 1  0/6 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  0/40 (0.00%)  2/33 (6.06%) 
Thrombosis in device * 1  1/6 (16.67%)  1/6 (16.67%)  0/3 (0.00%)  0/10 (0.00%)  0/40 (0.00%)  0/33 (0.00%) 
Fatigue * 1  0/6 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  0/40 (0.00%)  1/33 (3.03%) 
Mucosal inflammation * 1  0/6 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  1/40 (2.50%)  0/33 (0.00%) 
Device deployment issue * 1  0/6 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/10 (10.00%)  0/40 (0.00%)  0/33 (0.00%) 
Hepatobiliary disorders             
Hepatocellular injury * 1  1/6 (16.67%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  0/40 (0.00%)  1/33 (3.03%) 
Cholecystitis * 1  1/6 (16.67%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  0/40 (0.00%)  0/33 (0.00%) 
Hepatic pain * 1  0/6 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/10 (10.00%)  0/40 (0.00%)  0/33 (0.00%) 
Infections and infestations             
Viral infection * 1  0/6 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/10 (0.00%)  1/40 (2.50%)  1/33 (3.03%) 
Anal abscess * 1  0/6 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  1/40 (2.50%)  0/33 (0.00%) 
Pyelonephritis acute * 1  0/6 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  0/40 (0.00%)  1/33 (3.03%) 
Urinary tract infection * 1  0/6 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  0/40 (0.00%)  1/33 (3.03%) 
Injury, poisoning and procedural complications             
Tibia fracture * 1  0/6 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/10 (10.00%)  0/40 (0.00%)  0/33 (0.00%) 
Metabolism and nutrition disorders             
Dehydration * 1  0/6 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  1/40 (2.50%)  0/33 (0.00%) 
Musculoskeletal and connective tissue disorders             
Myalgia * 1  0/6 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/10 (10.00%)  0/40 (0.00%)  0/33 (0.00%) 
Psychiatric disorders             
Anxiety * 1  0/6 (0.00%)  0/6 (0.00%)  1/3 (33.33%)  0/10 (0.00%)  0/40 (0.00%)  0/33 (0.00%) 
Confusional state * 1  0/6 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  1/40 (2.50%)  0/33 (0.00%) 
Reproductive system and breast disorders             
Uterine polyp * 1  0/6 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  0/40 (0.00%)  1/33 (3.03%) 
Respiratory, thoracic and mediastinal disorders             
Pneumonitis * 1  0/6 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  1/40 (2.50%)  0/33 (0.00%) 
Respiratory failure * 1  0/6 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  1/40 (2.50%)  0/33 (0.00%) 
Skin and subcutaneous tissue disorders             
Melanoderma * 1  0/6 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  2/40 (5.00%)  0/33 (0.00%) 
Dermatitis exfoliative * 1  0/6 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  1/40 (2.50%)  0/33 (0.00%) 
Dermatomyositis * 1  0/6 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  1/40 (2.50%)  0/33 (0.00%) 
Skin hyperpigmentation * 1  0/6 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  1/40 (2.50%)  0/33 (0.00%) 
Vascular disorders             
Haematoma * 1  0/6 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/10 (10.00%)  0/40 (0.00%)  0/33 (0.00%) 
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA (16.1)
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
