Breast Cancer
Conditions
Brief summary
This single arm study will evaluate alterations in molecular marker expression in HER2-positive targeted therapy, and will evaluate the effect of continued treatment with Herceptin and Xeloda beyond progression following initial Herceptin-taxane chemotherapy. Patients who develop progressive disease will receive first-line Herceptin (8mg/kg iv loading dose and 6mg/kg iv every 3 weeks) + taxane therapy. patients who develop progressive disease within 9 weeks of treatment will continue treatment with Herceptin in combination with Xeloda (1000mg/m2 po bid on days 1-14 of each 3-week cycle).Biopsies of tumor tissue will be taken for biomarker and gene profiling evaluation. The anticipated time on study treatment is until disease progression, intolerable side effects or patient choice, and the target sample size is 100 individuals.
Interventions
DRUGStandard taxane therapy
As prescribed
DRUGcapecitabine [Xeloda]
1000mg/m2 po bid on days 1-14 of each 3-week cycle (only in patients who have progressed)
8mg/kg iv loading dose on day 1 of first 3-week cycle, and 6mg/kg iv on day 1 of each subsequent cycle
Sponsors
Hoffmann-La Roche
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* female patients, \>=18 years of age; * HER2-positive breast cancer; * al least one metastatic site amenable for core biopsy; * left ventricular ejection fraction \>50%.
Exclusion criteria
* prior adjuvant/neoadjuvant Herceptin within past 6 months; * prior adjuvant taxane therapy within past 12 months; * use of chemotherapy, immunotherapy or biological anticancer therapy within past 3 weeks; * known bleeding diatheses.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part I: Progression Free Survival (PFS) by Biomarker | End of first 2 Cycles (Weeks 3 and 6), every 3 Cycles for 18 weeks, then every 4 cycles until progression, unacceptable toxicity or participant decision to cease treatment up to 46 months | Progression was defined as an increase by at least 20 percent (%) from the smallest value in the Sum of Longest Diameter (SLD) of lesions. Biomarkers investigated: p95 human epidermal growth factor receptor 2 (p95HER2) positive (+ve) and negative (-ve) , insulin growth factor-1 receptor (IGF1R) less than (\<) median and greater than or equal to (≥) median membrane H score, c-MET \<median and ≥median membrane H score, phosphatase and tensin homolog gene (PTEN) \<median and ≥median cytoplasm H score, HER2 \<median and ≥median membrane H score, phosphatidylinositol-3-kinase (PI3K) catalytic subunit wild type (WT) and mutation (M), and FC gamma receptors IIIa homozygous Phenyl alanine (FF), heterozygous Phenyl alanine/Valine (VF) and homozygous Valine (VV), receptor IIa Phenotypes homozygous Histidine (HH), heterozygous Histidine/Arginine (HR) and homozygous Arginine (RR) IIb phenotypes homozygous Isoleucien (II),heterozygous Isoleucine/Threonine (IT) and homozygous Threonine (TT) . |
| Part II: Progression Free Survival (PFS) by Biomarker | End of first 2 Cycles (Weeks 3 and 6), every 3 cycles for 18 weeks, then every 4 cycles until progression, unacceptable toxicity or participant decision to cease treatment up to 46 months | PFS was calculated from first study medication in Part II to date of progression or death.The relationship between PFS and the following biomarker variables was investigated in each of study Part 1 and 2: p95HER2 +ve and -ve population, IGF1R \<median and ≥ median membrane H score, c-MET \<median and ≥median membrane H score, PTEN \<median and ≥median cytoplasm H score, HER2 \<median and ≥median membrane H score, PI3K catalytic subunit WT and M, and FC gamma receptors IIIa, IIa and IIb Phenotypes FF, VF and VV, HH, HR and RR, and II, IT and TT. |
| Part I: Time to Progression (TTP) by Biomarker | End of first 2 Cycles (Weeks 3 and 6), every 3 Cycles for 18 weeks, then every 4 cycles until progression, unacceptable toxicity or participant decision to cease treatment up to 46 weeks | Progression was defined as an increase by at least 20% from the smallest value in the SLD of lesions.TTP was determined as the time in months from the date of screening until first progression.The relationship between PFS and the following biomarker variables was investigated in each of study Part 1 and 2: p95 HER2 +ve and -ve population, IGF1R \<median and ≥median, c-MET \<median and ≥median, PTEN \<median and ≥median, HER2 \<median and ≥median, PI3K catalytic subunit WT and M, and FC gamma receptors IIIa, IIa and IIb Phenotypes FF, VF and VV, HH, HR and RR, and II, IT and TT . The correlation between the biomarker variables and TTP were investigated using a univariate Cox regression model and time-to-event methods (Kaplan-Meier). |
| Part II: TTP by Biomarker | End of first 2 Cycles (Weeks 3 and 6), every 3 cycles for 18 weeks, then every 4 cycles until progression, unacceptable toxicity or participant decision to cease treatment up to 46 months | TTP was calculated from first study medication in Part II to date of progression. The relationship between TTP and the following biomarker variables was investigated in each of study Part 1 and 2: p95 HER2 +ve and -ve population, IGF1R \<median and ≥median, c-MET \<median and ≥median, PTEN \<median and ≥median, HER2 \<median and ≥median, PI3K catalytic subunit WT and M, and FC gamma receptors IIIa, IIa and IIb Phenotypes FF, VF and VV, HH, HR and RR, and II, IT and TT . |
| Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | End of first 2 Cycles (Weeks 3 and 6), every 3 cycles for 18 weeks, then every 4 cycles until progression, unacceptable toxicity or participant decision to cease treatment up to 46 weeks | BOR was defined according to the Response Evaluation Criteria In Solid Tumors (RECIST). CR: disappearance of all target lesions and all pathological lymph nodes below 10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. PD: At least a 20% increase in the sum of diameters of target lesions, and the sum must also demonstrate an absolute increase of at least 5 mm or persistence of non-target lesions. The relationship between best response and the following biomarkers was investigated: p95 HER2 (+ve/-ve), IGF1R, c-MET, PTEN, HER2 (median/≥median), PI3K catalytic subunit (WT/M), and FC gamma receptors IIIa, IIa and IIb (phenotypes FF, VF, VV, HH, HR, RR and II, IT and TT respectively). The correlation between the biomarker variables and percentage of participants with best response were investigated using a univariate regression analysis. |
| Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | End of first 2 Cycles (Weeks 3 and 6), every 3 cycles for 18 weeks, then every 4 cycles until progression, unacceptable toxicity or participant decision to cease treatment up to 46 months | Best Overall response was defined according to RECIST. CR: disappearance of all target lesions and all pathological lymph nodes below 10 mm.PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. PD: At least a 20% increase in the sum of diameters of target lesions, and the sum must also demonstrate an absolute increase of at least 5 mm or persistence of non-target lesions. The relationship between best response and the following biomarkers was investigated: p95 HER2 (+ve/-ve), IGF1R, c-MET, PTEN, HER2 (\<median/≥median) , PI3K catalytic subunit (WT/M), and FC gamma receptors IIIa, IIa and IIb (phenotypes FF, VF, VV, HH, HR, RR and II, IT and TT respectively). The correlation between the biomarker variables and percentage of participants with best response were investigated using a univariate regression analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part I and II: Percentage of Participants With a Best Overall Response of CR or PR in ITT Population | End of first 2 Cycles (Weeks 3 and 6), every 3 Cycles for 18 weeks, then every 4 cycles until progression, unacceptable toxicity or participant decision to cease treatment up to 46 months | Best Overall response was defined according to RECIST. CR: disappearance of all target lesions and all pathological lymph nodes below 10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. PD: At least a 20% increase in the sum of diameters of target lesions, and the sum must also demonstrate an absolute increase of at least 5 mm or persistence of non-target lesions. |
