TRAXHER2: A Combination Study of Kadcyla (Trastuzumab Emtansine) and Capecitabine in Participants With Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Metastatic Breast Cancer (mBC) or HER2-Positive Locally Advanced/Metastatic Gastric Cancer (LA/mGC)

• Sponsor: Hoffmann-La Roche (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT01702558
• Collaborator: (none)
• Enrollment: 182
• Locations: 40
• Arms: 4
• Actual Duration (Months): 53.9
• Patients Per Site: 4.6
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This multicenter study will assess the maximum tolerated dose (MTD) of capecitabine in combination with Kadcyla (trastuzumab emtansine) in participants with HER2-positive mBC or HER2-positive LA/mGC using a Phase 1 design, followed by a randomized, open-label Phase 2 part to explore the efficacy and safety of the combination of Kadcyla and capecitabine compared with Kadcyla alone in participants with mBC. The anticipated time on study treatment is until disease progression, intolerable toxicity, withdrawal of consent, or study end.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer; Gastric Cancer	Drug: Capecitabine; Drug: Trastuzumab emtansine (T-DM1); Drug: Trastuzumab emtansine (T-DM1); Drug: Capecitabine	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 182 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: Dec 3, 2012
• Actual Primary Completion Date: May 31, 2017
• Actual Study Completion Date: May 31, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Phase 1 (mBC) Cohort 1: T-DM1 + Capecitabine In Phase 1, Cohort 1 participants (with mBC) will receive 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 at de-escalating dose levels (starting from 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, or study end.	Drug: Capecitabine; Capecitabine will be administered at de-escalating doses (starting from 750 mg/m^2) to determine the MTD.; Other Names: Xeloda ; Drug: Trastuzumab emtansine (T-DM1); Trastuzumab emtansine will be administered at a dose of 3.6 mg/kg via IV infusion every 3 weeks.; Other Names: Kadcyla, RO5304020
Experimental: Phase 1 (LA/mGC) Cohort 2: T-DM1 + Capecitabine In Phase 1, Cohort 2 participants (with LA/mGC) will receive trastuzumab emtansine at a dose of 2.4 mg/kg via IV infusion on Day 1 (on Day 2 of first week) of every week along with capecitabine at MTD (determined in Cohort 1) 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, or study end.	Drug: Trastuzumab emtansine (T-DM1); Trastuzumab emtansine will be administered at a dose of 2.4 mg/kg via IV infusion every week.; Other Names: Kadcyla, RO5304020 ; Drug: Capecitabine; Capecitabine will be administered at the MTD determined in Cohort 1.; Other Names: Xeloda
Active Comparator: Phase 2 (mBC): T-DM1 + Capecitabine In Phase 2, participants (with mBC) who will be randomized to this group, will receive 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 MTD via tablet orally twice daily on Days 1-14 of each 21-day cycle until unacceptable toxicity, withdrawal of consent, PD, death, or study end.	Drug: Trastuzumab emtansine (T-DM1); Trastuzumab emtansine will be administered at a dose of 3.6 mg/kg via IV infusion every 3 weeks.; Other Names: Kadcyla, RO5304020 ; Drug: Capecitabine; Capecitabine will be administered at the MTD determined in Cohort 1.; Other Names: Xeloda
Experimental: Phase 2 (mBC): T-DM1 In Phase 2, participants (with mBC) who will be randomized to this group, will receive 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, or study end.	Drug: Trastuzumab emtansine (T-DM1); Trastuzumab emtansine will be administered at a dose of 3.6 mg/kg via IV infusion every 3 weeks.; Other Names: Kadcyla, RO5304020

Outcome Measures

Primary Outcome Measures

1. Phase 1 (mBC): Percentage of Participants With Dose-Limiting Toxicities (DLTs) [Continuously during Cycle 1 (up to 3 weeks)]

   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 greater than or equal to (>/=) 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 (%).

2. Phase 1 (mBC): Maximum Tolerated Dose (MTD) of Capecitabine When Combined With Trastuzumab Emtansine (3.6 mg/kg Every 3 Weeks) [Continuously during Cycle 1 (up to 3 weeks)]

   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%.

3. Phase 2 (mBC): Percentage of Participants With Best Overall Response (BOR) as Assessed by the Investigator According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) [Baseline until CR/PR, consent withdrawal, or study end whichever occurred first (up to approximately 2.5 years overall)]

   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.

4. Phase 1 (LA/mGC): Percentage of Participants With DLTs [Continuously during 3 weeks]

   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%.

5. Phase 1 (LA/mGC): MTD of Capecitabine When Combined With Trastuzumab Emtansine (2.4 mg/kg QW) [Continuously during 3 weeks]

   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%.

Secondary Outcome Measures

1. Phase 1 (mBC): Percentage of Participants With BOR as Assessed by the Investigator According to RECIST v1.1 [Baseline until CR/PR, consent withdrawal, or study end whichever occurred first (up to approximately 3.5 years overall)]

   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.

2. Phase 1 (mBC): Serum Concentration of Trastuzumab Emtansine [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)]

3. Phase 1 (mBC): Serum Concentration of Trastuzumab [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)]

   Trastuzumab was derived from trastuzumab emtansine.

4. Phase 1 (mBC): Maximum Observed Plasma Concentration (Cmax) of Capecitabine [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]

   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%) and not for standard deviation.

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

   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% and not for standard deviation.

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

   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% and not for standard deviation.

7. Phase 1 (mBC): Cmax of 5-Fluorouracil (Metabolite of Capecitabine) [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]

   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% and not for standard deviation.

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

   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% and not for standard deviation.

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

   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% and not for standard deviation.

10. Phase 2 (mBC): Time to Response (TTR) as Assessed by the Investigator According to RECIST v1.1 [Baseline until first documentation of confirmed PR or CR, whichever occurred first (up to approximately 2.5 years overall)]

    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.

11. Phase 2 (mBC): Duration of Response (DoR) as Assessed by the Investigator According to RECIST v1.1 [From the documentation of response until PD, death, consent withdrawal, or study end whichever occurred first (up to approximately 2.5 years overall)]

    Tumor response was assessed by the investigator according to RECIST v1.1. 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. 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. 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.

12. Phase 2 (mBC): Percentage of Participants With PD as Assessed by the Investigator According to RECIST v1.1 [Baseline until PD, consent withdrawal, or study end whichever occurred first (up to approximately 2.5 years overall)]

    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.

13. Phase 2 (mBC): Time to Progression (TTP) as Assessed by the Investigator According to RECIST v1.1 [Baseline until PD, consent withdrawal, or study end whichever occurred first (up to approximately 2.5 years overall)]

    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.

14. Phase 2 (mBC): Percentage of Participants With Treatment Failure as Assessed by the Investigator According to RECIST v1.1 [Baseline until treatment failure, consent withdrawal, or study end whichever occurred first (up to approximately 2.5 years overall)]

    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.

15. Phase 2 (mBC): Time to Treatment Failure (TTF) as Assessed by the Investigator According to RECIST v1.1 [Baseline until treatment failure, consent withdrawal, or study end whichever occurred first (up to approximately 2.5 years overall)]

    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.

16. Phase 2 (mBC): Percentage of Participants With PD as Assessed by the Investigator According to RECIST v1.1 or Death From Any Cause [Baseline until PD, death from any cause, consent withdrawal, or study end whichever occurred first (up to approximately 2.5 years overall)]

    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.

17. Phase 2 (mBC): Progression-Free Survival (PFS) as Assessed by the Investigator According to RECIST v1.1 [Baseline until PD, death from any cause, consent withdrawal, or study end whichever occurred first (up to approximately 2.5 years overall)]

    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.

18. Phase 2 (mBC): Percentage of Participants With Clinical Benefit as Assessed by the Investigator According to RECIST v1.1 [Baseline until clinical benefit response, consent withdrawal, or study end whichever occurred first (up to approximately 2.5 years overall)]

    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.

19. Phase 2 (mBC): Percentage of Participants Who Died of Any Cause [Baseline until death or study end whichever occurred first (up to approximately 2.5 years overall)]

20. Phase 2 (mBC): Overall Survival (OS) [Baseline until death or study end whichever occurred first (up to approximately 2.5 years overall)]

    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 as having no event (alive) on the date of last contact. The median OS and 90% CI was estimated using Kaplan-Meier method, which use the patients at risk as denominator rather than the whole number of patients.