MBC: T-DM1 2.4 mg/kg + Doc 75 mg/m^2 (Over 2 Days) MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Over 2 Days) MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (Same Day) MBC: T-DM1 3.6 mg/kg + Doc 60 mg/m^2 (Same Day) LABC: T-DM1 + Doc (Doublet Regimen) LABC: T-DM1 + Doc + Pertuzumab (Triplet Regimen)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   6/6 (100.00%)   6/6 (100.00%)   3/3 (100.00%)   10/10 (100.00%)   40/40 (100.00%)   33/33 (100.00%) 
Blood and lymphatic system disorders             
Neutropenia * 1  6/6 (100.00%)  5/6 (83.33%)  1/3 (33.33%)  7/10 (70.00%)  11/40 (27.50%)  12/33 (36.36%) 
Thrombocytopenia * 1  4/6 (66.67%)  4/6 (66.67%)  0/3 (0.00%)  8/10 (80.00%)  9/40 (22.50%)  7/33 (21.21%) 
Leukopenia * 1  5/6 (83.33%)  3/6 (50.00%)  1/3 (33.33%)  4/10 (40.00%)  3/40 (7.50%)  3/33 (9.09%) 
Lymphopenia * 1  5/6 (83.33%)  1/6 (16.67%)  0/3 (0.00%)  3/10 (30.00%)  3/40 (7.50%)  4/33 (12.12%) 
Anaemia * 1  1/6 (16.67%)  1/6 (16.67%)  1/3 (33.33%)  3/10 (30.00%)  4/40 (10.00%)  4/33 (12.12%) 
Cardiac disorders             
Palpitations * 1  0/6 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  1/10 (10.00%)  0/40 (0.00%)  0/33 (0.00%) 
Systolic dysfunction * 1  0/6 (0.00%)  0/6 (0.00%)  1/3 (33.33%)  0/10 (0.00%)  0/40 (0.00%)  0/33 (0.00%) 
Ear and labyrinth disorders             
Ear pain * 1  0/6 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  2/40 (5.00%)  1/33 (3.03%) 
Tinnitus * 1  1/6 (16.67%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  0/40 (0.00%)  0/33 (0.00%) 
Vertigo * 1  0/6 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/10 (10.00%)  0/40 (0.00%)  0/33 (0.00%) 
Eye disorders             
Lacrimation increased * 1  1/6 (16.67%)  2/6 (33.33%)  1/3 (33.33%)  4/10 (40.00%)  15/40 (37.50%)  16/33 (48.48%) 
Conjunctivitis * 1  0/6 (0.00%)  2/6 (33.33%)  1/3 (33.33%)  1/10 (10.00%)  6/40 (15.00%)  2/33 (6.06%) 
Dry eye * 1  1/6 (16.67%)  1/6 (16.67%)  0/3 (0.00%)  1/10 (10.00%)  3/40 (7.50%)  5/33 (15.15%) 
Vision blurred * 1  0/6 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/10 (0.00%)  6/40 (15.00%)  2/33 (6.06%) 
Xerophthalmia * 1  0/6 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  2/40 (5.00%)  2/33 (6.06%) 
Blepharospasm * 1  1/6 (16.67%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  2/40 (5.00%)  0/33 (0.00%) 
Conjunctival oedema * 1  0/6 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  2/40 (5.00%)  1/33 (3.03%) 
Eye disorder * 1  0/6 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  3/40 (7.50%)  0/33 (0.00%) 
Conjunctival haemorrhage * 1  0/6 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/10 (10.00%)  0/40 (0.00%)  1/33 (3.03%) 
Eye pain * 1  0/6 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/10 (10.00%)  1/40 (2.50%)  0/33 (0.00%) 
Photophobia * 1  0/6 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/10 (10.00%)  1/40 (2.50%)  0/33 (0.00%) 
Visual acuity reduced * 1  1/6 (16.67%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  1/40 (2.50%)  0/33 (0.00%) 
Visual impairment * 1  1/6 (16.67%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  0/40 (0.00%)  1/33 (3.03%) 
Dacryostenosis acquired * 1  1/6 (16.67%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  0/40 (0.00%)  0/33 (0.00%) 
Eyelids pruritus * 1  0/6 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/10 (0.00%)  0/40 (0.00%)  0/33 (0.00%) 
Gastrointestinal disorders             
Nausea * 1  1/6 (16.67%)  5/6 (83.33%)  1/3 (33.33%)  4/10 (40.00%)  16/40 (40.00%)  16/33 (48.48%) 
Diarrhoea * 1  3/6 (50.00%)  3/6 (50.00%)  1/3 (33.33%)  3/10 (30.00%)  12/40 (30.00%)  18/33 (54.55%) 