| Part I: TTP in Intent to Treat (ITT) Population | End of first 2 Cycles (Weeks 3 and 6), every 3 cycles for 18 weeks, then every 4 cycles until progression, unacceptable toxicity or participant decision to cease treatment up to 46 months | TTP was determined as the time in months from the date of screening until first progression. In participants with measurable disease, progression was defined according to RECIST (SLD increased by at least 20% from the smallest value on study \[including baseline, if that is the smallest\]). In participants with non-measurable disease, progression was defined as the presence of new lesions or unequivocal progression during treatment. |
| Part I and II: Percentage of Participants With a Response by Best Overall Response by CR, PR, SD or PD in ITT Population | End of first 2 Cycles (Weeks 3 and 6), every 3 cycles for 18 weeks, then every 4 cycles until progression, unacceptable toxicity or participant decision to cease treatment up to 46 months | Best Overall response was defined according to RECIST. CR: disappearance of all target lesions and all pathological lymph nodes below 10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. PD: At least a 20% increase in the sum of diameters of target lesions, and the sum must also demonstrate an absolute increase of at least 5 mm or persistence of non-target lesions. |
| Part I: PFS in ITT Population | End of first 2 Cycles (Weeks 3 and 6), every 3 cycles for 18 weeks, then every 4 cycles until progression, unacceptable toxicity or participant decision to cease treatment up to 46 months | PFS was determined as the time in months from the date of screening until first progression. In participants with measurable disease, progression was defined according to RECIST (SLD increased by at least 20% from the smallest value on study \[including baseline, if that is the smallest\]).. In participants with non-measurable disease, progression was defined as the presence of new lesions or unequivocal progression during treatment. |
| Part II: TTP in Intent to Treat (ITT) Population | End of first 2 Cycles (Weeks 3 and 6), every 3 Cycles for 18 weeks, then every 4 cycles until progression, unacceptable toxicity or participant decision to cease treatment up to 46 months | TTP was calculated from first study medication in Part II to date of progression. In participants with measurable disease progression was defined according to RECIST(SLD increased by at least 20% from the smallest value on study \[including baseline, if that is the smallest\]). In participants with non-measurable disease, progression was defined as the presence of new lesions or unequivocal progression during treatment. |
| Part II: PFS in ITT Population | End of first 2 Cycles (Weeks 3 and 6), every 3 cycles for 18 weeks, then every 4 cycles until progression, unacceptable toxicity or participant decision to cease treatment up to 46 months | PFS was calculated from first study medication in Part II to date of progression or death. In participants with measurable disease progression was defined according to RECIST (SLD increased by at least 20% from the smallest value on study \[including baseline, if that is the smallest\]). In participants with non-measurable disease, progression was defined as the presence of new lesions or unequivocal progression during treatment. |
| Overall Survival in Per Protocol Population | End of first 2 Cycles (Weeks 3 and 6), every 3 cycles for 18 weeks, then every 4 cycles until death (up to 46 months) | Overall survival was calculated in months from the day of screening until death. |
| Overall Survival in ITT Population | End of first 2 Cycles (Weeks 3 and 6), every 3 cycles for 18 weeks, then every 4 cycles until death (up to 46 months) | Overall survival was calculated in months from the day of screening until death. |
Countries
Australia, Spain, Sweden, United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) This group included participants who progressed after at least six weeks of trastuzumab/taxane treatment. In Part I of the study, participants received standard first-line therapy with trastuzumab and, at the discretion of treating clinician, either paclitaxel or docetaxel. Paclitaxel and docetaxel were administered according to one of following regimens: docetaxel 75 mg/m\^2 or 100 mg/m\^2 3-weekly (if docetaxel-naïve) or docetaxel 75 mg/m\^2 3-weekly (if prior adjuvant docetaxel) or docetaxel 60 mg/m\^2 3-weekly (if liver dysfunction due to metastatic involvement) or paclitaxel 80 mg/m\^2 weekly or 175 mg/m\^2 3-weekly until first disease progression. In Part II of the study, participants received capecitabine twice-daily 1000 mg/m\^2 or higher, calculated based on BSA on days 1 to 14 while continuing trastuzumab treatment per standard practice until disease progression, unmanageable toxicity or participant request for discontinuation. | 31 |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks This group included participants who progressed within less than six weeks of trastuzumab/taxane treatment. In Part I of the study, participants received standard first-line therapy with trastuzumab and, at the discretion of treating clinician, either paclitaxel or docetaxel. Paclitaxel and docetaxel were administered according to one of following regimens: docetaxel 75 mg/m\^2 or 100 mg/m\^2 3-weekly (if docetaxel-naïve) or docetaxel 75 mg/m\^2 3-weekly (if prior adjuvant docetaxel) or docetaxel 60 mg/m\^2 3-weekly (if liver dysfunction due to metastatic involvement) or paclitaxel 80 mg/m\^2 weekly or 175 mg/m\^2 3-weekly until first disease progression. In Part II of the study, participants received capecitabine twice-daily 1000 mg/m\^2 or higher, calculated based on BSA on days 1 to 14 while continuing trastuzumab treatment per standard practice until disease progression, unmanageable toxicity or participant request for discontinuation. | 1 |
| No Group This group included participants who died before any on study disease assessments or post-baseline biopsies. In Part 1 of the study, participants received standard first-line therapy with trastuzumab and, at the discretion of treating clinician, either paclitaxel or docetaxel. Paclitaxel and docetaxel were administered according to one of following regimens: docetaxel 75 mg/m\^2 or 100 mg/m\^2 3-weekly (if docetaxel-naïve) or docetaxel 75 mg/m\^2 3-weekly (if prior adjuvant docetaxel) or docetaxel 60 mg/m\^2 3-weekly (if liver dysfunction due to metastatic involvement) or paclitaxel 80 mg/m\^2 weekly or 175 mg/m\^2 3-weekly until first disease progression. | 1 |
| Total | 33 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Part II: Trastuzumab + Capecitabine. | Unknown Reason | 5 | 0 | 0 |
| Part I: Trastuzumab+Taxane | Adverse Event | 1 | 0 | 0 |
| Part I: Trastuzumab+Taxane | Death | 0 | 0 | 1 |
| Part I: Trastuzumab+Taxane | Sufficient Response Achieved | 1 | 0 | 0 |
| Part I: Trastuzumab+Taxane | Unknown Reason | 16 | 0 | 0 |
Baseline characteristics
| Characteristic | Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | No Group | Total |
|---|---|---|---|---|
| Age, Continuous | 55.5 years STANDARD_DEVIATION 11.73 | 37.0 years | 85.0 years | 55.9 years STANDARD_DEVIATION 12.91 |
| Sex: Female, Male Female | 31 Participants | 1 Participants | 1 Participants | 33 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 33 / 33 |
| serious Total, serious adverse events | 9 / 33 |
Outcome results
Primary
Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker
Best Overall response was defined according to RECIST. CR: disappearance of all target lesions and all pathological lymph nodes below 10 mm.PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. PD: At least a 20% increase in the sum of diameters of target lesions, and the sum must also demonstrate an absolute increase of at least 5 mm or persistence of non-target lesions. The relationship between best response and the following biomarkers was investigated: p95 HER2 (+ve/-ve), IGF1R, c-MET, PTEN, HER2 (\<median/≥median) , PI3K catalytic subunit (WT/M), and FC gamma receptors IIIa, IIa and IIb (phenotypes FF, VF, VV, HH, HR, RR and II, IT and TT respectively). The correlation between the biomarker variables and percentage of participants with best response were investigated using a univariate regression analysis.
