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Clinical Trial Results:
An Open-label, Multi-center Phase I/II Study of the Safety And Tolerability of the Combination of Trastuzumab-MCC-DM1 (T-DM1) with Docetaxel, and Potentially Pertuzumab, for Treatment for Patients with Advanced Breast Cancer

Summary
EudraCT number	2009-010000-28
Trial protocol	GB FR
Global end of trial date	24 Oct 2013

Results information
Results version number	v1(current)
This version publication date	04 Mar 2016
First version publication date	04 Mar 2016
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

BP22572

ISRCTN number

US NCT number

NCT00934856

WHO universal trial number (UTN)

Sponsor organisation name

F. Hoffmann-La Roche AG

Sponsor organisation address

Grenzacherstrasse 124, Basel, Switzerland, CH-4070

Public contact

Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 61 6878333, global.trial_information@roche.com

Scientific contact

Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 61 6878333, global.trial_information@roche.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

24 Oct 2013

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

24 Oct 2013

Was the trial ended prematurely?

Main objective of the trial

This was an open-label, multicenter, non-randomized study of the safety and tolerability of combination of trastuzumab emtansine (T-DM1) plus docetaxel for the treatment of participants with metastatic breast cancer (MBC) and of T-DM1 plus docetaxel with/without pertuzumab for the treatment of participants with locally advanced breast cancer (LABC).

Protection of trial subjects

The study was conducted in accordance with the principles of the “Declaration of Helsinki” and Good Clinical Practice (GCP) according to the regulations and procedures described in the protocol. The investigator, or a person designated by the investigator obtained written informed consent from each participant participating in this study, after adequate explanation of the aims, methods, anticipated benefits, and potential hazards of the study. For participants not qualified or incapable of giving legal consent, written consent was obtained from the legally acceptable representative. Approval from the Independent Ethics Committees (IEC) /Institutional Review Board (IRB) was obtained before starting the study. The protocol amendments were prepared by the Sponsor and approved by the IEC/IRB.

Background therapy

Evidence for comparator

Actual start date of recruitment

21 Jul 2009

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Spain: 52

Country: Number of subjects enrolled

United Kingdom: 12

Country: Number of subjects enrolled

France: 21

Country: Number of subjects enrolled

United States: 13

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

Overall 152 participants were screened, of which 98 participants were enrolled (25 participants with MBC and 73 participants with LABC) and included in the study.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

MBC: T-DM1 2.4 mg/kg + Doc 75 mg/m^2 (over 2 days)

Arm description

Participants received docetaxel (Doc) 75 milligram per square meter (mg/m^2) administered intravenously on Day 1 and T-DM1 2.4 milligrams per kilogram (mg/kg) administered intravenously on Day 2 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.

Arm type

Experimental

Investigational medicinal product name

Trastuzumab emtansine

Investigational medicinal product code

Other name

T-DM1

Pharmaceutical forms

Powder for concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

T-DM1 was administered intravenously on Day 1 or Day 2 of each 3-week cycle.

Investigational medicinal product name

Docetaxel

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Docetaxel was administered on Day 1 of each 3-week cycle.

MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (over 2 days)

Arm description

Participants received docetaxel 60 mg/m^2 administered intravenously on Day 1 and T-DM1 2.4 mg/kg administered intravenously on Day 2 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.

Arm type

Experimental

Investigational medicinal product name

Trastuzumab emtansine

Investigational medicinal product code

Other name

T-DM1

Pharmaceutical forms

Powder for concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

T-DM1 was administered intravenously on Day 1 or Day 2 of each 3-week cycle.

Investigational medicinal product name

Docetaxel

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Docetaxel was administered on Day 1 of each 3-week cycle.

MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (same day)

Arm description

Participants received docetaxel 60 mg/m^2 administered intravenously and T-DM1 2.4 mg/kg administered intravenously 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.

Arm type

Experimental

Investigational medicinal product name

Trastuzumab emtansine

Investigational medicinal product code

Other name

T-DM1

Pharmaceutical forms

Powder for concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

T-DM1 was administered intravenously on Day 1 or Day 2 of each 3-week cycle.

Investigational medicinal product name

Docetaxel

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Docetaxel was administered on Day 1 of each 3-week cycle.

MBC: T-DM1 3.6 mg/kg + Doc 60 mg/m^2 (same day)

Arm description

Participants received docetaxel 60 mg/m^2 administered intravenously and T-DM1 3.6 mg/kg administered intravenously 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.

Arm type

Experimental

Investigational medicinal product name

Trastuzumab emtansine

Investigational medicinal product code

Other name

T-DM1

Pharmaceutical forms

Powder for concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

T-DM1 was administered intravenously on Day 1 or Day 2 of each 3-week cycle.

Investigational medicinal product name

Docetaxel

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Docetaxel was administered on Day 1 of each 3-week cycle.

LABC: T-DM1 + Doc (Doublet Regimen)

Arm description

Participants received T-DM1 3.6 mg/kg administered intravenously and docetaxel 60/75/100 mg/m^2 administered intravenously 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.

Arm type

Experimental

Investigational medicinal product name

Trastuzumab emtansine

Investigational medicinal product code

Other name

T-DM1

Pharmaceutical forms

Powder for concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

T-DM1 was administered intravenously on Day 1 or Day 2 of each 3-week cycle.

Investigational medicinal product name

Docetaxel

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Docetaxel was administered on Day 1 of each 3-week cycle.

LABC: T-DM1 + Doc + Pertuzumab (Triplet Regimen)

Arm description

Participants received T-DM1 3.6 mg/kg administered intravenously, docetaxel 60/75 mg/m^2 administered intravenously, and pertuzumab 840 mg (for Cycle 1) or 420 mg (for remaining cycles) 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.

Arm type

Experimental

Investigational medicinal product name

Trastuzumab emtansine

Investigational medicinal product code

Other name

T-DM1

Pharmaceutical forms

Powder for concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

T-DM1 was administered intravenously on Day 1 or Day 2 of each 3-week cycle.

Investigational medicinal product name

Docetaxel

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Docetaxel was administered on Day 1 of each 3-week cycle.

Investigational medicinal product name

Pertuzumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Pertuzumab at a loading dose of 840 mg intravenous on Day 1, Cycle 1, followed by 420 mg of each 3-week cycle.

Number of subjects in period 1	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)
Started	6	6	3	10	40	33
Completed	1	1	0	3	36	25
Not completed	5	5	3	7	4	8
Physician decision	-	-	1	-	-	-
Subject Withdrawal	-	-	-	1	-	1
Non-compliance with drug	-	-	-	-	-	1
Adverse event	1	1	-	2	4	6
Progressive disease	4	4	2	4	-	-

Baseline characteristics

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Reporting group title

MBC: T-DM1 2.4 mg/kg + Doc 75 mg/m^2 (over 2 days)

Reporting group description

Reporting group title

MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (over 2 days)

Reporting group description

Reporting group title

MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (same day)

Reporting group description

Reporting group title

MBC: T-DM1 3.6 mg/kg + Doc 60 mg/m^2 (same day)

Reporting group description

Reporting group title

LABC: T-DM1 + Doc (Doublet Regimen)

Reporting group description

Reporting group title

LABC: T-DM1 + Doc + Pertuzumab (Triplet Regimen)

Reporting group description

Reporting group values	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
Number of subjects	6	6	3	10	40	33	98
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	43 ± 7.16	50.7 ± 4.84	57 ± 12.12	48 ± 9.39	48.6 ± 9.73	54.2 ± 11.43	-
Gender categorical
Units: Subjects
Female	6	6	3	10	40	33	98
Male	0	0	0	0	0	0	0

End points

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Reporting group title

MBC: T-DM1 2.4 mg/kg + Doc 75 mg/m^2 (over 2 days)

Reporting group description

Reporting group title

MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (over 2 days)

Reporting group description

Reporting group title

MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (same day)

Reporting group description

Reporting group title

MBC: T-DM1 3.6 mg/kg + Doc 60 mg/m^2 (same day)

Reporting group description

Reporting group title

LABC: T-DM1 + Doc (Doublet Regimen)

Reporting group description

Reporting group title

LABC: T-DM1 + Doc + Pertuzumab (Triplet Regimen)

Reporting group description

Subject analysis set title

LABC: T-DM1 3.6 mg/kg + Doc 100 mg/m^2

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants received T-DM1 3.6 mg/kg administered intravenously and docetaxel 100 mg/m^2 administered intravenously 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.

Subject analysis set title

LABC: T-DM1 3.6 mg/kg + Doc 75 mg/m^2 +Pertuzumab 420 mg

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants received T-DM1 3.6 mg/kg administered intravenously, docetaxel 75 mg/m^2 administered intravenously, and pertuzumab 420 mg 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.

Subject analysis set title

Overall MBC Participants

Subject analysis set type

Full analysis

Subject analysis set description

This analysis set included participants enrolled in the MBC part of the study.

Subject analysis set title

Overall MBC and LABC Participants

Subject analysis set type

Full analysis

Subject analysis set description

This analysis set included all participants enrolled in the study.

Subject analysis set title

MBC: T-DM1 2.4 mg/kg

Subject analysis set type

Sub-group analysis

Subject analysis set description

This analysis set included all MBC participants who received T-DM1 2.4 mg/kg administered intravenously.

Subject analysis set title

MBC: T-DM1 3.6 mg/kg

Subject analysis set type

Sub-group analysis

Subject analysis set description

This analysis set included all MBC participants who received T-DM1 3.6 mg/kg administered intravenously.

Subject analysis set title

LABC: T-DM1 3.6 mg/kg

Subject analysis set type

Sub-group analysis

Subject analysis set description

This analysis set included all LABC participants who received T-DM1 3.6 mg/kg administered intravenously.

Subject analysis set title

MBC: Docetaxel 75 mg/m^2

Subject analysis set type

Sub-group analysis

Subject analysis set description

This analysis set included all MBC participants who received docetaxel 75 mg/m^2 administered intravenously.

Subject analysis set title

MBC: Docetaxel 60 mg/m^2

Subject analysis set type

Sub-group analysis

Subject analysis set description

This analysis set included all MBC participants who received docetaxel 60 mg/m^2 administered intravenously.

Subject analysis set title

LABC: Docetaxel 60 mg/m^2

Subject analysis set type

Sub-group analysis

Subject analysis set description

This analysis set included all LABC participants who received docetaxel 60 mg/m^2 administered intravenously.

