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Clinical Trial Results:
Phase I Study of the Combination of Trastuzumab Emtansine (T-DM1) and Capecitabine in HER2-Positive Metastatic Breast Cancer and HER2-Positive Locally Advanced/Metastatic Gastric Cancer Patients, Followed by a Randomized, Open-Label Phase II Study of Trastuzumab Emtansine and Capecitabine versus Trastuzumab Emtansine Alone in HER2-Positive Metastatic Breast Cancer

Summary
EudraCT number	2012-001547-46
Trial protocol	ES FR PT SK IT DE GR
Global end of trial date	31 May 2017

Results information
Results version number	v1(current)
This version publication date	14 Jun 2018
First version publication date	14 Jun 2018
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

MO28230

ISRCTN number

US NCT number

NCT01702558

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

31 May 2017

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

31 May 2017

Was the trial ended prematurely?

Yes

Main objective of the trial

Phase 1: The primary objective was to determine the maximum tolerated dose (MTD) of the combination of trastuzumab emtansine and capecitabine in participants with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC) and locally advanced/metastatic gastric cancer (LA/mGC). Phase 2: The primary objective was to explore the efficacy of the combination of trastuzumab emtansine and capecitabine compared with trastuzumab emtansine alone in participants with HER2-positive mBC, as measured by overall response rate (ORR) according to Response Evaluation Criteria for Solid Tumors Version 1.1 (RECIST v1.1) per investigator local assessment.

Protection of trial subjects

The study was conducted in accordance with the principles of the “Declaration of Helsinki” and International Council for Harmonisation (ICH) guideline for Good Clinical Practice (GCP). Approval from the Independent Ethics Committee (IEC)/Institutional Review Board (IRB) was obtained before study start and was documented in a letter to the investigator specifying the date on which the committee met and granted the approval. No modifications were made to the protocol after receipt of the IEC/IRB approval.

Background therapy

Evidence for comparator

Actual start date of recruitment

03 Dec 2012

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Argentina: 6

Country: Number of subjects enrolled

Brazil: 10

Country: Number of subjects enrolled

Canada: 12

Country: Number of subjects enrolled

France: 17

Country: Number of subjects enrolled

Germany: 13

Country: Number of subjects enrolled

Greece: 16

Country: Number of subjects enrolled

Italy: 24

Country: Number of subjects enrolled

Portugal: 6

Country: Number of subjects enrolled

Russian Federation: 40

Country: Number of subjects enrolled

Serbia: 6

Country: Number of subjects enrolled

Slovakia: 14

Country: Number of subjects enrolled

Spain: 15

Worldwide total number of subjects

179

EEA total number of subjects

105

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)

148

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

A total of 234 participants were screened, out of which, 182 participants were enrolled into the study. Out of the 182 enrolled participants, 3 participants were excluded from all safety and efficacy analyses because they did not sign correct Informed Consent Form (ICF).

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape

Arm description

In Phase 1, Cohort 1 participants (with mBC) received trastuzumab emtansine (T-DM1) at a dose of 3.6 milligrams per kilogram (mg/kg) via intravenous (IV) infusion (on Day 1 [on Day 2 for Cycle 1] of each 21-day cycle) along with capecitabine (Cape) at a dose level (DL) of 750 milligrams per meter squared (mg/m^2) via tablet orally twice daily on Days 1-14 of each 21-day cycle until unacceptable toxicity, withdrawal of consent, disease progression (PD), death, reasons deemed by the treating physician, or study termination by the sponsor.

Arm type

Experimental

Investigational medicinal product name

Capecitabine

Investigational medicinal product code

Other name

Xeloda

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Capecitabine was administered at dose level 1 (750 mg/m^2) via tablet orally twice daily on Days 1-14 of each 21-day cycle.

Investigational medicinal product name

Trastuzumab emtansine

Investigational medicinal product code

Other name

Kadcyla, RO5304020

Pharmaceutical forms

Powder for concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Trastuzumab emtansine was administered at a dose of 3.6 mg/kg via IV infusion on Day 1 (on Day 2 of Cycle 1) of each 21-day cycle.

Phase 1 (mBC) Cohort 1 (DL -1): T-DM1 + Cape

Arm description

In Phase 1, Cohort 1 participants (with mBC) received trastuzumab emtansine at a dose of 3.6 mg/kg via IV infusion (on Day 1 [on Day 2 for Cycle 1] of each 21-day cycle) along with capecitabine at a dose level of 700 mg/m^2 via tablet orally twice daily on Days 1-14 of each 21-day cycle until unacceptable toxicity, withdrawal of consent, PD, death, reasons deemed by the treating physician, or study termination by the sponsor.

Arm type

Experimental

Investigational medicinal product name

Capecitabine

Investigational medicinal product code

Other name

Xeloda

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Capecitabine was administered at dose level -1 (700 mg/m^2) via tablet orally twice daily on Days 1-14 of each 21-day cycle.

Investigational medicinal product name

Trastuzumab emtansine

Investigational medicinal product code

Other name

Kadcyla, RO5304020

Pharmaceutical forms

Powder for concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Trastuzumab emtansine was administered at a dose of 3.6 mg/kg via IV infusion on Day 1 (on Day 2 of Cycle 1) of each 21-day cycle.

Phase 1 (LA/mGC) Cohort 2 (DL -1): T-DM1 + Cape

Arm description

In Phase 1, Cohort 2 participants (with LA/mGC) received trastuzumab emtansine at a dose of 2.4 mg/kg via IV infusion on Day 1 (Day 2 of first week) of every week along with capecitabine at a dose level of 700 mg/m^2 via tablet orally twice daily on Days 1-14 followed by a 7-day rest period, in each 21-day cycle until unacceptable toxicity, withdrawal of consent, PD, death, reasons deemed by the treating physician, or study termination by the sponsor.

Arm type

Experimental

Investigational medicinal product name

Capecitabine

Investigational medicinal product code

Other name

Xeloda

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Capecitabine was administered at MTD (700 mg/m^2) via tablet orally twice daily on Days 1-14 followed by a 7-day rest period.

Investigational medicinal product name

Trastuzumab emtansine

Investigational medicinal product code

Other name

Kadcyla, RO5304020

Pharmaceutical forms

Powder for concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Trastuzumab emtansine was administered at a dose of 2.4 mg/kg via IV infusion on Day 1 (Day 2 of first week) every week.

Phase 2 (mBC): T-DM1 + Cape

Arm description

In Phase 2, participants (with mBC) who were randomized to this group received trastuzumab emtansine at a dose of 3.6 mg/kg via IV infusion on Day 1 of each 21-day cycle along with capecitabine at a dose level of 700 mg/m^2 via tablet orally twice daily on Days 1-14 of each 21-day cycle until unacceptable toxicity, withdrawal of consent, PD, death, reasons deemed by the treating physician, or study termination by the sponsor.

Arm type

Experimental

Investigational medicinal product name

Capecitabine

Investigational medicinal product code

Other name

Xeloda

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Capecitabine was administered at MTD (700 mg/m^2) via tablet orally twice daily on Days 1-14 of each 21-day cycle.

Investigational medicinal product name

Trastuzumab emtansine

Investigational medicinal product code

Other name

Kadcyla

Pharmaceutical forms

Powder for concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Trastuzumab emtansine was administered at a dose of 3.6 mg/kg via IV infusion on Day 1 of each 21-day cycle.

Phase 2 (mBC): T-DM1

Arm description

In Phase 2, participants (with mBC) who were randomized to this group received trastuzumab emtansine at a dose of 3.6 mg/kg via IV infusion on Day 1 of each 21-day cycle until investigator-assessed PD, unacceptable toxicity, withdrawal of consent, death, reasons deemed by the treating physician, or study termination by the Sponsor.

Arm type

Active comparator

Investigational medicinal product name

Trastuzumab emtansine

Investigational medicinal product code

Other name

Kadcyla

Pharmaceutical forms

Powder for concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Trastuzumab emtansine was administered at a dose of 3.6 mg/kg via IV infusion on Day 1 of each 21-day cycle.

Number of subjects in period 1	Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape	Phase 1 (mBC) Cohort 1 (DL -1): T-DM1 + Cape	Phase 1 (LA/mGC) Cohort 2 (DL -1): T-DM1 + Cape	Phase 2 (mBC): T-DM1 + Cape	Phase 2 (mBC): T-DM1
Started	7	5	6	81	80
Completed	3	1	1	34	38
Not completed	4	4	5	47	42
Consent withdrawn by subject	-	-	-	12	4
Death	4	3	3	16	20
Safety Follow-Up less than 3 Months	-	-	2	-	-
Unspecified	-	-	-	16	17
Study Terminated by Sponsor	-	1	-	-	1
Lost to follow-up	-	-	-	3	-

Baseline characteristics

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Reporting group title

Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape

Reporting group description

Reporting group title

Phase 1 (mBC) Cohort 1 (DL -1): T-DM1 + Cape

Reporting group description

Reporting group title

Phase 1 (LA/mGC) Cohort 2 (DL -1): T-DM1 + Cape

Reporting group description

Reporting group title

Phase 2 (mBC): T-DM1 + Cape

Reporting group description

Reporting group title

Phase 2 (mBC): T-DM1

Reporting group description

Reporting group values	Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape	Phase 1 (mBC) Cohort 1 (DL -1): T-DM1 + Cape	Phase 1 (LA/mGC) Cohort 2 (DL -1): T-DM1 + Cape	Phase 2 (mBC): T-DM1 + Cape	Phase 2 (mBC): T-DM1	Total
Number of subjects	7	5	6	81	80	179
Age categorical
Units: Subjects
Age Continuous
Units: years
arithmetic mean (standard deviation)	55.9 ( 10.75 )	50.8 ( 7.76 )	60.0 ( 7.40 )	53.4 ( 11.71 )	52.7 ( 11.33 )	-
Sex: Female, Male
Units: Subjects
Female	6	5	0	80	80	171
Male	1	0	6	1	0	8
Race, Customized
Units: Subjects
Race: Caucasian	6	4	6	70	67	153
Race: N/A (as per local regulation)	1	1	0	10	7	19
Race: Black	0	0	0	0	2	2
Race: Asian	0	0	0	1	1	2
Race: Mixed	0	0	0	0	3	3
Ethnicity, Customized
Units: Subjects
Ethnicity: Hispanic/Latino	0	1	0	5	10	16
Ethnicity: Chinese	0	0	0	1	0	1
Ethnicity: Other	6	0	0	38	36	80
Ethnicity: N/A (as per local regulation)	1	1	6	32	30	70
Ethnicity: Unknown	0	2	0	5	4	11
Ethnicity: Mixed	0	1	0	0	0	1

End points

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Reporting group title

Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape

Reporting group description

Reporting group title

Phase 1 (mBC) Cohort 1 (DL -1): T-DM1 + Cape

Reporting group description

Reporting group title

Phase 1 (LA/mGC) Cohort 2 (DL -1): T-DM1 + Cape

Reporting group description

Reporting group title

Phase 2 (mBC): T-DM1 + Cape

Reporting group description

Reporting group title

Phase 2 (mBC): T-DM1

Reporting group description

Subject analysis set title

Phase 1 (mBC) Cohort 1: T-DM1 + Cape

Subject analysis set type

Sub-group analysis

Subject analysis set description

In Phase 1, Cohort 1 participants (with mBC) received trastuzumab emtansine at a dose of 3.6 mg/kg via IV infusion (on Day 1 [on Day 2 for Cycle 1] of each 21-day cycle) along with capecitabine at a dose level of 700 or 750 mg/m^2 via tablet orally twice daily on Days 1-14 of each 21-day cycle until unacceptable toxicity, withdrawal of consent, PD, death, reasons deemed by the treating physician, or study termination by the sponsor.

