Breast Cancer, Gastric Cancer
Conditions
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.
Interventions
DRUGCapecitabine
Capecitabine will be administered at de-escalating doses (starting from 750 mg/m\^2) to determine the MTD.
Trastuzumab emtansine will be administered at a dose of 3.6 mg/kg via IV infusion every 3 weeks.
Sponsors
Hoffmann-La Roche
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 (%). |
| 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%. |
| 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. |
| 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%. |
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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) | — |
| 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. |
| 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. |
| 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) | — |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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) | — |
| 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. |
| 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. |
| 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. |
Countries
Argentina, Brazil, Canada, France, Germany, Greece, Italy, Portugal, Russia, Serbia, Slovakia, Spain
Participant flow
Pre-assignment details
A total of 234 participants were screened, out of which, 182 participants were enrolled into the study. Out of the 182 enrolled participants, 3 participants were excluded from all safety and efficacy analyses because they did not sign correct Informed Consent Form (ICF).
Participants by arm
| Arm | Count |
|---|---|
| Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape 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. | 7 |
| Phase 1 (mBC) Cohort 1 (DL -1): T-DM1 + Cape 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. | 5 |
| Phase 1 (LA/mGC) Cohort 2 (DL -1): T-DM1 + Cape 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. | 6 |
| Phase 2 (mBC): T-DM1 + Cape 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. | 82 |
| Phase 2 (mBC): T-DM1 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. | 78 |
| Total | 178 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Death | 4 | 3 | 3 | 16 | 20 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 3 | 0 |
| Overall Study | Other | 0 | 0 | 0 | 16 | 17 |
| Overall Study | Safety Follow-Up less than 3 Months | 0 | 0 | 2 | 0 | 0 |
| Overall Study | Study Terminated by Sponsor | 0 | 1 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 12 | 4 |
Baseline characteristics
| Characteristic | Total | Phase 2 (mBC): T-DM1 | Phase 2 (mBC): 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 1 (mBC) Cohort 1 (DL -1): T-DM1 + Cape |
|---|---|---|---|---|---|---|
| Age, Continuous | 53.2 years STANDARD_DEVIATION 11.22 | 52.6 years STANDARD_DEVIATION 11.19 | 53.3 years STANDARD_DEVIATION 11.69 | 55.9 years STANDARD_DEVIATION 10.75 | 60.0 years STANDARD_DEVIATION 7.4 | 50.8 years STANDARD_DEVIATION 7.76 |
| Race/Ethnicity, Customized Ethnicity: Chinese | 1 participants | 0 participants | 1 participants | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Ethnicity: Hispanic/Latino | 16 participants | 10 participants | 5 participants | 0 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Ethnicity: Mixed | 1 participants | 0 participants | 0 participants | 0 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Ethnicity: N/A (as per local regulation) | 69 participants | 29 participants | 32 participants | 1 participants | 6 participants | 1 participants |
| Race/Ethnicity, Customized Ethnicity: Other | 80 participants | 35 participants | 39 participants | 6 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Ethnicity: Unknown | 11 participants | 4 participants | 5 participants | 0 participants | 0 participants | 2 participants |
| Race/Ethnicity, Customized Race: Asian | 2 participants | 1 participants | 1 participants | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Race: Black | 2 participants | 2 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Race: Caucasian | 152 participants | 65 participants | 71 participants | 6 participants | 6 participants | 4 participants |
| Race/Ethnicity, Customized Race: Mixed | 3 participants | 3 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Race: N/A (as per local regulation) | 19 participants | 7 participants | 10 participants | 1 participants | 0 participants | 1 participants |
| Sex: Female, Male Female | 170 Participants | 78 Participants | 81 Participants | 6 Participants | 0 Participants | 5 Participants |
| Sex: Female, Male Male | 8 Participants | 0 Participants | 1 Participants | 1 Participants | 6 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 4 / 7 | 3 / 5 | 3 / 6 | 18 / 82 | 21 / 78 |
| other Total, other adverse events | 7 / 7 | 5 / 5 | 6 / 6 | 75 / 82 | 64 / 78 |
| serious Total, serious adverse events | 0 / 7 | 2 / 5 | 4 / 6 | 11 / 82 | 10 / 78 |
Outcome results
Primary
Phase 1 (LA/mGC): MTD of Capecitabine When Combined With Trastuzumab Emtansine (2.4 mg/kg QW)
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
Population: Analysis was performed on Phase 1 DLT-evaluable population for LA/mGC cohort.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape | Phase 1 (LA/mGC): MTD of Capecitabine When Combined With Trastuzumab Emtansine (2.4 mg/kg QW) | 700 mg/m^2 |
Primary
Phase 1 (LA/mGC): Percentage of Participants With DLTs
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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape | Phase 1 (LA/mGC): Percentage of Participants With DLTs | 0.0 percentage of participants |
Primary
Phase 1 (mBC): Maximum Tolerated Dose (MTD) of Capecitabine When Combined With Trastuzumab Emtansine (3.6 mg/kg Every 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%.