Constipation * 1  1/6 (16.67%)  1/6 (16.67%)  3/3 (100.00%)  3/10 (30.00%)  19/40 (47.50%)  11/33 (33.33%) 
Dry mouth * 1  1/6 (16.67%)  1/6 (16.67%)  2/3 (66.67%)  3/10 (30.00%)  14/40 (35.00%)  10/33 (30.30%) 
Vomiting * 1  1/6 (16.67%)  2/6 (33.33%)  1/3 (33.33%)  5/10 (50.00%)  11/40 (27.50%)  11/33 (33.33%) 
Stomatitis * 1  3/6 (50.00%)  4/6 (66.67%)  0/3 (0.00%)  5/10 (50.00%)  4/40 (10.00%)  5/33 (15.15%) 
Abdominal pain * 1  2/6 (33.33%)  1/6 (16.67%)  0/3 (0.00%)  2/10 (20.00%)  5/40 (12.50%)  4/33 (12.12%) 
Abdominal pain upper * 1  2/6 (33.33%)  3/6 (50.00%)  0/3 (0.00%)  1/10 (10.00%)  3/40 (7.50%)  5/33 (15.15%) 
Haemorrhoids * 1  0/6 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/10 (0.00%)  4/40 (10.00%)  3/33 (9.09%) 
Odynophagia * 1  0/6 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/10 (0.00%)  5/40 (12.50%)  2/33 (6.06%) 
Dyspepsia * 1  1/6 (16.67%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  3/40 (7.50%)  3/33 (9.09%) 
Gastritis * 1  0/6 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  4/40 (10.00%)  3/33 (9.09%) 
Gingival bleeding * 1  0/6 (0.00%)  2/6 (33.33%)  0/3 (0.00%)  2/10 (20.00%)  3/40 (7.50%)  0/33 (0.00%) 
Gastrooesophageal reflux disease * 1  1/6 (16.67%)  0/6 (0.00%)  0/3 (0.00%)  3/10 (30.00%)  0/40 (0.00%)  2/33 (6.06%) 
Rectal haemorrhage * 1  0/6 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  1/10 (10.00%)  3/40 (7.50%)  0/33 (0.00%) 
Cheilitis * 1  0/6 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  1/10 (10.00%)  1/40 (2.50%)  1/33 (3.03%) 
Oral pain * 1  0/6 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/10 (10.00%)  2/40 (5.00%)  1/33 (3.03%) 
Abdominal discomfort * 1  1/6 (16.67%)  0/6 (0.00%)  0/3 (0.00%)  1/10 (10.00%)  0/40 (0.00%)  1/33 (3.03%) 
Flatulence * 1  1/6 (16.67%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  0/40 (0.00%)  2/33 (6.06%) 
Aphthous Stomatitis * 1  1/6 (16.67%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  1/40 (2.50%)  0/33 (0.00%) 
Gingival pain * 1  0/6 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/10 (10.00%)  0/40 (0.00%)  1/33 (3.03%) 
Proctalgia * 1  0/6 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/10 (10.00%)  0/40 (0.00%)  1/33 (3.03%) 
Mouth ulceration * 1  0/6 (0.00%)  0/6 (0.00%)  1/3 (33.33%)  0/10 (0.00%)  0/40 (0.00%)  1/33 (3.03%) 
Breath odour * 1  0/6 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/10 (10.00%)  0/40 (0.00%)  0/33 (0.00%) 
Epulis * 1  0/6 (0.00%)  0/6 (0.00%)  1/3 (33.33%)  0/10 (0.00%)  0/40 (0.00%)  0/33 (0.00%) 
Food poisoning * 1  1/6 (16.67%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  0/40 (0.00%)  0/33 (0.00%) 
Tooth loss * 1  0/6 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/10 (10.00%)  0/40 (0.00%)  0/33 (0.00%) 
Toothache * 1  1/6 (16.67%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  0/40 (0.00%)  0/33 (0.00%) 
General disorders             
Asthenia * 1  6/6 (100.00%)  5/6 (83.33%)  1/3 (33.33%)  6/10 (60.00%)  25/40 (62.50%)  20/33 (60.61%) 
Mucosal inflammation * 1  1/6 (16.67%)  3/6 (50.00%)  1/3 (33.33%)  3/10 (30.00%)  20/40 (50.00%)  15/33 (45.45%) 
Pyrexia * 1  1/6 (16.67%)  5/6 (83.33%)  0/3 (0.00%)  2/10 (20.00%)  8/40 (20.00%)  10/33 (30.30%) 
Fatigue * 1  0/6 (0.00%)  1/6 (16.67%)  1/3 (33.33%)  1/10 (10.00%)  10/40 (25.00%)  9/33 (27.27%) 
Oedema peripheral * 1  0/6 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  2/10 (20.00%)  3/40 (7.50%)  1/33 (3.03%) 