Subject analysis set title

Phase 1 (mBC) Cohort 1 (DL -1): T-DM1 + Cape

Subject analysis set type

Sub-group analysis

Subject analysis set description

In Phase 1, participants with mBC received trastuzumab emtansine at a dose of 3.6 mg/kg via IV infusion (on Day 1 [on Day 2 for Cycle 1] of each 21-day cycle) along with capecitabine at a dose level of 700 mg/m^2 via tablet orally twice daily on days 1-14 of each 21-day cycle until unacceptable toxicity, withdrawal of consent, PD, death, reasons deemed by the treating physician, or study termination by the sponsor.

Primary: Phase 1 (mBC): Percentage of Participants with Dose-Limiting Toxicities (DLTs)

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End point title

Phase 1 (mBC): Percentage of Participants with Dose-Limiting Toxicities (DLTs) ^[1] ^[2]

End point description

A DLT was defined as any one of the following study treatment-related toxicities: Uncomplicated Grade 4 thrombocytopenia that does not recover before Day 21; thrombocytopenia complicated with clinically significant bleeding requiring medical intervention; Grade 4 neutropenia lasting more than (>) 7 consecutive days; febrile neutropenia with absolute neutrophil count (ANC) less than (<) 1000 cells/millimeter cube (mm^3); Grade >/=3 diarrhea or Grade 3 hand-foot syndrome (in absence of dihydropyrimidine dehydrogenase [DPD] deficiency, only for DL 1); any other Grade >/=3 toxicity prohibiting start of Cycle 2; Grade 2 toxicity requiring treatment interruption for >14 days (>7 days for DL 1); for DL -1 only: <14 full doses of capecitabine; Cycle 2 dose level <100 percent (%). Analysis was performed on Phase 1 DLT-evaluable population for mBC cohort, which included all enrolled and treated mBC participants who did not experience any major protocol deviation and completed Cycle 1.

End point type

Primary

End point timeframe

Continuously during Cycle 1 (up to 3 weeks)

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: Results were reported descriptively and were not planned to be analyzed for statistically significant differences between groups.
[2] - 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: Reported analysis was planned to be carried out in the indicated arm(s) only.

End point values	Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape	Phase 1 (mBC) Cohort 1 (DL -1): T-DM1 + Cape
Number of subjects analysed	6	5
Units: percentage of participants
number (not applicable)	33.3	0.0

No statistical analyses for this end point

Primary: Phase 1 (mBC): MTD of Capecitabine when Combined with Trastuzumab Emtansine (3.6 mg/kg every 3 weeks)

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End point title

Phase 1 (mBC): MTD of Capecitabine when Combined with Trastuzumab Emtansine (3.6 mg/kg every 3 weeks) ^[3]

End point description

MTD was defined as the dose level for which the probability of DLT is equal to a protocol-specified target probability. A DLT was defined as any one of the following study treatment related toxicities: Uncomplicated Grade 4 thrombocytopenia that does not recover before Day 21; thrombocytopenia complicated with clinically significant bleeding requiring medical intervention; Grade 4 neutropenia lasting >7 consecutive days; febrile neutropenia with ANC <1000 cells/mm^3; Grade >/=3 diarrhea or Grade 3 hand-foot syndrome (in absence of DPD deficiency only for DL 1); any other Grade >/=3 toxicity prohibiting start of Cycle 2; Grade 2 toxicity requiring treatment interruption for >14 days (>7 days for DL 1); for DL -1 only: <14 full doses of capecitabine; Cycle 2 dose level <100%. Analysis was performed on Phase 1 DLT-evaluable population for mBC cohort.

End point type

Primary

End point timeframe

Continuously during Cycle 1 (up to 3 weeks)

Notes
[3] - 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: Results were reported descriptively and were not planned to be analyzed for statistically significant differences between groups.

End point values	Phase 1 (mBC) Cohort 1: T-DM1 + Cape
Number of subjects analysed	11
Units: mg/m^2
number (not applicable)	700

No statistical analyses for this end point

Primary: Phase 2 (mBC): Percentage of Participants with Best Overall Response (BOR) as Assessed by the Investigator According to RECIST v1.1

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End point title

Phase 2 (mBC): Percentage of Participants with Best Overall Response (BOR) as Assessed by the Investigator According to RECIST v1.1 ^[4]

End point description

Tumor response was assessed by the investigator according to RECIST v1.1. BOR was defined as percentage of participants with a complete response (CR) or partial response (PR) that was confirmed by repeat assessments >/=4 weeks after initial documentation. CR was defined as the disappearance of all target lesions (TLs) and non-TLs; short axis (SA) reduction to <10 millimeters (mm) for nodal TLs/non-TLs; and no new lesions. PR was defined as >/=30% decrease in sum of diameters (SoD) of TLs, taking as reference the baseline SoD; no progression in non-TLs; and no new lesions. The 90% confidence Interval (CI) was computed using Clopper-Pearson approach. Analysis was performed on Intent-to-Treat (ITT) Population, which included all participants in the randomized Phase 2 part of the study. Participants were analyzed as per the initial randomization. Participants without tumor assessment after start of study treatment were considered as non-responders.

End point type

Primary

End point timeframe

Baseline until CR/PR, consent withdrawal, or study end whichever occurred first (up to approximately 2.5 years overall)

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: Reported analysis was planned to be carried out in the indicated arm(s) only.

End point values	Phase 2 (mBC): T-DM1 + Cape	Phase 2 (mBC): T-DM1
Number of subjects analysed	81	80
Units: percentage of participants
number (confidence interval 90%)	44.4 (35.0 to 54.2)	36.3 (27.3 to 46.0)

Statistical Analysis 1

Comparison groups

Phase 2 (mBC): T-DM1 + Cape v Phase 2 (mBC): T-DM1

Number of subjects included in analysis

161

Analysis specification

Pre-specified

Analysis type

superiority ^[5]

P-value

= 0.336

Method

Fisher exact

Parameter type

Difference in Response Rates

Point estimate

8.2

Confidence interval

level

90%

sides

2-sided

lower limit

-4.5

upper limit

20.9

Notes
[5] - 90% CI was estimated using Hauck-Anderson approach.

Primary: Phase 1 (LA/mGC): Percentage of Participants with DLTs

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End point title

Phase 1 (LA/mGC): Percentage of Participants with DLTs ^[6] ^[7]

End point description

A DLT was defined as any one of the following study treatment related toxicities: Uncomplicated Grade 4 thrombocytopenia that does not recover before Day 21; thrombocytopenia complicated with clinically significant bleeding requiring medical intervention; Grade 4 neutropenia lasting >7 consecutive days; febrile neutropenia with ANC <1000 cells/mm^3; Grade >/=3 diarrhea or Grade 3 hand-foot syndrome; any other Grade >/=3 toxicity prohibiting start of Cycle 2; Grade 2 toxicity requiring treatment interruption for >14 days; <14 full doses of capecitabine; Cycle 2 dose level <100%. Analysis was performed on Phase 1 DLT-evaluable population for LA/mGC Cohort, which included all enrolled and treated LA/mGC participants who did not experience any major protocol deviation and completed Cycle 1.

End point type

Primary

End point timeframe

Continuously during 3 weeks

Notes
[6] - 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: Results were reported descriptively and were not planned to be analyzed for statistically significant differences between groups.
[7] - 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: Reported analysis was planned to be carried out in the indicated arm(s) only.

End point values	Phase 1 (LA/mGC) Cohort 2 (DL -1): T-DM1 + Cape
Number of subjects analysed	6
Units: percentage of participants
number (not applicable)	0.0

No statistical analyses for this end point

Primary: Phase 1 (LA/mGC): MTD of Capecitabine when Combined with Trastuzumab Emtansine (2.4 mg/kg QW)

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End point title

Phase 1 (LA/mGC): MTD of Capecitabine when Combined with Trastuzumab Emtansine (2.4 mg/kg QW) ^[8] ^[9]

End point description

MTD was defined as the dose level for which the probability of DLT is equal to a protocol-specified target probability. A DLT was defined as any one of the following study treatment related toxicities: Uncomplicated Grade 4 thrombocytopenia that does not recover before Day 21; thrombocytopenia complicated with clinically significant bleeding requiring medical intervention; Grade 4 neutropenia lasting >7 consecutive days; febrile neutropenia with ANC <1000 cells/mm^3; Grade >/=3 diarrhea or Grade 3 hand-foot syndrome; any other Grade >/=3 toxicity prohibiting start of Cycle 2; Grade 2 toxicity requiring treatment interruption for >14 days; <14 full doses of capecitabine; Cycle 2 dose level <100%. Analysis was performed on Phase 1 DLT-evaluable population for LA/mGC cohort.

End point type

Primary

End point timeframe

Continuously during 3 weeks

Notes
[8] - 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: Results were reported descriptively and were not planned to be analyzed for statistically significant differences between groups.
[9] - 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: Reported analysis was planned to be carried out in the indicated arm(s) only.

End point values	Phase 1 (LA/mGC) Cohort 2 (DL -1): T-DM1 + Cape
Number of subjects analysed	6
Units: mg/m^2
number (not applicable)	700

No statistical analyses for this end point

Secondary: Phase 1 (mBC): Percentage of Participants with BOR as Assessed by the Investigator According to RECIST v1.1

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End point title

Phase 1 (mBC): Percentage of Participants with BOR as Assessed by the Investigator According to RECIST v1.1 ^[10]

End point description

Tumor response was assessed by the investigator according to RECIST v1.1. BOR in Phase 1 was defined as percentage of participants with a CR or PR. CR was defined as the disappearance of all TLs and non-TLs; SA reduction to <10 mm for nodal TLs/non-TLs; and no new lesions. PR was defined as >/=30% decrease in SoD of TLs, taking as reference the baseline SoD; no progression in non-TLs; and no new lesions. Analysis was performed on Phase 1 DLT-evaluable population for mBC cohort.

End point type

Secondary

End point timeframe

Baseline until CR/PR, consent withdrawal, or study end whichever occurred first (up to approximately 3.5 years overall)

Notes
[10] - 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: Reported analysis was planned to be carried out in the indicated arm(s) only.

End point values	Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape	Phase 1 (mBC) Cohort 1 (DL -1): T-DM1 + Cape
Number of subjects analysed	6	5
Units: percentage of participants
number (not applicable)	83.3	100.0

No statistical analyses for this end point

Secondary: Phase 1 (mBC): Serum Concentration of Trastuzumab Emtansine

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End point title

Phase 1 (mBC): Serum Concentration of Trastuzumab Emtansine ^[11]

End point description

Analysis was performed on Phase 1 pharmacokinetic (PK) analysis population for mBC cohort, which included all mBC participants who received at least one dose of study medication during Phase 1 and had at least one reported serum or plasma result for PK.

End point type

Secondary

End point timeframe

Pre-trastuzumab emtansine dose (0 hour [h]) on Day 1 Cycle 2; 15-30 minutes (min) after end of trastuzumab emtansine infusion (maximum infusion duration = 90 min) on Day 2 Cycle 1 and Day 1 Cycle 2 (cycle length=21 days)

Notes
[11] - 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: Reported analysis was planned to be carried out in the indicated arm(s) only.

End point values	Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape	Phase 1 (mBC) Cohort 1 (DL -1): T-DM1 + Cape
Number of subjects analysed	7	6
Units: micrograms per milliliter (mcg/mL)
arithmetic mean (standard deviation)
Cycle 1, Post-dose	81.3 ( 13.3 )	78.6 ( 14.6 )
Cycle 2, Pre-dose	1.17 ( 1.25 )	2.1 ( 1.49 )
Cycle 2, Post-dose	70.5 ( 13.3 )	78.5 ( 14.9 )

No statistical analyses for this end point

Secondary: Phase 1 (mBC): Serum Concentration of Trastuzumab

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End point title

Phase 1 (mBC): Serum Concentration of Trastuzumab ^[12]

End point description

Trastuzumab was derived from trastuzumab emtansine. Analysis was performed on Phase 1 PK analysis population for mBC cohort.