Time frame: Continuously during Cycle 1 (up to 3 weeks)
Population: Analysis was performed on Phase 1 DLT-evaluable population for mBC cohort.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape | Phase 1 (mBC): Maximum Tolerated Dose (MTD) of Capecitabine When Combined With Trastuzumab Emtansine (3.6 mg/kg Every 3 Weeks) | 700 mg/m^2 |
Primary
Phase 1 (mBC): Percentage of Participants With Dose-Limiting Toxicities (DLTs)
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)
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape | Phase 1 (mBC): Percentage of Participants With Dose-Limiting Toxicities (DLTs) | 33.3 percentage of participants |
| Phase 1 (mBC) Cohort 1 (DL -1): T-DM1 + Cape | Phase 1 (mBC): Percentage of Participants With Dose-Limiting Toxicities (DLTs) | 0.0 percentage of participants |
Primary
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)
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)
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape | 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) | 44.4 percentage of participants |
| Phase 1 (mBC) Cohort 1 (DL -1): T-DM1 + Cape | 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) | 36.3 percentage of participants |
p-value: 0.33690% CI: [-4.5, 20.9]Fisher Exact
Secondary
Phase 1 (LA/mGC): AUC(0-inf) of 5-Fluorouracil (Metabolite of Capecitabine)
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
Population: Analysis was performed on Phase 1 PK analysis population for LA/mGC cohort.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape | Phase 1 (LA/mGC): AUC(0-inf) of 5-Fluorouracil (Metabolite of Capecitabine) | 213 h*ng/mL | Standard Deviation 16.2 |
Secondary
Phase 1 (LA/mGC): AUC(0-inf) 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 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
Population: Analysis was performed on Phase 1 PK analysis population for LA/mGC cohort.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape | Phase 1 (LA/mGC): AUC(0-inf) of Capecitabine | 5131 h*ng/mL | Standard Deviation 24.6 |
Secondary
Phase 1 (LA/mGC): Cmax of 5-Fluorouracil (Metabolite of Capecitabine)
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
Population: Analysis was performed on Phase 1 PK analysis population for LA/mGC cohort.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape | Phase 1 (LA/mGC): Cmax of 5-Fluorouracil (Metabolite of Capecitabine) | 137 ng/mL | Standard Deviation 24.3 |
Secondary
Phase 1 (LA/mGC): Cmax of Capecitabine
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
Population: Analysis was performed on Phase 1 PK analysis population for LA/mGC cohort.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape | Phase 1 (LA/mGC): Cmax of Capecitabine | 4925 ng/mL | Standard Deviation 36.3 |
Secondary
Phase 1 (LA/mGC): Percentage of Participants With BOR as Assessed by the Investigator According to RECIST v1.1
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)
Population: Analysis was performed on Phase 1 DLT-evaluable population for LA/mGC cohort.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape | Phase 1 (LA/mGC): Percentage of Participants With BOR as Assessed by the Investigator According to RECIST v1.1 | 83.3 percentage of participants |
Secondary
Phase 1 (LA/mGC): Serum Concentration of Trastuzumab
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)
Population: Analysis was performed on Phase 1 PK analysis population for LA/mGC cohort.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape | Phase 1 (LA/mGC): Serum Concentration of Trastuzumab | Cycle 1, Post-dose | 33.1 mcg/mL | Standard Deviation 15.98 |
| Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape | Phase 1 (LA/mGC): Serum Concentration of Trastuzumab | Cycle 2, Pre-dose | 18.5 mcg/mL | Standard Deviation 7.57 |
| Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape | Phase 1 (LA/mGC): Serum Concentration of Trastuzumab | Cycle 2, Post-dose | 57.6 mcg/mL | Standard Deviation 13.55 |
Secondary
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)
Population: Analysis was performed on Phase 1 PK analysis population for LA/mGC cohort.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape | Phase 1 (LA/mGC): Serum Concentration of Trastuzumab Emtansine | Cycle 1, Post-dose | 30.1 mcg/mL | Standard Deviation 14.5 |
| Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape | Phase 1 (LA/mGC): Serum Concentration of Trastuzumab Emtansine | Cycle 2, Pre-dose | 10.1 mcg/mL | Standard Deviation 5.85 |
| Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape | Phase 1 (LA/mGC): Serum Concentration of Trastuzumab Emtansine | Cycle 2, Post-dose | 46.4 mcg/mL | Standard Deviation 7.74 |
Secondary
Phase 1 (LA/mGC): t1/2 of 5-Fluorouracil (Metabolite of Capecitabine)
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
Population: Analysis was performed on Phase 1 PK analysis population for LA/mGC cohort.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape | Phase 1 (LA/mGC): t1/2 of 5-Fluorouracil (Metabolite of Capecitabine) | 0.83 hours | Standard Deviation 17 |
Secondary
Phase 1 (LA/mGC): t1/2 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 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
Population: Analysis was performed on Phase 1 PK analysis population for LA/mGC cohort.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape | Phase 1 (LA/mGC): t1/2 of Capecitabine | 0.65 hours | Standard Deviation 34.5 |
Secondary
Phase 1 (mBC): Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC[0-inf]) 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 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
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape | Phase 1 (mBC): Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC[0-inf]) of Capecitabine | 3973 hours*nanograms per milliliter (h*ng/mL) | Standard Deviation 38 |
| Phase 1 (mBC) Cohort 1 (DL -1): T-DM1 + Cape | Phase 1 (mBC): Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC[0-inf]) of Capecitabine | 5440 hours*nanograms per milliliter (h*ng/mL) | Standard Deviation 57.7 |
Secondary
Phase 1 (mBC): AUC(0-inf) of 5-Fluorouracil (Metabolite of Capecitabine)
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
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape | Phase 1 (mBC): AUC(0-inf) of 5-Fluorouracil (Metabolite of Capecitabine) | 257 h*ng/mL | Standard Deviation 49.9 |
| Phase 1 (mBC) Cohort 1 (DL -1): T-DM1 + Cape | Phase 1 (mBC): AUC(0-inf) of 5-Fluorouracil (Metabolite of Capecitabine) | 244 h*ng/mL | Standard Deviation 38.2 |
Secondary
Phase 1 (mBC): Cmax of 5-Fluorouracil (Metabolite of Capecitabine)
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
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape | Phase 1 (mBC): Cmax of 5-Fluorouracil (Metabolite of Capecitabine) | 148 ng/mL | Standard Deviation 49.9 |
| Phase 1 (mBC) Cohort 1 (DL -1): T-DM1 + Cape | Phase 1 (mBC): Cmax of 5-Fluorouracil (Metabolite of Capecitabine) | 143 ng/mL | Standard Deviation 45.6 |
Secondary
Phase 1 (mBC): Maximum Observed Plasma Concentration (Cmax) of Capecitabine
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
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape | Phase 1 (mBC): Maximum Observed Plasma Concentration (Cmax) of Capecitabine | 2990 nanograms per milliliter (ng/mL) | Standard Deviation 38.4 |
| Phase 1 (mBC) Cohort 1 (DL -1): T-DM1 + Cape | Phase 1 (mBC): Maximum Observed Plasma Concentration (Cmax) of Capecitabine | 5652 nanograms per milliliter (ng/mL) | Standard Deviation 91.1 |
Secondary
Phase 1 (mBC): Percentage of Participants With BOR as Assessed by the Investigator According to RECIST v1.1
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)
Population: Analysis was performed on Phase 1 DLT-evaluable population for mBC cohort.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape | Phase 1 (mBC): Percentage of Participants With BOR as Assessed by the Investigator According to RECIST v1.1 | 83.3 percentage of participants |
| Phase 1 (mBC) Cohort 1 (DL -1): T-DM1 + Cape | Phase 1 (mBC): Percentage of Participants With BOR as Assessed by the Investigator According to RECIST v1.1 | 100.0 percentage of participants |
Secondary
Phase 1 (mBC): Plasma Terminal Half-Life (t1/2) 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 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
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape | Phase 1 (mBC): Plasma Terminal Half-Life (t1/2) of Capecitabine | 0.70 hours | Standard Deviation 131.9 |
| Phase 1 (mBC) Cohort 1 (DL -1): T-DM1 + Cape | Phase 1 (mBC): Plasma Terminal Half-Life (t1/2) of Capecitabine | 0.39 hours | Standard Deviation 38.8 |
Secondary
Phase 1 (mBC): Serum Concentration of Trastuzumab
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)
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape | Phase 1 (mBC): Serum Concentration of Trastuzumab | Cycle 1, Post-dose | 89.1 mcg/mL | Standard Deviation 24.37 |
| Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape | Phase 1 (mBC): Serum Concentration of Trastuzumab | Cycle 2, Pre-dose | 11.8 mcg/mL | Standard Deviation 13.28 |
| Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape | Phase 1 (mBC): Serum Concentration of Trastuzumab | Cycle 2, Post-dose | 74.8 mcg/mL | Standard Deviation 18.89 |
| Phase 1 (mBC) Cohort 1 (DL -1): T-DM1 + Cape | Phase 1 (mBC): Serum Concentration of Trastuzumab | Cycle 1, Post-dose | 92.9 mcg/mL | Standard Deviation 22.13 |
| Phase 1 (mBC) Cohort 1 (DL -1): T-DM1 + Cape | Phase 1 (mBC): Serum Concentration of Trastuzumab | Cycle 2, Pre-dose | 14.0 mcg/mL | Standard Deviation 12.53 |
| Phase 1 (mBC) Cohort 1 (DL -1): T-DM1 + Cape | Phase 1 (mBC): Serum Concentration of Trastuzumab | Cycle 2, Post-dose | 94.7 mcg/mL | Standard Deviation 24.6 |
Secondary
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)
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape | Phase 1 (mBC): Serum Concentration of Trastuzumab Emtansine | Cycle 1, Post-dose | 81.3 micrograms per milliliter (mcg/mL) | Standard Deviation 13.3 |
| Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape | Phase 1 (mBC): Serum Concentration of Trastuzumab Emtansine | Cycle 2, Pre-dose | 1.17 micrograms per milliliter (mcg/mL) | Standard Deviation 1.25 |
| Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape | Phase 1 (mBC): Serum Concentration of Trastuzumab Emtansine | Cycle 2, Post-dose | 70.5 micrograms per milliliter (mcg/mL) | Standard Deviation 13.3 |
| Phase 1 (mBC) Cohort 1 (DL -1): T-DM1 + Cape | Phase 1 (mBC): Serum Concentration of Trastuzumab Emtansine | Cycle 1, Post-dose | 78.6 micrograms per milliliter (mcg/mL) | Standard Deviation 14.6 |
| Phase 1 (mBC) Cohort 1 (DL -1): T-DM1 + Cape | Phase 1 (mBC): Serum Concentration of Trastuzumab Emtansine | Cycle 2, Pre-dose | 2.1 micrograms per milliliter (mcg/mL) | Standard Deviation 1.49 |
| Phase 1 (mBC) Cohort 1 (DL -1): T-DM1 + Cape | Phase 1 (mBC): Serum Concentration of Trastuzumab Emtansine | Cycle 2, Post-dose | 78.5 micrograms per milliliter (mcg/mL) | Standard Deviation 14.9 |
Secondary
Phase 1 (mBC): t1/2 of 5-Fluorouracil (Metabolite of Capecitabine)
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
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape | Phase 1 (mBC): t1/2 of 5-Fluorouracil (Metabolite of Capecitabine) | 0.63 hours | Standard Deviation 39.5 |
| Phase 1 (mBC) Cohort 1 (DL -1): T-DM1 + Cape | Phase 1 (mBC): t1/2 of 5-Fluorouracil (Metabolite of Capecitabine) | 0.64 hours | Standard Deviation 18.3 |
Secondary
Phase 2 (mBC): Duration of Response (DoR) as Assessed by the Investigator According to RECIST v1.1
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)
Population: Analysis was performed on ITT Population. Only participants with a BOR of CR or PR were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape | Phase 2 (mBC): Duration of Response (DoR) as Assessed by the Investigator According to RECIST v1.1 | 11.30 months |
| Phase 1 (mBC) Cohort 1 (DL -1): T-DM1 + Cape | Phase 2 (mBC): Duration of Response (DoR) as Assessed by the Investigator According to RECIST v1.1 | 12.22 months |
Secondary
Phase 2 (mBC): Overall Survival (OS)
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)
Population: Analysis was performed on ITT Population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape | Phase 2 (mBC): Overall Survival (OS) | NA months |
| Phase 1 (mBC) Cohort 1 (DL -1): T-DM1 + Cape | Phase 2 (mBC): Overall Survival (OS) | 24.71 months |
Secondary
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)
Population: Analysis was performed on ITT Population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape | Phase 2 (mBC): Percentage of Participants Who Died of Any Cause | 22.2 percentage of participants |
| Phase 1 (mBC) Cohort 1 (DL -1): T-DM1 + Cape | Phase 2 (mBC): Percentage of Participants Who Died of Any Cause | 26.3 percentage of participants |
Secondary
Phase 2 (mBC): Percentage of Participants With Clinical Benefit as Assessed by the Investigator According to RECIST v1.1
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)
Population: Analysis was performed on ITT Population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape | Phase 2 (mBC): Percentage of Participants With Clinical Benefit as Assessed by the Investigator According to RECIST v1.1 | 66.7 percentage of participants |