Time frame: End of first 2 Cycles (Weeks 3 and 6), every 3 cycles for 18 weeks, then every 4 cycles until progression, unacceptable toxicity or participant decision to cease treatment up to 46 months
Population: PP population; n = number of participants with biomarker data available for the specified biomarker. Data are reported for Group A only as there were no evaluable participants in Group B.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | PTEN ≥median CR (n=2) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | PI3K Amino Acids WT PD (n=7) | 14.3 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | PI3K Amino Acids M CR (n=2) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | FC Gamma Receptor IIa R166H HH CR (n=0) | NA percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | FC Gamma Receptor IIb I232T TT PD (n=4) | 25.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | p95 HER2 +ve CR (n=2) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | p95 HER2 +ve PR (n=2) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | p95 HER2 +ve SD (n=2) | 100.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | p95 HER2 +ve PD (n=2) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | p95 HER2 -ve CR (n=4) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | p95 HER2 -ve PR (n=4) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | p95 HER2 -ve SD (n=4) | 50.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | p95 HER2 -ve PD (n=4) | 50.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | IGF1R <median CR (n=3) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | IGF1R <median PR (n=3) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | IGF1R <median SD (n=3) | 66.7 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | IGF1R <median PD (n=3) | 33.3 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | IGF1R ≥median CR (n=3) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | IGF1R ≥median PR (n=3) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | IGF1R ≥median SD (n=3) | 66.7 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | IGF1R ≥median PD (n=3) | 33.3 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | c-MET <median CR (n=2) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | c-MET <median PR (n=2) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | c-MET <median SD (n=2) | 100.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | c-MET <median PD (n=2) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | c-MET ≥median CR (n=4) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | c-MET ≥median PR (n=4) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | c-MET ≥median SD (n=4) | 50.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | c-MET ≥median PD (n=4) | 50.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | PTEN <median CR (n=4) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | PTEN <median PR (n=4) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | PTEN <median SD (n=4) | 75.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | PTEN <median PD (n=4) | 25.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | PTEN ≥median PR (n=2) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | PTEN ≥median SD (n=2) | 50.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | PTEN ≥median PD (n=2) | 50.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | HER2 <median CR (n=2) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | HER2 <median PR (n=2) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | HER2 <median SD (n=2) | 100.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | HER2 <median PD (n=2) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | HER2 ≥median CR (n=4) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | HER2 ≥median PR (n=4) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | HER2 ≥median SD (n=4) | 50.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | HER2 ≥median PD (n=4) | 50.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | PI3K Amino Acids WT CR (n=7) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | PI3K Amino Acids WT PR (n=7) | 14.3 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | PI3K Amino Acids WT SD (n=7) | 71.4 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | PI3K Amino Acids M PR (n=2) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | PI3K Amino Acids M SD (n=2) | 50.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | PI3K Amino Acids M PD (n=2) | 50.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | FC Gamma Receptor IIIa F176V FF CR (n=3) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | FC Gamma Receptor IIIa F176V FF PR (n=3) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | FC Gamma Receptor IIIa F176V FF SD (n=3) | 66.7 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | FC Gamma Receptor IIIa F176V FF PD (n=3) | 33.3 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | FC Gamma Receptor IIIa F176V VF CR (n=1) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | FC Gamma Receptor IIIa F176V VF PR (n=1) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | FC Gamma Receptor IIIa F176V VF SD (n=1) | 100.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | FC Gamma Receptor IIIa F176V VF PD (n=1) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | FC Gamma Receptor IIIa F176V VV CR (n=1) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | FC Gamma Receptor IIIa F176V VV PR (n=1) | 100.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | FC Gamma Receptor IIIa F176V VV SD (n=1) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | FC Gamma Receptor IIIa F176V VV PD (n=1) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | FC Gamma Receptor IIa R166H HH PR (n=0) | NA percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | FC Gamma Receptor IIa R166H HH SD (n=0) | NA percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | FC Gamma Receptor IIa R166H HH PD (n=0) | NA percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | FC Gamma Receptor IIa R166H HR CR (n=5) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | FC Gamma Receptor IIa R166H HR PR (n=4) | 25.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | FC Gamma Receptor IIa R166H HR SD (n=4) | 50.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | FC Gamma Receptor IIa R166H HR PD (n=4) | 25.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | FC Gamma Receptor IIa R166H RR CR (n=4) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | FC Gamma Receptor IIa R166H RR PR (n=2) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | FC Gamma Receptor IIa R166H RR SD (n=2) | 100.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | FC Gamma Receptor IIa R166H RR PD (n=2) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | FC Gamma Receptor IIb I232T II CR (n=4) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | FC Gamma Receptor IIb I232T II PR (n=4) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | FC Gamma Receptor IIb I232T II SD (n=4) | 75.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | FC Gamma Receptor IIb I232T II PD (n=4) | 25.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | FC Gamma Receptor IIb I232T IT CR (N=0) | NA percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | FC Gamma Receptor IIb I232T IT PR (n=0) | NA percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | FC Gamma Receptor IIb I232T IT SD (n=0) | NA percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | FC Gamma Receptor IIb I232T IT PD (n=0) | NA percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | FC Gamma Receptor IIb I232T TT CR (n=4) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | FC Gamma Receptor IIb I232T TT PR (n=4) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Percentage of Participants With a Best Overall Response of CR, PR, SD or PD by Biomarker | FC Gamma Receptor IIb I232T TT SD (n=4) | 75.0 percentage of participants |
Primary
Part II: Progression Free Survival (PFS) by Biomarker
PFS was calculated from first study medication in Part II to date of progression or death.The relationship between PFS and the following biomarker variables was investigated in each of study Part 1 and 2: p95HER2 +ve and -ve population, IGF1R \<median and ≥ median membrane H score, c-MET \<median and ≥median membrane H score, PTEN \<median and ≥median cytoplasm H score, HER2 \<median and ≥median membrane H score, PI3K catalytic subunit WT and M, and FC gamma receptors IIIa, IIa and IIb Phenotypes FF, VF and VV, HH, HR and RR, and II, IT and TT.