End point type

Secondary

End point timeframe

Pre-trastuzumab emtansine dose (0 h) on Day 1 Cycle 2; 15-30 min after end of trastuzumab emtansine infusion (maximum infusion duration = 90 min) on Day 2 Cycle 1 and Day 1 Cycle 2 (cycle length=21 days)

Notes
[12] - 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: Reported analysis was planned to be carried out in the indicated arm(s) only.

End point values	Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape	Phase 1 (mBC) Cohort 1 (DL -1): T-DM1 + Cape
Number of subjects analysed	7	6
Units: mcg/mL
arithmetic mean (standard deviation)
Cycle 1, Post-dose	89.1 ( 24.37 )	92.9 ( 22.13 )
Cycle 2, Pre-dose	11.8 ( 13.28 )	14.0 ( 12.53 )
Cycle 2, Post-dose	74.8 ( 18.89 )	94.7 ( 24.60 )

No statistical analyses for this end point

Secondary: Phase 1 (mBC): Maximum Observed Plasma Concentration (Cmax) of Capecitabine

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End point title

Phase 1 (mBC): Maximum Observed Plasma Concentration (Cmax) of Capecitabine ^[13]

End point description

Cmax for Capecitabine was estimated from plasma concentration versus time data using non-compartmental methods of analysis. Reported dispersion values are for percent coefficient of variation (CV%). Analysis was performed on Phase 1 PK analysis population for mBC cohort.

End point type

Secondary

End point timeframe

Pre-capecitabine dose (0 h) and 0.5, 1, 1.5, 2, 2.5, 4, and 6 h post-capecitabine dose on Day 1 Cycle 1

Notes
[13] - 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: Reported analysis was planned to be carried out in the indicated arm(s) only.

End point values	Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape	Phase 1 (mBC) Cohort 1 (DL -1): T-DM1 + Cape
Number of subjects analysed	7	6
Units: nanograms per milliliter (ng/mL)
arithmetic mean (geometric coefficient of variation)	2990 ( 38.4 )	5652 ( 91.1 )

No statistical analyses for this end point

Secondary: Phase 1 (mBC): Area Under the Plasma Concentration-Time Curve From Time Zero to infinity (AUC[0-inf]) of Capecitabine

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End point title

Phase 1 (mBC): Area Under the Plasma Concentration-Time Curve From Time Zero to infinity (AUC[0-inf]) of Capecitabine ^[14]

End point description

AUC(0-inf) is the measure of total drug exposure and is dependent on the total amount of drug absorbed. AUC(0-inf) for capecitabine was estimated from plasma concentration versus time data using non-compartmental methods of analysis. Reported dispersion values are for CV%. Analysis was performed on Phase 1 PK analysis population for mBC cohort.

End point type

Secondary

End point timeframe

Pre-capecitabine dose (0 h) and 0.5, 1, 1.5, 2, 2.5, 4, and 6 h post-capecitabine dose on Day 1 Cycle 1

Notes
[14] - 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: Reported analysis was planned to be carried out in the indicated arm(s) only.

End point values	Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape	Phase 1 (mBC) Cohort 1 (DL -1): T-DM1 + Cape
Number of subjects analysed	7	6
Units: hoursnanograms per milliliter (hng/mL)
arithmetic mean (geometric coefficient of variation)	3973 ( 38.0 )	5440 ( 57.7 )

No statistical analyses for this end point

Secondary: Phase 1 (mBC): Plasma Terminal Half-Life (t1/2) of Capecitabine

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End point title

Phase 1 (mBC): Plasma Terminal Half-Life (t1/2) of Capecitabine ^[15]

End point description

Plasma terminal half-life is the time measured for the plasma drug concentration to decrease by one half during the elimination phase of the drug. t1/2 for capecitabine was estimated from plasma concentration versus time data using non-compartmental methods of analysis. Reported dispersion values are for CV%. Analysis was performed on Phase 1 PK analysis population for mBC cohort.

End point type

Secondary

End point timeframe

Pre-capecitabine dose (0 h) and 0.5, 1, 1.5, 2, 2.5, 4, and 6 h post-capecitabine dose on Day 1 Cycle 1

Notes
[15] - 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: Reported analysis was planned to be carried out in the indicated arm(s) only.

End point values	Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape	Phase 1 (mBC) Cohort 1 (DL -1): T-DM1 + Cape
Number of subjects analysed	7	6
Units: hours
arithmetic mean (geometric coefficient of variation)	0.70 ( 131.9 )	0.39 ( 38.8 )

No statistical analyses for this end point

Secondary: Phase 1 (mBC): Cmax of 5-Fluorouracil (Metabolite of Capecitabine)

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End point title

Phase 1 (mBC): Cmax of 5-Fluorouracil (Metabolite of Capecitabine) ^[16]

End point description

5-fluorouracil is a metabolite of capecitabine. Cmax for 5-fluorouracil was estimated from plasma concentration versus time data using non-compartmental methods of analysis. Reported dispersion values are for CV%. Analysis was performed on Phase 1 PK analysis population for mBC cohort.

End point type

Secondary

End point timeframe

Pre-capecitabine dose (0 h) and 0.5, 1, 1.5, 2, 2.5, 4, and 6 h post-capecitabine dose on Day 1 Cycle 1

Notes
[16] - 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: Reported analysis was planned to be carried out in the indicated arm(s) only.

End point values	Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape	Phase 1 (mBC) Cohort 1 (DL -1): T-DM1 + Cape
Number of subjects analysed	7	6
Units: ng/mL
arithmetic mean (geometric coefficient of variation)	148 ( 49.9 )	143 ( 45.6 )

No statistical analyses for this end point

Secondary: Phase 1 (mBC): AUC(0-inf) of 5-Fluorouracil (Metabolite of Capecitabine)

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End point title

Phase 1 (mBC): AUC(0-inf) of 5-Fluorouracil (Metabolite of Capecitabine) ^[17]

End point description

5-fluorouracil is a metabolite of capecitabine. AUC(0-inf) is the measure of total drug exposure and is dependent on the total amount of drug absorbed. AUC(0-inf) for 5-fluorouracil was estimated from plasma concentration versus time data using non-compartmental methods of analysis. Reported dispersion values are for CV%. Analysis was performed on Phase 1 PK analysis population for mBC cohort.

End point type

Secondary

End point timeframe

Pre-capecitabine dose (0 h) and 0.5, 1, 1.5, 2, 2.5, 4, and 6 h post-capecitabine dose on Day 1 Cycle 1

Notes
[17] - 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: Reported analysis was planned to be carried out in the indicated arm(s) only.

End point values	Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape	Phase 1 (mBC) Cohort 1 (DL -1): T-DM1 + Cape
Number of subjects analysed	7	6
Units: h*ng/mL
arithmetic mean (geometric coefficient of variation)	257 ( 49.9 )	244 ( 38.2 )

No statistical analyses for this end point

Secondary: Phase 1 (mBC): t1/2 of 5-Fluorouracil (Metabolite of Capecitabine)

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End point title

Phase 1 (mBC): t1/2 of 5-Fluorouracil (Metabolite of Capecitabine) ^[18]

End point description

5-fluorouracil is a metabolite of capecitabine. Plasma terminal half-life is the time measured for the plasma drug concentration to decrease by one half during the elimination phase of the drug. t1/2 for 5-fluorouracil was estimated from plasma concentration versus time data using non-compartmental methods of analysis. Reported dispersion values are for CV%. Analysis was performed on Phase 1 PK analysis population for mBC cohort.

End point type

Secondary

End point timeframe

Pre-capecitabine dose (0 h) and 0.5, 1, 1.5, 2, 2.5, 4, and 6 h post-capecitabine dose on Day 1 Cycle 1

Notes
[18] - 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: Reported analysis was planned to be carried out in the indicated arm(s) only.

End point values	Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape	Phase 1 (mBC) Cohort 1 (DL -1): T-DM1 + Cape
Number of subjects analysed	7	6
Units: hours
arithmetic mean (geometric coefficient of variation)	0.63 ( 39.5 )	0.64 ( 18.3 )

No statistical analyses for this end point

Secondary: Phase 2 (mBC): Time to Response (TTR) as Assessed by the Investigator According to RECIST v1.1

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End point title

Phase 2 (mBC): Time to Response (TTR) as Assessed by the Investigator According to RECIST v1.1 ^[19]

End point description

Tumor response was assessed by the investigator according to RECIST v1.1. TTR was defined as the time (in months) from randomization to first documentation of confirmed PR or CR (whichever occurred first). CR was defined as the disappearance of all TLs and non-TLs; SA reduction to <10 mm for nodal TLs/non-TLs; and no new lesions. PR was defined as >/=30% decrease in SoD of TLs, taking as reference the baseline SoD; no progression in non-TLs; and no new lesions. Analysis was performed on ITT Population. Only participants with a BOR of CR or PR were included in the analysis.

End point type

Secondary

End point timeframe

Baseline until first documentation of confirmed PR or CR, whichever occurred first (up to approximately 2.5 years overall)

Notes
[19] - 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: Reported analysis was planned to be carried out in the indicated arm(s) only.

End point values	Phase 2 (mBC): T-DM1 + Cape	Phase 2 (mBC): T-DM1
Number of subjects analysed	36	29
Units: months
median (full range (min-max))	2.10 (1.2 to 10.8)	2.10 (1.9 to 8.0)

No statistical analyses for this end point

Secondary: Phase 2 (mBC): Duration of Response (DoR) as Assessed by the Investigator According to RECIST v1.1

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End point title

Phase 2 (mBC): Duration of Response (DoR) as Assessed by the Investigator According to RECIST v1.1 ^[20]

End point description

DoR was defined as the time (in months) from the date of first recorded PR/CR until the date of PD or death from any cause. According to RECIST v1.1, CR: the disappearance of all TLs and non-TLs, SA reduction to <10 mm for nodal TLs/non-TLs, and no new lesions; PR: >/=30% decrease in SoD of TLs (taking as reference the baseline SoD), no progression in non-TLs, and no new lesions; PD: >/=20% relative increase with >/=5 mm of absolute increase in the SoD (taking as reference the smallest SoD recorded since treatment started), 1 or more new lesions, and/or unequivocal progression of non-TLs. Participants with no documented PD after CR/PR were censored at the time of last tumor assessment. Participants without post-baseline tumor assessment were censored at randomization plus 1 day. The median DOR and 90% CI were estimated using Kaplan-Meier method. ‘99999’=Upper limit of 90% CI could not be calculated due to insufficient number of participants who had an event.

End point type

Secondary

End point timeframe

From the documentation of response until PD, death, consent withdrawal, or study end whichever occurred first (up to approximately 2.5 years overall)

Notes
[20] - 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: Reported analysis was planned to be carried out in the indicated arm(s) only.

End point values	Phase 2 (mBC): T-DM1 + Cape	Phase 2 (mBC): T-DM1
Number of subjects analysed	36 ^[21]	29 ^[22]
Units: months
median (confidence interval 90%)	11.30 (8.61 to 99999)	12.22 (8.84 to 15.97)

Notes
[21] - ITT Population participants with a BOR of CR or PR were included in the analysis.
[22] - ITT Population participants with a BOR of CR or PR were included in the analysis.

