Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Symptoms and General Pathology

Breast Neoplasms

Disease Progression

Breast Diseases

Skin Diseases

Antineoplastic Agents

All Drugs and Chemicals

Capecitabine

Trastuzumab

Taxane

Antimetabolites

Antineoplastic Agents, Immunological

Standard taxane therapy

1000mg/m2 po bid on days 1-14 of each 3-week cycle (only in patients who have progressed)

capecitabine [Xeloda]

8mg/kg iv loading dose on day 1 of first 3-week cycle, and 6mg/kg iv on day 1 of each subsequent cycle

trastuzumab [Herceptin]

Clinical Trials

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.

A Study of Herceptin (Trastuzumab)and Biomarkers in Patients With HER2-Positive Metastatic Breast Cancer

A Prospective Study to Evaluate Alterations in Molecular Biomarkers in HER2 Neu Positive Metastatic Breast Cancer Together With Assessment of Trastuzumab Use Beyond Progression After Initial Response to Trastuzumab-taxane Based Treatment

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) .

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.

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).

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 .

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.

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.

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.

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.

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.

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 was calculated in months from the day of screening until death.

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.

Hoffmann-La Roche

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. Trastuzumab was administered according to SMPC. 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.

All Participants

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.

Group A: 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.

Group B: Trastuzumab+Taxane/ Capecitabine <6 Weeks

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.

No Group

Total

Age, Continuous

Sex: Female, Male

Intent-to-treat (ITT) population: All registered participants were included in the ITT population.

The study was prematurely terminated on December 31, 2012. The end of study follow-up was February 18, 2013.

Medical Communications

Univariate Cox regression Hazard ratio (Positive / Negative) for the biomarker p95.

Univariate Cox regression: Hazard ratio (Membrane H-Score: \<median / ≥median) for the biomarker IGF1R.

Univariate Cox regression Hazard ratio (Membrane H-Score: \<median / ≥median) for the biomarker c-MET.

Univariate Cox regression Hazard ratio (Cytoplasm H-Score: \<median / ≥median) for the biomarker PTEN.

Univariate Cox regression Hazard ratio (Membrane H-Score: \< median / ≥median) for the biomarker HER2.

Univariate Cox regression Hazard ratio (Mutation Status: Wild type / Mutation) for the biomarker PI3K amino acids.

Univariate Cox regression Hazard ratio (Phenotype: FF / VF) for the biomarker FC Gamma Receptor IIIa F176V.

Univariate Cox regression Hazard ratio (Phenotype: FF / VV) for the biomarker FC Gamma Receptor IIIa F176V.

Univariate Cox regression Hazard ratio (Phenotype: VF / VV) for the biomarker FC Gamma Receptor IIIa F176V.

Univariate Cox regression Hazard ratio (Phenotype: HH / HR) for the biomarker FC Gamma Receptor IIa R166H.

Univariate Cox regression Hazard ratio (Phenotype: HH / RR) for the biomarker FC Gamma Receptor IIa R166H.

Univariate Cox regression Hazard ratio (Phenotype: HR / RR) for the biomarker FC Gamma Receptor IIa R166H.

p95 HER2 +ve (n=9,0)

p95 HER2 -ve (n=15,1)

IGF1R <median (n=12,0)

IGF1R ≥median (n=14,1)

c-MET <median (n=10,1)

c-MET ≥median (n=15,0)

PTEN <median (n=12,0)

PTEN ≥median (n=14,1)

HER2 <median (n=11,1)

HER2 ≥median (n=14,0)

PI3K Amino Acids WT (n=17,1)

PI3K Amino Acids M (n=9,0)

FC Gamma Receptor IIIa F176V FF (n=9,0)

FC Gamma Receptor IIIa F176V VF (n=5,1)

FC Gamma Receptor IIIa F176V VV (n=4,0)

FC Gamma Receptor IIa R166H HH (n=3,0)

FC Gamma Receptor IIa R166H HR (n=8,1)

FC Gamma Receptor IIa R166H RR (n=8,0)

FC Gamma Receptor IIb I232T II (n=12,1)

FC Gamma Receptor IIb I232T IT (n=1,0)

FC Gamma Receptor IIb I232T TT (n=1,0)

This group included participants who progressed after at least six weeks of trastuzumab/taxane treatment. 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. 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.

This group included participants who progressed within less than six weeks of trastuzumab/taxane treatment. 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. 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.

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.

Part I: Progression Free Survival (PFS) by Biomarker

ITT population; Participant from Group B and from No group were not included in this analysis.

Part I: TTP in Intent to Treat (ITT) Population

p95 +ve (n=2,0)

p95 -ve (n=5,1)

IGF1R <median (n=4,0)

IGF1R ≥median (n=4,1)

c-MET<median (n=3,1)

c-MET≥median (n=4,0)

PTEN <median (n=4,0)

PTEN ≥median (n=3,1)

HER2 <median (n=2,1)

HER2 ≥median (n=5,0)

PI3K Amino Acids WT (n=10,1)

PI3K Amino Acids M (n=2,0)

FC Gamma Receptor IIIa F176V FF (n=4,0)

FC Gamma Receptor IIIa F176V VF (n=2,1)

FC Gamma Receptor IIIa F176V VV (n=2,0)

FC Gamma Receptor IIa R166H HH (n=1,0)

FC Gamma Receptor IIa R166H HR (n=5,1)

FC Gamma Receptor IIa R166H RR (n=3,0)

FC Gamma Receptor IIb I232T II (n=7,1)

PP population; n = number of participants with biomarker data available for the specified biomarker.