Time frame: End of first 2 Cycles (Weeks 3 and 6), every 3 cycles for 18 weeks, then every 4 cycles until progression, unacceptable toxicity or participant decision to cease treatment up to 46 months
Population: PP population; n = number of participants with biomarker data available for the specified biomarker.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Progression Free Survival (PFS) by Biomarker | HER2 ≥median (n=5,0) | 3.450 months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Progression Free Survival (PFS) by Biomarker | PI3K Amino Acids WT (n=10,1) | 5.651 months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Progression Free Survival (PFS) by Biomarker | c-MET<median (n=3,1) | 4.698 months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Progression Free Survival (PFS) by Biomarker | PI3K Amino Acids M (n=2,0) | 4.485 months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Progression Free Survival (PFS) by Biomarker | IGF1R <median (n=4,0) | 8.115 months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Progression Free Survival (PFS) by Biomarker | FC Gamma Receptor IIIa F176V FF (n=4,0) | 4.320 months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Progression Free Survival (PFS) by Biomarker | c-MET≥median (n=4,0) | 5.043 months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Progression Free Survival (PFS) by Biomarker | FC Gamma Receptor IIIa F176V VF (n=2,1) | 13.832 months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Progression Free Survival (PFS) by Biomarker | p95 -ve (n=5,1) | 3.450 months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Progression Free Survival (PFS) by Biomarker | FC Gamma Receptor IIIa F176V VV (n=2,0) | NA months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Progression Free Survival (PFS) by Biomarker | PTEN <median (n=4,0) | 4.698 months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Progression Free Survival (PFS) by Biomarker | FC Gamma Receptor IIa R166H HH (n=1,0) | 3.450 months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Progression Free Survival (PFS) by Biomarker | IGF1R ≥median (n=4,1) | 4.074 months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Progression Free Survival (PFS) by Biomarker | FC Gamma Receptor IIa R166H HR (n=5,1) | 8.115 months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Progression Free Survival (PFS) by Biomarker | PTEN ≥median (n=3,1) | 3.450 months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Progression Free Survival (PFS) by Biomarker | FC Gamma Receptor IIa R166H RR (n=3,0) | 5.651 months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Progression Free Survival (PFS) by Biomarker | HER2 <median (n=2,1) | 8.148 months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Progression Free Survival (PFS) by Biomarker | FC Gamma Receptor IIb I232T II (n=7,1) | 5.651 months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: Progression Free Survival (PFS) by Biomarker | p95 +ve (n=2,0) | 8.148 months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part II: Progression Free Survival (PFS) by Biomarker | FC Gamma Receptor IIb I232T II (n=7,1) | 13.832 months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part II: Progression Free Survival (PFS) by Biomarker | PTEN ≥median (n=3,1) | 13.832 months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part II: Progression Free Survival (PFS) by Biomarker | p95 +ve (n=2,0) | NA months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part II: Progression Free Survival (PFS) by Biomarker | p95 -ve (n=5,1) | 13.832 months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part II: Progression Free Survival (PFS) by Biomarker | IGF1R <median (n=4,0) | NA months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part II: Progression Free Survival (PFS) by Biomarker | IGF1R ≥median (n=4,1) | 13.832 months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part II: Progression Free Survival (PFS) by Biomarker | c-MET<median (n=3,1) | 13.832 months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part II: Progression Free Survival (PFS) by Biomarker | c-MET≥median (n=4,0) | NA months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part II: Progression Free Survival (PFS) by Biomarker | PTEN <median (n=4,0) | NA months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part II: Progression Free Survival (PFS) by Biomarker | HER2 <median (n=2,1) | 13.832 months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part II: Progression Free Survival (PFS) by Biomarker | PI3K Amino Acids WT (n=10,1) | 13.832 months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part II: Progression Free Survival (PFS) by Biomarker | PI3K Amino Acids M (n=2,0) | NA months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part II: Progression Free Survival (PFS) by Biomarker | FC Gamma Receptor IIIa F176V FF (n=4,0) | NA months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part II: Progression Free Survival (PFS) by Biomarker | FC Gamma Receptor IIIa F176V VF (n=2,1) | 13.832 months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part II: Progression Free Survival (PFS) by Biomarker | FC Gamma Receptor IIIa F176V VV (n=2,0) | NA months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part II: Progression Free Survival (PFS) by Biomarker | FC Gamma Receptor IIa R166H HH (n=1,0) | NA months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part II: Progression Free Survival (PFS) by Biomarker | FC Gamma Receptor IIa R166H HR (n=5,1) | 13.832 months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part II: Progression Free Survival (PFS) by Biomarker | FC Gamma Receptor IIa R166H RR (n=3,0) | NA months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part II: Progression Free Survival (PFS) by Biomarker | HER2 ≥median (n=5,0) | NA months |
Primary
Part II: TTP by Biomarker
TTP was calculated from first study medication in Part II to date of progression. The relationship between TTP and the following biomarker variables was investigated in each of study Part 1 and 2: p95 HER2 +ve and -ve population, IGF1R \<median and ≥median, c-MET \<median and ≥median, PTEN \<median and ≥median, HER2 \<median and ≥median, PI3K catalytic subunit WT and M, and FC gamma receptors IIIa, IIa and IIb Phenotypes FF, VF and VV, HH, HR and RR, and II, IT and TT .
Time frame: End of first 2 Cycles (Weeks 3 and 6), every 3 cycles for 18 weeks, then every 4 cycles until progression, unacceptable toxicity or participant decision to cease treatment up to 46 months
Population: PP population; n = number of participants with biomarker data available for the specified biomarker.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: TTP by Biomarker | p95 HER2 +ve (n=2,0) | 8.148 months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: TTP by Biomarker | PI3K Amino Acids WT (n=10,1) | 5.651 months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: TTP by Biomarker | c-MET <median (n=3,1) | 4.698 months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: TTP by Biomarker | PI3K Amino Acids M (n=2,0) | 4.485 months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: TTP by Biomarker | IGF1R <median (n=4,0) | 8.115 months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: TTP by Biomarker | FC Gamma Receptor IIIa F176V FF (n=4,0) | 4.320 months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: TTP by Biomarker | c-MET ≥median (n=4,0) | 5.043 months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: TTP by Biomarker | FC Gamma Receptor IIIa F176V VF (n=2,1) | NA months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: TTP by Biomarker | p95 HER2 -ve (n=5,1) | 3.450 months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: TTP by Biomarker | FC Gamma Receptor IIIa F176V VV (n=2,0) | NA months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: TTP by Biomarker | PTEN <median (n=4,0) | 4.698 months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: TTP by Biomarker | FC Gamma Receptor IIa R166H HH (n=1,0) | 3.450 months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: TTP by Biomarker | IGF1R ≥median (n=4,1) | 4.074 months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: TTP by Biomarker | FC Gamma Receptor IIa R166H HR (n=5,1) | 8.115 months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: TTP by Biomarker | PTEN ≥median (n=3,1) | 3.450 months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: TTP by Biomarker | FC Gamma Receptor IIa R166H RR (n=3,0) | 5.651 months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: TTP by Biomarker | HER2 <median (n=2,1) | 8.148 months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: TTP by Biomarker | FC Gamma Receptor IIb I232T II (n=7,1) | 5.651 months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: TTP by Biomarker | HER2 ≥median (n=5,0) | 3.450 months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part II: TTP by Biomarker | FC Gamma Receptor IIb I232T II (n=7,1) | 13.832 months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part II: TTP by Biomarker | HER2 <median (n=2,1) | 13.832 months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part II: TTP by Biomarker | p95 HER2 +ve (n=2,0) | NA months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part II: TTP by Biomarker | p95 HER2 -ve (n=5,1) | 13.832 months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part II: TTP by Biomarker | IGF1R <median (n=4,0) | NA months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part II: TTP by Biomarker | IGF1R ≥median (n=4,1) | 13.832 months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part II: TTP by Biomarker | c-MET <median (n=3,1) | 13.832 months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part II: TTP by Biomarker | c-MET ≥median (n=4,0) | NA months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part II: TTP by Biomarker | PTEN <median (n=4,0) | NA months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part II: TTP by Biomarker | HER2 ≥median (n=5,0) | NA months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part II: TTP by Biomarker | PI3K Amino Acids WT (n=10,1) | 13.832 months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part II: TTP by Biomarker | PI3K Amino Acids M (n=2,0) | NA months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part II: TTP by Biomarker | FC Gamma Receptor IIIa F176V FF (n=4,0) | NA months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part II: TTP by Biomarker | FC Gamma Receptor IIIa F176V VF (n=2,1) | 13.832 months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part II: TTP by Biomarker | FC Gamma Receptor IIIa F176V VV (n=2,0) | NA months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part II: TTP by Biomarker | FC Gamma Receptor IIa R166H HH (n=1,0) | NA months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part II: TTP by Biomarker | FC Gamma Receptor IIa R166H HR (n=5,1) | 13.832 months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part II: TTP by Biomarker | FC Gamma Receptor IIa R166H RR (n=3,0) | NA months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part II: TTP by Biomarker | PTEN ≥median (n=3,1) | 13.832 months |
Primary
Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker
BOR was defined according to the Response Evaluation Criteria In Solid Tumors (RECIST). CR: disappearance of all target lesions and all pathological lymph nodes below 10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. PD: At least a 20% increase in the sum of diameters of target lesions, and the sum must also demonstrate an absolute increase of at least 5 mm or persistence of non-target lesions. The relationship between best response and the following biomarkers was investigated: p95 HER2 (+ve/-ve), IGF1R, c-MET, PTEN, HER2 (median/≥median), PI3K catalytic subunit (WT/M), and FC gamma receptors IIIa, IIa and IIb (phenotypes FF, VF, VV, HH, HR, RR and II, IT and TT respectively). The correlation between the biomarker variables and percentage of participants with best response were investigated using a univariate regression analysis.