21. Phase 1 (LA/mGC): Percentage of Participants With BOR as Assessed by the Investigator According to RECIST v1.1 [Baseline until CR/PR, consent withdrawal, or study end whichever occurred first (up to approximately 1.5 years overall)]

    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.

22. Phase 1 (LA/mGC): Serum Concentration of Trastuzumab Emtansine [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)]

23. Phase 1 (LA/mGC): Serum Concentration of Trastuzumab [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)]

    Trastuzumab was derived from trastuzumab emtansine.

24. Phase 1 (LA/mGC): Cmax of Capecitabine [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]

    Cmax for capecitabine was estimated from plasma concentration versus time data using non-compartmental methods of analysis. Reported dispersion values are for CV% and not for standard deviation.

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

    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% and not for standard deviation.

26. Phase 1 (LA/mGC): t1/2 of Capecitabine [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]

    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% and not for standard deviation.

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

    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% and not for standard deviation.

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

    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% and not for standard deviation.

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

    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% and not for standard deviation.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

Metastatic Breast Cancer

• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2

• Adequate blood cell count

• Adequate liver, renal, and cardiac function

• Life expectancy greater than or equal to (>/=) 12 weeks

• Histologically or cytologically confirmed breast cancer

• Confirmed HER2-positive disease, defined as immunohistochemistry (IHC) 3+ or in situ hybridization (ISH)-positive

• mBC with at least one measurable lesion according to RECIST v1.1

• Disease progression on at least one prior regimen containing trastuzumab and chemotherapy either separately or in combination; participants may be eligible to receive study therapy in first-line setting if trastuzumab and chemotherapy were given in the neoadjuvant/adjuvant setting

• Participant must have recovered from previous treatments

Locally Advanced/Metastatic Gastric Cancer

• ECOG performance status of 0, 1, or 2

• Adequate blood cell count

• Adequate liver, renal, and cardiac function

• Life expectancy >/= 12 weeks

• Histologically or cytologically confirmed LA/mGC

• HER2-positive tumor (primary tumor or metastatic lesion), defined as either IHC 3+ or IHC 2+ and ISH-positive

• Inoperable LA/mGC

Exclusion Criteria:

Metastatic Breast Cancer

• Prior treatments before first study treatment:

1. Investigational therapy within 28 days or 5 half-lives, whichever is longer

2. Hormonal therapy within 14 days

3. Trastuzumab within 21 days

• Prior treatment with trastuzumab emtansine or prior enrollment in a trastuzumab emtansine-containing study, regardless of whether the patient received trastuzumab emtansine

• Prior treatment with capecitabine

• History of severe or unexpected reactions to fluoropyrimidine or known hypersensitivity to fluorouracil

• Related capecitabine contraindications

1. Treatment with sorivudine or chemically-related analogues

2. Rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption

3. Complete absence of dihydropyrimidine dehydrogenase (DPD) activity

• History of intolerance or hypersensitivity to trastuzumab or murine proteins or any product component

• History of exposure to high cumulative doses of anthracyclines

• Brain metastases that are symptomatic or require radiation, surgery, or steroid therapy to control symptoms within 28 days before study drug

• Current peripheral neuropathy of Grade >/=3

• History of other malignancy within the last 5 years, except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage I uterine cancer, or other cancers with a similar outcome

• Current unstable ventricular arrhythmia requiring treatment

• History of symptomatic congestive heart failure (CHF)

• History of myocardial infarction or unstable angina within 6 months prior to study drug

• History of left ventricular ejection fraction (LVEF) less than (<) 40% or symptomatic CHF with previous trastuzumab treatment

• Severe dyspnea at rest due to complications of advanced malignancy or currently requiring continuous oxygen therapy

• Clinically significant malabsorption syndrome or inability to take oral medication

• Current severe, uncontrolled systemic disease (such as clinically significant cardiovascular, pulmonary, or metabolic disease)

• Major surgical procedure or significant traumatic injury within 28 days before enrollment or anticipation of the need for major surgery during study treatment

• Current known active infection with human immunodeficiency virus (HIV) or hepatitis B or C

• Lapatinib within 14 days before study drug

Locally Advanced/Metastatic Gastric Cancer

• Same as above, with addition of previous chemotherapy for advanced/metastatic disease (prior adjuvant/neoadjuvant therapy is allowed if at least 6 months has elapsed between completion of adjuvant/neoadjuvant therapy and enrollment into the study)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Fundacion Investigar	Caba		Argentina	C1025ABI
2	Centro Oncologico Riojano Integral (CORI)	La Rioja		Argentina	F5300COE
3	Hospital Erasto Gaertner	Curitiba	PR	Brazil	81520-060
4	Instituto Oncologico de Ribeirao Preto - INORP	Ribeirao Preto	SP	Brazil	14025-270
5	Faculdade de Medicina de Sao Jose do Rio Preto - FAMERP*X*	Sao Jose do Rio Preto	SP	Brazil	15090-000
6	Instituto do Cancer do Estado de Sao Paulo - ICESP	Sao Paulo	SP	Brazil	01246-000
7	British Columbia Cancer Agency (Bcca) - Vancouver Cancer Centre	Vancouver	British Columbia	Canada	V5Z 4E6
8	ICO Paul Papin; Oncologie Medicale.	Angers		France	49055
9	Centre Leon Berard; Departement Oncologie Medicale	Lyon		France	69373
10	Institut Paoli Calmettes; Oncologie Medicale	Marseille		France	13273
11	Institut Curie; Oncologie Medicale	Paris		France	75231
12	Ico Rene Gauducheau; Oncologie	Saint Herblain		France	44805
13	Charité-Universitätsm. Berlin; Med. Klinik mit Schwerpunkt Hämatologie, Onkologie und Tumorimmunolo.	Berlin		Germany	10117
14	Onkologische Schwerpunktpraxis Bielefeld; Haemotologie & Internistische onkologie	Bielefeld		Germany	33604
15	Heinrich-Heine Universitätsklinik Düsseldorf	Düsseldorf		Germany	40225
16	Klinik Fulda, Medizinisches Versorgungszentrum Osthessen GmbH	Fulda		Germany	36043
17	Philipps-Universität Marburg; Klinik für Innere Med.; Schwerpunkt Hämatologie/Onkologie/Immunologie	Marburg		Germany	35043
18	Klinikum rechts der Isar der TU München; III. Medizinischen Klinik (Hämatologie/Onkologie)	München		Germany	81675
19	Klinikum rechts der Isar der TU München; Klinik und Poliklinik für Frauenheilkunde	München		Germany	81675
20	Alexandras General Hospital of Athens; Oncology Department	Athens		Greece	115 28
21	Univ General Hosp Heraklion; Medical Oncology	Heraklion		Greece	711 10
22	University Hospital of Patras Medical Oncology	Patras		Greece	265 04
23	Istituto Nazionale Tumori Irccs Fondazione g. PASCALE;U.O.C. Oncologia Medica Senologica	Napoli	Campania	Italy	80131
24	Istituto Europeo Di Oncologia	Milano	Lombardia	Italy	20141
25	Fondazione Del Piemonte Per L'oncologia Ircc Di Candiolo; Dipartimento Oncologico	Candiolo	Piemonte	Italy	10060
26	Azienda usl 5 Di Pisa-Ospedale Di Pontedera;U.O. Oncologia	Pontedera	Toscana	Italy	56025
27	Hospital da Luz; Departamento de Oncologia Medica	Lisboa		Portugal	1500-650
28	Hospital de Santa Maria; Servico de Oncologia Medica	Lisboa		Portugal	1649-035
29	IPO do Porto; Servico de Oncologia Medica	Porto		Portugal	4200-072
30	Ivanovo Regional Oncology Dispensary	Ivanovo		Russian Federation	153040
31	Blokhin Cancer Research Center; Combined Treatment	Moscow		Russian Federation	115478
32	City Clinical Oncology Hospital	Moscow		Russian Federation	143423
33	S-Pb clinical scientific practical center of specialized kinds of medical care (oncological)	Saint-Petersburg		Russian Federation	197758
34	City Oncology Dispensary	St Petersburg		Russian Federation
35	Bashkirian Republican Clinical Oncology Dispensary	UFA		Russian Federation	450054
36	Institute for Oncology and Radiology of Serbia; Medical Oncology	Belgrade		Serbia	11000
37	Clinical Centre Nis, Clinic for Oncology	Nis		Serbia	18000
38	Narodny Onkologicky Ustav; Oddelenie klinickej onkologie A	Bratislava		Slovakia	833 10
39	Fakultna nemocnica Trencín; Onkologicke odd.	Trencin		Slovakia	911 71
40	Hospital Univ Vall d'Hebron; Servicio de Oncologia	Barcelona		Spain	08035

Sponsors and Collaborators

• Hoffmann-La Roche

Investigators

• Study Director: Clinical Trials, Hoffmann-La Roche

Study Documents (Full-Text)

• Study Protocol - Mar 26, 2016
• Statistical Analysis Plan - Sep 7, 2017

More Information

Publications

None provided.