Subject analysis set title

LABC: Docetaxel 75 mg/m^2

Subject analysis set type

Sub-group analysis

Subject analysis set description

This analysis set included all LABC participants who received docetaxel 75 mg/m^2 administered intravenously.

Subject analysis set title

LABC: Docetaxel 100 mg/m^2

Subject analysis set type

Sub-group analysis

Subject analysis set description

This analysis set included all LABC participants who received docetaxel 100 mg/m^2 administered intravenously.

Primary: Percentage of Participants with Adverse Events (AEs) or Serious AEs (SAEs) – MBC and LABC Population

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End point title

Percentage of Participants with Adverse Events (AEs) or Serious AEs (SAEs) – MBC and LABC Population ^[1]

End point description

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 inpatient 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. Analysis population (AP): All participants who received at least one dose of study medication.

End point type

Primary

End point timeframe

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)

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: The study was of an explorative nature; therefore only descriptive and exploratory statistical methods were applied, and no statistical hypothesis testing was carried out.

End point values	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)
Number of subjects analysed	6	6	3	10	40	33
Units: percentage of participants
number (not applicable)
AEs	100	100	100	100	100	100
SAEs	33.3	33.3	66.7	40	22.5	27.3

No statistical analyses for this end point

Primary: Number of Participants with Dose Limiting Toxicity (DLT) - MBC and LABC Feasibility Population

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End point title

Number of Participants with Dose Limiting Toxicity (DLT) - MBC and LABC Feasibility Population ^[2] ^[3]

End point description

DLTs included (as per 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 at Day 21; Any non-hematological toxicity of Grade >/= 3 except for alopecia, fever, and chills, not improving to baseline or Grade </=1 at 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. AP: All participants who received at least one dose of study medication.

End point type

Primary

End point timeframe

Up to 21 days

Notes
[2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: The study was of an explorative nature; therefore only descriptive and exploratory statistical methods were applied, and no statistical hypothesis testing was carried out.
[3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Dose limiting toxicities were reported only in the MBC and LABC feasibility part of the study.

End point values	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 3.6 mg/kg + Doc 100 mg/m^2	LABC: T-DM1 3.6 mg/kg + Doc 75 mg/m^2 +Pertuzumab 420 mg
Number of subjects analysed	6	6	3	6	12	9
Units: participants
number (not applicable)	2	1	0	1	2	2

No statistical analyses for this end point

Secondary: Percentage of Participants with Progression-Free Survival (PFS) – MBC Population

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End point title

Percentage of Participants with Progression-Free Survival (PFS) – MBC Population

End point 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 (V) 1.0. 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 was calculated as the (number of participants with PFS) divided by (total number of participants), and then multiplied by 100. AP: All participants who received at least one dose of study medication.

End point type

Secondary

End point timeframe

Baseline until disease progression or death (up to 33.5 months)

End point values	Overall MBC Participants
Number of subjects analysed	25
Units: percentage of participants
number (not applicable)	60

No statistical analyses for this end point

Secondary: PFS – MBC Population

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End point title

PFS – MBC Population

End point 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 V 1.0. 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. Data for participants without PD or death was censored at the time of the last response assessment. AP: All participants who received at least one dose of study medication. A total of 9 participants were censored for PFS analysis.

End point type

Secondary

End point timeframe

Baseline until disease progression or death (up to 33.5 months)

End point values	Overall MBC Participants
Number of subjects analysed	25
Units: months
median (full range (min-max))	13.8 (1.6 to 33.5)

No statistical analyses for this end point

Secondary: Percentage of Participants with a Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR) - MBC Population

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End point title

Percentage of Participants with a Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR) - MBC Population

End point description

BOR was defined as CR or PR recorded from baseline until disease progression/recurrence according to RECIST V 1.0 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 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. AP: All participants who received at least one dose of study medication.

End point type

Secondary

End point timeframe

Baseline until PD or recurrence (up to 33.5 months)

End point values	Overall MBC Participants
Number of subjects analysed	25
Units: percentage of participants
number (confidence interval 95%)	80 (59.3 to 93.2)

No statistical analyses for this end point

Secondary: Percentage of Participants with Treatment Failure - MBC Population

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End point title

Percentage of Participants with Treatment Failure - MBC Population

End point 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 non-protocol 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. AP: All participants who received at least one dose of study medication.

End point type

Secondary

End point timeframe

Baseline until end of treatment (up to 39.8 months)

End point values	Overall MBC Participants
Number of subjects analysed	25
Units: percentage of participants
number (not applicable)	64

No statistical analyses for this end point

Secondary: Time to Treatment Failure (TTF) - MBC Population

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End point title

Time to Treatment Failure (TTF) - MBC Population

End point 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. AP: All participants who received at least one dose of study medication. A total of 9 participants were censored for analysis.

End point type

Secondary

End point timeframe

Baseline until end of treatment (up to 39.8 months)

End point values	Overall MBC Participants
Number of subjects analysed	25
Units: months
median (full range (min-max))	13.8 (1.4 to 39.8)

No statistical analyses for this end point

Secondary: Percentage of Participants with CR or PR or Stable Disease (SD) for at Least 6 months [Clinical Benefit Rate (CBR)] - MBC Population

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End point title

Percentage of Participants with CR or PR or Stable Disease (SD) for at Least 6 months [Clinical Benefit Rate (CBR)] - MBC Population

End point description

CBR was defined as % of participants experiencing SD of at least 6 months from the start of treatment plus CR or PR according to the RECIST V 1.0 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. % 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. AP: All participants who received at least one dose of study medication.

End point type

Secondary

End point timeframe

Baseline until PD, recurrence or death (up to 33.5 months)

End point values	Overall MBC Participants
Number of subjects analysed	25
Units: percentage of participants
number (confidence interval 95%)	92 (74 to 99)

No statistical analyses for this end point

Secondary: Duration of Response – MBC Population

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End point title

Duration of Response – MBC Population

End point description

Duration of response was calculated for participants whose best overall response was CR or PR based on the RECIST V 1.0 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 occured 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. AP: All participants who received at least one dose of study medication. A total of 7 participants were censored for analysis.

End point type

Secondary

End point timeframe

Baseline until PD, recurrence or death (up to 32.7 months)

End point values	Overall MBC Participants
Number of subjects analysed	25
Units: months
median (full range (min-max))	12.4 (3.9 to 32.7)

No statistical analyses for this end point

Secondary: Percentage of Participants with Pathological CR (pCR) – LABC Population

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End point title

Percentage of Participants with Pathological CR (pCR) – LABC Population ^[4]

End point description

The pCR rate was defined as the rate of absence of invasive neoplastic cells at microscopic examination of the tumor remnants and lymph nodes after surgery following primary systemic therapy. AP: All participants who received at least one dose of study medication.

End point type

Secondary

End point timeframe

Within 6 weeks of post-surgery (up to approximately 3 years)

Notes
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: pCR was reported only in the LABC part of the study.

End point values	LABC: T-DM1 + Doc (Doublet Regimen)	LABC: T-DM1 + Doc + Pertuzumab (Triplet Regimen)
Number of subjects analysed	40	33
Units: percentage of participants
number (confidence interval 95%)	60 (43.3 to 75.1)	60.6 (42.1 to 77.1)

No statistical analyses for this end point

Secondary: Percentage of Participants with a BOR of CR or PR – LABC Population

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End point title

Percentage of Participants with a BOR of CR or PR – LABC Population ^[5]

End point description

BOR was defined as CR or PR recorded from baseline until disease progression/recurrence according to RECIST V 1.0 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. AP: All participants who received at least one dose of study medication.

End point type

Secondary

End point timeframe

Baseline until PD, recurrence or death (up to approximately 3 years)

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: BOR of CR or PR was reported only in the LABC part of the study.

End point values	LABC: T-DM1 + Doc (Doublet Regimen)	LABC: T-DM1 + Doc + Pertuzumab (Triplet Regimen)
Number of subjects analysed	40	33
Units: percentage of participants
number (confidence interval 95%)	70 (53.5 to 83.4)	51.5 (33.5 to 69.2)

No statistical analyses for this end point

Secondary: Percentage of Participants With Anti-Therapeutic Antibody Response at Baseline and Post-Trazustumab Emtansine Dosing - MBC and LABC Population

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End point title

Percentage of Participants With Anti-Therapeutic Antibody Response at Baseline and Post-Trazustumab Emtansine Dosing - MBC and LABC Population

End point description

Percentage of participants with Human Anti-human Antibody response was reported. AP: All participants who received at least one dose of study medication.

End point type

Secondary

End point timeframe

Baseline and post-dose (up to approximately 3 years)

End point values	Overall MBC and LABC Participants
Number of subjects analysed	98
Units: percentage of participants
number (not applicable)
Baseline, positive and post-dose, positive	2
Baseline, positive and post-dose, negative	1
Baseline, positive and post-dose, missing	0
Baseline, negative and post-dose, positive	1
Baseline, negative and post-dose, negative	69
Baseline, negative and post-dose, missing	17
Baseline, missing and post-dose, positive	0
Baseline, missing and post-dose, negative	7
Baseline, missing and post-dose, missing	2

No statistical analyses for this end point

Secondary: Maximum Observed Concentration (Cmax) of Serum Trastuzumab Emtansine – MBC and LABC Population

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End point title

Maximum Observed Concentration (Cmax) of Serum Trastuzumab Emtansine – MBC and LABC Population

End point description

Number of participants analyzed = participants evaluable for this outcome and n= participants evaluable for specified cycle. PK analysis population: Pharmacokinetic-evaluable participants were defined as participants who received at least one dose of T-DM1 with at least one post-dose concentration data point.