Time frame: End of first 2 Cycles (Weeks 3 and 6), every 3 cycles for 18 weeks, then every 4 cycles until progression, unacceptable toxicity or participant decision to cease treatment up to 46 weeks
Population: PP population; n = number of participants with biomarker data available for the specified biomarker. Data are reported for Group A only as there were no evaluable participants in Group B.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | FC Gamma Receptor IIa R166H HR CR (n=5) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | p95 HER2 +ve CR (n=5) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | p95 HER2 +ve PR (n=5) | 25.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | p95 HER2 +ve SD (n=5) | 50.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | p95 HER2 +ve PD (n=5) | 25.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | p95 HER2 -ve CR (n=12) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | p95 HER2 -ve PR (n=12) | 91.7 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | p95 HER2 -ve SD (n=12) | 8.3 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | p95 HER2 -ve PD (n=12) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | IGF1R < median CR (n=9) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | IGF1R < median PR (n=9) | 62.5 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | IGF1R < median SD (n=9) | 37.5 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | IGF1R < median PD (n=9) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | IGF1R ≥median CR (n=9) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | IGF1R ≥median PR (n=9,0) | 88.9 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | IGF1R ≥median SD (n=9) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | IGF1R ≥median PD (n=9) | 11.1 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | c-MET <median CR (n=6) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | c-METt <median PR (n=6) | 83.3 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | c-MET <median SD (n=6) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | c-MET <median PD (n=6) | 16.7 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | c-MET ≥median CR (n=11) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | c-MET ≥median PR (n=11) | 70.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | c-MET ≥median SD (n=11) | 30.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | c-MET ≥median PD (n=11) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | PTEN <median CR (n=6) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | PTEN <median PR (n=6) | 83.3 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | PTEN <median SD (n=6) | 16.7 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | PTEN <median PD (n=6) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | PTEN ≥median CR (n=12) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | PTEN ≥median PR (n=12) | 72.7 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | PTEN ≥median SD (n=12) | 18.2 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | PTEN ≥median PD (n=12) | 9.1 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | HER2 <median CR (n=8) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | HER2 <median PR (n=8) | 75.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | HER2 <median SD (n=8) | 12.5 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | HER2 <median PD (n=8) | 12.5 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | HER2 ≥median CR (n=10) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | HER2 ≥median PR (n=10) | 77.8 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | HER2 ≥median SD (n=10) | 22.2 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | HER2 ≥median PD (n=10) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | PI3K Amino Acids WT CR (n=11) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | PI3K Amino Acids WT PR (n=11,0) | 90.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | PI3K Amino Acids WT SD (n=11) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | PI3K Amino Acids WT PD (n=11) | 10.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | PI3K Amino Acids M CR (n=7) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | PI3K Amino Acids M PR (n=7,0) | 57.1 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | PI3K Amino Acids M SD (n=7) | 42.9 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | PI3K Amino Acids M PD (n=7) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | FC Gamma Receptor IIIa F176V FF CR (n=6) | 16.7 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | FC Gamma Receptor IIIa F176V FF PR (n=6) | 50.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | FC Gamma Receptor IIIa F176V FF SD (n=6) | 16.7 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | FC Gamma Receptor IIIa F176V FF PD (n=6) | 16.7 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | FC Gamma Receptor IIIa F176V VF CR (n=4) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | FC Gamma Receptor IIIa F176V VF PR (n=4) | 66.7 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | FC Gamma Receptor IIIa F176V VF SD (n=4) | 33.3 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | FC Gamma Receptor IIIa F176V VF PD (n=4) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | FC Gamma Receptor IIIa F176V VV CR (n=2) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | FC Gamma Receptor IIIa F176V VV PR (n=2) | 100.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | FC Gamma Receptor IIIa F176V VV SD (n=2) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | FC Gamma Receptor IIIa F176V VV PD (n=2) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | FC Gamma Receptor IIa R166H HH CR (n=3) | 33.3 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | FC Gamma Receptor IIa R166H HH PR (n=3) | 66.7 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | FC Gamma Receptor IIa R166H HH SD (n=3) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | FC Gamma Receptor IIa R166H HH PD (n=3) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | FC Gamma Receptor IIa R166H HR PR (n=5) | 25.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | FC Gamma Receptor IIa R166H HR SD (n=5) | 50.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | FC Gamma Receptor IIa R166H HR PD (n=5) | 25.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | FC Gamma Receptor IIa R166H RR CR (n=5) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | FC Gamma Receptor IIa R166H RR PR (n=5) | 80.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | FC Gamma Receptor IIa R166H SD RR (n=5) | 20.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | FC Gamma Receptor IIa R166H RR PD (n=5) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | FC Gamma Receptor IIb I232T II CR (n=8) | 12.5 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | FC Gamma Receptor IIb I232T II PR (n=8) | 50.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | FC Gamma Receptor IIb I232T II SD (n=8) | 37.5 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | FC Gamma Receptor IIb I232T II PD (n=8) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | FC Gamma Receptor IIb I232T IT CR (n=1) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | FC Gamma Receptor IIb I232T IT PR (n=1) | 100.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | FC Gamma Receptor IIb I232T IT SD (n=1) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progrerssive Disease (PD) by Biomarker | FC Gamma Receptor IIb I232T IT PD (n=1) | 0.0 percentage of participants |
Comparison: Univariate logistic regression Odds ratio (Positive / Negative) for the biomarker p95 HER 2.95% CI: [0.001, 0.641]
Comparison: Univariate logistic regression Odds ratio (Membrane H-Score: ≥median /\<median) for the biomarker IGF1R.95% CI: [0.017, 2.6]
Comparison: Univariate logistic regression Odds ratio (Membrane H-Score: ≥ median /\<median) for the biomarker c-MET.95% CI: [0.169, 27.103]
Comparison: Univariate logistic regression Odds ratio (Cytoplasm H-Score: ≥ median /\< median) for the biomarker PTEN.95% CI: [0.15, 23.396]
Comparison: Univariate logistic regression Odds ratio (Membrane H-Score: ≥median /\< median) for the biomarker HER2.95% CI: [0.091, 8.075]
Comparison: Univariate logistic regression Odds ratio (PI3K mutation status: WT versus M) for the biomarker PI3K Amino Acids.95% CI: [0.012, 1.9]
Comparison: Univariate logistic regressionOdds ratio (Phenotype: FF / VF) for the biomarker FC Gamma Receptor IIIa F176V.95% CI: [0.053, 18.915]
Comparison: Univariate logistic regression Odds ratio (Phenotype: HR / RR) for the biomarker FC Gamma Receptor IIa R166H95% CI: [0.004, 1.945]
Primary
Part I: Progression Free Survival (PFS) by Biomarker
Progression was defined as an increase by at least 20 percent (%) from the smallest value in the Sum of Longest Diameter (SLD) of lesions. Biomarkers investigated: p95 human epidermal growth factor receptor 2 (p95HER2) positive (+ve) and negative (-ve) , insulin growth factor-1 receptor (IGF1R) less than (\<) median and greater than or equal to (≥) median membrane H score, c-MET \<median and ≥median membrane H score, phosphatase and tensin homolog gene (PTEN) \<median and ≥median cytoplasm H score, HER2 \<median and ≥median membrane H score, phosphatidylinositol-3-kinase (PI3K) catalytic subunit wild type (WT) and mutation (M), and FC gamma receptors IIIa homozygous Phenyl alanine (FF), heterozygous Phenyl alanine/Valine (VF) and homozygous Valine (VV), receptor IIa Phenotypes homozygous Histidine (HH), heterozygous Histidine/Arginine (HR) and homozygous Arginine (RR) IIb phenotypes homozygous Isoleucien (II),heterozygous Isoleucine/Threonine (IT) and homozygous Threonine (TT) .