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT01702558
• Other Study ID Numbers: MO28230; 2012-001547-46
• First Posted: Oct 8, 2012
• Last Update Posted: Jan 22, 2021
• Last Verified: Jan 1, 2021

• Additional relevant MeSH terms: Breast Neoplasms; Stomach Neoplasms; Capecitabine; Trastuzumab; Maytansine; Ado-Trastuzumab Emtansine

Study Results

Participant Flow

Pre-assignment Detail	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).

Arm/Group Title	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
Arm/Group 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.	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.	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.	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.	In Phase 2, participants (with mBC) who were randomized in 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.
Period Title: Overall Study
STARTED	7	5	6	81	80
COMPLETED	3	1	1	34	38
NOT COMPLETED	4	4	5	47	42

Baseline Characteristics

Arm/Group Title	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
Arm/Group 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 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.	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.	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.	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.	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.	Total of all reporting groups
Overall Participants	7	5	6	82	78	178
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	55.9 (10.75)	50.8 (7.76)	60.0 (7.40)	53.3 (11.69)	52.6 (11.19)	53.2 (11.22)
Sex: Female, Male (Count of Participants)
Female	6 85.7%	5 100%	0 0%	81 98.8%	78 100%	170 95.5%
Male	1 14.3%	0 0%	6 100%	1 1.2%	0 0%	8 4.5%
Race/Ethnicity, Customized (participants) [Number]
Race: Caucasian	6 85.7%	4 80%	6 100%	71 86.6%	65 83.3%	152 85.4%
Race: N/A (as per local regulation)	1 14.3%	1 20%	0 0%	10 12.2%	7 9%	19 10.7%
Race: Black	0 0%	0 0%	0 0%	0 0%	2 2.6%	2 1.1%
Race: Asian	0 0%	0 0%	0 0%	1 1.2%	1 1.3%	2 1.1%
Race: Mixed	0 0%	0 0%	0 0%	0 0%	3 3.8%	3 1.7%
Ethnicity: Hispanic/Latino	0 0%	1 20%	0 0%	5 6.1%	10 12.8%	16 9%
Ethnicity: Chinese	0 0%	0 0%	0 0%	1 1.2%	0 0%	1 0.6%
Ethnicity: Other	6 85.7%	0 0%	0 0%	39 47.6%	35 44.9%	80 44.9%
Ethnicity: N/A (as per local regulation)	1 14.3%	1 20%	6 100%	32 39%	29 37.2%	69 38.8%
Ethnicity: Unknown	0 0%	2 40%	0 0%	5 6.1%	4 5.1%	11 6.2%
Ethnicity: Mixed	0 0%	1 20%	0 0%	0 0%	0 0%	1 0.6%

Outcome Measures

1. Primary Outcome

Title	Phase 1 (mBC): Percentage of Participants With Dose-Limiting Toxicities (DLTs)
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 greater than or equal to (>/=) 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 (%).
Time Frame	Continuously during Cycle 1 (up to 3 weeks)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape	Phase 1 (mBC) Cohort 1 (DL -1): T-DM1 + Cape
Arm/Group 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 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.	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.
Measure Participants	6	5
Number [percentage of participants]	33.3 475.7%	0.0 0%

2. Primary Outcome

Title	Phase 1 (mBC): Maximum Tolerated Dose (MTD) of Capecitabine When Combined With Trastuzumab Emtansine (3.6 mg/kg Every 3 Weeks)
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%.
Time Frame	Continuously during Cycle 1 (up to 3 weeks)

Outcome Measure Data

Analysis Population Description

Analysis was performed on Phase 1 DLT-evaluable population for mBC cohort.

Arm/Group Title	Phase 1 (mBC) Cohort 1: T-DM1 + Cape
Arm/Group 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.
Measure Participants	11
Number [mg/m^2]	700

3. Primary Outcome

Title	Phase 2 (mBC): Percentage of Participants With Best Overall Response (BOR) as Assessed by the Investigator According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)
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.
Time Frame	Baseline until CR/PR, consent withdrawal, or study end whichever occurred first (up to approximately 2.5 years overall)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Phase 2 (mBC): T-DM1 + Cape	Phase 2 (mBC): T-DM1
Arm/Group 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.	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.
Measure Participants	81	80
Number (90% Confidence Interval) [percentage of participants]	44.4 634.3%	36.3 726%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape, Phase 1 (mBC) Cohort 1 (DL -1): T-DM1 + Cape
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.336
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Difference in Response Rates
	Estimated Value	8.2
	Confidence Interval	(2-Sided) 90%; -4.5 to 20.9
	Parameter Dispersion	Type: Value:
	Estimation Comments	90% CI was estimated using Hauck-Anderson approach.

4. Primary Outcome

Title	Phase 1 (LA/mGC): Percentage of Participants With DLTs
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%.
Time Frame	Continuously during 3 weeks

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Phase 1 (LA/mGC) Cohort 2 (DL -1): T-DM1 + Cape
Arm/Group 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.
Measure Participants	6
Number [percentage of participants]	0.0 0%

5. Primary Outcome

Title	Phase 1 (LA/mGC): MTD of Capecitabine When Combined With Trastuzumab Emtansine (2.4 mg/kg QW)
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%.
Time Frame	Continuously during 3 weeks

Outcome Measure Data

Analysis Population Description

Analysis was performed on Phase 1 DLT-evaluable population for LA/mGC cohort.

Arm/Group Title	Phase 1 (LA/mGC) Cohort 2 (DL -1): T-DM1 + Cape
Arm/Group 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.
Measure Participants	6
Number [mg/m^2]	700

6. Secondary Outcome

Title	Phase 1 (mBC): Percentage of Participants With BOR as Assessed by the Investigator According to RECIST v1.1
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.
Time Frame	Baseline until CR/PR, consent withdrawal, or study end whichever occurred first (up to approximately 3.5 years overall)

Outcome Measure Data

Analysis Population Description

Analysis was performed on Phase 1 DLT-evaluable population for mBC cohort.

Arm/Group Title	Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape	Phase 1 (mBC) Cohort 1 (DL -1): T-DM1 + Cape
Arm/Group 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 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.	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.
Measure Participants	6	5
Number [percentage of participants]	83.3 1190%	100.0 2000%

7. Secondary Outcome

Title	Phase 1 (mBC): Serum Concentration of Trastuzumab Emtansine
Time Frame	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)

Outcome Measure Data

Analysis Population Description

Phase 1 pharmacokinetic (PK) analysis population for mBC cohort; included all mBC participants receiving at least one dose of study medication during Phase 1 and had at least one reported serum/plasma result for PK. The PK analysis in mBC cohort included 1 patient who was excluded from the main safety and efficacy analyses due to ICF issues.

Arm/Group Title	Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape	Phase 1 (mBC) Cohort 1 (DL -1): T-DM1 + Cape
Arm/Group 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 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.	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.
Measure Participants	7	6
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)

8. Secondary Outcome

Title	Phase 1 (mBC): Serum Concentration of Trastuzumab
Description	Trastuzumab was derived from trastuzumab emtansine.
Time Frame	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)

Outcome Measure Data

Analysis Population Description

Analysis was performed on Phase 1 PK analysis population for mBC cohort. The PK analysis in the mBC cohort included 1 patient who was excluded from the main safety and efficacy analyses due to ICF issues.

Arm/Group Title	Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape	Phase 1 (mBC) Cohort 1 (DL -1): T-DM1 + Cape
Arm/Group 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 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.	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.
Measure Participants	7	6
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)

9. Secondary Outcome

Title	Phase 1 (mBC): Maximum Observed Plasma Concentration (Cmax) of Capecitabine
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%) and not for standard deviation.
Time Frame	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

Outcome Measure Data

Analysis Population Description

Analysis was performed on Phase 1 PK analysis population for mBC cohort. The PK analysis in the mBC cohort included 1 patient who was excluded from the main safety and efficacy analyses due to ICF issues.