No statistical analyses for this end point

Secondary: Phase 2 (mBC): Percentage of Participants with PD as Assessed by the Investigator According to RECIST v1.1

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End point title

Phase 2 (mBC): Percentage of Participants with PD as Assessed by the Investigator According to RECIST v1.1 ^[23]

End point description

Tumor response was assessed by the investigator according to RECIST v1.1. PD was defined as >/=20% relative increase with >/=5 mm of absolute increase in the SoD, taking as reference the smallest SoD recorded since treatment started; 1 or more new lesion(s); and/or unequivocal progression of non-TLs. Analysis was performed on ITT Population.

End point type

Secondary

End point timeframe

Baseline until PD, consent withdrawal, or study end whichever occurred first (up to approximately 2.5 years overall)

Notes
[23] - 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: Reported analysis was planned to be carried out in the indicated arm(s) only.

End point values	Phase 2 (mBC): T-DM1 + Cape	Phase 2 (mBC): T-DM1
Number of subjects analysed	81	80
Units: percentage of participants
number (not applicable)	64.2	70.0

No statistical analyses for this end point

Secondary: Phase 2 (mBC): Time to Progression (TTP) as Assessed by the Investigator According to RECIST v1.1

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End point title

Phase 2 (mBC): Time to Progression (TTP) as Assessed by the Investigator According to RECIST v1.1 ^[24]

End point description

Tumor response was assessed by the investigator according to RECIST v1.1. TTP was defined as the time (in months) from randomization to the first occurrence of PD. PD was defined as >/=20% relative increase with >/=5 mm of absolute increase in the SoD, taking as reference the smallest SoD recorded since treatment started; 1 or more new lesion(s); and/or unequivocal progression of non-TLs. Participants with no documented PD at the time of study end (including participants who died before PD) or who were lost to follow-up were censored on the date of the last tumor assessment. The median TTP and 90% CI was estimated using Kaplan-Meier method. Analysis was performed on ITT Population.

End point type

Secondary

End point timeframe

Baseline until PD, consent withdrawal, or study end whichever occurred first (up to approximately 2.5 years overall)

Notes
[24] - 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: Reported analysis was planned to be carried out in the indicated arm(s) only.

End point values	Phase 2 (mBC): T-DM1 + Cape	Phase 2 (mBC): T-DM1
Number of subjects analysed	81	80
Units: months
median (confidence interval 90%)	10.38 (7.85 to 12.91)	10.32 (7.56 to 13.27)

No statistical analyses for this end point

Secondary: Phase 2 (mBC): Percentage of Participants with Treatment Failure as Assessed by the Investigator According to RECIST v1.1

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End point title

Phase 2 (mBC): Percentage of Participants with Treatment Failure as Assessed by the Investigator According to RECIST v1.1 ^[25]

End point description

Treatment failure was defined as occurrence of any of the following event while on treatment: PD, death, withdrawal due to adverse event (AE) or laboratory abnormality, or refusal of treatment. PD as assessed by the investigator according to RECIST v1.1 was defined as >/=20% relative increase with >/=5 mm of absolute increase in the SoD, taking as reference the smallest SoD recorded since treatment started; 1 or more new lesion(s); and/or unequivocal progression of non-TLs. Analysis was performed on ITT Population.

End point type

Secondary

End point timeframe

Baseline until treatment failure, consent withdrawal, or study end whichever occurred first (up to approximately 2.5 years overall)

Notes
[25] - 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: Reported analysis was planned to be carried out in the indicated arm(s) only.

End point values	Phase 2 (mBC): T-DM1 + Cape	Phase 2 (mBC): T-DM1
Number of subjects analysed	81	80
Units: percentage of participants
number (not applicable)	77.8	83.8

No statistical analyses for this end point

Secondary: Phase 2 (mBC): Time to Treatment Failure (TTF) as Assessed by the Investigator According to RECIST v1.1

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End point title

Phase 2 (mBC): Time to Treatment Failure (TTF) as Assessed by the Investigator According to RECIST v1.1 ^[26]

End point description

TTF was defined as the time (in months) from randomization until treatment failure (PD, death, withdrawal due to AE or laboratory abnormality, or refusal of treatment). PD as assessed by the investigator according to RECIST v1.1 was defined as >/=20% relative increase with >/=5 mm of absolute increase in the SoD, taking as reference the smallest SoD recorded since treatment started; 1 or more new lesion(s); and/or unequivocal progression of non-TLs. Participants who did not experience any of the above events while on study were censored on the date of their last tumor assessment. The median TTF and 90% CI was estimated using Kaplan-Meier method. Analysis was performed on ITT Population.

End point type

Secondary

End point timeframe

Baseline until treatment failure, consent withdrawal, or study end whichever occurred first (up to approximately 2.5 years overall)

Notes
[26] - 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: Reported analysis was planned to be carried out in the indicated arm(s) only.

End point values	Phase 2 (mBC): T-DM1 + Cape	Phase 2 (mBC): T-DM1
Number of subjects analysed	81	80
Units: months
median (confidence interval 90%)	9.86 (7.62 to 10.68)	7.66 (6.54 to 10.68)

No statistical analyses for this end point

Secondary: Phase 2 (mBC): Percentage of Participants With PD as Assessed by the Investigator According to RECIST v1.1 or Death from any Cause

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End point title

Phase 2 (mBC): Percentage of Participants With PD as Assessed by the Investigator According to RECIST v1.1 or Death from any Cause ^[27]

End point description

End point type

Secondary

End point timeframe

Baseline until PD, death from any cause, consent withdrawal, or study end whichever occurred first (up to approximately 2.5 years overall)

Notes
[27] - 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: Reported analysis was planned to be carried out in the indicated arm(s) only.

End point values	Phase 2 (mBC): T-DM1 + Cape	Phase 2 (mBC): T-DM1
Number of subjects analysed	81	80
Units: percentage of participants
number (not applicable)	67.9	73.8

No statistical analyses for this end point

Secondary: Phase 2 (mBC): Progression-Free Survival (PFS) as Assessed by the Investigator According to RECIST v1.1

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End point title

Phase 2 (mBC): Progression-Free Survival (PFS) as Assessed by the Investigator According to RECIST v1.1 ^[28]

End point description

Tumor response was assessed by the investigator according to RECIST v1.1. PFS was defined as the time (in months) from randomization until the first documented PD or death from any cause, whichever occurred first. PD was defined as >/=20% relative increase with >/=5 mm of absolute increase in the SoD, taking as reference the smallest SoD recorded since treatment started; 1 or more new lesion(s); and/or unequivocal progression of non-TLs. Participants with no PFS events were censored on the date of the last tumor assessment. Participants without post-baseline tumor assessment were censored at randomization plus 1 day. The median PFS and 90% CI was estimated using Kaplan-Meier method. Analysis was performed on ITT Population.

End point type

Secondary

End point timeframe

Baseline until PD, death from any cause, consent withdrawal, or study end whichever occurred first (up to approximately 2.5 years overall)

Notes
[28] - 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: Reported analysis was planned to be carried out in the indicated arm(s) only.

End point values	Phase 2 (mBC): T-DM1 + Cape	Phase 2 (mBC): T-DM1
Number of subjects analysed	81	80
Units: months
median (confidence interval 90%)	10.15 (7.85 to 12.55)	9.82 (7.46 to 13.08)

No statistical analyses for this end point

Secondary: Phase 2 (mBC): Percentage of Participants with Clinical Benefit as Assessed by the Investigator According to RECIST v1.1

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End point title

Phase 2 (mBC): Percentage of Participants with Clinical Benefit as Assessed by the Investigator According to RECIST v1.1 ^[29]

End point description

The clinical benefit was defined as a confirmed response of CR, PR, or stable disease (SD) that lasted for at least 6 months. Tumor response was assessed by the investigator according to RECIST v1.1. CR: the disappearance of all TLs and non-TLs; SA reduction to <10 mm for nodal TLs/non-TLs; and no new lesions. PR: >/=30% decrease in SoD of TLs, taking as reference the baseline SoD; no progression in non-TLs; and no new lesions. PD: >/=20% relative increase with >/=5 mm of absolute increase in the SoD, taking as reference the smallest SoD recorded since treatment started; 1 or more new lesion(s); and/or unequivocal progression of non-TLs. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest SoD on study. The 90% CI was computed using Clopper-Pearson approach. Analysis was performed on ITT Population.

End point type

Secondary

End point timeframe

Baseline until clinical benefit response, consent withdrawal, or study end whichever occurred first (up to approximately 2.5 years overall)

Notes
[29] - 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: Reported analysis was planned to be carried out in the indicated arm(s) only.

End point values	Phase 2 (mBC): T-DM1 + Cape	Phase 2 (mBC): T-DM1
Number of subjects analysed	81	80
Units: percentage of participants
number (confidence interval 90%)	66.7 (57.1 to 75.3)	62.5 (52.7 to 71.6)

No statistical analyses for this end point

Secondary: Phase 2 (mBC): Percentage of Participants who Died of any Cause

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End point title

Phase 2 (mBC): Percentage of Participants who Died of any Cause ^[30]

End point description

Analysis was performed on ITT Population.

End point type

Secondary

End point timeframe

Baseline until death or study end whichever occurred first (up to approximately 2.5 years overall)

Notes
[30] - 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: Reported analysis was planned to be carried out in the indicated arm(s) only.

End point values	Phase 2 (mBC): T-DM1 + Cape	Phase 2 (mBC): T-DM1
Number of subjects analysed	81	80
Units: percentage of participants
number (not applicable)	22.2	26.3

No statistical analyses for this end point

Secondary: Phase 2 (mBC): Overall Survival (OS)

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End point title

Phase 2 (mBC): Overall Survival (OS) ^[31]

End point description

OS was defined as the time (in months) from randomization until death from any cause. Participants who were alive at the time of data cut-off were censored on the date of the last follow-up assessment. Participants who were lost to follow-up were censored on the date of last contact. The median OS and 90% CI was estimated using Kaplan-Meier method. Analysis was performed on ITT Population. The data ‘99999’ in the results signifies that Median and/or 90% CI could not be calculated due to insufficient number of participants who had an event.

End point type

Secondary

End point timeframe

Baseline until death or study end whichever occurred first (up to approximately 2.5 years overall)

Notes
[31] - 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: Reported analysis was planned to be carried out in the indicated arm(s) only.

End point values	Phase 2 (mBC): T-DM1 + Cape	Phase 2 (mBC): T-DM1
Number of subjects analysed	81	80
Units: months
median (confidence interval 90%)	99999 (99999 to 99999)	24.71 (24.28 to 99999)

No statistical analyses for this end point

Secondary: Phase 1 (LA/mGC): Percentage of Participants with BOR as Assessed by the Investigator According to RECIST v1.1

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End point title

Phase 1 (LA/mGC): Percentage of Participants with BOR as Assessed by the Investigator According to RECIST v1.1 ^[32]

End point description

End point type

Secondary

End point timeframe

Baseline until CR/PR, consent withdrawal, or study end whichever occurred first (up to approximately 1.5 years overall)

Notes
[32] - 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: Reported analysis was planned to be carried out in the indicated arm(s) only.

End point values	Phase 1 (LA/mGC) Cohort 2 (DL -1): T-DM1 + Cape
Number of subjects analysed	6
Units: percentage of participants
number (not applicable)	83.3

No statistical analyses for this end point

Secondary: Phase 1 (LA/mGC): Serum Concentration of Trastuzumab Emtansine

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End point title

Phase 1 (LA/mGC): Serum Concentration of Trastuzumab Emtansine ^[33]

End point description

Analysis was performed on Phase 1 PK analysis population for LA/mGC cohort.

End point type

Secondary

End point timeframe

Notes
[33] - 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: Reported analysis was planned to be carried out in the indicated arm(s) only.