Influenza like illness * 1  0/6 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  1/10 (10.00%)  4/40 (10.00%)  0/33 (0.00%) 
Chills * 1  0/6 (0.00%)  2/6 (33.33%)  1/3 (33.33%)  0/10 (0.00%)  1/40 (2.50%)  1/33 (3.03%) 
Mucosal dryness * 1  0/6 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  1/40 (2.50%)  3/33 (9.09%) 
Non-cardiac chest pain * 1  0/6 (0.00%)  3/6 (50.00%)  0/3 (0.00%)  0/10 (0.00%)  0/40 (0.00%)  1/33 (3.03%) 
Pain * 1  0/6 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  3/40 (7.50%)  0/33 (0.00%) 
Chest pain * 1  1/6 (16.67%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  0/40 (0.00%)  1/33 (3.03%) 
Feeling hot * 1  0/6 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/10 (0.00%)  1/40 (2.50%)  0/33 (0.00%) 
Axillary pain * 1  0/6 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/10 (0.00%)  0/40 (0.00%)  0/33 (0.00%) 
Local swelling * 1  0/6 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/10 (10.00%)  0/40 (0.00%)  0/33 (0.00%) 
Temperature intolerance * 1  0/6 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/10 (10.00%)  0/40 (0.00%)  0/33 (0.00%) 
Temperature regulation disorder * 1  0/6 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/10 (10.00%)  0/40 (0.00%)  0/33 (0.00%) 
Thrombosis in device * 1  1/6 (16.67%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  0/40 (0.00%)  0/33 (0.00%) 
Vaccination site reaction * 1  0/6 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/10 (10.00%)  0/40 (0.00%)  0/33 (0.00%) 
Hepatobiliary disorders             
Hepatocellular injury * 1  1/6 (16.67%)  2/6 (33.33%)  0/3 (0.00%)  2/10 (20.00%)  0/40 (0.00%)  0/33 (0.00%) 
Cholestasis * 1  1/6 (16.67%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  0/40 (0.00%)  0/33 (0.00%) 
Hepatitis * 1  1/6 (16.67%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  0/40 (0.00%)  0/33 (0.00%) 
Infections and infestations             
Nasopharyngitis * 1  3/6 (50.00%)  0/6 (0.00%)  1/3 (33.33%)  5/10 (50.00%)  7/40 (17.50%)  1/33 (3.03%) 
Urinary tract infection * 1  1/6 (16.67%)  1/6 (16.67%)  0/3 (0.00%)  3/10 (30.00%)  4/40 (10.00%)  3/33 (9.09%) 
Rhinitis * 1  1/6 (16.67%)  1/6 (16.67%)  1/3 (33.33%)  2/10 (20.00%)  4/40 (10.00%)  1/33 (3.03%) 
Upper respiratory tract infection * 1  2/6 (33.33%)  1/6 (16.67%)  0/3 (0.00%)  0/10 (0.00%)  2/40 (5.00%)  1/33 (3.03%) 
Candida infection * 1  0/6 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  4/40 (10.00%)  1/33 (3.03%) 
Influenza * 1  1/6 (16.67%)  1/6 (16.67%)  0/3 (0.00%)  0/10 (0.00%)  3/40 (7.50%)  0/33 (0.00%) 
Oral herpes * 1  1/6 (16.67%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  2/40 (5.00%)  1/33 (3.03%) 
Respiratory tract infection * 1  1/6 (16.67%)  0/6 (0.00%)  1/3 (33.33%)  0/10 (0.00%)  0/40 (0.00%)  2/33 (6.06%) 
Bronchitis * 1  1/6 (16.67%)  0/6 (0.00%)  0/3 (0.00%)  1/10 (10.00%)  0/40 (0.00%)  1/33 (3.03%) 
Cellulitis * 1  0/6 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  2/40 (5.00%)  1/33 (3.03%) 
Gingivitis * 1  0/6 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/10 (0.00%)  1/40 (2.50%)  1/33 (3.03%) 
Oral candidiasis * 1  0/6 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/10 (10.00%)  1/40 (2.50%)  1/33 (3.03%) 
Pharyngitis * 1  1/6 (16.67%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  1/40 (2.50%)  1/33 (3.03%) 
Cystitis * 1  1/6 (16.67%)  0/6 (0.00%)  0/3 (0.00%)  1/10 (10.00%)  0/40 (0.00%)  0/33 (0.00%) 