Arm/Group Title	Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape	Phase 1 (mBC) Cohort 1 (DL -1): T-DM1 + Cape
Arm/Group 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 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.	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.
Measure Participants	7	6
Mean (Standard Deviation) [nanograms per milliliter (ng/mL)]	2990 (38.4)	5652 (91.1)

10. Secondary Outcome

Title	Phase 1 (mBC): Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC[0-inf]) of Capecitabine
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% and not for standard deviation.
Time Frame	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

Outcome Measure Data

Analysis Population Description

Analysis was performed on Phase 1 PK analysis population for mBC cohort. The PK analysis in the mBC cohort included 1 patient who was excluded from the main safety and efficacy analyses due to ICF issues.

Arm/Group Title	Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape	Phase 1 (mBC) Cohort 1 (DL -1): T-DM1 + Cape
Arm/Group 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 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.	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.
Measure Participants	7	6
Mean (Standard Deviation) [hours*nanograms per milliliter (h*ng/mL)]	3973 (38.0)	5440 (57.7)

11. Secondary Outcome

Title	Phase 1 (mBC): Plasma Terminal Half-Life (t1/2) of Capecitabine
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% and not for standard deviation.
Time Frame	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

Outcome Measure Data

Analysis Population Description

Analysis was performed on Phase 1 PK analysis population for mBC cohort. The PK analysis in the mBC cohort included 1 patient who was excluded from the main safety and efficacy analyses due to ICF issues.

Arm/Group Title	Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape	Phase 1 (mBC) Cohort 1 (DL -1): T-DM1 + Cape
Arm/Group 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 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.	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.
Measure Participants	7	6
Mean (Standard Deviation) [hours]	0.70 (131.9)	0.39 (38.8)

12. Secondary Outcome

Title	Phase 1 (mBC): Cmax of 5-Fluorouracil (Metabolite of Capecitabine)
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% and not for standard deviation.
Time Frame	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

Outcome Measure Data

Analysis Population Description

Analysis was performed on Phase 1 PK analysis population for mBC cohort. The PK analysis in the mBC cohort included 1 patient who was excluded from the main safety and efficacy analyses due to ICF issues.

Arm/Group Title	Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape	Phase 1 (mBC) Cohort 1 (DL -1): T-DM1 + Cape
Arm/Group 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 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.	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.
Measure Participants	7	6
Mean (Standard Deviation) [ng/mL]	148 (49.9)	143 (45.6)

13. Secondary Outcome

Title	Phase 1 (mBC): AUC(0-inf) of 5-Fluorouracil (Metabolite of Capecitabine)
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% and not for standard deviation.
Time Frame	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

Outcome Measure Data

Analysis Population Description

Analysis was performed on Phase 1 PK analysis population for mBC cohort. The PK analysis in the mBC cohort included 1 patient who was excluded from the main safety and efficacy analyses due to ICF issues.

Arm/Group Title	Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape	Phase 1 (mBC) Cohort 1 (DL -1): T-DM1 + Cape
Arm/Group 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 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.	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.
Measure Participants	7	6
Mean (Standard Deviation) [h*ng/mL]	257 (49.9)	244 (38.2)

14. Secondary Outcome

Title	Phase 1 (mBC): t1/2 of 5-Fluorouracil (Metabolite of Capecitabine)
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% and not for standard deviation.
Time Frame	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

Outcome Measure Data

Analysis Population Description

Analysis was performed on Phase 1 PK analysis population for mBC cohort. The PK analysis in the mBC cohort included 1 patient who was excluded from the main safety and efficacy analyses due to ICF issues.

Arm/Group Title	Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape	Phase 1 (mBC) Cohort 1 (DL -1): T-DM1 + Cape
Arm/Group 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 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.	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.
Measure Participants	7	6
Mean (Standard Deviation) [hours]	0.63 (39.5)	0.64 (18.3)

15. Secondary Outcome

Title	Phase 2 (mBC): Time to Response (TTR) as Assessed by the Investigator According to RECIST v1.1
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.
Time Frame	Baseline until first documentation of confirmed PR or CR, whichever occurred first (up to approximately 2.5 years overall)

Outcome Measure Data

Analysis Population Description

Analysis was performed on ITT Population. Only participants with a BOR of CR or PR were included in the analysis.

Arm/Group Title	Phase 2 (mBC): T-DM1 + Cape	Phase 2 (mBC): T-DM1
Arm/Group 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.	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.
Measure Participants	36	29
Median (Full Range) [months]	2.10	2.10

16. Secondary Outcome

Title	Phase 2 (mBC): Duration of Response (DoR) as Assessed by the Investigator According to RECIST v1.1
Description	Tumor response was assessed by the investigator according to RECIST v1.1. 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. 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. 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.
Time Frame	From the documentation of response until PD, death, consent withdrawal, or study end whichever occurred first (up to approximately 2.5 years overall)

Outcome Measure Data

Analysis Population Description

Analysis was performed on ITT Population. Only participants with a BOR of CR or PR were included in the analysis.

Arm/Group Title	Phase 2 (mBC): T-DM1 + Cape	Phase 2 (mBC): T-DM1
Arm/Group 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.	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.
Measure Participants	36	29
Median (90% Confidence Interval) [months]	11.30	12.22

17. Secondary Outcome

Title	Phase 2 (mBC): Percentage of Participants With PD as Assessed by the Investigator According to RECIST v1.1
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.
Time Frame	Baseline until PD, consent withdrawal, or study end whichever occurred first (up to approximately 2.5 years overall)

Outcome Measure Data

Analysis Population Description

Analysis was performed on ITT Population.

Arm/Group Title	Phase 2 (mBC): T-DM1 + Cape	Phase 2 (mBC): T-DM1
Arm/Group 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.	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.
Measure Participants	81	80
Number [percentage of participants]	64.2 917.1%	70.0 1400%

18. Secondary Outcome

Title	Phase 2 (mBC): Time to Progression (TTP) as Assessed by the Investigator According to RECIST v1.1
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.
Time Frame	Baseline until PD, consent withdrawal, or study end whichever occurred first (up to approximately 2.5 years overall)

Outcome Measure Data

Analysis Population Description

Analysis was performed on ITT Population.

Arm/Group Title	Phase 2 (mBC): T-DM1 + Cape	Phase 2 (mBC): T-DM1
Arm/Group 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.	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.
Measure Participants	81	80
Median (90% Confidence Interval) [months]	10.38	10.32

19. Secondary Outcome

Title	Phase 2 (mBC): Percentage of Participants With Treatment Failure as Assessed by the Investigator According to RECIST v1.1
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.
Time Frame	Baseline until treatment failure, consent withdrawal, or study end whichever occurred first (up to approximately 2.5 years overall)

Outcome Measure Data

Analysis Population Description

Analysis was performed on ITT Population.

Arm/Group Title	Phase 2 (mBC): T-DM1 + Cape	Phase 2 (mBC): T-DM1
Arm/Group 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.	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.
Measure Participants	81	80
Number [percentage of participants]	77.8 1111.4%	83.8 1676%

20. Secondary Outcome

Title	Phase 2 (mBC): Time to Treatment Failure (TTF) as Assessed by the Investigator According to RECIST v1.1
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.
Time Frame	Baseline until treatment failure, consent withdrawal, or study end whichever occurred first (up to approximately 2.5 years overall)

Outcome Measure Data

Analysis Population Description

Analysis was performed on ITT Population.

Arm/Group Title	Phase 2 (mBC): T-DM1 + Cape	Phase 2 (mBC): T-DM1
Arm/Group 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.	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.
Measure Participants	81	80
Median (90% Confidence Interval) [months]	9.86	7.66

21. Secondary Outcome

Title	Phase 2 (mBC): Percentage of Participants With PD as Assessed by the Investigator According to RECIST v1.1 or Death From Any Cause
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.
Time Frame	Baseline until PD, death from any cause, consent withdrawal, or study end whichever occurred first (up to approximately 2.5 years overall)

Outcome Measure Data

Analysis Population Description

Analysis was performed on ITT Population.