End point values	Phase 1 (LA/mGC) Cohort 2 (DL -1): T-DM1 + Cape
Number of subjects analysed	6
Units: mcg/mL
arithmetic mean (standard deviation)
Cycle 1, Post-dose	30.1 ( 14.5 )
Cycle 2, Pre-dose	10.1 ( 5.85 )
Cycle 2, Post-dose	46.4 ( 7.74 )

No statistical analyses for this end point

Secondary: Phase 1 (LA/mGC): Serum Concentration of Trastuzumab

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End point title

Phase 1 (LA/mGC): Serum Concentration of Trastuzumab ^[34]

End point description

Trastuzumab was derived from trastuzumab emtansine. Analysis was performed on Phase 1 PK analysis population for LA/mGC cohort.

End point type

Secondary

End point timeframe

Notes
[34] - 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: Reported analysis was planned to be carried out in the indicated arm(s) only.

End point values	Phase 1 (LA/mGC) Cohort 2 (DL -1): T-DM1 + Cape
Number of subjects analysed	6
Units: mcg/mL
arithmetic mean (standard deviation)
Cycle 1, Post-dose	33.1 ( 15.98 )
Cycle 2, Pre-dose	18.5 ( 7.57 )
Cycle 2, Post-dose	57.6 ( 13.55 )

No statistical analyses for this end point

Secondary: Phase 1 (LA/mGC): Cmax of Capecitabine

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End point title

Phase 1 (LA/mGC): Cmax of Capecitabine ^[35]

End point description

Cmax for capecitabine was estimated from plasma concentration versus time data using non-compartmental methods of analysis. Reported dispersion values are for CV%. Analysis was performed on Phase 1 PK analysis population for LA/mGC cohort.

End point type

Secondary

End point timeframe

Pre-capecitabine dose (0 h) and 0.5, 1, 1.5, 2, 2.5, 4, and 6 h post-capecitabine dose on Day 1 Cycle 1

Notes
[35] - 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: Reported analysis was planned to be carried out in the indicated arm(s) only.

End point values	Phase 1 (LA/mGC) Cohort 2 (DL -1): T-DM1 + Cape
Number of subjects analysed	6
Units: ng/mL
arithmetic mean (geometric coefficient of variation)	4925 ( 36.3 )

No statistical analyses for this end point

Secondary: Phase 1 (LA/mGC): AUC(0-inf) of Capecitabine

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End point title

Phase 1 (LA/mGC): AUC(0-inf) of Capecitabine ^[36]

End point description

End point type

Secondary

End point timeframe

Pre-capecitabine dose (0h) and 0.5, 1, 1.5, 2, 2.5, 4, and 6 h post-capecitabine dose on Day 1 Cycle 1

Notes
[36] - 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: Reported analysis was planned to be carried out in the indicated arm(s) only.

End point values	Phase 1 (LA/mGC) Cohort 2 (DL -1): T-DM1 + Cape
Number of subjects analysed	6
Units: h*ng/mL
arithmetic mean (geometric coefficient of variation)	5131 ( 24.6 )

No statistical analyses for this end point

Secondary: Phase 1 (LA/mGC): t1/2 of Capecitabine

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End point title

Phase 1 (LA/mGC): t1/2 of Capecitabine ^[37]

End point description

End point type

Secondary

End point timeframe

Pre-capecitabine dose (0 h) and 0.5, 1, 1.5, 2, 2.5, 4, and 6 h post-capecitabine dose on Day 1 Cycle 1

Notes
[37] - 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: Reported analysis was planned to be carried out in the indicated arm(s) only.

End point values	Phase 1 (LA/mGC) Cohort 2 (DL -1): T-DM1 + Cape
Number of subjects analysed	6
Units: hours
arithmetic mean (geometric coefficient of variation)	0.65 ( 34.5 )

No statistical analyses for this end point

Secondary: Phase 1 (LA/mGC): Cmax of 5-Fluorouracil (Metabolite of Capecitabine)

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End point title

Phase 1 (LA/mGC): Cmax of 5-Fluorouracil (Metabolite of Capecitabine) ^[38]

End point description

End point type

Secondary

End point timeframe

Pre-capecitabine dose (0 h) and 0.5, 1, 1.5, 2, 2.5, 4, and 6 h post-capecitabine dose on Day 1 Cycle 1

Notes
[38] - 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: Reported analysis was planned to be carried out in the indicated arm(s) only.

End point values	Phase 1 (LA/mGC) Cohort 2 (DL -1): T-DM1 + Cape
Number of subjects analysed	6
Units: ng/mL
arithmetic mean (geometric coefficient of variation)	137 ( 24.3 )

No statistical analyses for this end point

Secondary: Phase 1 (LA/mGC): AUC(0-inf) of 5-Fluorouracil (Metabolite of Capecitabine)

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End point title

Phase 1 (LA/mGC): AUC(0-inf) of 5-Fluorouracil (Metabolite of Capecitabine) ^[39]

End point description

End point type

Secondary

End point timeframe

Pre-capecitabine dose (0 h) and 0.5, 1, 1.5, 2, 2.5, 4, and 6 h post-capecitabine dose on Day 1 Cycle 1

Notes
[39] - 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: Reported analysis was planned to be carried out in the indicated arm(s) only.

End point values	Phase 1 (LA/mGC) Cohort 2 (DL -1): T-DM1 + Cape
Number of subjects analysed	6
Units: h*ng/mL
arithmetic mean (geometric coefficient of variation)	213 ( 16.2 )

No statistical analyses for this end point

Secondary: Phase 1 (LA/mGC): t1/2 of 5-Fluorouracil (Metabolite of Capecitabine)

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End point title

Phase 1 (LA/mGC): t1/2 of 5-Fluorouracil (Metabolite of Capecitabine) ^[40]

End point description

End point type

Secondary

End point timeframe

Pre-capecitabine dose (0 h) and 0.5, 1, 1.5, 2, 2.5, 4, and 6 h post-capecitabine dose on Day 1 Cycle 1

Notes
[40] - 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: Reported analysis was planned to be carried out in the indicated arm(s) only.

End point values	Phase 1 (LA/mGC) Cohort 2 (DL -1): T-DM1 + Cape
Number of subjects analysed	6
Units: hours
arithmetic mean (geometric coefficient of variation)	0.83 ( 17.0 )

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Baseline up to 42 days after last dose (up to 4.5 years overall)

Adverse event reporting additional description

Safety population: Participants who received >/=1 dose of study drug, analyzed as per actual treatment received. In Phase 2, of 161 participants, 1 was randomized in error(received no treatment) and was excluded from safety analysis and 1 who was randomized to T-DM1 alone Arm received Capecitabine throughout study and was counted in T-DM1+Cape Arm.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

20.0

Reporting group title

Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape

Reporting group description

In Phase 1, participants with mBC received trastuzumab emtansine at a dose of 3.6 mg/kg via IV infusion (on Day 1 [on Day 2 for Cycle 1] of each 21-day cycle) along with capecitabine at a dose level of 750 mg/m^2 via tablet orally twice daily on days 1-14 of each 21-day cycle until unacceptable toxicity, withdrawal of consent, PD, death, reasons deemed by the treating physician, or study termination by the sponsor.

Reporting group title

Phase 1 (mBC) Cohort 1 (DL -1): T-DM1 + Cape

Reporting group description

Reporting group title

Phase 1 (LA/mGC) Cohort 2 (DL -1): T-DM1 + Cape

Reporting group description

In Phase 1, participants with LA/mGC received trastuzumab emtansine at a dose of 2.4 mg/kg via IV infusion on Day 1 (Day 2 of first week) QW along with capecitabine at a dose level of 700 mg/m^2 via tablet orally twice daily on days 1-14 followed by a 7-day rest period until unacceptable toxicity, withdrawal of consent, PD, death, reasons deemed by the treating physician, or study termination by the sponsor.

Reporting group title

Phase 2 (mBC): T-DM1 + Cape

Reporting group description

In Phase 2, participants with mBC received trastuzumab emtansine at a dose of 3.6 mg/kg via IV infusion on Day 1 of each 21-day cycle along with capecitabine at a dose level of 700 mg/m^2 via tablet orally twice daily on days 1-14 of each 21-day cycle until unacceptable toxicity, withdrawal of consent, PD, death, reasons deemed by the treating physician, or study termination by the sponsor.

Reporting group title

Phase 2 (mBC): T-DM1

Reporting group description

In Pahse 2, participants with mBC received trastuzumab emtansine at a dose of 3.6 mg/kg via IV infusion on Day 1 of each 21-day cycle until investigator-assessed PD, unacceptable toxicity, withdrawal of consent, death, reasons deemed by the treating physician, or study termination by the Sponsor.