End point type

Secondary

End point timeframe

Cycle 1 (pre-dose, 15 minutes and 4 hours after end of infusion of T-DM1 on Day 2, Day 3, and Day 8); Cycle 2 (pre-dose, 15 minutes and 4 hours after end of infusion of T-DM1 on Day 1, Day 8)

End point values	MBC: T-DM1 2.4 mg/kg	MBC: T-DM1 3.6 mg/kg	LABC: T-DM1 3.6 mg/kg
Number of subjects analysed	15	10	73
Units: micrograms per milliliter (mcg/mL)
arithmetic mean (standard deviation)
Cycle 1 (n= 15, 10, 73)	78.6 ± 16.6	76.2 ± 36.4	85.7 ± 15.3
Cycle 2 (n= 14, 9, 67)	78.7 ± 16.7	93.7 ± 27.6	80.2 ± 18.4

No statistical analyses for this end point

Secondary: Apparent Terminal Half-Life (t1/2) of Serum Trastuzumab Emtansine – MBC and LABC Population

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End point title

Apparent Terminal Half-Life (t1/2) of Serum Trastuzumab Emtansine – MBC and LABC Population

End point description

t1/2 was calculated as per ‘natural logarithm of 2 [ln(2)]/λz’ formula, and λz was the terminal rate constant. λz reflects the speed of drug elimination invivo (within the living), and was obtained from linear regression of the log-transformed terminal part of the concentration-time curve. Here, Number of participants analyzed = participants evaluable for this outcome and n= participants evaluable for specified cycle. PK analysis population: Pharmacokinetic-evaluable participants were defined as participants who received at least one dose of T-DM1 with at least one post-dose concentration data point.

End point type

Secondary

End point timeframe

Cycle 1 (pre-dose, 15 minutes and 4 hours after end of infusion of T-DM1 on Day 2, Day 3, and Day 8); Cycle 2 (pre-dose, 15 minutes and 4 hours after end of infusion of T-DM1 on Day 1 and Day 8)

End point values	MBC: T-DM1 2.4 mg/kg	MBC: T-DM1 3.6 mg/kg	LABC: T-DM1 3.6 mg/kg
Number of subjects analysed	15	8	72
Units: days
arithmetic mean (standard deviation)
Cycle 1 (n= 15, 7, 72)	2.79 ± 0.637	3.45 ± 0.779	3.46 ± 0.558
Cycle 2 (n= 14, 8, 63)	3.14 ± 0.574	3.85 ± 0.568	3.62 ± 0.516

No statistical analyses for this end point

Secondary: AUCinf of Serum Trastuzumab Emtansine – MBC and LABC Population

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End point title

AUCinf of Serum Trastuzumab Emtansine – MBC and LABC Population

End point description

AUCinf is defined as the area under the serum concentration-time curve (AUC) from time 0 extrapolated to infinity. Here, Number of participants analyzed = participants evaluable for this outcome and n= participants evaluable for specified cycle. PK analysis population: Pharmacokinetic-evaluable participants were defined as participants who received at least one dose of T-DM1 with at least one post-dose concentration data point.

End point type

Secondary

End point timeframe

Cycle 1 (pre-dose, 15 minutes and 4 hours after end of infusion of T-DM1 on Day 2, Day 3, and Day 8); Cycle 2 (pre-dose, 15 minutes and 4 hours after end of infusion of T-DM1 on Day 1 and Day 8)

End point values	MBC: T-DM1 2.4 mg/kg	MBC: T-DM1 3.6 mg/kg	LABC: T-DM1 3.6 mg/kg
Number of subjects analysed	15	8	72
Units: day*mcg/mL
arithmetic mean (standard deviation)
Cycle 1 (n= 15, 7, 72)	396 ± 124	447 ± 144	442 ± 90.7
Cycle 2 (n= 14, 8, 63)	471 ± 94.5	556 ± 223	488 ± 123

No statistical analyses for this end point

Secondary: Clearence (CL) of Serum Trastuzumab Emtansine – MBC and LABC Population

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End point title

Clearence (CL) of Serum Trastuzumab Emtansine – MBC and LABC Population

End point description

CL was estimated as dose divided by AUCinf. Here, Number of participants analyzed = participants evaluable for this outcome and n= participants evaluable for specified cycle. PK analysis population: Pharmacokinetic-evaluable participants were defined as participants who received at least one dose of T-DM1 with at least one post-dose concentration data point.

End point type

Secondary

End point timeframe

Cycle 1 (pre-dose, 15 minutes and 4 hours after end of infusion of T-DM1 on Day 2, Day 3, and Day 8); Cycle 2 (pre-dose, 15 minutes and 4 hours after end of infusion of T-DM1 on Day 1 and Day 8)

End point values	MBC: T-DM1 2.4 mg/kg	MBC: T-DM1 3.6 mg/kg	LABC: T-DM1 3.6 mg/kg
Number of subjects analysed	15	8	72
Units: milliliter/day/kilogram (mL/day/kg)
arithmetic mean (standard deviation)
Cycle 1 (n= 15, 7, 72)	8.94 ± 12	8.87 ± 2.96	8.48 ± 1.86
Cycle 2 (n= 14, 8, 63)	5.21 ± 1.27	7.16 ± 2.95	7.68 ± 2.73

No statistical analyses for this end point

Secondary: Vss of Serum Trastuzumab Emtansine – MBC and LABC Population

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End point title

Vss of Serum Trastuzumab Emtansine – MBC and LABC Population

End point description

Vss is defined as the volume of distribution at steady state. Here, Number of participants analyzed = participants evaluable for this outcome and n= participants evaluable for specified cycle. PK analysis population: Pharmacokinetic-evaluable participants were defined as participants who received at least one dose of T-DM1 with at least one post-dose concentration data point.

End point type

Secondary

End point timeframe

Cycle 1 (pre-dose, 15 minutes and 4 hours after end of infusion of T-DM1 on Day 2, Day 3, and Day 8); Cycle 2 (pre-dose, 15 minutes and 4 hours after end of infusion of T-DM1 on Day 1, Day 8)

End point values	MBC: T-DM1 2.4 mg/kg	MBC: T-DM1 3.6 mg/kg	LABC: T-DM1 3.6 mg/kg
Number of subjects analysed	15	8	72
Units: mL/kg
arithmetic mean (standard deviation)
Cycle 1 (n= 15, 7, 72)	22.1 ± 6.74	33.2 ± 9.13	33.2 ± 8.36
Cycle 2 (n= 14, 8, 63)	17.7 ± 4.73	31.4 ± 16.9	28.8 ± 9.32

No statistical analyses for this end point

Secondary: Cmax of Total Serum Trastuzumab – MBC and LABC Population

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End point title

Cmax of Total Serum Trastuzumab – MBC and LABC Population

End point description

Here, Number of participants analyzed = participants evaluable for this outcome and n= participants evaluable for specified cycle. PK analysis population: Pharmacokinetic-evaluable participants were defined as participants who received at least one dose of T-DM1 with at least one post-dose concentration data point.

End point type

Secondary

End point timeframe

Cycle 1 (pre-dose, 15 minutes and 4 hours after end of infusion of T-DM1 on Day 2, Day 3, and Day 8); Cycle 2 (pre-dose, 15 minutes and 4 hours after end of infusion of T-DM1 on Day 1 and Day 8)

End point values	MBC: T-DM1 2.4 mg/kg	MBC: T-DM1 3.6 mg/kg	LABC: T-DM1 3.6 mg/kg
Number of subjects analysed	15	10	73
Units: mcg/mL
arithmetic mean (standard deviation)
Cycle 1 (n= 15, 10, 73)	88.7 ± 22.6	89.2 ± 47.4	120 ± 46.6
Cycle 2 (n= 14, 9, 67)	85.8 ± 17.5	97.7 ± 29.4	113 ± 43.8

No statistical analyses for this end point

Secondary: T1/2 of Total Serum Trastuzumab – MBC and LABC Population

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End point title

T1/2 of Total Serum Trastuzumab – MBC and LABC Population

End point description

End point type

Secondary

End point timeframe

Cycle 1 (pre-dose, 15 minutes and 4 hours after end of infusion of T-DM1 on Day 2, Day 3, and Day 8); Cycle 2 (pre-dose, 15 minutes and 4 hours after end of infusion of T-DM1 on Day 1 and Day 8)

End point values	MBC: T-DM1 2.4 mg/kg	MBC: T-DM1 3.6 mg/kg	LABC: T-DM1 3.6 mg/kg
Number of subjects analysed	15	8	73
Units: days
arithmetic mean (standard deviation)
Cycle 1 (n= 15, 7, 73)	6.44 ± 2.6	6.38 ± 1.41	8.12 ± 4.2
Cycle 2 (n= 13, 8, 62)	6.67 ± 1.92	7.83 ± 1.68	9.91 ± 5.01

No statistical analyses for this end point

Secondary: AUCinf of Total Serum Trastuzumab – MBC and LABC Population

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End point title

AUCinf of Total Serum Trastuzumab – MBC and LABC Population

End point description

AUCinf is defined as the AUC from time 0 extrapolated to infinity. Here, Number of participants analyzed = participants evaluable for this outcome and n= participants evaluable for specified cycle. PK analysis population: Pharmacokinetic-evaluable participants were defined as participants who received at least one dose of T-DM1 with at least one post-dose concentration data point.

End point type

Secondary

End point timeframe

Cycle 1 (pre-dose, 15 minutes and 4 hours after end of infusion of T-DM1 on Day 2, Day 3, and Day 8); Cycle 2 (pre-dose, 15 minutes and 4 hours after end of infusion of T-DM1 on Day 1 and Day 8)

End point values	MBC: T-DM1 2.4 mg/kg	MBC: T-DM1 3.6 mg/kg	LABC: T-DM1 3.6 mg/kg
Number of subjects analysed	15	8	73
Units: day*mcg/mL
arithmetic mean (standard deviation)
Cycle 1 (n= 15, 7, 73)	785 ± 429	707 ± 201	1210 ± 856
Cycle 2 (n= 13, 8, 62)	809 ± 308	1040 ± 359	1570 ± 1180

No statistical analyses for this end point

Secondary: CL of Total Serum Trastuzumab – MBC and LABC Population

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End point title

CL of Total Serum Trastuzumab – MBC and LABC Population

End point description

End point type

Secondary

End point timeframe

Cycle 1 (pre-dose, 15 minutes and 4 hours after end of infusion of T-DM1 on Day 2, Day 3, and Day 8); Cycle 2 (pre-dose, 15 minutes and 4 hours after end of infusion of T-DM1 on Day 1 and Day 8)

End point values	MBC: T-DM1 2.4 mg/kg	MBC: T-DM1 3.6 mg/kg	LABC: T-DM1 3.6 mg/kg
Number of subjects analysed	15	8	73
Units: mL/day/kg
arithmetic mean (standard deviation)
Cycle 1 (n= 15, 7, 73)	6.78 ± 13.3	5.45 ± 1.46	4.22 ± 2.13
Cycle 2 (n= 13, 8, 62)	3.32 ± 1.53	3.71 ± 1.23	3.38 ± 2.11