Arm/Group Title	Phase 2 (mBC): T-DM1 + Cape	Phase 2 (mBC): T-DM1
Arm/Group 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.	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.
Measure Participants	81	80
Number [percentage of participants]	67.9 970%	73.8 1476%

22. Secondary Outcome

Title	Phase 2 (mBC): Progression-Free Survival (PFS) as Assessed by the Investigator According to RECIST v1.1
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.
Time Frame	Baseline until PD, death from any cause, consent withdrawal, or study end whichever occurred first (up to approximately 2.5 years overall)

Outcome Measure Data

Analysis Population Description

Analysis was performed on ITT Population.

Arm/Group Title	Phase 2 (mBC): T-DM1 + Cape	Phase 2 (mBC): T-DM1
Arm/Group 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.	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.
Measure Participants	81	80
Median (90% Confidence Interval) [months]	10.15	9.82

23. Secondary Outcome

Title	Phase 2 (mBC): Percentage of Participants With Clinical Benefit as Assessed by the Investigator According to RECIST v1.1
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.
Time Frame	Baseline until clinical benefit response, consent withdrawal, or study end whichever occurred first (up to approximately 2.5 years overall)

Outcome Measure Data

Analysis Population Description

Analysis was performed on ITT Population.

Arm/Group Title	Phase 2 (mBC): T-DM1 + Cape	Phase 2 (mBC): T-DM1
Arm/Group 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.	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.
Measure Participants	81	80
Number (90% Confidence Interval) [percentage of participants]	66.7 952.9%	62.5 1250%

24. Secondary Outcome

Title	Phase 2 (mBC): Percentage of Participants Who Died of Any Cause
Time Frame	Baseline until death or study end whichever occurred first (up to approximately 2.5 years overall)

Outcome Measure Data

Analysis Population Description

Analysis was performed on ITT Population.

Arm/Group Title	Phase 2 (mBC): T-DM1 + Cape	Phase 2 (mBC): T-DM1
Arm/Group 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.	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.
Measure Participants	81	80
Number [percentage of participants]	22.2 317.1%	26.3 526%

25. Secondary Outcome

Title	Phase 2 (mBC): Overall Survival (OS)
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 as having no event (alive) on the date of last contact. The median OS and 90% CI was estimated using Kaplan-Meier method, which use the patients at risk as denominator rather than the whole number of patients.
Time Frame	Baseline until death or study end whichever occurred first (up to approximately 2.5 years overall)

Outcome Measure Data

Analysis Population Description

Analysis was performed on ITT Population.

Arm/Group Title	Phase 2 (mBC): T-DM1 + Cape	Phase 2 (mBC): T-DM1
Arm/Group 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.	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.
Measure Participants	81	80
Median (90% Confidence Interval) [months]	NA	24.71

26. Secondary Outcome

Title	Phase 1 (LA/mGC): Percentage of Participants With BOR as Assessed by the Investigator According to RECIST v1.1
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.
Time Frame	Baseline until CR/PR, consent withdrawal, or study end whichever occurred first (up to approximately 1.5 years overall)

Outcome Measure Data

Analysis Population Description

Analysis was performed on Phase 1 DLT-evaluable population for LA/mGC cohort.

Arm/Group Title	Phase 1 (LA/mGC) Cohort 2 (DL -1): T-DM1 + Cape
Arm/Group 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.
Measure Participants	6
Number [percentage of participants]	83.3 1190%

27. Secondary Outcome

Title	Phase 1 (LA/mGC): Serum Concentration of Trastuzumab Emtansine
Time Frame	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)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Phase 1 (LA/mGC) Cohort 2 (DL -1): T-DM1 + Cape
Arm/Group 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.
Measure Participants	6
Cycle 1, Post-dose	30.1 (14.5)
Cycle 2, Pre-dose	10.1 (5.85)
Cycle 2, Post-dose	46.4 (7.74)

28. Secondary Outcome

Title	Phase 1 (LA/mGC): Serum Concentration of Trastuzumab
Description	Trastuzumab was derived from trastuzumab emtansine.
Time Frame	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)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Phase 1 (LA/mGC) Cohort 2 (DL -1): T-DM1 + Cape
Arm/Group 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.
Measure Participants	6
Cycle 1, Post-dose	33.1 (15.98)
Cycle 2, Pre-dose	18.5 (7.57)
Cycle 2, Post-dose	57.6 (13.55)

29. Secondary Outcome

Title	Phase 1 (LA/mGC): Cmax of Capecitabine
Description	Cmax for capecitabine was estimated from plasma concentration versus time data using non-compartmental methods of analysis. Reported dispersion values are for CV% and not for standard deviation.
Time Frame	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Phase 1 (LA/mGC) Cohort 2 (DL -1): T-DM1 + Cape
Arm/Group 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.
Measure Participants	6
Mean (Standard Deviation) [ng/mL]	4925 (36.3)

30. Secondary Outcome

Title	Phase 1 (LA/mGC): AUC(0-inf) of Capecitabine
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% and not for standard deviation.
Time Frame	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Phase 1 (LA/mGC) Cohort 2 (DL -1): T-DM1 + Cape
Arm/Group 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.
Measure Participants	6
Mean (Standard Deviation) [h*ng/mL]	5131 (24.6)

31. Secondary Outcome

Title	Phase 1 (LA/mGC): t1/2 of Capecitabine
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% and not for standard deviation.
Time Frame	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Phase 1 (LA/mGC) Cohort 2 (DL -1): T-DM1 + Cape
Arm/Group 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.
Measure Participants	6
Mean (Standard Deviation) [hours]	0.65 (34.5)

32. Secondary Outcome

Title	Phase 1 (LA/mGC): Cmax of 5-Fluorouracil (Metabolite of Capecitabine)
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% and not for standard deviation.
Time Frame	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Phase 1 (LA/mGC) Cohort 2 (DL -1): T-DM1 + Cape
Arm/Group 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.
Measure Participants	6
Mean (Standard Deviation) [ng/mL]	137 (24.3)

33. Secondary Outcome

Title	Phase 1 (LA/mGC): AUC(0-inf) of 5-Fluorouracil (Metabolite of Capecitabine)
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% and not for standard deviation.
Time Frame	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Phase 1 (LA/mGC) Cohort 2 (DL -1): T-DM1 + Cape
Arm/Group 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.
Measure Participants	6
Mean (Standard Deviation) [h*ng/mL]	213 (16.2)

34. Secondary Outcome

Title	Phase 1 (LA/mGC): t1/2 of 5-Fluorouracil (Metabolite of Capecitabine)
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% and not for standard deviation.
Time Frame	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Phase 1 (LA/mGC) Cohort 2 (DL -1): T-DM1 + Cape
Arm/Group 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.
Measure Participants	6
Mean (Standard Deviation) [hours]	0.83 (17.0)