Eye infection * 1  0/6 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  0/40 (0.00%)  2/33 (6.06%) 
Herpes zoster * 1  0/6 (0.00%)  2/6 (33.33%)  0/3 (0.00%)  0/10 (0.00%)  0/40 (0.00%)  0/33 (0.00%) 
Hordeolum * 1  1/6 (16.67%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  0/40 (0.00%)  1/33 (3.03%) 
Device related infection * 1  1/6 (16.67%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  0/40 (0.00%)  0/33 (0.00%) 
Folliculitis * 1  0/6 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/10 (0.00%)  0/40 (0.00%)  0/33 (0.00%) 
Fungal skin infection * 1  1/6 (16.67%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  0/40 (0.00%)  0/33 (0.00%) 
Gastroenteritis * 1  1/6 (16.67%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  0/40 (0.00%)  0/33 (0.00%) 
Genital herpes * 1  0/6 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/10 (0.00%)  0/40 (0.00%)  0/33 (0.00%) 
Herpes virus infection * 1  0/6 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/10 (0.00%)  0/40 (0.00%)  0/33 (0.00%) 
Laryngitis * 1  1/6 (16.67%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  0/40 (0.00%)  0/33 (0.00%) 
Lower respiratory tract infection * 1  0/6 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/10 (10.00%)  0/40 (0.00%)  0/33 (0.00%) 
Mastitis * 1  0/6 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/10 (0.00%)  0/40 (0.00%)  0/33 (0.00%) 
Viral upper respiratory tract infection * 1  0/6 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/10 (10.00%)  0/40 (0.00%)  0/33 (0.00%) 
Vulvovaginal mycotic infection * 1  1/6 (16.67%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  0/40 (0.00%)  0/33 (0.00%) 
Wound infection * 1  1/6 (16.67%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  0/40 (0.00%)  0/33 (0.00%) 
Injury, poisoning and procedural complications             
Infusion related reaction * 1  1/6 (16.67%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  0/40 (0.00%)  0/33 (0.00%) 
Laceration * 1  0/6 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/10 (10.00%)  0/40 (0.00%)  0/33 (0.00%) 
Ligament sprain * 1  1/6 (16.67%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  0/40 (0.00%)  0/33 (0.00%) 
Limb injury * 1  0/6 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/10 (10.00%)  0/40 (0.00%)  0/33 (0.00%) 
Recall phenomenon * 1  0/6 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/10 (0.00%)  0/40 (0.00%)  0/33 (0.00%) 
Tooth avulsion * 1  0/6 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/10 (10.00%)  0/40 (0.00%)  0/33 (0.00%) 
Investigations             
Alanine aminotransferase increased * 1  1/6 (16.67%)  1/6 (16.67%)  0/3 (0.00%)  1/10 (10.00%)  11/40 (27.50%)  7/33 (21.21%) 
Aspartate aminotransferase increased * 1  1/6 (16.67%)  1/6 (16.67%)  0/3 (0.00%)  1/10 (10.00%)  8/40 (20.00%)  4/33 (12.12%) 
Gamma-glutamyltransferase increased * 1  3/6 (50.00%)  0/6 (0.00%)  0/3 (0.00%)  1/10 (10.00%)  3/40 (7.50%)  0/33 (0.00%) 
Blood lactate dehydrogenase increased * 1  2/6 (33.33%)  0/6 (0.00%)  0/3 (0.00%)  1/10 (10.00%)  0/40 (0.00%)  0/33 (0.00%) 
Weight decreased * 1  0/6 (0.00%)  0/6 (0.00%)  1/3 (33.33%)  0/10 (0.00%)  2/40 (5.00%)  0/33 (0.00%) 
Blood bilirubin increased * 1  0/6 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/10 (0.00%)  0/40 (0.00%)  0/33 (0.00%) 
Body temperature increased * 1  0/6 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/10 (0.00%)  0/40 (0.00%)  0/33 (0.00%) 
Metabolism and nutrition disorders             