No statistical analyses for this end point

Secondary: Vss of Total Serum Trastuzumab – MBC and LABC Population

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End point title

Vss of Total Serum Trastuzumab – MBC and LABC Population

End point description

End point type

Secondary

End point timeframe

Cycle 1 (pre-dose, 15 minutes and 4 hours after end of infusion of T-DM1 on Day 2, Day 3, and Day 8); Cycle 2 (pre-dose, 15 minutes and 4 hours after end of infusion of T-DM1 on Day 1 and Day 8)

End point values	MBC: T-DM1 2.4 mg/kg	MBC: T-DM1 3.6 mg/kg	LABC: T-DM1 3.6 mg/kg
Number of subjects analysed	15	8	73
Units: mL/kg
arithmetic mean (standard deviation)
Cycle 1 (n= 15, 7, 73)	27 ± 7.16	41.3 ± 9.24	36.5 ± 12.7
Cycle 2 (n= 13, 8, 62)	24.6 ± 5.05	36.4 ± 11.3	35.2 ± 12

No statistical analyses for this end point

Secondary: Cmax of Plasma DM1 – MBC and LABC Population

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End point title

Cmax of Plasma DM1 – MBC and LABC Population

End point description

End point type

Secondary

End point timeframe

Cycle 1 (pre-dose, 15 minutes and 4 hours after end of infusion of T-DM1 on Day 2, Day 3, and Day 8); Cycle 2 (pre-dose, 15 minutes and 4 hours after end of infusion of T-DM1 on Day 1 and Day 8)

End point values	MBC: T-DM1 2.4 mg/kg	MBC: T-DM1 3.6 mg/kg	LABC: T-DM1 3.6 mg/kg
Number of subjects analysed	13	9	73
Units: nanograms per milliliter (ng/mL)
arithmetic mean (standard deviation)
Cycle 1 (n= 13, 9, 73)	3.55 ± 1.6	3.42 ± 0.944	4.51 ± 1.38
Cycle 2 (n= 13, 9, 67)	3.34 ± 0.815	3.9 ± 1.19	4.65 ± 1.57

No statistical analyses for this end point

Secondary: T1/2 of Plasma DM1 – MBC and LABC Population

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End point title

T1/2 of Plasma DM1 – MBC and LABC Population

End point description

End point type

Secondary

End point timeframe

Cycle 1 (pre-dose, 15 minutes and 4 hours after end of infusion of T-DM1 on Day 2, Day 3, and Day 8); Cycle 2 (pre-dose, 15 minutes and 4 hours after end of infusion of T-DM1 on Day 1 and Day 8)

End point values	MBC: T-DM1 2.4 mg/kg	MBC: T-DM1 3.6 mg/kg	LABC: T-DM1 3.6 mg/kg
Number of subjects analysed	12	7	68
Units: days
arithmetic mean (standard deviation)
Cycle 1 (n= 12, 7, 68)	1.12 ± 0.702	1.2 ± 0.985	1.87 ± 1.63
Cycle 2 (n= 2, 1, 31)	3.75 ± 0.912	2.91 ± 99999	3.32 ± 0.7

No statistical analyses for this end point

Secondary: AUCinf of Plasma DM1 – MBC and LABC Population

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End point title

AUCinf of Plasma DM1 – MBC and LABC Population

End point description

AUCinf is the area under the serum concentration-time curve from time 0 extrapolated to infinity. Here, Number of participants analyzed = participants evaluable for this outcome and n= participants evaluable for specified cycle. PK analysis population: Pharmacokinetic-evaluable participants were defined as participants who received at least one dose of T-DM1 with at least one post-dose concentration data point. ‘99999’ signifies that SD was not calculable due to only 1 participant available for PK analysis.

End point type

Secondary

End point timeframe

Cycle 1 (pre-dose, 15 minutes and 4 hours after end of infusion of T-DM1 on Day 2, Day 3, and Day 8); Cycle 2 (pre-dose, 15 minutes and 4 hours after end of infusion of T-DM1 on Day 1 and Day 8)

End point values	MBC: T-DM1 2.4 mg/kg	MBC: T-DM1 3.6 mg/kg	LABC: T-DM1 3.6 mg/kg
Number of subjects analysed	12	7	68
Units: day*ng/mL
arithmetic mean (standard deviation)
Cycle 1 (n= 12, 7, 68)	5.72 ± 5.16	5.01 ± 2.54	9.38 ± 9.33
Cycle 2 (n= 2, 1, 31)	17.8 ± 4.6	20 ± 99999	18.5 ± 4.28

No statistical analyses for this end point

Secondary: Cmax of Docetaxel – MBC and LABC Population

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End point title

Cmax of Docetaxel – MBC and LABC Population

End point description

Here, Number of participants analyzed = participants evaluable for this outcome and n= participants evaluable for specified cycle. PK analysis population: Pharmacokinetic-evaluable participants were defined as participants who received at least one dose of docetaxel with at least one post-dose concentration data point.

End point type

Secondary

End point timeframe

Day 1, Cycle 1, (pre-dose, at 15 and 30 minutes, 1, 2, 4, 8 and 23 hours after end of infusion), Day 1, Cycle 2 (pre-dose, at 30 minutes and 59 minutes after the start of infusion), and 15 and 30 minutes, 1, 2, 4, 8 and 23 hours after end of infusion

End point values	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
Number of subjects analysed	6	19	14	36	22
Units: ng/mL
arithmetic mean (standard deviation)
Cycle 1 (n= 6, 19, 14, 36, 22)	500 ± 216	1300 ± 829	1470 ± 551	1710 ± 426	2950 ± 1540
Cycle 2 (n= 6, 17, 12, 35, 19)	791 ± 637	1320 ± 826	1590 ± 441	1960 ± 552	2790 ± 979

No statistical analyses for this end point

Secondary: T1/2 of Docetaxel – MBC and LABC Population

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End point title

T1/2 of Docetaxel – MBC and LABC Population

End point description

t1/2 was calculated as per ‘natural logarithm of 2 [ln(2)]/λz’ formula, and λz was the terminal rate constant. λz reflects the speed of drug elimination invivo (within the living), and was obtained from linear regression of the log-transformed terminal part of the concentration-time curve. Here, Number of participants analyzed = participants evaluable for this outcome and n= participants evaluable for specified cycle. PK analysis population: Pharmacokinetic-evaluable participants were defined as participants who received at least one dose of docetaxel with at least one post-dose concentration data point.

End point type

Secondary

End point timeframe

End point values	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
Number of subjects analysed	6	19	14	36	22
Units: hours (hr)
arithmetic mean (standard deviation)
Cycle 1 (n= 6, 19, 14, 36, 22)	6.83 ± 4.22	5.17 ± 4.02	4.25 ± 5.61	8.29 ± 5.75	8.76 ± 3.82
Cycle 2 (n= 6, 17, 12, 35, 19)	7.7 ± 4.15	7.88 ± 6.18	5.9 ± 3.83	6.69 ± 5.55	7.24 ± 3.58

No statistical analyses for this end point

Secondary: AUCinf of Docetaxel – MBC and LABC Population

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End point title

AUCinf of Docetaxel – MBC and LABC Population

End point description

AUCinf is the AUC from time 0 extrapolated to infinity. Here, Number of participants analyzed = participants evaluable for this outcome and n= participants evaluable for specified cycle. PK analysis population: Pharmacokinetic-evaluable participants were defined as participants who received at least one dose of docetaxel with at least one post-dose concentration data point.

End point type

Secondary

End point timeframe

End point values	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
Number of subjects analysed	6	19	14	36	22
Units: hr*ng/mL
arithmetic mean (standard deviation)
Cycle 1 (n= 6, 19, 14, 36, 22)	1050 ± 475	1560 ± 874	1540 ± 421	2140 ± 669	4020 ± 2120
Cycle 2 (n= 6, 17, 12, 35, 19)	1700 ± 1190	1710 ± 875	3260 ± 5100	2420 ± 887	3840 ± 1930

No statistical analyses for this end point

Secondary: CL of Docetaxel – MBC and LABC Population

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End point title

CL of Docetaxel – MBC and LABC Population

End point description

CL was estimated as dose divided by AUCinf. Here, Number of participants analyzed = participants evaluable for this outcome and n= participants evaluable for specified cycle. PK analysis population: Pharmacokinetic-evaluable participants were defined as participants who received at least one dose of docetaxel with at least one post-dose concentration data point.

End point type

Secondary

End point timeframe

End point values	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
Number of subjects analysed	6	19	14	36	22
Units: L/hr/m^2
arithmetic mean (standard deviation)
Cycle 1 (n= 6, 19, 14, 36, 22)	82.2 ± 32.6	58.3 ± 40.9	42.8 ± 16.4	39.5 ± 16.8	30.5 ± 14.5
Cycle 2 (n= 6, 17, 12, 35, 19)	59 ± 29.9	51.2 ± 38.5	32.6 ± 13.1	33.6 ± 11.9	27.9 ± 9.13

No statistical analyses for this end point

Secondary: Vss of Docetaxel – MBC and LABC Population

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End point title

Vss of Docetaxel – MBC and LABC Population

End point description

Vss is defined as the volume of distribution at steady state. Here, Number of participants analyzed = participants evaluable for this outcome and n= participants evaluable for specified cycle. PK analysis population: Pharmacokinetic-evaluable participants were defined as participants who received at least one dose of docetaxel with at least one post-dose concentration data point.

End point type

Secondary

End point timeframe

Day 1, Cycle 1, (pre-dose, at 15 and 30 minutes, 1, 2, 4, 8 and 23 hours after end of infusion), Day 1, Cycle 2 (pre- dose, at 30 minutes and 59 minutes after the start of infusion), and 15 and 30 minutes, 1, 2, 4, 8 and 23 hours after end of infusion

End point values	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
Number of subjects analysed	6	19	14	36	22
Units: L/m^2
arithmetic mean (standard deviation)
Cycle 1 (n= 6, 19, 14, 36, 22)	530 ± 398	203 ± 275	75 ± 113	126 ± 86.7	116 ± 73.3
Cycle 2 (n= 6, 17, 12, 35, 19)	380 ± 257	253 ± 234	93.2 ± 64.7	79 ± 53.6	84.8 ± 39.1

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

16.1

Reporting group title

MBC: T-DM1 2.4 mg/kg + Doc 75 mg/m^2 (over 2 days)

Reporting group description

Participants received docetaxel 75 mg/m^2 administered intravenously on Day 1 and T-DM1 2.4 mg/kg administered intravenously on Day 2 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.