Time frame: End of first 2 Cycles (Weeks 3 and 6), every 3 Cycles for 18 weeks, then every 4 cycles until progression, unacceptable toxicity or participant decision to cease treatment up to 46 months
Population: Per Protocol (PP) population included all participants who had received a complete first dose of study medication and had baseline and at least one on-treatment biomarker assessment. Number (n) equals (=) number of participants with biomarker data available for the specified biomarker.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Progression Free Survival (PFS) by Biomarker | c-MET <median (n=10,1) | 18.595 months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Progression Free Survival (PFS) by Biomarker | PI3K Amino Acids WT (n=17,1) | 13.848 months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Progression Free Survival (PFS) by Biomarker | p95 HER2 +ve (n=9,0) | NA months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Progression Free Survival (PFS) by Biomarker | c-MET ≥median (n=15,0) | 13.733 months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Progression Free Survival (PFS) by Biomarker | FC Gamma Receptor IIIa F176V FF (n=9,0) | 10.612 months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Progression Free Survival (PFS) by Biomarker | IGF1R <median (n=12,0) | 12.649 months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Progression Free Survival (PFS) by Biomarker | FC Gamma Receptor IIIa F176V VF (n=5,1) | 11.335 months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Progression Free Survival (PFS) by Biomarker | PTEN <median (n=12,0) | 22.209 months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Progression Free Survival (PFS) by Biomarker | FC Gamma Receptor IIIa F176V VV (n=4,0) | 22.407 months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Progression Free Survival (PFS) by Biomarker | PI3K Amino Acids M (n=9,0) | 22.407 months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Progression Free Survival (PFS) by Biomarker | FC Gamma Receptor IIa R166H HH (n=3,0) | NA months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Progression Free Survival (PFS) by Biomarker | PTEN ≥median (n=14,1) | 13.963 months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Progression Free Survival (PFS) by Biomarker | FC Gamma Receptor IIa R166H HR (n=8,1) | 22.209 months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Progression Free Survival (PFS) by Biomarker | IGF1R ≥median (n=14,1) | 22.209 months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Progression Free Survival (PFS) by Biomarker | FC Gamma Receptor IIa R166H RR (n=8,0) | 13.963 months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Progression Free Survival (PFS) by Biomarker | HER2 <median (n=11,1) | 13.733 months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Progression Free Survival (PFS) by Biomarker | FC Gamma Receptor IIb I232T II (n=12,1) | 11.335 months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Progression Free Survival (PFS) by Biomarker | FC Gamma Receptor IIb I232T IT (n=1,0) | NA months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Progression Free Survival (PFS) by Biomarker | p95 HER2 -ve (n=15,1) | 13.963 months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Progression Free Survival (PFS) by Biomarker | FC Gamma Receptor IIb I232T TT (n=1,0) | NA months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Progression Free Survival (PFS) by Biomarker | HER2 ≥median (n=14,0) | 22.209 months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part I: Progression Free Survival (PFS) by Biomarker | FC Gamma Receptor IIb I232T TT (n=1,0) | NA months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part I: Progression Free Survival (PFS) by Biomarker | p95 HER2 +ve (n=9,0) | NA months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part I: Progression Free Survival (PFS) by Biomarker | p95 HER2 -ve (n=15,1) | 1.216 months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part I: Progression Free Survival (PFS) by Biomarker | IGF1R <median (n=12,0) | NA months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part I: Progression Free Survival (PFS) by Biomarker | IGF1R ≥median (n=14,1) | 1.216 months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part I: Progression Free Survival (PFS) by Biomarker | c-MET <median (n=10,1) | 1.216 months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part I: Progression Free Survival (PFS) by Biomarker | c-MET ≥median (n=15,0) | NA months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part I: Progression Free Survival (PFS) by Biomarker | PTEN <median (n=12,0) | NA months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part I: Progression Free Survival (PFS) by Biomarker | PTEN ≥median (n=14,1) | 1.216 months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part I: Progression Free Survival (PFS) by Biomarker | HER2 <median (n=11,1) | 1.216 months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part I: Progression Free Survival (PFS) by Biomarker | HER2 ≥median (n=14,0) | NA months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part I: Progression Free Survival (PFS) by Biomarker | PI3K Amino Acids WT (n=17,1) | 1.216 months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part I: Progression Free Survival (PFS) by Biomarker | PI3K Amino Acids M (n=9,0) | NA months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part I: Progression Free Survival (PFS) by Biomarker | FC Gamma Receptor IIIa F176V FF (n=9,0) | NA months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part I: Progression Free Survival (PFS) by Biomarker | FC Gamma Receptor IIIa F176V VF (n=5,1) | 1.216 months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part I: Progression Free Survival (PFS) by Biomarker | FC Gamma Receptor IIIa F176V VV (n=4,0) | NA months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part I: Progression Free Survival (PFS) by Biomarker | FC Gamma Receptor IIa R166H HH (n=3,0) | NA months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part I: Progression Free Survival (PFS) by Biomarker | FC Gamma Receptor IIa R166H HR (n=8,1) | 1.216 months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part I: Progression Free Survival (PFS) by Biomarker | FC Gamma Receptor IIa R166H RR (n=8,0) | NA months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part I: Progression Free Survival (PFS) by Biomarker | FC Gamma Receptor IIb I232T IT (n=1,0) | NA months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part I: Progression Free Survival (PFS) by Biomarker | FC Gamma Receptor IIb I232T II (n=12,1) | 1.216 months |
Comparison: Univariate Cox regression Hazard ratio (Positive / Negative) for the biomarker p95.95% CI: [0.109, 1.535]
Comparison: Univariate Cox regression: Hazard ratio (Membrane H-Score: \<median / ≥median) for the biomarker IGF1R.95% CI: [0.43, 3.282]
Comparison: Univariate Cox regression Hazard ratio (Membrane H-Score: \<median / ≥median) for the biomarker c-MET.95% CI: [0.306, 2.425]
Comparison: Univariate Cox regression Hazard ratio (Cytoplasm H-Score: \<median / ≥median) for the biomarker PTEN.95% CI: [0.164, 1.453]
Comparison: Univariate Cox regression Hazard ratio (Membrane H-Score: \< median / ≥median) for the biomarker HER2.95% CI: [0.377, 3.16]
Comparison: Univariate Cox regression Hazard ratio (Mutation Status: Wild type / Mutation) for the biomarker PI3K amino acids.95% CI: [0.409, 4.132]
Comparison: Univariate Cox regression Hazard ratio (Phenotype: FF / VF) for the biomarker FC Gamma Receptor IIIa F176V.95% CI: [0.226, 6.197]
Comparison: Univariate Cox regression Hazard ratio (Phenotype: FF / VV) for the biomarker FC Gamma Receptor IIIa F176V.95% CI: [0.378, 10.47]
Comparison: Univariate Cox regression Hazard ratio (Phenotype: VF / VV) for the biomarker FC Gamma Receptor IIIa F176V.95% CI: [0.235, 12.783]
Comparison: Univariate Cox regression Hazard ratio (Phenotype: HH / HR) for the biomarker FC Gamma Receptor IIa R166H.95% CI: [0.067, 4.968]
Comparison: Univariate Cox regression Hazard ratio (Phenotype: HH / RR) for the biomarker FC Gamma Receptor IIa R166H.95% CI: [0.082, 6.72]
Comparison: Univariate Cox regression Hazard ratio (Phenotype: HR / RR) for the biomarker FC Gamma Receptor IIa R166H.95% CI: [0.274, 4.199]
Primary
Part I: Time to Progression (TTP) by Biomarker
Progression was defined as an increase by at least 20% from the smallest value in the SLD of lesions.TTP was determined as the time in months from the date of screening until first progression.The relationship between PFS and the following biomarker variables was investigated in each of study Part 1 and 2: p95 HER2 +ve and -ve population, IGF1R \<median and ≥median, c-MET \<median and ≥median, PTEN \<median and ≥median, HER2 \<median and ≥median, PI3K catalytic subunit WT and M, and FC gamma receptors IIIa, IIa and IIb Phenotypes FF, VF and VV, HH, HR and RR, and II, IT and TT . The correlation between the biomarker variables and TTP were investigated using a univariate Cox regression model and time-to-event methods (Kaplan-Meier).