| Phase 1 (mBC) Cohort 1 (DL -1): T-DM1 + Cape | Phase 2 (mBC): Percentage of Participants With Clinical Benefit as Assessed by the Investigator According to RECIST v1.1 | 62.5 percentage of participants |
Secondary
Phase 2 (mBC): Percentage of Participants With PD as Assessed by the Investigator According to RECIST v1.1
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)
Population: Analysis was performed on ITT Population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape | Phase 2 (mBC): Percentage of Participants With PD as Assessed by the Investigator According to RECIST v1.1 | 64.2 percentage of participants |
| Phase 1 (mBC) Cohort 1 (DL -1): T-DM1 + Cape | Phase 2 (mBC): Percentage of Participants With PD as Assessed by the Investigator According to RECIST v1.1 | 70.0 percentage of participants |
Secondary
Phase 2 (mBC): Percentage of Participants With PD as Assessed by the Investigator According to RECIST v1.1 or Death From Any Cause
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)
Population: Analysis was performed on ITT Population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape | Phase 2 (mBC): Percentage of Participants With PD as Assessed by the Investigator According to RECIST v1.1 or Death From Any Cause | 67.9 percentage of participants |
| Phase 1 (mBC) Cohort 1 (DL -1): T-DM1 + Cape | Phase 2 (mBC): Percentage of Participants With PD as Assessed by the Investigator According to RECIST v1.1 or Death From Any Cause | 73.8 percentage of participants |
Secondary
Phase 2 (mBC): Percentage of Participants With Treatment Failure as Assessed by the Investigator According to RECIST v1.1
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)
Population: Analysis was performed on ITT Population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape | Phase 2 (mBC): Percentage of Participants With Treatment Failure as Assessed by the Investigator According to RECIST v1.1 | 77.8 percentage of participants |
| Phase 1 (mBC) Cohort 1 (DL -1): T-DM1 + Cape | Phase 2 (mBC): Percentage of Participants With Treatment Failure as Assessed by the Investigator According to RECIST v1.1 | 83.8 percentage of participants |
Secondary
Phase 2 (mBC): Progression-Free Survival (PFS) as Assessed by the Investigator According to RECIST v1.1
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)
Population: Analysis was performed on ITT Population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape | Phase 2 (mBC): Progression-Free Survival (PFS) as Assessed by the Investigator According to RECIST v1.1 | 10.15 months |
| Phase 1 (mBC) Cohort 1 (DL -1): T-DM1 + Cape | Phase 2 (mBC): Progression-Free Survival (PFS) as Assessed by the Investigator According to RECIST v1.1 | 9.82 months |
Secondary
Phase 2 (mBC): Time to Progression (TTP) as Assessed by the Investigator According to RECIST v1.1
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)
Population: Analysis was performed on ITT Population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape | Phase 2 (mBC): Time to Progression (TTP) as Assessed by the Investigator According to RECIST v1.1 | 10.38 months |
| Phase 1 (mBC) Cohort 1 (DL -1): T-DM1 + Cape | Phase 2 (mBC): Time to Progression (TTP) as Assessed by the Investigator According to RECIST v1.1 | 10.32 months |
Secondary
Phase 2 (mBC): Time to Response (TTR) as Assessed by the Investigator According to RECIST v1.1
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)
Population: Analysis was performed on ITT Population. Only participants with a BOR of CR or PR were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape | Phase 2 (mBC): Time to Response (TTR) as Assessed by the Investigator According to RECIST v1.1 | 2.10 months |
| Phase 1 (mBC) Cohort 1 (DL -1): T-DM1 + Cape | Phase 2 (mBC): Time to Response (TTR) as Assessed by the Investigator According to RECIST v1.1 | 2.10 months |
Secondary
Phase 2 (mBC): Time to Treatment Failure (TTF) as Assessed by the Investigator According to RECIST v1.1
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)
Population: Analysis was performed on ITT Population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 (mBC) Cohort 1 (DL 1): T-DM1 + Cape | Phase 2 (mBC): Time to Treatment Failure (TTF) as Assessed by the Investigator According to RECIST v1.1 | 9.86 months |
| Phase 1 (mBC) Cohort 1 (DL -1): T-DM1 + Cape | Phase 2 (mBC): Time to Treatment Failure (TTF) as Assessed by the Investigator According to RECIST v1.1 | 7.66 months |