Reporting group title

MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (over 2 days)

Reporting group description

Participants received docetaxel 60 mg/m^2 administered intravenously on Day 1 and T-DM1 2.4 mg/kg administered intravenously on Day 2 of each 3-week cycle for a minimum of 6 cycles. After 6 cy,cles, 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

Reporting group title

MBC: T-DM1 2.4 mg/kg + Doc 60 mg/m^2 (same day)

Reporting group description

Reporting group title

MBC: T-DM1 3.6 mg/kg + Doc 60 mg/m^2 (same day)

Reporting group description

Reporting group title

LABC: T-DM1 + Doc (Doublet Regimen)

Reporting group description

Reporting group title

LABC: T-DM1 + Doc + Pertuzumab (Triplet Regimen)

Reporting group description

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)
Total subjects affected by serious adverse events
subjects affected / exposed	2 / 6 (33.33%)	2 / 6 (33.33%)	2 / 3 (66.67%)	4 / 10 (40.00%)	9 / 40 (22.50%)	9 / 33 (27.27%)
number of deaths (all causes)	0	0	0	0	2	0
number of deaths resulting from adverse events
Vascular disorders
Haematoma
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	0 / 40 (0.00%)	2 / 33 (6.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thrombosis in device
subjects affected / exposed	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 10 (0.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Device deployment issue
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fatigue
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	0 / 40 (0.00%)	1 / 33 (3.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mucosal inflammation
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	1 / 40 (2.50%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Uterine polyp
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	0 / 40 (0.00%)	1 / 33 (3.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pneumonitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	1 / 40 (2.50%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
Respiratory failure
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	1 / 40 (2.50%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
Psychiatric disorders
Anxiety
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 10 (0.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Confusional state
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	1 / 40 (2.50%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Tibia fracture
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Febrile neutropenia
subjects affected / exposed	1 / 6 (16.67%)	1 / 6 (16.67%)	1 / 3 (33.33%)	0 / 10 (0.00%)	1 / 40 (2.50%)	1 / 33 (3.03%)
occurrences causally related to treatment / all	1 / 1	1 / 1	1 / 1	0 / 0	2 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 10 (0.00%)	1 / 40 (2.50%)	2 / 33 (6.06%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	1 / 1	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	1 / 40 (2.50%)	1 / 33 (3.03%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	2 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	0 / 40 (0.00%)	1 / 33 (3.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Hepatocellular injury
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	0 / 40 (0.00%)	1 / 33 (3.03%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Melanoderma
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	2 / 40 (5.00%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dermatitis exfoliative
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	1 / 40 (2.50%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dermatomyositis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	1 / 40 (2.50%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin hyperpigmentation
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	1 / 40 (2.50%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Myalgia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Viral infection
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 10 (0.00%)	1 / 40 (2.50%)	1 / 33 (3.03%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Anal abscess
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	1 / 40 (2.50%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis acute
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	0 / 40 (0.00%)	1 / 33 (3.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	0 / 40 (0.00%)	1 / 33 (3.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	1 / 40 (2.50%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-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)
Total subjects affected by non serious adverse events
subjects affected / exposed	6 / 6 (100.00%)	6 / 6 (100.00%)	3 / 3 (100.00%)	10 / 10 (100.00%)	40 / 40 (100.00%)	33 / 33 (100.00%)
Vascular disorders
Hot flush
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 10 (0.00%)	5 / 40 (12.50%)	0 / 33 (0.00%)
occurrences all number	0	1	0	0	5	0
Flushing
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	1 / 40 (2.50%)	1 / 33 (3.03%)
occurrences all number	1	0	0	0	1	1
Haematoma
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	0	0	1	0	0
Pallor
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	0	0	1	0	0
Varicose vein
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	0	0	1	0	0
Surgical and medical procedures
Tooth repair
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	1	0	0	0	0	0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	6 / 6 (100.00%)	5 / 6 (83.33%)	1 / 3 (33.33%)	6 / 10 (60.00%)	25 / 40 (62.50%)	20 / 33 (60.61%)
occurrences all number	25	26	4	32	55	40
Mucosal inflammation
subjects affected / exposed	1 / 6 (16.67%)	3 / 6 (50.00%)	1 / 3 (33.33%)	3 / 10 (30.00%)	20 / 40 (50.00%)	15 / 33 (45.45%)
occurrences all number	1	4	4	3	27	23
Pyrexia
subjects affected / exposed	1 / 6 (16.67%)	5 / 6 (83.33%)	0 / 3 (0.00%)	2 / 10 (20.00%)	8 / 40 (20.00%)	10 / 33 (30.30%)
occurrences all number	1	7	0	2	10	11
Fatigue
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 3 (33.33%)	1 / 10 (10.00%)	10 / 40 (25.00%)	9 / 33 (27.27%)
occurrences all number	0	1	1	1	12	13
Oedema peripheral
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	2 / 10 (20.00%)	3 / 40 (7.50%)	1 / 33 (3.03%)
occurrences all number	0	1	0	4	3	1
Influenza like illness
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	1 / 10 (10.00%)	4 / 40 (10.00%)	0 / 33 (0.00%)
occurrences all number	0	1	0	1	5	0
Chills
subjects affected / exposed	0 / 6 (0.00%)	2 / 6 (33.33%)	1 / 3 (33.33%)	0 / 10 (0.00%)	1 / 40 (2.50%)	1 / 33 (3.03%)
occurrences all number	0	5	1	0	1	1
Mucosal dryness
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	1 / 40 (2.50%)	3 / 33 (9.09%)
occurrences all number	0	0	0	0	1	3
Non-cardiac chest pain
subjects affected / exposed	0 / 6 (0.00%)	3 / 6 (50.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	0 / 40 (0.00%)	1 / 33 (3.03%)
occurrences all number	0	5	0	0	0	1
Pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	3 / 40 (7.50%)	0 / 33 (0.00%)
occurrences all number	0	0	0	0	3	0
Chest pain
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	0 / 40 (0.00%)	1 / 33 (3.03%)
occurrences all number	1	0	0	0	0	1
Feeling hot
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 10 (0.00%)	1 / 40 (2.50%)	0 / 33 (0.00%)
occurrences all number	0	1	0	0	1	0
Axillary pain
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 10 (0.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	1	0	0	0	0
Local swelling
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	0	0	2	0	0
Temperature intolerance
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	0	0	1	0	0
Temperature regulation disorder
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	0	0	1	0	0
Thrombosis in device
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	1	0	0	0	0	0
Vaccination site reaction
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	0	0	1	0	0
Reproductive system and breast disorders
Metrorrhagia
subjects affected / exposed	2 / 6 (33.33%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)	2 / 40 (5.00%)	1 / 33 (3.03%)
occurrences all number	3	0	0	1	5	1
Menstruation irregular
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	4 / 40 (10.00%)	1 / 33 (3.03%)
occurrences all number	0	0	0	0	4	1
Breast pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	1 / 10 (10.00%)	1 / 40 (2.50%)	1 / 33 (3.03%)
occurrences all number	0	0	1	1	1	1
Menorrhagia
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	2	0	0	1	0	0
Pelvic pain
subjects affected / exposed	0 / 6 (0.00%)	2 / 6 (33.33%)	0 / 3 (0.00%)	0 / 10 (0.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	5	0	0	0	0
Vaginal haemorrhage
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 10 (0.00%)	1 / 40 (2.50%)	0 / 33 (0.00%)
occurrences all number	0	1	0	0	1	0
Respiratory, thoracic and mediastinal disorders
Epistaxis
subjects affected / exposed	2 / 6 (33.33%)	5 / 6 (83.33%)	1 / 3 (33.33%)	6 / 10 (60.00%)	21 / 40 (52.50%)	19 / 33 (57.58%)
occurrences all number	14	20	2	41	28	40
Cough
subjects affected / exposed	3 / 6 (50.00%)	3 / 6 (50.00%)	0 / 3 (0.00%)	4 / 10 (40.00%)	4 / 40 (10.00%)	3 / 33 (9.09%)
occurrences all number	3	4	0	4	5	4
Dyspnoea
subjects affected / exposed	1 / 6 (16.67%)	2 / 6 (33.33%)	2 / 3 (66.67%)	4 / 10 (40.00%)	4 / 40 (10.00%)	1 / 33 (3.03%)
occurrences all number	2	2	2	6	4	1
Rhinorrhoea
subjects affected / exposed	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 3 (0.00%)	2 / 10 (20.00%)	2 / 40 (5.00%)	6 / 33 (18.18%)
occurrences all number	1	1	0	5	2	8
Nasal dryness
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	4 / 40 (10.00%)	1 / 33 (3.03%)
occurrences all number	0	0	0	0	6	1
Oropharyngeal pain
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)	1 / 40 (2.50%)	2 / 33 (6.06%)
occurrences all number	1	0	0	2	1	2
Nasal congestion
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	2 / 40 (5.00%)	1 / 33 (3.03%)
occurrences all number	1	0	0	0	2	1
Dysphonia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	2 / 40 (5.00%)	1 / 33 (3.03%)
occurrences all number	0	0	0	0	2	1
Nasal inflammation
subjects affected / exposed	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 10 (0.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	1	1	0	0	0	0
Pleuritic pain
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 10 (0.00%)	1 / 40 (2.50%)	0 / 33 (0.00%)
occurrences all number	0	1	0	0	1	0
Increased bronchial secretion
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 10 (0.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	1	0	0	0	0
Lung disorder
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	0	0	1	0	0
Nasal discomfort
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 10 (0.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	1	0	0	0	0
Rhinitis allergic
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	0	0	1	0	0
Suffocation feeling
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 10 (0.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	1	0	0	0	0
Psychiatric disorders
Insomnia