Decreased appetite * 1  2/6 (33.33%)  2/6 (33.33%)  1/3 (33.33%)  2/10 (20.00%)  9/40 (22.50%)  9/33 (27.27%) 
Hypokalaemia * 1  0/6 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  1/40 (2.50%)  2/33 (6.06%) 
Musculoskeletal and connective tissue disorders             
Myalgia * 1  4/6 (66.67%)  3/6 (50.00%)  0/3 (0.00%)  1/10 (10.00%)  18/40 (45.00%)  8/33 (24.24%) 
Arthralgia * 1  4/6 (66.67%)  4/6 (66.67%)  0/3 (0.00%)  3/10 (30.00%)  9/40 (22.50%)  3/33 (9.09%) 
Musculoskeletal pain * 1  2/6 (33.33%)  0/6 (0.00%)  1/3 (33.33%)  4/10 (40.00%)  10/40 (25.00%)  6/33 (18.18%) 
Back pain * 1  2/6 (33.33%)  3/6 (50.00%)  0/3 (0.00%)  4/10 (40.00%)  6/40 (15.00%)  3/33 (9.09%) 
Bone pain * 1  3/6 (50.00%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  6/40 (15.00%)  3/33 (9.09%) 
Pain in extremity * 1  1/6 (16.67%)  1/6 (16.67%)  0/3 (0.00%)  3/10 (30.00%)  4/40 (10.00%)  3/33 (9.09%) 
Musculoskeletal stiffness * 1  0/6 (0.00%)  2/6 (33.33%)  1/3 (33.33%)  1/10 (10.00%)  1/40 (2.50%)  0/33 (0.00%) 
Muscle spasms * 1  0/6 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  1/10 (10.00%)  1/40 (2.50%)  1/33 (3.03%) 
Muscle twitching * 1  0/6 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/10 (10.00%)  2/40 (5.00%)  1/33 (3.03%) 
Musculoskeletal chest pain * 1  1/6 (16.67%)  0/6 (0.00%)  1/3 (33.33%)  0/10 (0.00%)  0/40 (0.00%)  0/33 (0.00%) 
Muscular weakness * 1  1/6 (16.67%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  0/40 (0.00%)  0/33 (0.00%) 
Musculoskeletal discomfort * 1  0/6 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/10 (0.00%)  0/40 (0.00%)  0/33 (0.00%) 
Osteoarthritis * 1  0/6 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/10 (10.00%)  0/40 (0.00%)  0/33 (0.00%) 
Osteopenia * 1  1/6 (16.67%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  0/40 (0.00%)  0/33 (0.00%) 
Spinal pain * 1  1/6 (16.67%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  0/40 (0.00%)  0/33 (0.00%) 
Nervous system disorders             
Dysgeusia * 1  3/6 (50.00%)  1/6 (16.67%)  1/3 (33.33%)  4/10 (40.00%)  19/40 (47.50%)  13/33 (39.39%) 
Headache * 1  2/6 (33.33%)  1/6 (16.67%)  1/3 (33.33%)  4/10 (40.00%)  12/40 (30.00%)  11/33 (33.33%) 
Neuropathy peripheral * 1  2/6 (33.33%)  3/6 (50.00%)  1/3 (33.33%)  2/10 (20.00%)  8/40 (20.00%)  5/33 (15.15%) 
Paraesthesia * 1  1/6 (16.67%)  3/6 (50.00%)  0/3 (0.00%)  3/10 (30.00%)  4/40 (10.00%)  1/33 (3.03%) 
Peripheral sensory neuropathy * 1  0/6 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/10 (0.00%)  3/40 (7.50%)  1/33 (3.03%) 
Restless legs syndrome * 1  0/6 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  4/40 (10.00%)  1/33 (3.03%) 
Dysaesthesia * 1  1/6 (16.67%)  1/6 (16.67%)  0/3 (0.00%)  0/10 (0.00%)  1/40 (2.50%)  0/33 (0.00%) 
Hypoaesthesia * 1  1/6 (16.67%)  1/6 (16.67%)  0/3 (0.00%)  1/10 (10.00%)  0/40 (0.00%)  0/33 (0.00%) 
Aphonia * 1  0/6 (0.00%)  0/6 (0.00%)  1/3 (33.33%)  0/10 (0.00%)  1/40 (2.50%)  0/33 (0.00%) 
Migraine * 1  0/6 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  2/10 (20.00%)  0/40 (0.00%)  0/33 (0.00%) 
Sciatica * 1  0/6 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/10 (0.00%)  1/40 (2.50%)  0/33 (0.00%) 
Burning sensation * 1  0/6 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/10 (0.00%)  0/40 (0.00%)  0/33 (0.00%) 
Memory impairment * 1  0/6 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/10 (10.00%)  0/40 (0.00%)  0/33 (0.00%) 