Serious adverse events	Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape	Phase 1 (mBC) Cohort 1 (DL -1): T-DM1 + Cape	Phase 1 (LA/mGC) Cohort 2 (DL -1): T-DM1 + Cape	Phase 2 (mBC): T-DM1 + Cape	Phase 2 (mBC): T-DM1
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 7 (0.00%)	2 / 5 (40.00%)	4 / 6 (66.67%)	11 / 82 (13.41%)	10 / 78 (12.82%)
number of deaths (all causes)	4	3	3	18	21
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour haemorrhage
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	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
Surgical and medical procedures
Tumour excision
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	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
Reproductive system and breast disorders
Uterine polyp
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 82 (1.22%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pleural effusion
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	1 / 78 (1.28%)
occurrences causally related to treatment / all	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
Pleurisy
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	1 / 78 (1.28%)
occurrences causally related to treatment / all	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
Pulmonary embolism
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 82 (1.22%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	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
Investigations
Hepatic enzyme increased
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 82 (1.22%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	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
Injury, poisoning and procedural complications
Radiation necrosis
subjects affected / exposed	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	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
Fracture displacement
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	1 / 78 (1.28%)
occurrences causally related to treatment / all	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
Cardiac disorders
Myocardial infarction
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	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
Nervous system disorders
Brain oedema
subjects affected / exposed	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	1 / 82 (1.22%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebral cyst
subjects affected / exposed	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	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
Sciatica
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 82 (1.22%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Thrombocytopenia
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 82 (1.22%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	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
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	1 / 82 (1.22%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	2 / 82 (2.44%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	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
Colitis ischaemic
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 82 (1.22%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	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
Intestinal haematoma
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	1 / 78 (1.28%)
occurrences causally related to treatment / all	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
Mesenteric vein thrombosis
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 82 (1.22%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	1 / 78 (1.28%)
occurrences causally related to treatment / all	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
Hepatobiliary disorders
Cholecystitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	1 / 78 (1.28%)
occurrences causally related to treatment / all	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
Hepatocellular injury
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	1 / 78 (1.28%)
occurrences causally related to treatment / all	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
Renal and urinary disorders
Renal colic
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	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
Haematuria
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 82 (1.22%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	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
Anuria
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 82 (1.22%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Muscular weakness
subjects affected / exposed	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	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
Pathological fracture
subjects affected / exposed	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	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
Infections and infestations
Device related sepsis
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	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
Gastroenteritis
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	1 / 78 (1.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bacterial sepsis
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	1 / 78 (1.28%)
occurrences causally related to treatment / all	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
Device related infection
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	1 / 78 (1.28%)
occurrences causally related to treatment / all	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
Upper respiratory tract infection
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	1 / 78 (1.28%)
occurrences causally related to treatment / all	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
Urinary tract infection
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 82 (1.22%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Wound sepsis
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	1 / 78 (1.28%)
occurrences causally related to treatment / all	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
Metabolism and nutrition disorders
Diabetes mellitus
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	1 / 78 (1.28%)
occurrences causally related to treatment / all	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
Hyperglycaemia
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 82 (1.22%)	0 / 78 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape	Phase 1 (mBC) Cohort 1 (DL -1): T-DM1 + Cape	Phase 1 (LA/mGC) Cohort 2 (DL -1): T-DM1 + Cape	Phase 2 (mBC): T-DM1 + Cape	Phase 2 (mBC): T-DM1
Total subjects affected by non serious adverse events
subjects affected / exposed	7 / 7 (100.00%)	5 / 5 (100.00%)	6 / 6 (100.00%)	75 / 82 (91.46%)	64 / 78 (82.05%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Skin papilloma
subjects affected / exposed	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	1	0	0	0
Vascular disorders
Flushing
subjects affected / exposed	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	1	0	0	0	0
Bloody discharge
subjects affected / exposed	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	1	0	0	0
Hot flush
subjects affected / exposed	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	1	0	0	0	0
Thrombosis
subjects affected / exposed	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	1	0	0	0	0
Deep vein thrombosis
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	0	1	0	0
Hypertension
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	0	1	0	0
Surgical and medical procedures
Skin lesion excision
subjects affected / exposed	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	1	0	0	0	0
Tooth extraction
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	0	1	0	0
Tumour excision
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	0	1	0	0
General disorders and administration site conditions
Non-cardiac chest pain
subjects affected / exposed	1 / 7 (14.29%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	17	1	0	0	0
Fatigue
subjects affected / exposed	2 / 7 (28.57%)	1 / 5 (20.00%)	4 / 6 (66.67%)	10 / 82 (12.20%)	11 / 78 (14.10%)
occurrences all number	4	6	5	13	18
Asthenia
subjects affected / exposed	3 / 7 (42.86%)	1 / 5 (20.00%)	0 / 6 (0.00%)	17 / 82 (20.73%)	15 / 78 (19.23%)
occurrences all number	3	3	0	37	77
Chills
subjects affected / exposed	2 / 7 (28.57%)	1 / 5 (20.00%)	0 / 6 (0.00%)	1 / 82 (1.22%)	5 / 78 (6.41%)
occurrences all number	2	1	0	1	5
Gait disturbance
subjects affected / exposed	1 / 7 (14.29%)	2 / 5 (40.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	3	2	0	0	0
Peripheral swelling
subjects affected / exposed	2 / 7 (28.57%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	5	0	0	0	0
Pain
subjects affected / exposed	2 / 7 (28.57%)	2 / 5 (40.00%)	1 / 6 (16.67%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	2	2	1	0	0
Pyrexia
subjects affected / exposed	2 / 7 (28.57%)	0 / 5 (0.00%)	1 / 6 (16.67%)	13 / 82 (15.85%)	15 / 78 (19.23%)
occurrences all number	2	0	1	28	34
Mucosal inflammation
subjects affected / exposed	2 / 7 (28.57%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	2	1	0	0	0
Oedema peripheral
subjects affected / exposed	1 / 7 (14.29%)	1 / 5 (20.00%)	2 / 6 (33.33%)	3 / 82 (3.66%)	4 / 78 (5.13%)
occurrences all number	2	1	2	5	6
Influenza like illness
subjects affected / exposed	0 / 7 (0.00%)	1 / 5 (20.00%)	2 / 6 (33.33%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	2	2	0	0
Malaise
subjects affected / exposed	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	2	0	0	0	0
Catheter site rash
subjects affected / exposed	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	1	0	0	0
Mucosal dryness
subjects affected / exposed	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	1	0	0	0
Impaired healing
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	0	1	0	0
Immune system disorders
Hypersensitivity
subjects affected / exposed	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	1	0	0	0
Reproductive system and breast disorders
Breast mass
subjects affected / exposed	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	1	0	0	0
Benign prostatic hyperplasia
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	0	1	0	0
Respiratory, thoracic and mediastinal disorders
Epistaxis
subjects affected / exposed	4 / 7 (57.14%)	3 / 5 (60.00%)	1 / 6 (16.67%)	15 / 82 (18.29%)	10 / 78 (12.82%)
occurrences all number	12	14	1	22	18
Cough
subjects affected / exposed	2 / 7 (28.57%)	2 / 5 (40.00%)	2 / 6 (33.33%)	5 / 82 (6.10%)	6 / 78 (7.69%)
occurrences all number	4	3	2	5	7
Rhinorrhoea
subjects affected / exposed	1 / 7 (14.29%)	3 / 5 (60.00%)	1 / 6 (16.67%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	1	5	1	0	0
Haemoptysis
subjects affected / exposed	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	1	0	0	0	0
Nasal ulcer
subjects affected / exposed	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	1	0	0	0	0
Oropharyngeal pain
subjects affected / exposed	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	1	0	0	0	0
Pleural effusion
subjects affected / exposed	0 / 7 (0.00%)	1 / 5 (20.00%)	1 / 6 (16.67%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	1	1	0	0
Rhinitis allergic
subjects affected / exposed	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	1	0	0	0
Sleep apnoea syndrome
subjects affected / exposed	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	1	0	0	0	0
Dyspnoea
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	2 / 82 (2.44%)	4 / 78 (5.13%)
occurrences all number	0	0	1	3	5
Nasal inflammation
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	0	1	0	0
Productive cough
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	0	1	0	0
Rales
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	0	1	0	0
Sinus disorder
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	0	1	0	0
Psychiatric disorders
Insomnia
subjects affected / exposed	2 / 7 (28.57%)	1 / 5 (20.00%)	2 / 6 (33.33%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	2	2	2	0	0
Depression
subjects affected / exposed	1 / 7 (14.29%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	2	1	0	0	0
Affect lability
subjects affected / exposed	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	1	0	0	0	0
Confusional state
subjects affected / exposed	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	1	0	0	0
Investigations
Aspartate aminotransferase increased
subjects affected / exposed	4 / 7 (57.14%)	1 / 5 (20.00%)	1 / 6 (16.67%)	27 / 82 (32.93%)	31 / 78 (39.74%)
occurrences all number	5	2	1	49	63
Platelet count decreased
subjects affected / exposed	4 / 7 (57.14%)	0 / 5 (0.00%)	0 / 6 (0.00%)	12 / 82 (14.63%)	13 / 78 (16.67%)
occurrences all number	5	0	0	23	33
Alanine aminotransferase increased
subjects affected / exposed	4 / 7 (57.14%)	0 / 5 (0.00%)	1 / 6 (16.67%)	20 / 82 (24.39%)	24 / 78 (30.77%)
occurrences all number	4	0	1	31	48
Blood bilirubin increased
subjects affected / exposed	1 / 7 (14.29%)	0 / 5 (0.00%)	1 / 6 (16.67%)	6 / 82 (7.32%)	4 / 78 (5.13%)
occurrences all number	2	0	1	23	8
Blood lactate dehydrogenase increased
subjects affected / exposed	1 / 7 (14.29%)	0 / 5 (0.00%)	2 / 6 (33.33%)	9 / 82 (10.98%)	10 / 78 (12.82%)
occurrences all number	2	0	2	11	14
Gamma-glutamyltransferase increased
subjects affected / exposed	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 6 (0.00%)	8 / 82 (9.76%)	16 / 78 (20.51%)
occurrences all number	2	0	0	15	24
Aspartate aminotransferase
subjects affected / exposed	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	1	0	0	0	0
Transaminases increased
subjects affected / exposed	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	1	0	0	0	0
Weight decreased
subjects affected / exposed	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	1	0	0	0
White blood cell count decreased
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	0	3	0	0
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	5 / 82 (6.10%)	15 / 78 (19.23%)
occurrences all number	0	0	1	5	24
Blood creatinine increased
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	0	1	0	0
International normalised ratio increased
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	0	1	0	0
Neutrophil count decreased
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	0	1	0	0
Liver palpable
subjects affected / exposed	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	1	0	0	0
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	2 / 7 (28.57%)	3 / 5 (60.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	6	5	0	0	0
Procedural headache
subjects affected / exposed	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	3	0	0	0
Arthropod sting
subjects affected / exposed	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	2	0	0	0
Eye contusion
subjects affected / exposed	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	1	0	0	0	0
Skin abrasion
subjects affected / exposed	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	1	0	0	0	0
Skin injury
subjects affected / exposed	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	1	0	0	0	0
Periorbital haematoma
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	0	1	0	0
Thermal burn
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	0	1	0	0
Congenital, familial and genetic disorders
Gilbert's syndrome
subjects affected / exposed	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	1	0	0	0
Cardiac disorders
Cardiac failure
subjects affected / exposed	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	1	0	0	0
Tachycardia
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	1 / 82 (1.22%)	5 / 78 (6.41%)
occurrences all number	0	0	1	1	5
Sinus tachycardia
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	0	1	0	0
Nervous system disorders
Headache
subjects affected / exposed	4 / 7 (57.14%)	3 / 5 (60.00%)	0 / 6 (0.00%)	8 / 82 (9.76%)	5 / 78 (6.41%)
occurrences all number	12	8	0	8	8
Neuropathy peripheral
subjects affected / exposed	2 / 7 (28.57%)	2 / 5 (40.00%)	0 / 6 (0.00%)	2 / 82 (2.44%)	4 / 78 (5.13%)
occurrences all number	6	6	0	4	8
Dizziness
subjects affected / exposed	1 / 7 (14.29%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	3	1	0	0	0
Migraine
subjects affected / exposed	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	4	0	0	0
Balance disorder
subjects affected / exposed	1 / 7 (14.29%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	1	1	0	0	0
Hypoaesthesia
subjects affected / exposed	2 / 7 (28.57%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	2	0	0	0	0
Amnesia
subjects affected / exposed	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	1	0	0	0	0
Aphonia
subjects affected / exposed	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	1	0	0	0	0
Hemiparesis
subjects affected / exposed	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	1	0	0	0
Neuralgia
subjects affected / exposed	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	1	0	0	0	0
Neurotoxicity
subjects affected / exposed	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	1	0	0	0	0
Seizure
subjects affected / exposed	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	1	0	0	0
Tremor
subjects affected / exposed	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	1	0	0	0