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	3 / 10 (30.00%)	8 / 40 (20.00%)	6 / 33 (18.18%)
occurrences all number	0	1	0	3	10	6
Anxiety
subjects affected / exposed	0 / 6 (0.00%)	2 / 6 (33.33%)	0 / 3 (0.00%)	1 / 10 (10.00%)	1 / 40 (2.50%)	3 / 33 (9.09%)
occurrences all number	0	2	0	1	1	3
Depression
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	2 / 40 (5.00%)	0 / 33 (0.00%)
occurrences all number	0	0	0	0	2	0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 3 (0.00%)	1 / 10 (10.00%)	11 / 40 (27.50%)	7 / 33 (21.21%)
occurrences all number	2	2	0	1	16	16
Aspartate aminotransferase increased
subjects affected / exposed	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 3 (0.00%)	1 / 10 (10.00%)	8 / 40 (20.00%)	4 / 33 (12.12%)
occurrences all number	1	1	0	1	10	7
Gamma-glutamyltransferase increased
subjects affected / exposed	3 / 6 (50.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)	3 / 40 (7.50%)	0 / 33 (0.00%)
occurrences all number	3	0	0	1	3	0
Blood lactate dehydrogenase increased
subjects affected / exposed	2 / 6 (33.33%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	2	0	0	1	0	0
Weight decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 10 (0.00%)	2 / 40 (5.00%)	0 / 33 (0.00%)
occurrences all number	0	0	1	0	2	0
Blood bilirubin increased
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 10 (0.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	1	0	0	0	0
Body temperature increased
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 10 (0.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	1	0	0	0	0
Injury, poisoning and procedural complications
Infusion related reaction
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	1	0	0	0	0	0
Laceration
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	0	0	1	0	0
Ligament sprain
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	1	0	0	0	0	0
Limb injury
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	0	0	1	0	0
Recall phenomenon
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 10 (0.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	1	0	0	0	0
Tooth avulsion
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	0	0	1	0	0
Cardiac disorders
Palpitations
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	1 / 10 (10.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	1	0	1	0	0
Systolic dysfunction
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 10 (0.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	0	1	0	0	0
Nervous system disorders
Dysgeusia
subjects affected / exposed	3 / 6 (50.00%)	1 / 6 (16.67%)	1 / 3 (33.33%)	4 / 10 (40.00%)	19 / 40 (47.50%)	13 / 33 (39.39%)
occurrences all number	4	1	4	5	23	16
Headache
subjects affected / exposed	2 / 6 (33.33%)	1 / 6 (16.67%)	1 / 3 (33.33%)	4 / 10 (40.00%)	12 / 40 (30.00%)	11 / 33 (33.33%)
occurrences all number	28	6	1	9	15	16
Neuropathy peripheral
subjects affected / exposed	2 / 6 (33.33%)	3 / 6 (50.00%)	1 / 3 (33.33%)	2 / 10 (20.00%)	8 / 40 (20.00%)	5 / 33 (15.15%)
occurrences all number	3	3	1	3	9	5
Paraesthesia
subjects affected / exposed	1 / 6 (16.67%)	3 / 6 (50.00%)	0 / 3 (0.00%)	3 / 10 (30.00%)	4 / 40 (10.00%)	1 / 33 (3.03%)
occurrences all number	1	3	0	3	5	1
Peripheral sensory neuropathy
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 10 (0.00%)	3 / 40 (7.50%)	1 / 33 (3.03%)
occurrences all number	0	1	0	0	3	1
Restless legs syndrome
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	4 / 40 (10.00%)	1 / 33 (3.03%)
occurrences all number	0	0	0	0	4	1
Dysaesthesia
subjects affected / exposed	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 10 (0.00%)	1 / 40 (2.50%)	0 / 33 (0.00%)
occurrences all number	1	1	0	0	1	0
Hypoaesthesia
subjects affected / exposed	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 3 (0.00%)	1 / 10 (10.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	1	1	0	1	0	0
Aphonia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 10 (0.00%)	1 / 40 (2.50%)	0 / 33 (0.00%)
occurrences all number	0	0	1	0	2	0
Migraine
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	2 / 10 (20.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	0	0	3	0	0
Sciatica
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 10 (0.00%)	1 / 40 (2.50%)	0 / 33 (0.00%)
occurrences all number	0	1	0	0	2	0
Burning sensation
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 10 (0.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	1	0	0	0	0
Memory impairment
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	0	0	1	0	0
Sinus headache
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	1	0	0	0	0	0
Somnolence
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	1	0	0	0	0	0
Blood and lymphatic system disorders
Neutropenia
subjects affected / exposed	6 / 6 (100.00%)	5 / 6 (83.33%)	1 / 3 (33.33%)	7 / 10 (70.00%)	11 / 40 (27.50%)	12 / 33 (36.36%)
occurrences all number	39	19	11	20	23	15
Thrombocytopenia
subjects affected / exposed	4 / 6 (66.67%)	4 / 6 (66.67%)	0 / 3 (0.00%)	8 / 10 (80.00%)	9 / 40 (22.50%)	7 / 33 (21.21%)
occurrences all number	8	7	0	17	13	8
Leukopenia
subjects affected / exposed	5 / 6 (83.33%)	3 / 6 (50.00%)	1 / 3 (33.33%)	4 / 10 (40.00%)	3 / 40 (7.50%)	3 / 33 (9.09%)
occurrences all number	17	12	5	10	3	4
Lymphopenia
subjects affected / exposed	5 / 6 (83.33%)	1 / 6 (16.67%)	0 / 3 (0.00%)	3 / 10 (30.00%)	3 / 40 (7.50%)	4 / 33 (12.12%)
occurrences all number	11	6	0	8	5	7
Anaemia
subjects affected / exposed	1 / 6 (16.67%)	1 / 6 (16.67%)	1 / 3 (33.33%)	3 / 10 (30.00%)	4 / 40 (10.00%)	4 / 33 (12.12%)
occurrences all number	1	1	1	6	4	5
Ear and labyrinth disorders
Ear pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	2 / 40 (5.00%)	1 / 33 (3.03%)
occurrences all number	0	0	0	0	2	1
Tinnitus
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	1	0	0	0	0	0
Vertigo
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	0	0	1	0	0
Eye disorders
Lacrimation increased
subjects affected / exposed	1 / 6 (16.67%)	2 / 6 (33.33%)	1 / 3 (33.33%)	4 / 10 (40.00%)	15 / 40 (37.50%)	16 / 33 (48.48%)
occurrences all number	1	4	1	6	17	20
Conjunctivitis
subjects affected / exposed	0 / 6 (0.00%)	2 / 6 (33.33%)	1 / 3 (33.33%)	1 / 10 (10.00%)	6 / 40 (15.00%)	2 / 33 (6.06%)
occurrences all number	0	2	2	1	7	2
Dry eye
subjects affected / exposed	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 3 (0.00%)	1 / 10 (10.00%)	3 / 40 (7.50%)	5 / 33 (15.15%)
occurrences all number	1	1	0	1	3	5
Vision blurred
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 10 (0.00%)	6 / 40 (15.00%)	2 / 33 (6.06%)
occurrences all number	0	1	0	0	8	2
Xerophthalmia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	2 / 40 (5.00%)	2 / 33 (6.06%)
occurrences all number	0	0	0	0	2	2
Blepharospasm
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	2 / 40 (5.00%)	0 / 33 (0.00%)
occurrences all number	1	0	0	0	2	0
Conjunctival oedema
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	2 / 40 (5.00%)	1 / 33 (3.03%)
occurrences all number	0	0	0	0	4	1
Eye disorder
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	3 / 40 (7.50%)	0 / 33 (0.00%)
occurrences all number	0	0	0	0	6	0
Conjunctival haemorrhage
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)	0 / 40 (0.00%)	1 / 33 (3.03%)
occurrences all number	0	0	0	1	0	1
Eye pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)	1 / 40 (2.50%)	0 / 33 (0.00%)
occurrences all number	0	0	0	1	1	0
Photophobia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)	1 / 40 (2.50%)	0 / 33 (0.00%)
occurrences all number	0	0	0	1	1	0
Visual acuity reduced
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	1 / 40 (2.50%)	0 / 33 (0.00%)
occurrences all number	1	0	0	0	1	0
Visual impairment
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	0 / 40 (0.00%)	1 / 33 (3.03%)
occurrences all number	1	0	0	0	0	1
Dacryostenosis acquired
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	1	0	0	0	0	0
Eyelids pruritus
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 10 (0.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	1	0	0	0	0
Gastrointestinal disorders
Nausea
subjects affected / exposed	1 / 6 (16.67%)	5 / 6 (83.33%)	1 / 3 (33.33%)	4 / 10 (40.00%)	16 / 40 (40.00%)	16 / 33 (48.48%)
occurrences all number	18	31	4	14	30	25
Diarrhoea
subjects affected / exposed	3 / 6 (50.00%)	3 / 6 (50.00%)	1 / 3 (33.33%)	3 / 10 (30.00%)	12 / 40 (30.00%)	18 / 33 (54.55%)
occurrences all number	5	3	1	3	23	33
Constipation
subjects affected / exposed	1 / 6 (16.67%)	1 / 6 (16.67%)	3 / 3 (100.00%)	3 / 10 (30.00%)	19 / 40 (47.50%)	11 / 33 (33.33%)
occurrences all number	1	9	8	6	21	14
Dry mouth
subjects affected / exposed	1 / 6 (16.67%)	1 / 6 (16.67%)	2 / 3 (66.67%)	3 / 10 (30.00%)	14 / 40 (35.00%)	10 / 33 (30.30%)
occurrences all number	4	1	2	3	18	12
Vomiting
subjects affected / exposed	1 / 6 (16.67%)	2 / 6 (33.33%)	1 / 3 (33.33%)	5 / 10 (50.00%)	11 / 40 (27.50%)	11 / 33 (33.33%)
occurrences all number	2	2	1	6	13	14
Stomatitis
subjects affected / exposed	3 / 6 (50.00%)	4 / 6 (66.67%)	0 / 3 (0.00%)	5 / 10 (50.00%)	4 / 40 (10.00%)	5 / 33 (15.15%)
occurrences all number	10	8	0	7	4	7
Abdominal pain
subjects affected / exposed	2 / 6 (33.33%)	1 / 6 (16.67%)	0 / 3 (0.00%)	2 / 10 (20.00%)	5 / 40 (12.50%)	4 / 33 (12.12%)
occurrences all number	3	1	0	7	7	4
Abdominal pain upper
subjects affected / exposed	2 / 6 (33.33%)	3 / 6 (50.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)	3 / 40 (7.50%)	5 / 33 (15.15%)
occurrences all number	5	5	0	1	3	7
Haemorrhoids
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 10 (0.00%)	4 / 40 (10.00%)	3 / 33 (9.09%)
occurrences all number	0	1	0	0	4	3
Odynophagia
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 10 (0.00%)	5 / 40 (12.50%)	2 / 33 (6.06%)
occurrences all number	0	2	0	0	8	2
Dyspepsia
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	3 / 40 (7.50%)	3 / 33 (9.09%)
occurrences all number	3	0	0	0	3	5
Gastritis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	4 / 40 (10.00%)	3 / 33 (9.09%)
occurrences all number	0	0	0	0	4	4
Gingival bleeding
subjects affected / exposed	0 / 6 (0.00%)	2 / 6 (33.33%)	0 / 3 (0.00%)	2 / 10 (20.00%)	3 / 40 (7.50%)	0 / 33 (0.00%)
occurrences all number	0	11	0	4	4	0
Gastrooesophageal reflux disease
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	3 / 10 (30.00%)	0 / 40 (0.00%)	2 / 33 (6.06%)
occurrences all number	1	0	0	5	0	2
Rectal haemorrhage
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	1 / 10 (10.00%)	3 / 40 (7.50%)	0 / 33 (0.00%)
occurrences all number	0	1	0	1	4	0
Cheilitis
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	1 / 10 (10.00%)	1 / 40 (2.50%)	1 / 33 (3.03%)
occurrences all number	0	1	0	1	1	1
Oral pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)	2 / 40 (5.00%)	1 / 33 (3.03%)
occurrences all number	0	0	0	1	3	1
Abdominal discomfort
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)	0 / 40 (0.00%)	1 / 33 (3.03%)
occurrences all number	2	0	0	1	0	1
Flatulence
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	0 / 40 (0.00%)	2 / 33 (6.06%)
occurrences all number	1	0	0	0	0	2
Aphthous Stomatitis
