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Completed

NCT Number: NCT00667251

Chemotherapy and Lapatinib or Trastuzumab in Treating Women With HER2/Neu-Positive Metastatic Breast Cancer

This was a multi-center, multinational, randomized, open-label, Phase III study comparing combination taxane-based chemotherapy plus lapatinib to combination taxane-based chemotherapy plus trastuzumab in women with documented evidence of human epidermal growth factor receptor 2 (HER2) positive metastatic breast cancer (MBC) (by local or central laboratory testing) who had received no prior chemotherapy or HER2 targeted therapy in the metastatic setting.

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Key information

Conditions

Breast Cancer Breast Diseases Breast Neoplasms Neoplasms Neoplasms by Site Skin Diseases Skin and Connective Tissue Diseases

Age range

18 year and older

Sex eligibility

Female

Study type

Interventional

Phase

Phase 3

Primary location

Novartis Investigative Site, Capital Federal, Buenos Aires, Argentina

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About this study

Subjects were stratified by

  • Prior (neo) adjuvant HER2/neu targeted therapy (yes, no)
  • Prior (neo) adjuvant taxane chemotherapy (yes, no)
  • Planned taxane treatment (once weekly paclitaxel versus docetaxel once every 3 weeks)
  • Liver metastasis (yes, no)

Subjects were randomized 1:1 to the following treatments to a planned sample size of approximately 600 subjects (to achieve 536 centrally confirmed HER2 positive subjects):

  • Taxane based chemotherapy plus lapatinib for 24 weeks followed by single agent lapatinib
  • Taxane based chemotherapy plus trastuzumab for 24 weeks followed by single agent trastuzumab

The choice of taxane (once weekly paclitaxel versus docetaxel once every 3 weeks) was at the discretion of the treating physician and was specified at the time of subject randomization.

A protocol-specified interim analysis was conducted on 27-Apr-2012, following which the participants in the Lapatinib plus taxane based chemotherapy arm could cross over to Taxane based chemotherapy plus Trastuzumab.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Key inclusion criteria:

  • Histologically confirmed adenocarcinoma of the breast.
  • MBC (stage IV) at primary diagnosis or at relapse after curative intent therapy.
  • Local or central laboratory confirmed HER2/neu overexpressing and/or amplified disease in the invasive component of the primary or metastatic lesion as defined by:
  • 3+ over expression by immunohistochemistry (IHC) (>30% of invasive tumour cells);
  • 2+ or 3+ (in 30% or less neoplastic cells) overexpression by IHC analysis AND fluorescence or chromogenic in situ hybridization (FISH/CISH) test demonstrating HER2/neu gene amplification;
  • HER2/neu gene amplification by FISH/CISH [>6 HER2/neu gene copies per nucleus, or a FISH/CISH ratio (HER2 gene copies to chromosome 17 signals) of >=2.2]
  • Subjects must have had evidence of metastatic disease, but measurable disease was not mandatory. To be considered evaluable for overall response rate (CR and PR), subjects must have had at least 1 measurable lesion as follows:
  • X-ray, physical exam >=20 mm.
  • Conventional computed tomography (CT) scan, magnetic resonance imaging (MRI) >=20 mm.
  • Spiral CT scan >=10 mm.

Key exclusion criteria:

  • Subjects with a history of other malignancies, except: adequately treated ductal carcinoma in-situ or lobular carcinoma in-situ, adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, or other solid tumor (non-breast) curatively treated with no evidence of disease for >=5 years.
  • Subjects who had received prior chemotherapy, immunotherapy, biologic therapy or HER2/neu targeted therapy for recurrent or MBC.
  • Subjects receiving ongoing anti-cancer treatment or other investigational anti-cancer agents for breast cancer or subjects who had used an investigational drug within 30 days or 5 half-lives (if known), whichever was longer, preceding the date of randomization.
  • Subjects with: CNS metastases (including leptomeningeal involvement), serious cardiac illness, peripheral neuropathy grade 2 or greater, subjects with gastrointestinal tract disease, subjects receiving CYP3A4 inhibitors or inducers, and subjects with history of allergic or hypersensitivity reactions to any study drug or their excipients.

Treatment and study plan

trastuzumab

Biological

IV q weekly (loading dose 4mg/kg; subsequent doses 2mg/kg) or IV q 3 weekly (loading dose 8mg/kg, subsequent doses 6mg/kg).

docetaxel

Drug

75mg/m2 IV q 3 weekly, day 1 of a 3 week cycle for 8 cycles plus G-CSF (when given together with lapatinib).

Lapatinib Ditosylate

Drug

1250 mg once daily (while given with taxane). 1500mg once daily (when given alone after taxane completion).

paclitaxel

Drug

80mg/m2 IV q weekly days 1, 8 and 15 of a 4-week cycle for 6 cycles.

Primary outcomes

  1. Progression Free Survival (PFS) at the Time of Primary Results

    Time frame: From date of randomization until date of progression or date of death from any cause, whichever comes first, assessed up to approximately 39 months

    Progression-free survival (PFS) is the time from randomization to the earliest date of RECIST 1.0 assessment of disease progression (with radiological evidence), death from any cause, or censoring. Disease progression was assessed by the Investigator and defined by RECIST v1.0 as a 20% increase in the sum of the longest diameter of target lesions, a measurable increase in a non-target lesion, or the appearance of new lesions.