Sinus headache * 1  1/6 (16.67%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  0/40 (0.00%)  0/33 (0.00%) 
Somnolence * 1  1/6 (16.67%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  0/40 (0.00%)  0/33 (0.00%) 
Allodynia * 1  1/6 (16.67%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  0/40 (0.00%)  0/33 (0.00%) 
Psychiatric disorders             
Insomnia * 1  0/6 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  3/10 (30.00%)  8/40 (20.00%)  6/33 (18.18%) 
Anxiety * 1  0/6 (0.00%)  2/6 (33.33%)  0/3 (0.00%)  1/10 (10.00%)  1/40 (2.50%)  3/33 (9.09%) 
Depression * 1  0/6 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  2/40 (5.00%)  0/33 (0.00%) 
Renal and urinary disorders             
Dysuria * 1  0/6 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/10 (0.00%)  1/40 (2.50%)  5/33 (15.15%) 
Haematuria * 1  1/6 (16.67%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  0/40 (0.00%)  0/33 (0.00%) 
Pyelocaliectasis * 1  1/6 (16.67%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  0/40 (0.00%)  0/33 (0.00%) 
Reproductive system and breast disorders             
Metrorrhagia * 1  2/6 (33.33%)  0/6 (0.00%)  0/3 (0.00%)  1/10 (10.00%)  2/40 (5.00%)  1/33 (3.03%) 
Menstruation irregular * 1  0/6 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  4/40 (10.00%)  1/33 (3.03%) 
Breast pain * 1  0/6 (0.00%)  0/6 (0.00%)  1/3 (33.33%)  1/10 (10.00%)  1/40 (2.50%)  1/33 (3.03%) 
Menorrhagia * 1  1/6 (16.67%)  0/6 (0.00%)  0/3 (0.00%)  1/10 (10.00%)  0/40 (0.00%)  0/33 (0.00%) 
Pelvic pain * 1  0/6 (0.00%)  2/6 (33.33%)  0/3 (0.00%)  0/10 (0.00%)  0/40 (0.00%)  0/33 (0.00%) 
Vaginal haemorrhage * 1  0/6 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/10 (0.00%)  1/40 (2.50%)  0/33 (0.00%) 
Respiratory, thoracic and mediastinal disorders             
Epistaxis * 1  2/6 (33.33%)  5/6 (83.33%)  1/3 (33.33%)  6/10 (60.00%)  21/40 (52.50%)  19/33 (57.58%) 
Cough * 1  3/6 (50.00%)  3/6 (50.00%)  0/3 (0.00%)  4/10 (40.00%)  4/40 (10.00%)  3/33 (9.09%) 
Dyspnoea * 1  1/6 (16.67%)  2/6 (33.33%)  2/3 (66.67%)  4/10 (40.00%)  4/40 (10.00%)  1/33 (3.03%) 
Rhinorrhoea * 1  1/6 (16.67%)  1/6 (16.67%)  0/3 (0.00%)  2/10 (20.00%)  2/40 (5.00%)  6/33 (18.18%) 
Nasal dryness * 1  0/6 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  4/40 (10.00%)  1/33 (3.03%) 
Oropharyngeal pain * 1  1/6 (16.67%)  0/6 (0.00%)  0/3 (0.00%)  1/10 (10.00%)  1/40 (2.50%)  2/33 (6.06%) 
Nasal congestion * 1  1/6 (16.67%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  2/40 (5.00%)  1/33 (3.03%) 
Dysphonia * 1  0/6 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  2/40 (5.00%)  1/33 (3.03%) 
Nasal inflammation * 1  1/6 (16.67%)  1/6 (16.67%)  0/3 (0.00%)  0/10 (0.00%)  0/40 (0.00%)  0/33 (0.00%) 
Pleuritic pain * 1  0/6 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/10 (0.00%)  1/40 (2.50%)  0/33 (0.00%) 
Increased bronchial secretion * 1  0/6 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/10 (0.00%)  0/40 (0.00%)  0/33 (0.00%) 
Lung disorder * 1  0/6 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/10 (10.00%)  0/40 (0.00%)  0/33 (0.00%) 
Nasal discomfort * 1  0/6 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/10 (0.00%)  0/40 (0.00%)  0/33 (0.00%) 
Rhinitis allergic * 1  0/6 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/10 (10.00%)  0/40 (0.00%)  0/33 (0.00%) 
Suffocation feeling * 1  0/6 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/10 (0.00%)  0/40 (0.00%)  0/33 (0.00%) 
Skin and subcutaneous tissue disorders             