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	1 / 40 (2.50%)	0 / 33 (0.00%)
occurrences all number	1	0	0	0	1	0
Gingival pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)	0 / 40 (0.00%)	1 / 33 (3.03%)
occurrences all number	0	0	0	1	0	1
Proctalgia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)	0 / 40 (0.00%)	1 / 33 (3.03%)
occurrences all number	0	0	0	1	0	1
Mouth ulceration
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 10 (0.00%)	0 / 40 (0.00%)	1 / 33 (3.03%)
occurrences all number	0	0	1	0	0	1
Breath odour
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	0	0	1	0	0
Epulis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 10 (0.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	0	1	0	0	0
Food poisoning
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	1	0	0	0	0	0
Tooth loss
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	0	0	1	0	0
Toothache
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	1	0	0	0	0	0
Hepatobiliary disorders
Hepatocellular injury
subjects affected / exposed	1 / 6 (16.67%)	2 / 6 (33.33%)	0 / 3 (0.00%)	2 / 10 (20.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	8	3	0	2	0	0
Cholestasis
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	1	0	0	0	0	0
Hepatitis
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	1	0	0	0	0	0
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	4 / 6 (66.67%)	4 / 6 (66.67%)	0 / 3 (0.00%)	4 / 10 (40.00%)	20 / 40 (50.00%)	12 / 33 (36.36%)
occurrences all number	4	4	0	4	20	12
Rash
subjects affected / exposed	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 3 (0.00%)	1 / 10 (10.00%)	8 / 40 (20.00%)	11 / 33 (33.33%)
occurrences all number	1	1	0	2	13	15
Nail disorder
subjects affected / exposed	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 10 (0.00%)	8 / 40 (20.00%)	4 / 33 (12.12%)
occurrences all number	1	1	0	0	8	4
Palmar-plantar erythrodysaesthesia syndrome
subjects affected / exposed	0 / 6 (0.00%)	2 / 6 (33.33%)	0 / 3 (0.00%)	0 / 10 (0.00%)	9 / 40 (22.50%)	3 / 33 (9.09%)
occurrences all number	0	2	0	0	9	3
Nail dystrophy
subjects affected / exposed	0 / 6 (0.00%)	2 / 6 (33.33%)	0 / 3 (0.00%)	1 / 10 (10.00%)	5 / 40 (12.50%)	1 / 33 (3.03%)
occurrences all number	0	3	0	2	6	1
Dry skin
subjects affected / exposed	2 / 6 (33.33%)	0 / 6 (0.00%)	0 / 3 (0.00%)	2 / 10 (20.00%)	1 / 40 (2.50%)	2 / 33 (6.06%)
occurrences all number	3	0	0	2	1	2
Erythema
subjects affected / exposed	0 / 6 (0.00%)	2 / 6 (33.33%)	0 / 3 (0.00%)	0 / 10 (0.00%)	2 / 40 (5.00%)	2 / 33 (6.06%)
occurrences all number	0	2	0	0	2	2
Eczema
subjects affected / exposed	0 / 6 (0.00%)	2 / 6 (33.33%)	0 / 3 (0.00%)	0 / 10 (0.00%)	1 / 40 (2.50%)	2 / 33 (6.06%)
occurrences all number	0	2	0	0	1	2
Pruritus
subjects affected / exposed	0 / 6 (0.00%)	2 / 6 (33.33%)	0 / 3 (0.00%)	1 / 10 (10.00%)	1 / 40 (2.50%)	1 / 33 (3.03%)
occurrences all number	0	3	0	1	1	2
Rash generalised
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	3 / 40 (7.50%)	1 / 33 (3.03%)
occurrences all number	0	0	0	0	3	2
Onychalgia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	2 / 40 (5.00%)	1 / 33 (3.03%)
occurrences all number	0	0	0	0	2	1
Onycholysis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 10 (0.00%)	2 / 40 (5.00%)	0 / 33 (0.00%)
occurrences all number	0	0	1	0	2	0
Skin discolouration
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	2 / 40 (5.00%)	1 / 33 (3.03%)
occurrences all number	0	0	0	0	2	1
Skin lesion
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	1 / 10 (10.00%)	0 / 40 (0.00%)	1 / 33 (3.03%)
occurrences all number	0	1	0	1	0	1
Blister
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	1	0	0	0	0	0
Cold sweat
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 10 (0.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	0	1	0	0	0
Madarosis
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 10 (0.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	1	0	0	0	0
Papule
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 10 (0.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	1	0	0	0	0
Skin toxicity
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 10 (0.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	1	0	0	0	0
Toxic skin eruption
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 10 (0.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	1	0	0	0	0
Renal and urinary disorders
Dysuria
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 10 (0.00%)	1 / 40 (2.50%)	5 / 33 (15.15%)
occurrences all number	0	1	0	0	1	5
Haematuria
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	2	0	0	0	0	0
Pyelocaliectasis
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	2	0	0	0	0	0
Musculoskeletal and connective tissue disorders
Myalgia
subjects affected / exposed	4 / 6 (66.67%)	3 / 6 (50.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)	18 / 40 (45.00%)	8 / 33 (24.24%)
occurrences all number	6	4	0	1	37	10
Arthralgia
subjects affected / exposed	4 / 6 (66.67%)	4 / 6 (66.67%)	0 / 3 (0.00%)	3 / 10 (30.00%)	9 / 40 (22.50%)	3 / 33 (9.09%)
occurrences all number	4	4	0	8	17	4
Musculoskeletal pain
subjects affected / exposed	2 / 6 (33.33%)	0 / 6 (0.00%)	1 / 3 (33.33%)	4 / 10 (40.00%)	10 / 40 (25.00%)	6 / 33 (18.18%)
occurrences all number	3	0	1	4	16	6
Back pain
subjects affected / exposed	2 / 6 (33.33%)	3 / 6 (50.00%)	0 / 3 (0.00%)	4 / 10 (40.00%)	6 / 40 (15.00%)	3 / 33 (9.09%)
occurrences all number	6	3	0	7	8	3
Bone pain
subjects affected / exposed	3 / 6 (50.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	6 / 40 (15.00%)	3 / 33 (9.09%)
occurrences all number	24	0	0	0	8	3
Pain in extremity
subjects affected / exposed	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 3 (0.00%)	3 / 10 (30.00%)	4 / 40 (10.00%)	3 / 33 (9.09%)
occurrences all number	1	1	0	5	4	3
Musculoskeletal stiffness
subjects affected / exposed	0 / 6 (0.00%)	2 / 6 (33.33%)	1 / 3 (33.33%)	1 / 10 (10.00%)	1 / 40 (2.50%)	0 / 33 (0.00%)
occurrences all number	0	3	1	1	1	0
Muscle spasms
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	1 / 10 (10.00%)	1 / 40 (2.50%)	1 / 33 (3.03%)
occurrences all number	0	1	0	4	1	1
Muscle twitching
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)	2 / 40 (5.00%)	1 / 33 (3.03%)
occurrences all number	0	0	0	1	2	1
Musculoskeletal chest pain
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 10 (0.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	1	0	2	0	0	0
Muscular weakness
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	1	0	0	0	0	0
Musculoskeletal discomfort
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 10 (0.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	1	0	0	0	0
Osteoarthritis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	0	0	1	0	0
Osteopenia
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	1	0	0	0	0	0
Spinal pain
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	1	0	0	0	0	0
Infections and infestations
Nasopharyngitis
subjects affected / exposed	3 / 6 (50.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	5 / 10 (50.00%)	7 / 40 (17.50%)	1 / 33 (3.03%)
occurrences all number	7	0	1	5	9	1
Urinary tract infection
subjects affected / exposed	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 3 (0.00%)	3 / 10 (30.00%)	4 / 40 (10.00%)	3 / 33 (9.09%)
occurrences all number	1	1	0	3	5	4
Rhinitis
subjects affected / exposed	1 / 6 (16.67%)	1 / 6 (16.67%)	1 / 3 (33.33%)	2 / 10 (20.00%)	4 / 40 (10.00%)	1 / 33 (3.03%)
occurrences all number	1	1	1	2	4	1
Upper respiratory tract infection
subjects affected / exposed	2 / 6 (33.33%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 10 (0.00%)	2 / 40 (5.00%)	1 / 33 (3.03%)
occurrences all number	2	2	0	0	2	2
Candida infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	4 / 40 (10.00%)	1 / 33 (3.03%)
occurrences all number	0	0	0	0	4	1
Influenza
subjects affected / exposed	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 10 (0.00%)	3 / 40 (7.50%)	0 / 33 (0.00%)
occurrences all number	1	1	0	0	3	0
Oral herpes
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	2 / 40 (5.00%)	1 / 33 (3.03%)
occurrences all number	1	0	0	0	2	1
Respiratory tract infection
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 10 (0.00%)	0 / 40 (0.00%)	2 / 33 (6.06%)
occurrences all number	1	0	1	0	0	2
Bronchitis
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)	0 / 40 (0.00%)	1 / 33 (3.03%)
occurrences all number	1	0	0	1	0	1
Cellulitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	2 / 40 (5.00%)	1 / 33 (3.03%)
occurrences all number	0	0	0	0	2	1
Gingivitis
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 10 (0.00%)	1 / 40 (2.50%)	1 / 33 (3.03%)
occurrences all number	0	1	0	0	1	1
Oral candidiasis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)	1 / 40 (2.50%)	1 / 33 (3.03%)
occurrences all number	0	0	0	2	1	1
Pharyngitis
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	1 / 40 (2.50%)	1 / 33 (3.03%)
occurrences all number	1	0	0	0	1	1
Cystitis
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	1	0	0	1	0	0
Eye infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	0 / 40 (0.00%)	2 / 33 (6.06%)
occurrences all number	0	0	0	0	0	3
Herpes zoster
subjects affected / exposed	0 / 6 (0.00%)	2 / 6 (33.33%)	0 / 3 (0.00%)	0 / 10 (0.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	4	0	0	0	0
Hordeolum
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	0 / 40 (0.00%)	1 / 33 (3.03%)
occurrences all number	1	0	0	0	0	1
Device related infection
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	1	0	0	0	0	0
Folliculitis
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 10 (0.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	1	0	0	0	0
Fungal skin infection
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	1	0	0	0	0	0
Gastroenteritis
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	1	0	0	0	0	0
Genital herpes
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 10 (0.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	2	0	0	0	0
Herpes virus infection
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 10 (0.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	8	0	0	0	0
Laryngitis
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	1	0	0	0	0	0
Lower respiratory tract infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	0	0	3	0	0
Mastitis
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 10 (0.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	1	0	0	0	0
Viral upper respiratory tract infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	0	0	0	1	0	0
Vulvovaginal mycotic infection
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	1	0	0	0	0	0
Wound infection
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	0 / 40 (0.00%)	0 / 33 (0.00%)
occurrences all number	1	0	0	0	0	0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	2 / 6 (33.33%)	2 / 6 (33.33%)	1 / 3 (33.33%)	2 / 10 (20.00%)	9 / 40 (22.50%)	9 / 33 (27.27%)
occurrences all number	2	4	3	2	11	13
Hypokalaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)	1 / 40 (2.50%)	2 / 33 (6.06%)
occurrences all number	0	0	0	0	1	2