Adverse Events

Time Frame	Phase 1: Baseline up to 42 days after last dose (up to approximately 1.5 years overall); Phase 2: Baseline up to 42 days after last dose (up to approximately 2.5 years overall)
Adverse Event Reporting Description	Safety population included all participants who received >/=1 dose of study drug. Participants were analyzed as per actual treatment received. In Phase 2, out of 161 participants, 1 participant was randomized in error (did not receive any treatment) and was excluded from safety analysis and 1 participant who was randomized to T-DM1 alone Arm received Capecitabine throughout study and was counted in T-DM1+Cape Arm.
Arm/Group Title	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
Arm/Group 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 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.		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.		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.		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.		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.
All Cause Mortality
	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
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/7 (57.1%)		3/5 (60%)		3/6 (50%)		18/82 (22%)		21/78 (26.9%)
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
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/7 (0%)		2/5 (40%)		4/6 (66.7%)		11/82 (13.4%)		10/78 (12.8%)
Blood and lymphatic system disorders
Thrombocytopenia	0/7 (0%)		0/5 (0%)		0/6 (0%)		1/82 (1.2%)		0/78 (0%)
Cardiac disorders
Myocardial infarction	0/7 (0%)		0/5 (0%)		1/6 (16.7%)		0/82 (0%)		0/78 (0%)
Gastrointestinal disorders
Diarrhoea	0/7 (0%)		0/5 (0%)		1/6 (16.7%)		1/82 (1.2%)		0/78 (0%)
Abdominal pain	0/7 (0%)		0/5 (0%)		0/6 (0%)		2/82 (2.4%)		0/78 (0%)
Colitis ischaemic	0/7 (0%)		0/5 (0%)		0/6 (0%)		1/82 (1.2%)		0/78 (0%)
Intestinal haematoma	0/7 (0%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		1/78 (1.3%)
Mesenteric vein thrombosis	0/7 (0%)		0/5 (0%)		0/6 (0%)		1/82 (1.2%)		0/78 (0%)
Vomiting	0/7 (0%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		1/78 (1.3%)
Hepatobiliary disorders
Cholecystitis	0/7 (0%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		1/78 (1.3%)
Hepatocellular injury	0/7 (0%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		1/78 (1.3%)
Infections and infestations
Device related sepsis	0/7 (0%)		0/5 (0%)		1/6 (16.7%)		0/82 (0%)		0/78 (0%)
Gastroenteritis	0/7 (0%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		1/78 (1.3%)
Bacterial sepsis	0/7 (0%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		1/78 (1.3%)
Device related infection	0/7 (0%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		1/78 (1.3%)
Upper respiratory tract infection	0/7 (0%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		1/78 (1.3%)
Urinary tract infection	0/7 (0%)		0/5 (0%)		0/6 (0%)		1/82 (1.2%)		0/78 (0%)
Wound sepsis	0/7 (0%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		1/78 (1.3%)
Injury, poisoning and procedural complications
Radiation necrosis	0/7 (0%)		1/5 (20%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Fracture displacement	0/7 (0%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		1/78 (1.3%)
Investigations
Hepatic enzyme increased	0/7 (0%)		0/5 (0%)		0/6 (0%)		1/82 (1.2%)		0/78 (0%)
Metabolism and nutrition disorders
Diabetes mellitus	0/7 (0%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		1/78 (1.3%)
Hyperglycaemia	0/7 (0%)		0/5 (0%)		0/6 (0%)		1/82 (1.2%)		0/78 (0%)
Musculoskeletal and connective tissue disorders
Muscular weakness	0/7 (0%)		1/5 (20%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Pathological fracture	0/7 (0%)		1/5 (20%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour haemorrhage	0/7 (0%)		0/5 (0%)		1/6 (16.7%)		0/82 (0%)		0/78 (0%)
Nervous system disorders
Brain oedema	0/7 (0%)		1/5 (20%)		0/6 (0%)		1/82 (1.2%)		0/78 (0%)
Cerebral cyst	0/7 (0%)		1/5 (20%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Sciatica	0/7 (0%)		0/5 (0%)		0/6 (0%)		1/82 (1.2%)		0/78 (0%)
Renal and urinary disorders
Renal colic	0/7 (0%)		0/5 (0%)		1/6 (16.7%)		0/82 (0%)		0/78 (0%)
Haematuria	0/7 (0%)		0/5 (0%)		0/6 (0%)		1/82 (1.2%)		0/78 (0%)
Anuria	0/7 (0%)		0/5 (0%)		0/6 (0%)		1/82 (1.2%)		0/78 (0%)
Reproductive system and breast disorders
Uterine polyp	0/7 (0%)		0/5 (0%)		0/6 (0%)		1/82 (1.2%)		0/78 (0%)
Respiratory, thoracic and mediastinal disorders
Pleural effusion	0/7 (0%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		1/78 (1.3%)
Pleurisy	0/7 (0%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		1/78 (1.3%)
Pulmonary embolism	0/7 (0%)		0/5 (0%)		0/6 (0%)		1/82 (1.2%)		0/78 (0%)
Surgical and medical procedures
Tumour excision	0/7 (0%)		0/5 (0%)		1/6 (16.7%)		0/82 (0%)		0/78 (0%)
Other (Not Including 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
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/7 (100%)		5/5 (100%)		6/6 (100%)		75/82 (91.5%)		64/78 (82.1%)
Blood and lymphatic system disorders
Thrombocytopenia	3/7 (42.9%)		4/5 (80%)		0/6 (0%)		35/82 (42.7%)		21/78 (26.9%)
Neutropenia	2/7 (28.6%)		1/5 (20%)		0/6 (0%)		13/82 (15.9%)		6/78 (7.7%)
Anaemia	2/7 (28.6%)		1/5 (20%)		4/6 (66.7%)		9/82 (11%)		13/78 (16.7%)
Lymphadenopathy	0/7 (0%)		0/5 (0%)		1/6 (16.7%)		0/82 (0%)		0/78 (0%)
Cardiac disorders
Cardiac failure	0/7 (0%)		1/5 (20%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Tachycardia	0/7 (0%)		0/5 (0%)		1/6 (16.7%)		1/82 (1.2%)		5/78 (6.4%)
Sinus tachycardia	0/7 (0%)		0/5 (0%)		1/6 (16.7%)		0/82 (0%)		0/78 (0%)
Congenital, familial and genetic disorders
Gilbert's syndrome	0/7 (0%)		1/5 (20%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Ear and labyrinth disorders
Tinnitus	1/7 (14.3%)		1/5 (20%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Deafness unilateral	1/7 (14.3%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Middle ear effusion	1/7 (14.3%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Vertigo	0/7 (0%)		0/5 (0%)		2/6 (33.3%)		0/82 (0%)		0/78 (0%)
Endocrine disorders
Cushingoid	0/7 (0%)		1/5 (20%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Eye disorders
Dry eye	1/7 (14.3%)		1/5 (20%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Lacrimation increased	2/7 (28.6%)		1/5 (20%)		1/6 (16.7%)		6/82 (7.3%)		3/78 (3.8%)
Ocular hyperaemia	2/7 (28.6%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Eye haemorrhage	0/7 (0%)		1/5 (20%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Eye pain	0/7 (0%)		1/5 (20%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Blepharospasm	0/7 (0%)		1/5 (20%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Blindness	1/7 (14.3%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Keratitis	1/7 (14.3%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Pterygium	1/7 (14.3%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Retinal ischaemia	1/7 (14.3%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Vision blurred	0/7 (0%)		1/5 (20%)		1/6 (16.7%)		0/82 (0%)		0/78 (0%)
Visual impairment	1/7 (14.3%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Gastrointestinal disorders
Nausea	3/7 (42.9%)		4/5 (80%)		3/6 (50%)		27/82 (32.9%)		18/78 (23.1%)
Diarrhoea	2/7 (28.6%)		3/5 (60%)		1/6 (16.7%)		7/82 (8.5%)		7/78 (9%)
Constipation	3/7 (42.9%)		4/5 (80%)		4/6 (66.7%)		8/82 (9.8%)		8/78 (10.3%)
Gingival bleeding	2/7 (28.6%)		3/5 (60%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Vomiting	2/7 (28.6%)		1/5 (20%)		1/6 (16.7%)		16/82 (19.5%)		8/78 (10.3%)
Abdominal pain upper	2/7 (28.6%)		3/5 (60%)		1/6 (16.7%)		6/82 (7.3%)		5/78 (6.4%)
Dry mouth	1/7 (14.3%)		2/5 (40%)		1/6 (16.7%)		3/82 (3.7%)		6/78 (7.7%)
Toothache	2/7 (28.6%)		1/5 (20%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Abdominal distension	0/7 (0%)		1/5 (20%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Abdominal pain	2/7 (28.6%)		0/5 (0%)		2/6 (33.3%)		7/82 (8.5%)		2/78 (2.6%)