Vocal cord paralysis
subjects affected / exposed	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	1	0	0	0	0
Paraesthesia
subjects affected / exposed	1 / 7 (14.29%)	0 / 5 (0.00%)	1 / 6 (16.67%)	5 / 82 (6.10%)	2 / 78 (2.56%)
occurrences all number	1	0	1	5	3
Dysgeusia
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	2 / 6 (33.33%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	0	2	0	0
Syncope
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	0	2	0	0
Peripheral sensory neuropathy
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	0	1	0	0
Restless legs syndrome
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	0	1	0	0
Blood and lymphatic system disorders
Thrombocytopenia
subjects affected / exposed	3 / 7 (42.86%)	4 / 5 (80.00%)	0 / 6 (0.00%)	35 / 82 (42.68%)	21 / 78 (26.92%)
occurrences all number	6	6	0	93	35
Neutropenia
subjects affected / exposed	2 / 7 (28.57%)	1 / 5 (20.00%)	0 / 6 (0.00%)	13 / 82 (15.85%)	6 / 78 (7.69%)
occurrences all number	3	1	0	19	6
Anaemia
subjects affected / exposed	2 / 7 (28.57%)	1 / 5 (20.00%)	4 / 6 (66.67%)	9 / 82 (10.98%)	13 / 78 (16.67%)
occurrences all number	2	1	6	12	15
Lymphadenopathy
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	0	1	0	0
Ear and labyrinth disorders
Tinnitus
subjects affected / exposed	1 / 7 (14.29%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	2	2	0	0	0
Deafness unilateral
subjects affected / exposed	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	1	0	0	0	0
Middle ear effusion
subjects affected / exposed	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	1	0	0	0	0
Vertigo
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	2 / 6 (33.33%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	0	3	0	0
Eye disorders
Dry eye
subjects affected / exposed	1 / 7 (14.29%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	1	2	0	0	0
Lacrimation increased
subjects affected / exposed	2 / 7 (28.57%)	1 / 5 (20.00%)	1 / 6 (16.67%)	6 / 82 (7.32%)	3 / 78 (3.85%)
occurrences all number	2	1	3	9	3
Ocular hyperaemia
subjects affected / exposed	2 / 7 (28.57%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	3	0	0	0	0
Eye haemorrhage
subjects affected / exposed	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	2	0	0	0
Eye pain
subjects affected / exposed	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	2	0	0	0
Blepharospasm
subjects affected / exposed	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	1	0	0	0
Blindness
subjects affected / exposed	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	1	0	0	0	0
Keratitis
subjects affected / exposed	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	1	0	0	0	0
Pterygium
subjects affected / exposed	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	1	0	0	0	0
Retinal ischaemia
subjects affected / exposed	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	1	0	0	0	0
Vision blurred
subjects affected / exposed	0 / 7 (0.00%)	1 / 5 (20.00%)	1 / 6 (16.67%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	1	1	0	0
Visual impairment
subjects affected / exposed	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	1	0	0	0	0
Gastrointestinal disorders
Nausea
subjects affected / exposed	3 / 7 (42.86%)	4 / 5 (80.00%)	3 / 6 (50.00%)	27 / 82 (32.93%)	18 / 78 (23.08%)
occurrences all number	15	10	5	44	55
Diarrhoea
subjects affected / exposed	2 / 7 (28.57%)	3 / 5 (60.00%)	1 / 6 (16.67%)	7 / 82 (8.54%)	7 / 78 (8.97%)
occurrences all number	9	4	1	12	10
Constipation
subjects affected / exposed	3 / 7 (42.86%)	4 / 5 (80.00%)	4 / 6 (66.67%)	8 / 82 (9.76%)	8 / 78 (10.26%)
occurrences all number	3	6	4	9	18
Gingival bleeding
subjects affected / exposed	2 / 7 (28.57%)	3 / 5 (60.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	2	6	0	0	0
Vomiting
subjects affected / exposed	2 / 7 (28.57%)	1 / 5 (20.00%)	1 / 6 (16.67%)	16 / 82 (19.51%)	8 / 78 (10.26%)
occurrences all number	6	1	1	17	9
Abdominal pain upper
subjects affected / exposed	2 / 7 (28.57%)	3 / 5 (60.00%)	1 / 6 (16.67%)	6 / 82 (7.32%)	5 / 78 (6.41%)
occurrences all number	2	4	1	11	5
Dry mouth
subjects affected / exposed	1 / 7 (14.29%)	2 / 5 (40.00%)	1 / 6 (16.67%)	3 / 82 (3.66%)	6 / 78 (7.69%)
occurrences all number	1	5	1	4	8
Toothache
subjects affected / exposed	2 / 7 (28.57%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	3	1	0	0	0
Abdominal distension
subjects affected / exposed	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	2	0	0	0
Abdominal pain
subjects affected / exposed	2 / 7 (28.57%)	0 / 5 (0.00%)	2 / 6 (33.33%)	7 / 82 (8.54%)	2 / 78 (2.56%)
occurrences all number	2	0	2	7	2
Haematochezia
subjects affected / exposed	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	2	0	0	0	0
Rectal haemorrhage
subjects affected / exposed	1 / 7 (14.29%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	1	1	0	0	0
Anal fissure
subjects affected / exposed	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	1	0	0	0	0
Anal haemorrhage
subjects affected / exposed	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	1	0	0	0	0
Chapped lips
subjects affected / exposed	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	1	0	0	0
Dental caries
subjects affected / exposed	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	1	0	0	0	0
Dyspepsia
subjects affected / exposed	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	1	0	0	0
Dysphagia
subjects affected / exposed	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	1	0	0	0	0
Eructation
subjects affected / exposed	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	1	0	0	0
Flatulence
subjects affected / exposed	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	1	0	0	0
Frequent bowel movements
subjects affected / exposed	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	1	0	0	0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	1	0	0	0
Gingival pain
subjects affected / exposed	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	1	0	0	0	0
Glossodynia
subjects affected / exposed	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	1	0	0	0
Haemorrhoidal haemorrhage
subjects affected / exposed	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	1	0	0	0
Hypoaesthesia oral
subjects affected / exposed	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	1	0	0	0	0
Ascites
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	0	1	0	0
Melaena
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	2 / 6 (33.33%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	0	2	0	0
Stomatitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	2 / 6 (33.33%)	3 / 82 (3.66%)	5 / 78 (6.41%)
occurrences all number	0	0	2	4	6
Gastric haemorrhage
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	0	1	0	0
Gastritis
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	4 / 78 (5.13%)
occurrences all number	0	0	0	0	4
Hepatobiliary disorders
Hyperbilirubinaemia
subjects affected / exposed	1 / 7 (14.29%)	2 / 5 (40.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	2	8	0	0	0
Hepatocellular injury
subjects affected / exposed	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	2	0	0	0	0
Jaundice
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	0	1	0	0
Skin and subcutaneous tissue disorders
Palmar-plantar erythrodysaesthesia syndrome
subjects affected / exposed	3 / 7 (42.86%)	2 / 5 (40.00%)	1 / 6 (16.67%)	17 / 82 (20.73%)	2 / 78 (2.56%)
occurrences all number	5	3	1	18	2
Rash macular
subjects affected / exposed	2 / 7 (28.57%)	3 / 5 (60.00%)	1 / 6 (16.67%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	3	4	1	0	0
Dry skin
subjects affected / exposed	1 / 7 (14.29%)	2 / 5 (40.00%)	1 / 6 (16.67%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	1	3	1	0	0
Rash
subjects affected / exposed	1 / 7 (14.29%)	2 / 5 (40.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	2	2	0	0	0
Pruritus
subjects affected / exposed	2 / 7 (28.57%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	2	1	0	0	0
Macule
subjects affected / exposed	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	2	0	0	0
Acne
subjects affected / exposed	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	1	0	0	0	0
Alopecia
subjects affected / exposed	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 82 (1.22%)	5 / 78 (6.41%)
occurrences all number	1	0	0	1	5
Blister
subjects affected / exposed	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	1	0	0	0	0
Dermatitis acneiform
subjects affected / exposed	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	1	0	0	0	0
Ecchymosis
subjects affected / exposed	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	1	0	0	0
Eczema
subjects affected / exposed	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	1	0	0	0
Ingrowing nail
subjects affected / exposed	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	1	0	0	0	0
Nail discolouration
subjects affected / exposed	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	1	0	0	0
Onycholysis
subjects affected / exposed	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	1	0	0	0	0
Rash erythematous
subjects affected / exposed	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	1	0	0	0	0
Rash maculo-papular
subjects affected / exposed	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	1	0	0	0	0
Rash pruritic
subjects affected / exposed	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	1	0	0	0	0
Skin discolouration
subjects affected / exposed	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	1	0	0	0
Skin mass
subjects affected / exposed	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	1	0	0	0	0
Skin ulcer
subjects affected / exposed	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	1	0	0	0	0
Swelling face
subjects affected / exposed	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	1	0	0	0	0
Onychoclasis
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	2 / 6 (33.33%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	0	2	0	0
Erythema
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	0	1	0	0
Erythema multiforme
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	0	1	0	0
Rash papular
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	0	1	0	0
Spider naevus
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	0	1	0	0
Telangiectasia
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	0	1	0	0
Renal and urinary disorders
Dysuria
subjects affected / exposed	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	1	0	0	0	0
Endocrine disorders
Cushingoid
subjects affected / exposed	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	1	0	0	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	3 / 7 (42.86%)	1 / 5 (20.00%)	2 / 6 (33.33%)	11 / 82 (13.41%)	9 / 78 (11.54%)
occurrences all number	12	3	2	14	9
Back pain
subjects affected / exposed	2 / 7 (28.57%)	2 / 5 (40.00%)	1 / 6 (16.67%)	4 / 82 (4.88%)	4 / 78 (5.13%)
occurrences all number	6	4	1	4	4
Muscle spasms
subjects affected / exposed	2 / 7 (28.57%)	2 / 5 (40.00%)	1 / 6 (16.67%)	5 / 82 (6.10%)	0 / 78 (0.00%)
occurrences all number	5	5	2	6	0
Muscular weakness
subjects affected / exposed	1 / 7 (14.29%)	2 / 5 (40.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	2	3	0	0	0
Musculoskeletal pain
subjects affected / exposed	3 / 7 (42.86%)	1 / 5 (20.00%)	0 / 6 (0.00%)	4 / 82 (4.88%)	6 / 78 (7.69%)
occurrences all number	3	2	0	5	8
Myalgia
subjects affected / exposed	1 / 7 (14.29%)	2 / 5 (40.00%)	1 / 6 (16.67%)	7 / 82 (8.54%)	2 / 78 (2.56%)
occurrences all number	1	3	1	8	3
Pain in extremity
subjects affected / exposed	2 / 7 (28.57%)	0 / 5 (0.00%)	0 / 6 (0.00%)	3 / 82 (3.66%)	5 / 78 (6.41%)
occurrences all number	4	0	0	3	5
Bone pain
subjects affected / exposed	1 / 7 (14.29%)	1 / 5 (20.00%)	1 / 6 (16.67%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	1	2	2	0	0
Joint stiffness
subjects affected / exposed	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	3	0	0	0	0
Joint swelling
subjects affected / exposed	2 / 7 (28.57%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	3	0	0	0	0
Musculoskeletal chest pain
subjects affected / exposed	1 / 7 (14.29%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	2	1	0	0	0
Neck pain
subjects affected / exposed	1 / 7 (14.29%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	2	1	0	0	0
Joint range of motion decreased
subjects affected / exposed	2 / 7 (28.57%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	2	0	0	0	0
Muscle twitching
subjects affected / exposed	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	2	0	0	0
Musculoskeletal stiffness
subjects affected / exposed	1 / 7 (14.29%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	1	1	0	0	0
Arthritis
subjects affected / exposed	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	1	0	0	0	0
Coccydynia
subjects affected / exposed	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	1	0	0	0
Flank pain
subjects affected / exposed	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	1	0	0	0	0
Groin pain
subjects affected / exposed	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	1	0	0	0
Limb mass
subjects affected / exposed	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	1	0	0	0	0
Osteonecrosis of jaw
subjects affected / exposed	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	1	0	0	0
Tendonitis
subjects affected / exposed	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	1	0	0	0
Weight bearing difficulty
subjects affected / exposed	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	1	0	0	0
Infections and infestations
Influenza
subjects affected / exposed	2 / 7 (28.57%)	2 / 5 (40.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	3	5	0	0	0
Urinary tract infection
subjects affected / exposed	2 / 7 (28.57%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	5	0	0	0	0
Viral upper respiratory tract infection
subjects affected / exposed	1 / 7 (14.29%)	2 / 5 (40.00%)	2 / 6 (33.33%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	1	3	2	0	0
Conjunctivitis
subjects affected / exposed	1 / 7 (14.29%)	1 / 5 (20.00%)	1 / 6 (16.67%)	1 / 82 (1.22%)	4 / 78 (5.13%)
occurrences all number	1	1	3	1	4
Cystitis
subjects affected / exposed	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	2	0	0	0	0
Herpes zoster
subjects affected / exposed	2 / 7 (28.57%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	2	0	0	0	0
Pharyngitis
subjects affected / exposed	1 / 7 (14.29%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	1	1	0	0	0
Pneumonia
subjects affected / exposed	1 / 7 (14.29%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	1	1	0	0	0
Sinusitis
subjects affected / exposed	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	2	0	0	0	0
Ear infection
subjects affected / exposed	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	1	0	0	0	0
Eye infection
subjects affected / exposed	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	1	0	0	0	0
Folliculitis
subjects affected / exposed	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	1	0	0	0	0
Fungal skin infection
subjects affected / exposed	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	1	0	0	0
Furuncle
subjects affected / exposed	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	1	0	0	0	0
Laryngitis
subjects affected / exposed	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	1	0	0	0	0
Localised infection
subjects affected / exposed	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	1	0	0	0	0
Oral candidiasis
subjects affected / exposed	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	1	0	0	0	0
Paronychia
subjects affected / exposed	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	1	0	0	0
Oral herpes
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	0	1	0	0
Pleural infection
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	0	1	0	0
Skin infection
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	0	1	0	0
Streptococcal infection
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	0	1	0	0
Upper respiratory tract infection
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	5 / 82 (6.10%)	1 / 78 (1.28%)
occurrences all number	0	0	0	5	1
Metabolism and nutrition disorders
Hypomagnesaemia
subjects affected / exposed	1 / 7 (14.29%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	10	3	0	0	0
Hypokalaemia
subjects affected / exposed	2 / 7 (28.57%)	2 / 5 (40.00%)	0 / 6 (0.00%)	4 / 82 (4.88%)	4 / 78 (5.13%)
occurrences all number	5	2	0	4	10
Decreased appetite
subjects affected / exposed	2 / 7 (28.57%)	0 / 5 (0.00%)	2 / 6 (33.33%)	10 / 82 (12.20%)	11 / 78 (14.10%)
occurrences all number	2	0	3	21	41
Cell death
subjects affected / exposed	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	1	0	0	0
Hypoalbuminaemia
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	2 / 6 (33.33%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	0	2	0	0
Hyperkalaemia
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	0	1	0	0
Hyponatraemia
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	0	1	0	0
Hypoproteinaemia
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 82 (0.00%)	0 / 78 (0.00%)
occurrences all number	0	0	1	0	0
Hyperglycaemia
subjects affected / exposed	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	3 / 82 (3.66%)	5 / 78 (6.41%)
occurrences all number	0	0	0	7	8