Alopecia * 1  4/6 (66.67%)  4/6 (66.67%)  0/3 (0.00%)  4/10 (40.00%)  20/40 (50.00%)  12/33 (36.36%) 
Rash * 1  1/6 (16.67%)  1/6 (16.67%)  0/3 (0.00%)  1/10 (10.00%)  8/40 (20.00%)  11/33 (33.33%) 
Nail disorder * 1  1/6 (16.67%)  1/6 (16.67%)  0/3 (0.00%)  0/10 (0.00%)  8/40 (20.00%)  4/33 (12.12%) 
Palmar-plantar erythrodysaesthesia syndrome * 1  0/6 (0.00%)  2/6 (33.33%)  0/3 (0.00%)  0/10 (0.00%)  9/40 (22.50%)  3/33 (9.09%) 
Nail dystrophy * 1  0/6 (0.00%)  2/6 (33.33%)  0/3 (0.00%)  1/10 (10.00%)  5/40 (12.50%)  1/33 (3.03%) 
Dry skin * 1  2/6 (33.33%)  0/6 (0.00%)  0/3 (0.00%)  2/10 (20.00%)  1/40 (2.50%)  2/33 (6.06%) 
Erythema * 1  0/6 (0.00%)  2/6 (33.33%)  0/3 (0.00%)  0/10 (0.00%)  2/40 (5.00%)  2/33 (6.06%) 
Eczema * 1  0/6 (0.00%)  2/6 (33.33%)  0/3 (0.00%)  0/10 (0.00%)  1/40 (2.50%)  2/33 (6.06%) 
Pruritus * 1  0/6 (0.00%)  2/6 (33.33%)  0/3 (0.00%)  1/10 (10.00%)  1/40 (2.50%)  1/33 (3.03%) 
Rash generalised * 1  0/6 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  3/40 (7.50%)  1/33 (3.03%) 
Onychalgia * 1  0/6 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  2/40 (5.00%)  1/33 (3.03%) 
Onycholysis * 1  0/6 (0.00%)  0/6 (0.00%)  1/3 (33.33%)  0/10 (0.00%)  2/40 (5.00%)  0/33 (0.00%) 
Skin discolouration * 1  0/6 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  2/40 (5.00%)  1/33 (3.03%) 
Skin lesion * 1  0/6 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  1/10 (10.00%)  0/40 (0.00%)  1/33 (3.03%) 
Blister * 1  1/6 (16.67%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  0/40 (0.00%)  0/33 (0.00%) 
Cold sweat * 1  0/6 (0.00%)  0/6 (0.00%)  1/3 (33.33%)  0/10 (0.00%)  0/40 (0.00%)  0/33 (0.00%) 
Madarosis * 1  0/6 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/10 (0.00%)  0/40 (0.00%)  0/33 (0.00%) 
Papule * 1  0/6 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/10 (0.00%)  0/40 (0.00%)  0/33 (0.00%) 
Skin toxicity * 1  0/6 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/10 (0.00%)  0/40 (0.00%)  0/33 (0.00%) 
Toxic skin eruption * 1  0/6 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/10 (0.00%)  0/40 (0.00%)  0/33 (0.00%) 
Surgical and medical procedures             
Tooth repair * 1  1/6 (16.67%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  0/40 (0.00%)  0/33 (0.00%) 
Vascular disorders             
Hot flush * 1  0/6 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/10 (0.00%)  5/40 (12.50%)  0/33 (0.00%) 
Flushing * 1  1/6 (16.67%)  0/6 (0.00%)  0/3 (0.00%)  0/10 (0.00%)  1/40 (2.50%)  1/33 (3.03%) 
Haematoma * 1  0/6 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/10 (10.00%)  0/40 (0.00%)  0/33 (0.00%) 
Pallor * 1  0/6 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/10 (10.00%)  0/40 (0.00%)  0/33 (0.00%) 
Varicose vein * 1  0/6 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/10 (10.00%)  0/40 (0.00%)  0/33 (0.00%) 
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA (16.1)
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: Medical Communications
Organization: Hoffmann-La Roche
Phone: 800-821-8590
EMail: global-roche-genentech-trials@gene.com
Layout table for additonal information
Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT00934856     History of Changes
Other Study ID Numbers: BP22572
2009-010000-28 ( EudraCT Number )
First Submitted: July 6, 2009
First Posted: July 8, 2009
Results First Submitted: February 20, 2017
Results First Posted: April 6, 2017
Last Update Posted: April 6, 2017