Haematochezia	1/7 (14.3%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Rectal haemorrhage	1/7 (14.3%)		1/5 (20%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Anal fissure	1/7 (14.3%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Anal haemorrhage	1/7 (14.3%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Chapped lips	0/7 (0%)		1/5 (20%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Dental caries	1/7 (14.3%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Dyspepsia	0/7 (0%)		1/5 (20%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Dysphagia	1/7 (14.3%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Eructation	0/7 (0%)		1/5 (20%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Flatulence	0/7 (0%)		1/5 (20%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Frequent bowel movements	0/7 (0%)		1/5 (20%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Gastrooesophageal reflux disease	0/7 (0%)		1/5 (20%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Gingival pain	1/7 (14.3%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Glossodynia	0/7 (0%)		1/5 (20%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Haemorrhoidal haemorrhage	0/7 (0%)		1/5 (20%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Hypoaesthesia oral	1/7 (14.3%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Ascites	0/7 (0%)		0/5 (0%)		1/6 (16.7%)		0/82 (0%)		0/78 (0%)
Melaena	0/7 (0%)		0/5 (0%)		2/6 (33.3%)		0/82 (0%)		0/78 (0%)
Stomatitis	0/7 (0%)		0/5 (0%)		2/6 (33.3%)		3/82 (3.7%)		5/78 (6.4%)
Gastric haemorrhage	0/7 (0%)		0/5 (0%)		1/6 (16.7%)		0/82 (0%)		0/78 (0%)
Gastritis	0/7 (0%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		4/78 (5.1%)
General disorders
Non-cardiac chest pain	1/7 (14.3%)		1/5 (20%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Fatigue	2/7 (28.6%)		1/5 (20%)		4/6 (66.7%)		10/82 (12.2%)		11/78 (14.1%)
Asthenia	3/7 (42.9%)		1/5 (20%)		0/6 (0%)		17/82 (20.7%)		15/78 (19.2%)
Chills	2/7 (28.6%)		1/5 (20%)		0/6 (0%)		1/82 (1.2%)		5/78 (6.4%)
Gait disturbance	1/7 (14.3%)		2/5 (40%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Peripheral swelling	2/7 (28.6%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Pain	2/7 (28.6%)		2/5 (40%)		1/6 (16.7%)		0/82 (0%)		0/78 (0%)
Pyrexia	2/7 (28.6%)		0/5 (0%)		1/6 (16.7%)		13/82 (15.9%)		15/78 (19.2%)
Mucosal inflammation	2/7 (28.6%)		1/5 (20%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Oedema peripheral	1/7 (14.3%)		1/5 (20%)		2/6 (33.3%)		3/82 (3.7%)		4/78 (5.1%)
Influenza like illness	0/7 (0%)		1/5 (20%)		2/6 (33.3%)		0/82 (0%)		0/78 (0%)
Malaise	1/7 (14.3%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Catheter site rash	0/7 (0%)		1/5 (20%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Mucosal dryness	0/7 (0%)		1/5 (20%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Impaired healing	0/7 (0%)		0/5 (0%)		1/6 (16.7%)		0/82 (0%)		0/78 (0%)
Hepatobiliary disorders
Hyperbilirubinaemia	1/7 (14.3%)		2/5 (40%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Hepatocellular injury	1/7 (14.3%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Jaundice	0/7 (0%)		0/5 (0%)		1/6 (16.7%)		0/82 (0%)		0/78 (0%)
Immune system disorders
Hypersensitivity	0/7 (0%)		1/5 (20%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Infections and infestations
Influenza	2/7 (28.6%)		2/5 (40%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Urinary tract infection	2/7 (28.6%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Viral upper respiratory tract infection	1/7 (14.3%)		2/5 (40%)		2/6 (33.3%)		0/82 (0%)		0/78 (0%)
Conjunctivitis	1/7 (14.3%)		1/5 (20%)		1/6 (16.7%)		1/82 (1.2%)		4/78 (5.1%)
Cystitis	1/7 (14.3%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Herpes zoster	2/7 (28.6%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Pharyngitis	1/7 (14.3%)		1/5 (20%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Pneumonia	1/7 (14.3%)		1/5 (20%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Sinusitis	1/7 (14.3%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Ear infection	1/7 (14.3%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Eye infection	1/7 (14.3%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Folliculitis	1/7 (14.3%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Fungal skin infection	0/7 (0%)		1/5 (20%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Furuncle	1/7 (14.3%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Laryngitis	1/7 (14.3%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Localised infection	1/7 (14.3%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Oral candidiasis	1/7 (14.3%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Paronychia	0/7 (0%)		1/5 (20%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Oral herpes	0/7 (0%)		0/5 (0%)		1/6 (16.7%)		0/82 (0%)		0/78 (0%)
Pleural infection	0/7 (0%)		0/5 (0%)		1/6 (16.7%)		0/82 (0%)		0/78 (0%)
Skin infection	0/7 (0%)		0/5 (0%)		1/6 (16.7%)		0/82 (0%)		0/78 (0%)
Streptococcal infection	0/7 (0%)		0/5 (0%)		1/6 (16.7%)		0/82 (0%)		0/78 (0%)
Upper respiratory tract infection	0/7 (0%)		0/5 (0%)		0/6 (0%)		5/82 (6.1%)		1/78 (1.3%)
Injury, poisoning and procedural complications
Contusion	2/7 (28.6%)		3/5 (60%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Procedural headache	0/7 (0%)		1/5 (20%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Arthropod sting	0/7 (0%)		1/5 (20%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Eye contusion	1/7 (14.3%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Skin abrasion	1/7 (14.3%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Skin injury	1/7 (14.3%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Periorbital haematoma	0/7 (0%)		0/5 (0%)		1/6 (16.7%)		0/82 (0%)		0/78 (0%)
Thermal burn	0/7 (0%)		0/5 (0%)		1/6 (16.7%)		0/82 (0%)		0/78 (0%)
Investigations
Aspartate aminotransferase increased	4/7 (57.1%)		1/5 (20%)		1/6 (16.7%)		27/82 (32.9%)		31/78 (39.7%)
Platelet count decreased	4/7 (57.1%)		0/5 (0%)		0/6 (0%)		12/82 (14.6%)		13/78 (16.7%)
Alanine aminotransferase increased	4/7 (57.1%)		0/5 (0%)		1/6 (16.7%)		20/82 (24.4%)		24/78 (30.8%)
Blood bilirubin increased	1/7 (14.3%)		0/5 (0%)		1/6 (16.7%)		6/82 (7.3%)		4/78 (5.1%)
Blood lactate dehydrogenase increased	1/7 (14.3%)		0/5 (0%)		2/6 (33.3%)		9/82 (11%)		10/78 (12.8%)
Gamma-glutamyltransferase increased	1/7 (14.3%)		0/5 (0%)		0/6 (0%)		8/82 (9.8%)		16/78 (20.5%)
Aspartate aminotransferase	1/7 (14.3%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Transaminases increased	1/7 (14.3%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Weight decreased	0/7 (0%)		1/5 (20%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
White blood cell count decreased	0/7 (0%)		0/5 (0%)		1/6 (16.7%)		0/82 (0%)		0/78 (0%)
Blood alkaline phosphatase increased	0/7 (0%)		0/5 (0%)		1/6 (16.7%)		5/82 (6.1%)		15/78 (19.2%)
Blood creatinine increased	0/7 (0%)		0/5 (0%)		1/6 (16.7%)		0/82 (0%)		0/78 (0%)
International normalised ratio increased	0/7 (0%)		0/5 (0%)		1/6 (16.7%)		0/82 (0%)		0/78 (0%)
Neutrophil count decreased	0/7 (0%)		0/5 (0%)		1/6 (16.7%)		0/82 (0%)		0/78 (0%)
Liver palpable	0/7 (0%)		1/5 (20%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Metabolism and nutrition disorders
Hypomagnesaemia	1/7 (14.3%)		1/5 (20%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Hypokalaemia	2/7 (28.6%)		2/5 (40%)		0/6 (0%)		4/82 (4.9%)		4/78 (5.1%)
Decreased appetite	2/7 (28.6%)		0/5 (0%)		2/6 (33.3%)		10/82 (12.2%)		11/78 (14.1%)
Cell death	0/7 (0%)		1/5 (20%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Hypoalbuminaemia	0/7 (0%)		0/5 (0%)		2/6 (33.3%)		0/82 (0%)		0/78 (0%)
Hyperkalaemia	0/7 (0%)		0/5 (0%)		1/6 (16.7%)		0/82 (0%)		0/78 (0%)
Hyponatraemia	0/7 (0%)		0/5 (0%)		1/6 (16.7%)		0/82 (0%)		0/78 (0%)
Hypoproteinaemia	0/7 (0%)		0/5 (0%)		1/6 (16.7%)		0/82 (0%)		0/78 (0%)
Hyperglycaemia	0/7 (0%)		0/5 (0%)		0/6 (0%)		3/82 (3.7%)		5/78 (6.4%)
Musculoskeletal and connective tissue disorders
Arthralgia	3/7 (42.9%)		1/5 (20%)		2/6 (33.3%)		11/82 (13.4%)		9/78 (11.5%)
Back pain	2/7 (28.6%)		2/5 (40%)		1/6 (16.7%)		4/82 (4.9%)		4/78 (5.1%)
Muscle spasms	2/7 (28.6%)		2/5 (40%)		1/6 (16.7%)		5/82 (6.1%)		0/78 (0%)