More information

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Were there any global substantial amendments to the protocol? Yes

03 Sep 2013

Dose modification guidance and DLT definition were updated in line with the most recent investigator brochure (IB) (Version 7.0); Participant retention on combination regimen was clarified to allow an additional safety follow-up and collection of tumor response data from these participants; Design of the Phase 2 part of the study was changed to the open-label, randomized exploration of efficacy and safety of the combination of trastuzumab emtansine with capecitabine compared with trastuzumab emtansine alone. Number of participants to be enrolled into Phase 2 was changed accordingly; The IDMC for Phase 2 was introduced to monitor safety outcomes.

30 Jun 2014

Design of the study was changed to increase the sample size for the randomized Phase 2 part from 117 participants to 210 participants; The protocol was simplified following the determination of the MTD in Phase 1 to remove information relating to dose de-escalation that was no longer relevant; The advice on contraception was updated in line with the latest trastuzumab (Herceptin) IB (Version 14).

23 Mar 2016

The section of risks associated with capecitabine was updated following the inclusion of the contraindication in the capecitabine summary of product characteristics (SmPC) for participants with known complete absence of DPD activity; Side effects associated with capecitabine were updated; Information regarding the risk of taking leucovorin was added as it may increase the toxicity of capecitabine; The safety reporting requirements for pregnancies was updated; Sections on assessment of causality of new AEs, AEs occurring secondary to other events, deaths, and pre-existing medical conditions were updated in line with the latest sponsor guidance; Sections describing the reporting of abnormal vital sign values, abnormal liver function tests (LFTs), and AEs associated with an overdose or error in drug administration were added; Medical monitor and statistician for the study were replaced; The number of participants in the Phase 2 part of the study were reduced from 210 participants to 160 participants, due to slow recruitment and difficulty finding participants.

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.

The sponsor decided to terminate the study after 70% of participants had experienced a PFS event. Participants were allowed to continue treatment by enrolling into study NCT00781612 or by moving to commercial drug, depending on their country.

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IMP with orphan designation in the indication
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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Phase 1 (mBC): Percentage of Participants with Dose-Limiting Toxicities (DLTs)

Primary: Phase 1 (mBC): Percentage of Participants with Dose-Limiting Toxicities (DLTs)

Primary: Phase 1 (mBC): MTD of Capecitabine when Combined with Trastuzumab Emtansine (3.6 mg/kg every 3 weeks)

Primary: Phase 1 (mBC): MTD of Capecitabine when Combined with Trastuzumab Emtansine (3.6 mg/kg every 3 weeks)

Primary: Phase 2 (mBC): Percentage of Participants with Best Overall Response (BOR) as Assessed by the Investigator According to RECIST v1.1

Primary: Phase 2 (mBC): Percentage of Participants with Best Overall Response (BOR) as Assessed by the Investigator According to RECIST v1.1

Primary: Phase 1 (LA/mGC): Percentage of Participants with DLTs

Primary: Phase 1 (LA/mGC): Percentage of Participants with DLTs

Primary: Phase 1 (LA/mGC): MTD of Capecitabine when Combined with Trastuzumab Emtansine (2.4 mg/kg QW)

Primary: Phase 1 (LA/mGC): MTD of Capecitabine when Combined with Trastuzumab Emtansine (2.4 mg/kg QW)

Secondary: Phase 1 (mBC): Percentage of Participants with BOR as Assessed by the Investigator According to RECIST v1.1

Secondary: Phase 1 (mBC): Percentage of Participants with BOR as Assessed by the Investigator According to RECIST v1.1

Secondary: Phase 1 (mBC): Serum Concentration of Trastuzumab Emtansine

Secondary: Phase 1 (mBC): Serum Concentration of Trastuzumab Emtansine

Secondary: Phase 1 (mBC): Serum Concentration of Trastuzumab

Secondary: Phase 1 (mBC): Serum Concentration of Trastuzumab

Secondary: Phase 1 (mBC): Maximum Observed Plasma Concentration (Cmax) of Capecitabine

Secondary: Phase 1 (mBC): Maximum Observed Plasma Concentration (Cmax) of Capecitabine

Secondary: Phase 1 (mBC): Area Under the Plasma Concentration-Time Curve From Time Zero to infinity (AUC[0-inf]) of Capecitabine

Secondary: Phase 1 (mBC): Area Under the Plasma Concentration-Time Curve From Time Zero to infinity (AUC[0-inf]) of Capecitabine

Secondary: Phase 1 (mBC): Plasma Terminal Half-Life (t1/2) of Capecitabine

Secondary: Phase 1 (mBC): Plasma Terminal Half-Life (t1/2) of Capecitabine

Secondary: Phase 1 (mBC): Cmax of 5-Fluorouracil (Metabolite of Capecitabine)

Secondary: Phase 1 (mBC): Cmax of 5-Fluorouracil (Metabolite of Capecitabine)

Secondary: Phase 1 (mBC): AUC(0-inf) of 5-Fluorouracil (Metabolite of Capecitabine)

Secondary: Phase 1 (mBC): AUC(0-inf) of 5-Fluorouracil (Metabolite of Capecitabine)

Secondary: Phase 1 (mBC): t1/2 of 5-Fluorouracil (Metabolite of Capecitabine)

Secondary: Phase 1 (mBC): t1/2 of 5-Fluorouracil (Metabolite of Capecitabine)

Secondary: Phase 2 (mBC): Time to Response (TTR) as Assessed by the Investigator According to RECIST v1.1

Secondary: Phase 2 (mBC): Time to Response (TTR) as Assessed by the Investigator According to RECIST v1.1

Secondary: Phase 2 (mBC): Duration of Response (DoR) as Assessed by the Investigator According to RECIST v1.1

Secondary: Phase 2 (mBC): Duration of Response (DoR) as Assessed by the Investigator According to RECIST v1.1

Secondary: Phase 2 (mBC): Percentage of Participants with PD as Assessed by the Investigator According to RECIST v1.1

Secondary: Phase 2 (mBC): Percentage of Participants with PD as Assessed by the Investigator According to RECIST v1.1

Secondary: Phase 2 (mBC): Time to Progression (TTP) as Assessed by the Investigator According to RECIST v1.1

Secondary: Phase 2 (mBC): Time to Progression (TTP) as Assessed by the Investigator According to RECIST v1.1

Secondary: Phase 2 (mBC): Percentage of Participants with Treatment Failure as Assessed by the Investigator According to RECIST v1.1

Secondary: Phase 2 (mBC): Percentage of Participants with Treatment Failure as Assessed by the Investigator According to RECIST v1.1

Secondary: Phase 2 (mBC): Time to Treatment Failure (TTF) as Assessed by the Investigator According to RECIST v1.1

Secondary: Phase 2 (mBC): Time to Treatment Failure (TTF) as Assessed by the Investigator According to RECIST v1.1

Secondary: Phase 2 (mBC): Percentage of Participants With PD as Assessed by the Investigator According to RECIST v1.1 or Death from any Cause

Secondary: Phase 2 (mBC): Percentage of Participants With PD as Assessed by the Investigator According to RECIST v1.1 or Death from any Cause

Secondary: Phase 2 (mBC): Progression-Free Survival (PFS) as Assessed by the Investigator According to RECIST v1.1

Secondary: Phase 2 (mBC): Progression-Free Survival (PFS) as Assessed by the Investigator According to RECIST v1.1

Secondary: Phase 2 (mBC): Percentage of Participants with Clinical Benefit as Assessed by the Investigator According to RECIST v1.1

Secondary: Phase 2 (mBC): Percentage of Participants with Clinical Benefit as Assessed by the Investigator According to RECIST v1.1

Secondary: Phase 2 (mBC): Percentage of Participants who Died of any Cause

Secondary: Phase 2 (mBC): Percentage of Participants who Died of any Cause

Secondary: Phase 2 (mBC): Overall Survival (OS)

Secondary: Phase 2 (mBC): Overall Survival (OS)

Secondary: Phase 1 (LA/mGC): Percentage of Participants with BOR as Assessed by the Investigator According to RECIST v1.1

Secondary: Phase 1 (LA/mGC): Percentage of Participants with BOR as Assessed by the Investigator According to RECIST v1.1

Secondary: Phase 1 (LA/mGC): Serum Concentration of Trastuzumab Emtansine

Secondary: Phase 1 (LA/mGC): Serum Concentration of Trastuzumab Emtansine

Secondary: Phase 1 (LA/mGC): Serum Concentration of Trastuzumab

Secondary: Phase 1 (LA/mGC): Serum Concentration of Trastuzumab

Secondary: Phase 1 (LA/mGC): Cmax of Capecitabine

Secondary: Phase 1 (LA/mGC): Cmax of Capecitabine

Secondary: Phase 1 (LA/mGC): AUC(0-inf) of Capecitabine

Secondary: Phase 1 (LA/mGC): AUC(0-inf) of Capecitabine

Secondary: Phase 1 (LA/mGC): t1/2 of Capecitabine

Secondary: Phase 1 (LA/mGC): t1/2 of Capecitabine

Secondary: Phase 1 (LA/mGC): Cmax of 5-Fluorouracil (Metabolite of Capecitabine)

Secondary: Phase 1 (LA/mGC): Cmax of 5-Fluorouracil (Metabolite of Capecitabine)

Secondary: Phase 1 (LA/mGC): AUC(0-inf) of 5-Fluorouracil (Metabolite of Capecitabine)

Secondary: Phase 1 (LA/mGC): AUC(0-inf) of 5-Fluorouracil (Metabolite of Capecitabine)

Secondary: Phase 1 (LA/mGC): t1/2 of 5-Fluorouracil (Metabolite of Capecitabine)

Secondary: Phase 1 (LA/mGC): t1/2 of 5-Fluorouracil (Metabolite of Capecitabine)

Adverse events

Adverse events

More information