Time frame: End of first 2 Cycles (Weeks 3 and 6), every 3 Cycles for 18 weeks, then every 4 cycles until progression, unacceptable toxicity or participant decision to cease treatment up to 46 weeks
Population: PP population; n = number of participants with biomarker data available for the specified biomarker.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Time to Progression (TTP) by Biomarker | p95 -ve (n=15,1) | 13.963 months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Time to Progression (TTP) by Biomarker | IGF1R <median (n=12,0) | 11.335 months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Time to Progression (TTP) by Biomarker | FC Gamma Receptor IIa R166H HH (n=3,0) | NA months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Time to Progression (TTP) by Biomarker | FC Gamma Receptor IIb I232T II (n=12,1) | 13.963 months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Time to Progression (TTP) by Biomarker | FC Gamma Receptor IIb I232T IT (n=1,0) | NA months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Time to Progression (TTP) by Biomarker | p95 +ve (n=9,0) | NA months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Time to Progression (TTP) by Biomarker | IGF1R ≥median (n=14,1) | 22.407 months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Time to Progression (TTP) by Biomarker | c-MET <median (n=10,1) | 31.179 months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Time to Progression (TTP) by Biomarker | c-MET ≥median (n=15,0) | 22.209 months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Time to Progression (TTP) by Biomarker | PTEN <median (n=12,0) | 22.209 months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Time to Progression (TTP) by Biomarker | PTEN ≥median (n=14,1) | 13.963 months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Time to Progression (TTP) by Biomarker | HER2 <median (n=11,1) | NA months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Time to Progression (TTP) by Biomarker | HER2 ≥median (n=14,0) | 22.209 months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Time to Progression (TTP) by Biomarker | PI3K Amino Acids WT (n=17,1) | 13.963 months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Time to Progression (TTP) by Biomarker | PI3K Amino Acids M (n=9,00) | 22.407 months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Time to Progression (TTP) by Biomarker | FC Gamma Receptor IIIa F176V FF (n=9,0) | 13.963 months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Time to Progression (TTP) by Biomarker | FC Gamma Receptor IIIa F176V VF (n=5,1) | 11.335 months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Time to Progression (TTP) by Biomarker | FC Gamma Receptor IIIa F176V VV (n=4,0) | 22.407 months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Time to Progression (TTP) by Biomarker | FC Gamma Receptor IIa R166H HR (n=8,1) | 22.209 months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Time to Progression (TTP) by Biomarker | FC Gamma Receptor IIa R166H RR (n=8,0) | 13.963 months |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: Time to Progression (TTP) by Biomarker | FC Gamma Receptor IIb I232T TT (n=1,0) | NA months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part I: Time to Progression (TTP) by Biomarker | FC Gamma Receptor IIIa F176V VV (n=4,0) | NA months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part I: Time to Progression (TTP) by Biomarker | HER2 ≥median (n=14,0) | NA months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part I: Time to Progression (TTP) by Biomarker | FC Gamma Receptor IIb I232T IT (n=1,0) | NA months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part I: Time to Progression (TTP) by Biomarker | FC Gamma Receptor IIb I232T II (n=12,1) | 1.216 months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part I: Time to Progression (TTP) by Biomarker | PI3K Amino Acids WT (n=17,1) | 1.216 months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part I: Time to Progression (TTP) by Biomarker | FC Gamma Receptor IIa R166H HH (n=3,0) | NA months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part I: Time to Progression (TTP) by Biomarker | p95 +ve (n=9,0) | NA months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part I: Time to Progression (TTP) by Biomarker | p95 -ve (n=15,1) | 1.216 months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part I: Time to Progression (TTP) by Biomarker | IGF1R <median (n=12,0) | NA months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part I: Time to Progression (TTP) by Biomarker | PI3K Amino Acids M (n=9,00) | NA months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part I: Time to Progression (TTP) by Biomarker | IGF1R ≥median (n=14,1) | 1.216 months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part I: Time to Progression (TTP) by Biomarker | FC Gamma Receptor IIa R166H RR (n=8,0) | NA months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part I: Time to Progression (TTP) by Biomarker | c-MET <median (n=10,1) | 1.216 months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part I: Time to Progression (TTP) by Biomarker | FC Gamma Receptor IIIa F176V FF (n=9,0) | NA months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part I: Time to Progression (TTP) by Biomarker | c-MET ≥median (n=15,0) | NA months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part I: Time to Progression (TTP) by Biomarker | FC Gamma Receptor IIa R166H HR (n=8,1) | 1.216 months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part I: Time to Progression (TTP) by Biomarker | PTEN <median (n=12,0) | NA months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part I: Time to Progression (TTP) by Biomarker | FC Gamma Receptor IIIa F176V VF (n=5,1) | 1.216 months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part I: Time to Progression (TTP) by Biomarker | PTEN ≥median (n=14,1) | 1.216 months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part I: Time to Progression (TTP) by Biomarker | FC Gamma Receptor IIb I232T TT (n=1,0) | NA months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part I: Time to Progression (TTP) by Biomarker | HER2 <median (n=11,1) | 1.216 months |
Comparison: Univariate Cox regression Hazard ratio (Positive / Negative) for the biomarker p95 HER2.95% CI: [0.12, 1.79]
Comparison: Univariate Cox regressionHazard ratio (Membrane H-Score: \<median / ≥median) for the biomarker IGF1R.95% CI: [0.394, 3.518]
Comparison: Univariate Cox regression Hazard ratio (Membrane H-Score: \< median / ≥median) for the biomarker c-met.95% CI: [0.268, 2.514]
Comparison: Univariate Cox regression Hazard ratio (Cytoplasm H-Score: \< median / ≥median) for the marker PTEN.95% CI: [0.183, 1.768]
Comparison: Univariate Cox regression Hazard ratio (Membrane H-Score: \< median / ≥median) for the biomarker HER2.95% CI: [0.242, 2.733]
Comparison: Univariate Cox regressionHazard ratio (Mutation Status: Wild type / Mutation) for the biomarker PI3K amino acids.95% CI: [0.337, 3.632]
Comparison: Hazard ratio (Phenotype: FF / VF) for the biomarker FC Gamma Receptor IIIa F176V.95% CI: [0.172, 5.336]
Comparison: Hazard ratio (Phenotype: FF / VV) for the biomarker FC Gamma Receptor IIIa F176V.95% CI: [0.298, 9.305]
Comparison: Hazard ratio (Phenotype: VF / VV) for the biomarker FC Gamma Receptor IIIa F176V.95% CI: [0.235, 12.783]
Comparison: Univariate Cox regression Hazard ratio (Phenotype: HH / HR) for the biomarker FC Gamma Receptor IIa R166H.95% CI: [0.067, 4.968]
Comparison: Univariate Cox regression Hazard ratio (Phenotype: HH / RR) for the biomarker FC Gamma Receptor IIa R166H.95% CI: [0.098, 9.319]
Comparison: Univariate Cox regression Hazard ratio (Phenotype: HR / RR) for the biomarker FC Gamma Receptor IIa R166H.95% CI: [0.296, 5.64]
Secondary
Overall Survival in ITT Population
Overall survival was calculated in months from the day of screening until death.