Secondary outcomes

  1. Progression Free Survival (PFS) at the Time of Final Analysis

    Time frame: From date of randomization until date of progression or date of death from any cause, whichever comes first, assessed up to approximately 45 months

    Progression-free survival (PFS) is the time from randomization to the earliest date of RECIST 1.0 assessment of disease progression (with radiological evidence), death from any cause, or censoring. Disease progression was assessed by the Investigator and defined by RECIST v1.0 as a 20% increase in the sum of the longest diameter of target lesions, a measurable increase in a non-target lesion, or the appearance of new lesions. Subjects who crossover the treatment to Trastuzumab (TTax/T) after interim analysis, were censored at the last PFS assessment before crossover.

  2. Overall Survival (OS) (IIT Population)

    Time frame: From date of randomization until date of death from any cause, assessed up approximately 165 months

    Overall Survival (OS) was defined as the time interval between the date of randomization and the date of death from any cause. Subjects who were still alive at the time of the final analysis or became lost to follow-up, were censored at their last contact date. Subjects who crossover the treatment to Trastuzumab (TTax/T) after interim analysis, were censored at last known alive date prior to crossover.

  3. Overall Survival (OS) (Central HER2+ Population)

    Time frame: From date of randomization until date of death from any cause, assessed up approximately 165 months

    Overall Survival (OS) was defined as the time interval between the date of randomization and the date of death from any cause. Subjects who were still alive at the time of the final analysis or became lost to follow-up, were censored at their last contact date. Subjects who crossover the treatment to Trastuzumab (TTax/T) after interim analysis, were censored at last known alive date prior to crossover.

  4. Incidence of Central Nervous System (CNS) Metastasis at First Progression (IIT Population)

    Time frame: From date of randomization to CNS metastases at time of first progression, assessed up approximately 45 months

    The incidence of Central Nervous System (CNS) metastasis at first progression was defined as the ratio of the number of subjects with CNS metastasis at progression over the total number of subjects.

  5. Incidence of Central Nervous System (CNS) Metastasis at First Progression (Central HER2+ Population)

    Time frame: From date of randomization to CNS metastases at time of first progression, assessed up approximately 45 months

    The incidence of Central Nervous System (CNS) metastasis at first progression was defined as the ratio of the number of subjects with CNS metastasis at progression over the total number of subjects.

  6. Time to Central Nervous System (CNS) Metastasis (IIT Population)

    Time frame: From date of randomization to CNS metastases at time of first progression, assessed up approximately 45 months

    Time to Central Nervous System (CNS) metastasis was defined as the time from randomization until disease progression where CNS metastasis was documented at the time of first breast cancer progression. Subjects who crossed over the treatment to Trastuzumab (TTax/T) after interim analysis, were censored at RECIST assessment prior to crossover.

  7. Time to Central Nervous System (CNS) Metastasis (Central HER2+ Population)

    Time frame: From date of randomization to CNS metastases at time of first progression, assessed up approximately 45 months

    Time to Central Nervous System (CNS) metastasis was defined as the time from randomization until disease progression where CNS metastasis was documented at the time of first breast cancer progression. Subjects who crossed over the treatment to Trastuzumab (TTax/T) after interim analysis, were censored at RECIST assessment prior to crossover.

  8. Overall Response Rate (ORR) (IIT Population)

    Time frame: From date of randomization until date of progression or date of death from any cause, whichever comes first, assessed up approximately 45 months

    Overall Response Rate (ORR) was defined as the proportion of participants with Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR). The ORR was calculated from the Investigator's assessment of response based on RECIST 1.1. Subjects with an unknown or missing response were treated as non-responders; i.e., they were included in the denominator when calculating the percentages.

    Per Response Evaluation Criteria In Solid Tumors (RECIST v1.1) for target lesions and assessed by MRI:

    • Complete Response (CR): Disappearance of all target and non-target lesions.
    • Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as a reference the Baseline sum LD.
    • Overall Response (OR): CR + PR.

  9. Overall Response Rate (ORR) (Central HER2+ Population)

    Time frame: From date of randomization until date of progression or date of death from any cause, whichever comes first, assessed up approximately 45 months

    Overall Response Rate (ORR) was defined as the proportion of participants with Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR). The ORR was calculated from the Investigator's assessment of response based on RECIST 1.1. Subjects with an unknown or missing response were treated as non-responders; i.e., they were included in the denominator when calculating the percentages.

    Per Response Evaluation Criteria In Solid Tumors (RECIST v1.1) for target lesions and assessed by MRI:

    • Complete Response (CR): Disappearance of all target and non-target lesions.
    • Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as a reference the Baseline sum LD.
    • Overall Response (OR): CR + PR.

