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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche
ClinicalTrials.gov Identifier:
NCT00885755
First received: March 16, 2009
Last updated: April 2, 2016
Last verified: April 2016
  Purpose
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.

Condition Intervention Phase
Breast Cancer
Drug: Standard taxane therapy
Drug: capecitabine [Xeloda]
Drug: trastuzumab [Herceptin]
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Hoffmann-La Roche:

Primary Outcome Measures:
  • Part I: Progression Free Survival (PFS) by Biomarker [ 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 ] [ Designated as safety issue: No ]
    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 [ 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 ] [ Designated as safety issue: No ]
    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 [ 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 ] [ Designated as safety issue: No ]
    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 [ 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 ] [ Designated as safety issue: No ]
    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 [ 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 ] [ Designated as safety issue: No ]
    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 [ 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 ] [ Designated as safety issue: No ]
    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 Outcome Measures:
  • Part I: TTP in Intent to Treat (ITT) Population [ 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 ] [ Designated as safety issue: No ]
    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: PFS in ITT Population [ 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 ] [ Designated as safety issue: No ]
    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 [ 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 ] [ Designated as safety issue: No ]
    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 [ 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 ] [ Designated as safety issue: No ]
    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 [ 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) ] [ Designated as safety issue: No ]
    Overall survival was calculated in months from the day of screening until death.

  • Overall Survival in ITT Population [ 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) ] [ Designated as safety issue: No ]
    Overall survival was calculated in months from the day of screening until death.

  • Part I and II: Percentage of Participants With a Best Overall Response of CR or PR in ITT Population [ 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 ] [ Designated as safety issue: No ]
    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 and II: Percentage of Participants With a Response by Best Overall Response by CR, PR, SD or PD in ITT Population [ 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 ] [ Designated as safety issue: No ]
    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.


Enrollment: 33
Study Start Date: August 2009
Study Completion Date: April 2013
Primary Completion Date: April 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1 Drug: Standard taxane therapy
As prescribed
Drug: capecitabine [Xeloda]
1000mg/m2 po bid on days 1-14 of each 3-week cycle (only in patients who have progressed)
Drug: trastuzumab [Herceptin]
8mg/kg iv loading dose on day 1 of first 3-week cycle, and 6mg/kg iv on day 1 of each subsequent cycle

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00885755

Locations
Australia, New South Wales
Camperdown, New South Wales, Australia, 2050
St. Leonards, New South Wales, Australia, 2065
Australia, Victoria
East Ringwood, Victoria, Australia, 3135
Wodonga, Victoria, Australia, 3690
Australia, Western Australia
Perth, Western Australia, Australia, 6000
Spain
Santander, Cantabria, Spain, 39008
Valencia, Spain, 46010
Sweden
Stockholm, Sweden, 17176
Uppsala, Sweden, 75185
United Kingdom
Hull, United Kingdom, HU3 2JZ
Manchester, United Kingdom, M20 4QL
Nottingham, United Kingdom, NG5 1PB
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
Study Director: Clinical Trials Hoffmann-La Roche
  More Information

Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT00885755     History of Changes
Other Study ID Numbers: MO22004  2008-004013-94 
Study First Received: March 16, 2009
Results First Received: September 1, 2015
Last Updated: April 2, 2016
Health Authority: Australia: National Health and Medical Research Council

Additional relevant MeSH terms:
Breast Neoplasms
Breast Diseases
Neoplasms
Neoplasms by Site
Skin Diseases
Trastuzumab
Antineoplastic Agents
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on May 04, 2016