Muscular weakness	1/7 (14.3%)		2/5 (40%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Musculoskeletal pain	3/7 (42.9%)		1/5 (20%)		0/6 (0%)		4/82 (4.9%)		6/78 (7.7%)
Myalgia	1/7 (14.3%)		2/5 (40%)		1/6 (16.7%)		7/82 (8.5%)		2/78 (2.6%)
Pain in extremity	2/7 (28.6%)		0/5 (0%)		0/6 (0%)		3/82 (3.7%)		5/78 (6.4%)
Bone pain	1/7 (14.3%)		1/5 (20%)		1/6 (16.7%)		0/82 (0%)		0/78 (0%)
Joint stiffness	1/7 (14.3%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Joint swelling	2/7 (28.6%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Musculoskeletal chest pain	1/7 (14.3%)		1/5 (20%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Neck pain	1/7 (14.3%)		1/5 (20%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Joint range of motion decreased	2/7 (28.6%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Muscle twitching	0/7 (0%)		1/5 (20%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Musculoskeletal stiffness	1/7 (14.3%)		1/5 (20%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Arthritis	1/7 (14.3%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Coccydynia	0/7 (0%)		1/5 (20%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Flank pain	1/7 (14.3%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Groin pain	0/7 (0%)		1/5 (20%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Limb mass	1/7 (14.3%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Osteonecrosis of jaw	0/7 (0%)		1/5 (20%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Tendonitis	0/7 (0%)		1/5 (20%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Weight bearing difficulty	0/7 (0%)		1/5 (20%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Skin papilloma	0/7 (0%)		1/5 (20%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Nervous system disorders
Headache	4/7 (57.1%)		3/5 (60%)		0/6 (0%)		8/82 (9.8%)		5/78 (6.4%)
Neuropathy peripheral	2/7 (28.6%)		2/5 (40%)		0/6 (0%)		2/82 (2.4%)		4/78 (5.1%)
Dizziness	1/7 (14.3%)		1/5 (20%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Migraine	0/7 (0%)		1/5 (20%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Balance disorder	1/7 (14.3%)		1/5 (20%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Hypoaesthesia	2/7 (28.6%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Amnesia	1/7 (14.3%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Aphonia	1/7 (14.3%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Hemiparesis	0/7 (0%)		1/5 (20%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Neuralgia	1/7 (14.3%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Neurotoxicity	1/7 (14.3%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Seizure	0/7 (0%)		1/5 (20%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Tremor	0/7 (0%)		1/5 (20%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Vocal cord paralysis	1/7 (14.3%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Paraesthesia	1/7 (14.3%)		0/5 (0%)		1/6 (16.7%)		5/82 (6.1%)		2/78 (2.6%)
Dysgeusia	0/7 (0%)		0/5 (0%)		2/6 (33.3%)		0/82 (0%)		0/78 (0%)
Syncope	0/7 (0%)		0/5 (0%)		1/6 (16.7%)		0/82 (0%)		0/78 (0%)
Peripheral sensory neuropathy	0/7 (0%)		0/5 (0%)		1/6 (16.7%)		0/82 (0%)		0/78 (0%)
Restless legs syndrome	0/7 (0%)		0/5 (0%)		1/6 (16.7%)		0/82 (0%)		0/78 (0%)
Psychiatric disorders
Insomnia	2/7 (28.6%)		1/5 (20%)		2/6 (33.3%)		0/82 (0%)		0/78 (0%)
Depression	1/7 (14.3%)		1/5 (20%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Affect lability	1/7 (14.3%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Confusional state	0/7 (0%)		1/5 (20%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Renal and urinary disorders
Dysuria	1/7 (14.3%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Reproductive system and breast disorders
Breast mass	0/7 (0%)		1/5 (20%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Benign prostatic hyperplasia	0/7 (0%)		0/5 (0%)		1/6 (16.7%)		0/82 (0%)		0/78 (0%)
Respiratory, thoracic and mediastinal disorders
Epistaxis	4/7 (57.1%)		3/5 (60%)		1/6 (16.7%)		15/82 (18.3%)		10/78 (12.8%)
Cough	2/7 (28.6%)		2/5 (40%)		2/6 (33.3%)		5/82 (6.1%)		6/78 (7.7%)
Rhinorrhoea	1/7 (14.3%)		3/5 (60%)		1/6 (16.7%)		0/82 (0%)		0/78 (0%)
Haemoptysis	1/7 (14.3%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Nasal ulcer	1/7 (14.3%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Oropharyngeal pain	1/7 (14.3%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Pleural effusion	0/7 (0%)		1/5 (20%)		1/6 (16.7%)		0/82 (0%)		0/78 (0%)
Rhinitis allergic	0/7 (0%)		1/5 (20%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Sleep apnoea syndrome	1/7 (14.3%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Dyspnoea	0/7 (0%)		0/5 (0%)		1/6 (16.7%)		2/82 (2.4%)		4/78 (5.1%)
Nasal inflammation	0/7 (0%)		0/5 (0%)		1/6 (16.7%)		0/82 (0%)		0/78 (0%)
Productive cough	0/7 (0%)		0/5 (0%)		1/6 (16.7%)		0/82 (0%)		0/78 (0%)
Rales	0/7 (0%)		0/5 (0%)		1/6 (16.7%)		0/82 (0%)		0/78 (0%)
Sinus disorder	0/7 (0%)		0/5 (0%)		1/6 (16.7%)		0/82 (0%)		0/78 (0%)
Skin and subcutaneous tissue disorders
Palmar-plantar erythrodysaesthesia syndrome	3/7 (42.9%)		2/5 (40%)		1/6 (16.7%)		17/82 (20.7%)		2/78 (2.6%)
Rash macular	2/7 (28.6%)		3/5 (60%)		1/6 (16.7%)		0/82 (0%)		0/78 (0%)
Dry skin	1/7 (14.3%)		2/5 (40%)		1/6 (16.7%)		0/82 (0%)		0/78 (0%)
Rash	1/7 (14.3%)		2/5 (40%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Pruritus	2/7 (28.6%)		1/5 (20%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Macule	0/7 (0%)		1/5 (20%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Acne	1/7 (14.3%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Alopecia	1/7 (14.3%)		0/5 (0%)		0/6 (0%)		1/82 (1.2%)		5/78 (6.4%)
Blister	1/7 (14.3%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Dermatitis acneiform	1/7 (14.3%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Ecchymosis	0/7 (0%)		1/5 (20%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Eczema	0/7 (0%)		1/5 (20%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Ingrowing nail	1/7 (14.3%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Nail discolouration	0/7 (0%)		1/5 (20%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Onycholysis	1/7 (14.3%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Rash erythematous	1/7 (14.3%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Rash maculo-papular	1/7 (14.3%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Rash pruritic	1/7 (14.3%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Skin discolouration	0/7 (0%)		1/5 (20%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Skin mass	1/7 (14.3%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Skin ulcer	1/7 (14.3%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Swelling face	1/7 (14.3%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Onychoclasis	0/7 (0%)		0/5 (0%)		2/6 (33.3%)		0/82 (0%)		0/78 (0%)
Erythema	0/7 (0%)		0/5 (0%)		1/6 (16.7%)		0/82 (0%)		0/78 (0%)
Erythema multiforme	0/7 (0%)		0/5 (0%)		1/6 (16.7%)		0/82 (0%)		0/78 (0%)
Rash papular	0/7 (0%)		0/5 (0%)		1/6 (16.7%)		0/82 (0%)		0/78 (0%)
Spider naevus	0/7 (0%)		0/5 (0%)		1/6 (16.7%)		0/82 (0%)		0/78 (0%)
Telangiectasia	0/7 (0%)		0/5 (0%)		1/6 (16.7%)		0/82 (0%)		0/78 (0%)
Surgical and medical procedures
Skin lesion excision	1/7 (14.3%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Tooth extraction	0/7 (0%)		0/5 (0%)		1/6 (16.7%)		0/82 (0%)		0/78 (0%)
Tumour excision	0/7 (0%)		0/5 (0%)		1/6 (16.7%)		0/82 (0%)		0/78 (0%)
Vascular disorders
Flushing	1/7 (14.3%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Bloody discharge	0/7 (0%)		1/5 (20%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Hot flush	1/7 (14.3%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Thrombosis	1/7 (14.3%)		0/5 (0%)		0/6 (0%)		0/82 (0%)		0/78 (0%)
Deep vein thrombosis	0/7 (0%)		0/5 (0%)		1/6 (16.7%)		0/82 (0%)		0/78 (0%)
Hypertension	0/7 (0%)		0/5 (0%)		1/6 (16.7%)		0/82 (0%)		0/78 (0%)

Limitations/Caveats

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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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.