Time frame: End of first 2 Cycles (Weeks 3 and 6), every 3 cycles for 18 weeks, then every 4 cycles until death (up to 46 months)
Population: ITT population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Overall Survival in ITT Population | NA months |
Secondary
Overall Survival in Per Protocol Population
Overall survival was calculated in months from the day of screening until death.
Time frame: End of first 2 Cycles (Weeks 3 and 6), every 3 cycles for 18 weeks, then every 4 cycles until death (up to 46 months)
Population: PP population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Overall Survival in Per Protocol Population | 36.40 months |
Secondary
Part I and II: Percentage of Participants With a Best Overall Response of CR or PR in ITT Population
Best Overall response was defined according to RECIST. CR: disappearance of all target lesions and all pathological lymph nodes below 10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. PD: At least a 20% increase in the sum of diameters of target lesions, and the sum must also demonstrate an absolute increase of at least 5 mm or persistence of non-target lesions.
Time frame: End of first 2 Cycles (Weeks 3 and 6), every 3 Cycles for 18 weeks, then every 4 cycles until progression, unacceptable toxicity or participant decision to cease treatment up to 46 months
Population: ITT population; n = number of participants analyzed for the specified category.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I and II: Percentage of Participants With a Best Overall Response of CR or PR in ITT Population | Part I: Responders (n=20) | 75.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I and II: Percentage of Participants With a Best Overall Response of CR or PR in ITT Population | Part I: Non-Responders (n=20) | 20.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I and II: Percentage of Participants With a Best Overall Response of CR or PR in ITT Population | Part I: Missing (n=20) | 5.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I and II: Percentage of Participants With a Best Overall Response of CR or PR in ITT Population | Part II: Responders (n=9) | 11.1 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I and II: Percentage of Participants With a Best Overall Response of CR or PR in ITT Population | Part II: Non-Responders (n=9) | 88.9 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I and II: Percentage of Participants With a Best Overall Response of CR or PR in ITT Population | Part II: Missing (n=9) | 0.0 percentage of participants |
Secondary
Part I and II: Percentage of Participants With a Response by Best Overall Response by CR, PR, SD or PD in ITT Population
Best Overall response was defined according to RECIST. CR: disappearance of all target lesions and all pathological lymph nodes below 10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. PD: At least a 20% increase in the sum of diameters of target lesions, and the sum must also demonstrate an absolute increase of at least 5 mm or persistence of non-target lesions.
Time frame: End of first 2 Cycles (Weeks 3 and 6), every 3 cycles for 18 weeks, then every 4 cycles until progression, unacceptable toxicity or participant decision to cease treatment up to 46 months
Population: ITT population; n = number of participants analyzed for the specified category.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I and II: Percentage of Participants With a Response by Best Overall Response by CR, PR, SD or PD in ITT Population | Part I: PR (n=20) | 70.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I and II: Percentage of Participants With a Response by Best Overall Response by CR, PR, SD or PD in ITT Population | Part I: SD (n=20) | 15.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I and II: Percentage of Participants With a Response by Best Overall Response by CR, PR, SD or PD in ITT Population | Part I: PD (n=20) | 5.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I and II: Percentage of Participants With a Response by Best Overall Response by CR, PR, SD or PD in ITT Population | Part I: Missing (n=20) | 5.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I and II: Percentage of Participants With a Response by Best Overall Response by CR, PR, SD or PD in ITT Population | Part II: CR (n=9) | 0.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I and II: Percentage of Participants With a Response by Best Overall Response by CR, PR, SD or PD in ITT Population | Part I: CR (n=20) | 5.0 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I and II: Percentage of Participants With a Response by Best Overall Response by CR, PR, SD or PD in ITT Population | Part II: PR (n=9) | 11.1 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I and II: Percentage of Participants With a Response by Best Overall Response by CR, PR, SD or PD in ITT Population | Part II: SD (n=9) | 66.7 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I and II: Percentage of Participants With a Response by Best Overall Response by CR, PR, SD or PD in ITT Population | Part II: PD (n=9) | 22.2 percentage of participants |
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I and II: Percentage of Participants With a Response by Best Overall Response by CR, PR, SD or PD in ITT Population | Part II: Missing (n=9) | 0.0 percentage of participants |
Secondary
Part II: PFS in ITT Population
PFS was calculated from first study medication in Part II to date of progression or death. In participants with measurable disease progression was defined according to RECIST (SLD increased by at least 20% from the smallest value on study \[including baseline, if that is the smallest\]). In participants with non-measurable disease, progression was defined as the presence of new lesions or unequivocal progression during treatment.
Time frame: End of first 2 Cycles (Weeks 3 and 6), every 3 cycles for 18 weeks, then every 4 cycles until progression, unacceptable toxicity or participant decision to cease treatment up to 46 months
Population: ITT population; Participant from Group B and from No group were not included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: PFS in ITT Population | 5.65 months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part II: PFS in ITT Population | 13.83 months |
Secondary
Part II: TTP in Intent to Treat (ITT) Population
TTP was calculated from first study medication in Part II to date of progression. In participants with measurable disease progression was defined according to RECIST(SLD increased by at least 20% from the smallest value on study \[including baseline, if that is the smallest\]). In participants with non-measurable disease, progression was defined as the presence of new lesions or unequivocal progression during treatment.
Time frame: End of first 2 Cycles (Weeks 3 and 6), every 3 Cycles for 18 weeks, then every 4 cycles until progression, unacceptable toxicity or participant decision to cease treatment up to 46 months
Population: ITT population; Participant from Group B and from No group were not included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part II: TTP in Intent to Treat (ITT) Population | 5.65 months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part II: TTP in Intent to Treat (ITT) Population | 13.83 months |
Secondary
Part I: PFS in ITT Population
PFS was determined as the time in months from the date of screening until first progression. In participants with measurable disease, progression was defined according to RECIST (SLD increased by at least 20% from the smallest value on study \[including baseline, if that is the smallest\]).. In participants with non-measurable disease, progression was defined as the presence of new lesions or unequivocal progression during treatment.
Time frame: End of first 2 Cycles (Weeks 3 and 6), every 3 cycles for 18 weeks, then every 4 cycles until progression, unacceptable toxicity or participant decision to cease treatment up to 46 months
Population: ITT population; Participant from Group B and from No group were not included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: PFS in ITT Population | 18.60 months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part I: PFS in ITT Population | 1.22 months |
Secondary
Part I: TTP in Intent to Treat (ITT) Population
TTP was determined as the time in months from the date of screening until first progression. In participants with measurable disease, progression was defined according to RECIST (SLD increased by at least 20% from the smallest value on study \[including baseline, if that is the smallest\]). In participants with non-measurable disease, progression was defined as the presence of new lesions or unequivocal progression during treatment.
Time frame: End of first 2 Cycles (Weeks 3 and 6), every 3 cycles for 18 weeks, then every 4 cycles until progression, unacceptable toxicity or participant decision to cease treatment up to 46 months
Population: ITT population; Participant from Group B and from No group were not included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group A: Trastuzumab+Taxane /Capecitabine (6 Weeks) | Part I: TTP in Intent to Treat (ITT) Population | 22.21 months |
| Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks | Part I: TTP in Intent to Treat (ITT) Population | 1.22 months |