Part II: Progression Free Survival (PFS) by Biomarker

Univariate Cox regression Hazard ratio (Positive / Negative) for the biomarker p95 HER2.

Univariate Cox regressionHazard ratio (Membrane H-Score: \<median / ≥median) for the biomarker IGF1R.

Univariate Cox regression Hazard ratio (Membrane H-Score: \< median / ≥median) for the biomarker c-met.

Univariate Cox regression Hazard ratio (Cytoplasm H-Score: \< median / ≥median) for the marker PTEN.

Univariate Cox regressionHazard ratio (Mutation Status: Wild type / Mutation) for the biomarker PI3K amino acids.

Hazard ratio (Phenotype: FF / VF) for the biomarker FC Gamma Receptor IIIa F176V.

Hazard ratio (Phenotype: FF / VV) for the biomarker FC Gamma Receptor IIIa F176V.

Hazard ratio (Phenotype: VF / VV) for the biomarker FC Gamma Receptor IIIa F176V.

p95 +ve (n=9,0)

p95 -ve (n=15,1)

PI3K Amino Acids M (n=9,00)

Part I: Time to Progression (TTP) by Biomarker

Part I: PFS in ITT Population

Part II: TTP in Intent to Treat (ITT) Population

Part II: PFS in ITT Population

Overall Survival in Per Protocol Population

Overall Survival in ITT Population

Part I: Responders (n=20)

Part I: Non-Responders (n=20)

Part I: Missing (n=20)

Part II: Responders (n=9)

Part II: Non-Responders (n=9)

Part II: Missing (n=9)

Group A: Trastuzumab+Taxane /Capcetabine (6 Weeks)

ITT population; n = number of participants analyzed for the specified category.

Part I and II: Percentage of Participants With a Best Overall Response of CR or PR in ITT Population

p95 HER2 +ve (n=2,0)

p95 HER2 -ve (n=5,1)

c-MET <median (n=3,1)

c-MET ≥median (n=4,0)

Part II: TTP by Biomarker

Univariate logistic regression Odds ratio (Positive / Negative) for the biomarker p95 HER 2.

Univariate logistic regression Odds ratio (Membrane H-Score: ≥median /\<median) for the biomarker IGF1R.

Univariate logistic regression Odds ratio (Membrane H-Score: ≥ median /\<median) for the biomarker c-MET.

Univariate logistic regression Odds ratio (Cytoplasm H-Score: ≥ median /\< median) for the biomarker PTEN.

Univariate logistic regression Odds ratio (Membrane H-Score: ≥median /\< median) for the biomarker HER2.

Univariate logistic regression Odds ratio (PI3K mutation status: WT versus M) for the biomarker PI3K Amino Acids.

Univariate logistic regressionOdds ratio (Phenotype: FF / VF) for the biomarker FC Gamma Receptor IIIa F176V.

Univariate logistic regression Odds ratio (Phenotype: HR / RR) for the biomarker FC Gamma Receptor IIa R166H

p95 HER2 +ve CR (n=5)

p95 HER2 +ve PR (n=5)

p95 HER2 +ve SD (n=5)

p95 HER2 +ve PD (n=5)

p95 HER2 -ve CR (n=12)

p95 HER2 -ve PR (n=12)

p95 HER2 -ve SD (n=12)

p95 HER2 -ve PD (n=12)

IGF1R < median CR (n=9)

IGF1R < median PR (n=9)

IGF1R < median SD (n=9)

IGF1R < median PD (n=9)

IGF1R ≥median CR (n=9)

IGF1R ≥median PR (n=9,0)

IGF1R ≥median SD (n=9)

IGF1R ≥median PD (n=9)

c-MET <median CR (n=6)

c-METt <median PR (n=6)

c-MET <median SD (n=6)

c-MET <median PD (n=6)

c-MET ≥median CR (n=11)

c-MET ≥median PR (n=11)

c-MET ≥median SD (n=11)

c-MET ≥median PD (n=11)

PTEN <median CR (n=6)

PTEN <median PR (n=6)

PTEN <median SD (n=6)

PTEN <median PD (n=6)

PTEN ≥median CR (n=12)

PTEN ≥median PR (n=12)

PTEN ≥median SD (n=12)

PTEN ≥median PD (n=12)

HER2 <median CR (n=8)

HER2 <median PR (n=8)

HER2 <median SD (n=8)

HER2 <median PD (n=8)

HER2 ≥median CR (n=10)

HER2 ≥median PR (n=10)

HER2 ≥median SD (n=10)

HER2 ≥median PD (n=10)

PI3K Amino Acids WT CR (n=11)

PI3K Amino Acids WT PR (n=11,0)

PI3K Amino Acids WT SD (n=11)

PI3K Amino Acids WT PD (n=11)

PI3K Amino Acids M CR (n=7)

PI3K Amino Acids M PR (n=7,0)

PI3K Amino Acids M SD (n=7)

PI3K Amino Acids M PD (n=7)

FC Gamma Receptor IIIa F176V FF CR (n=6)

FC Gamma Receptor IIIa F176V FF PR (n=6)

FC Gamma Receptor IIIa F176V FF SD (n=6)

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.

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

Spots Global Cancer Trial Database for A Study of Herceptin (Trastuzumab)and Biomarkers in Patients With HER2-Positive Metastatic Breast Cancer

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Study Description

Keywords

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