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

12 Jun 2009

Version B: • Updated blood volume and schedule for PK sampling • Clarified that palliative radiotherapy was allowed for brain metastasis prior to study entry.

26 Aug 2009

Version C: Provision of better assessment of early safety parameters, via more intensive hematology and biochemistry assessments in Weeks 1 and 2 of Cycles 1-3.

02 Feb 2010

Version D: • Reduction of the maximum dose docetaxel from 100 mg/m^2 to 75 mg/m^2 in first-line participants • Addition of a third Cohort of 3 to 6 participants to receive 2.4 mg/kg T-DM1 + 60 mg/m^2 docetaxel, administered both on Day 1 of each cycle • Addition of Dose Level 4 (T-DM1 3.6 mg/kg and docetaxel 60 mg/m^2 every 3 weeks) and Dose Level 5 (T-DM1 3.0 mg/kg and docetaxel 60 mg/m^2 every 3 weeks) to study design • Updated participants numbers and PK sampling accordingly • Clarification of the DLT criteria regarding “nonhaematological” toxicities and dose modifications for hepatotoxicity/hematologic toxicity • Addition of exclusion criterion regarding alkaline phosphatase.

16 Jun 2010

Version E: Permission for participants who had newly developed isolated brain metastases that were treatable with radiation to continue with study treatment until systemic progression.

18 Feb 2011

Version F: • Inclusion of participants with newly diagnosed HER2-positive LABC, with option for docetaxel dose escalation • Closure of the feasibility part of the study in MBC • Removal of overall survival and time to tumour progression as secondary endpoints • Removal of censoring for non-protocol therapy from the analysis of PFS • Update of safety guidance with respect to drug-induced liver injury and pregnancy.

31 Aug 2011

Version G: Inclusion of addition of pertuzumab to T-DM1 and docetaxel in LABC participants.

11 Oct 2011

Version H: Addition of United States sites to the study.

23 Feb 2012

Version I: • Increase in participant numbers in extension part for LABC • Revision of hepatotoxicity information.

13 Feb 2013

Version J: Updated safety information for identified risks and adverse events of interest.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported.

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Clinical trials

Clinical Trial Results: An Open-label, Multi-center Phase I/II Study of the Safety And Tolerability of the Combination of Trastuzumab-MCC-DM1 (T-DM1) with Docetaxel, and Potentially Pertuzumab, for Treatment for Patients with Advanced Breast Cancer

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of Participants with Adverse Events (AEs) or Serious AEs (SAEs) – MBC and LABC Population

Primary: Percentage of Participants with Adverse Events (AEs) or Serious AEs (SAEs) – MBC and LABC Population

Primary: Number of Participants with Dose Limiting Toxicity (DLT) - MBC and LABC Feasibility Population

Primary: Number of Participants with Dose Limiting Toxicity (DLT) - MBC and LABC Feasibility Population

Secondary: Percentage of Participants with Progression-Free Survival (PFS) – MBC Population

Secondary: Percentage of Participants with Progression-Free Survival (PFS) – MBC Population

Secondary: PFS – MBC Population

Secondary: PFS – MBC Population

Secondary: Percentage of Participants with a Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR) - MBC Population

Secondary: Percentage of Participants with a Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR) - MBC Population

Secondary: Percentage of Participants with Treatment Failure - MBC Population

Secondary: Percentage of Participants with Treatment Failure - MBC Population

Secondary: Time to Treatment Failure (TTF) - MBC Population

Secondary: Time to Treatment Failure (TTF) - MBC Population

Secondary: Percentage of Participants with CR or PR or Stable Disease (SD) for at Least 6 months [Clinical Benefit Rate (CBR)] - MBC Population

Secondary: Percentage of Participants with CR or PR or Stable Disease (SD) for at Least 6 months [Clinical Benefit Rate (CBR)] - MBC Population

Secondary: Duration of Response – MBC Population

Secondary: Duration of Response – MBC Population

Secondary: Percentage of Participants with Pathological CR (pCR) – LABC Population

Secondary: Percentage of Participants with Pathological CR (pCR) – LABC Population

Secondary: Percentage of Participants with a BOR of CR or PR – LABC Population

Secondary: Percentage of Participants with a BOR of CR or PR – LABC Population

Secondary: Percentage of Participants With Anti-Therapeutic Antibody Response at Baseline and Post-Trazustumab Emtansine Dosing - MBC and LABC Population

Secondary: Percentage of Participants With Anti-Therapeutic Antibody Response at Baseline and Post-Trazustumab Emtansine Dosing - MBC and LABC Population

Secondary: Maximum Observed Concentration (Cmax) of Serum Trastuzumab Emtansine – MBC and LABC Population

Secondary: Maximum Observed Concentration (Cmax) of Serum Trastuzumab Emtansine – MBC and LABC Population

Secondary: Apparent Terminal Half-Life (t1/2) of Serum Trastuzumab Emtansine – MBC and LABC Population

Secondary: Apparent Terminal Half-Life (t1/2) of Serum Trastuzumab Emtansine – MBC and LABC Population

Secondary: AUCinf of Serum Trastuzumab Emtansine – MBC and LABC Population

Secondary: AUCinf of Serum Trastuzumab Emtansine – MBC and LABC Population

Secondary: Clearence (CL) of Serum Trastuzumab Emtansine – MBC and LABC Population

Secondary: Clearence (CL) of Serum Trastuzumab Emtansine – MBC and LABC Population

Secondary: Vss of Serum Trastuzumab Emtansine – MBC and LABC Population

Secondary: Vss of Serum Trastuzumab Emtansine – MBC and LABC Population

Secondary: Cmax of Total Serum Trastuzumab – MBC and LABC Population

Secondary: Cmax of Total Serum Trastuzumab – MBC and LABC Population

Secondary: T1/2 of Total Serum Trastuzumab – MBC and LABC Population

Secondary: T1/2 of Total Serum Trastuzumab – MBC and LABC Population

Secondary: AUCinf of Total Serum Trastuzumab – MBC and LABC Population

Secondary: AUCinf of Total Serum Trastuzumab – MBC and LABC Population

Secondary: CL of Total Serum Trastuzumab – MBC and LABC Population

Secondary: CL of Total Serum Trastuzumab – MBC and LABC Population

Secondary: Vss of Total Serum Trastuzumab – MBC and LABC Population

Secondary: Vss of Total Serum Trastuzumab – MBC and LABC Population

Secondary: Cmax of Plasma DM1 – MBC and LABC Population

Secondary: Cmax of Plasma DM1 – MBC and LABC Population

Secondary: T1/2 of Plasma DM1 – MBC and LABC Population

Secondary: T1/2 of Plasma DM1 – MBC and LABC Population

Secondary: AUCinf of Plasma DM1 – MBC and LABC Population

Secondary: AUCinf of Plasma DM1 – MBC and LABC Population

Secondary: Cmax of Docetaxel – MBC and LABC Population

Secondary: Cmax of Docetaxel – MBC and LABC Population

Secondary: T1/2 of Docetaxel – MBC and LABC Population

Secondary: T1/2 of Docetaxel – MBC and LABC Population

Secondary: AUCinf of Docetaxel – MBC and LABC Population

Secondary: AUCinf of Docetaxel – MBC and LABC Population

Secondary: CL of Docetaxel – MBC and LABC Population

Secondary: CL of Docetaxel – MBC and LABC Population

Secondary: Vss of Docetaxel – MBC and LABC Population

Secondary: Vss of Docetaxel – MBC and LABC Population

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
An Open-label, Multi-center Phase I/II Study of the Safety And Tolerability of the Combination of Trastuzumab-MCC-DM1 (T-DM1) with Docetaxel, and Potentially Pertuzumab, for Treatment for Patients with Advanced Breast Cancer