  10. Clinical Benefit Response (CBR) (IIT Population)

    Time frame: From date of randomization until date of progression or date of death from any cause, whichever comes first, assessed up approximately 45 months

    Clinical Benefit Response (CBR) was defined as the percentage with evidence of Complete Response (CR), Partial Response (PR) (participants with at least 1 measurable lesion at baseline), or maintaining Stable Disease (SD) for at least 24 weeks (all subjects, with or without measurable disease at baseline) while on study, according to the investigator assessment of response per RECIST 1.1 criteria. Participants were considered to be positive (Yes) for CBR if they experienced any CR or PR for any duration prior to progressive disease. Participants were considered to be negative (No) for CBR if they had progressive disease prior to Week 24 without prior confirmed CR or PR.

  11. Clinical Benefit Response (CBR) (Central HER2+ Population)

    Time frame: From date of randomization until date of progression or date of death from any cause, whichever comes first, assessed up approximately 45 months

    Clinical Benefit Response (CBR) was defined as the percentage with evidence of Complete Response (CR), Partial Response (PR) (participants with at least 1 measurable lesion at baseline), or maintaining Stable Disease (SD) for at least 24 weeks (all subjects, with or without measurable disease at baseline) while on study, according to the investigator assessment of response per RECIST 1.1 criteria. Participants were considered to be positive (Yes) for CBR if they experienced any CR or PR for any duration prior to progressive disease. Participants were considered to be negative (No) for CBR if they had progressive disease prior to Week 24 without prior confirmed CR or PR.

  12. Time to Response (TTR) (IIT Population)

    Time frame: From date of randomization until date of first response, assessed up approximately 45 months

    Time to Response was defined as the time from randomization to the earliest date of Complete Response (CR) or Partial Response (PR). The event of first response was the first CR or PR; censoring was at PD date for those who progressed or at the last RECIST date if no progression occurred.

  13. Time to Response (TTR) (Central HER2+ Population)

    Time frame: From date of randomization until date of progression or date of death from any cause, whichever comes first, assessed up approximately 45 months

    Time to Response was defined as the time from randomization to the earliest date of Complete Response (CR) or Partial Response (PR). The event of first response was the first CR or PR; censoring was at PD date for those who progressed or at the last RECIST date if no progression occurred.

  14. Duration of Response (DoR) (IIT Population)

    Time frame: From first documented evidence of CR or PR (the response prior to confirmation) until time of documented disease progression or death due to any cause, whichever comes first, assessed up approximately 165 months

    Duration of Response (DOR) was defined as the duration between the date of first documented Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR) and the date of first documented sign of Progressive Disease or Death, with censoring at the last RECIST date if no progression occurred.

  15. Duration of Response (DoR) (Central HER2+ Population)

    Time frame: From first documented evidence of CR or PR (the response prior to confirmation) until time of documented disease progression or death due to any cause, whichever comes first, assessed up approximately 165 months

    Duration of Response (DOR) was defined as the duration between the date of first documented Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR) and the date of first documented sign of Progressive Disease or Death, with censoring at the last RECIST date if no progression occurred.

  16. EORTC QLQ-C30 Global Score at 12 Weeks

    Time frame: Week 12

    The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQC-30) is a questionnaire developed to assess the quality of life of cancer patients. The global score ranges from 0-100, with higher values representing a better quality of life.

  17. Number of Participants Achieving European Quality of Life (EuroQol) - 5 Domain (EQ-5D) Score (Canadian and Australian Centers Only)

    Time frame: Week 12, Week 24, Week 36, Week 48, Week 60, Week 72, Week 84, Week 96, Week 120, Week 144

    The European Quality of Life (EuroQol) - 5 Domain (EQ-5D) self-administered questionnaire consists of two pages comprising the EQ-5D descriptive system and the EQ Visual Analogue Scale (VAS). The EQ-5D descriptive system comprises five dimensions of health (mobility, self-care, usual activities, pain/discomfort, anxiety/depression) and each dimension comprises three levels (no problems, some problems, extreme problems, unable to perform the activity).

  18. Change From Baseline in the EQ-VAS Score (Canadian and Australian Centers Only)

    Time frame: Baseline, Week 12, Week 24, Week 36, Week 48, Week 60, Week 72, Week 84, Week 96, Week 120, Week 144

    The European Quality of Life (EuroQol) - 5 Domain (EQ-5D) self-administered questionnaire consists of two pages comprising the EQ-5D descriptive system and the EQ Visual Analogue Scale (VAS). The EQ VAS records the patient's self-rated health on a vertical visual analogue 0-100 scale, where the endpoints are labelled 'The best health you can imagine' (100) and 'The worst health you can imagine' (0).

  19. Number of Participants With Healthcare Utilization (Canadian and Australian Centers Only)

    Time frame: From date of randomization till 28 days safety follow-up, assessed up to 40 months

    The measures of healthcare resource utilization collected were categorized: hospitalization/inpatient visit, Institutionalized, Outpatient visit.

  20. Number of Participant Hospitalized (Canadian and Australian Centers Only)

    Time frame: From date of randomization till 28 days safety follow-up, assessed up to 40 months

    The number of hospitalizations were categorized: >0 and =<2, >2 and =<4 and >4.

  21. Total and Average Duration of Hospitalization (Canadian and Australian Centers Only)

    Time frame: From date of randomization till 28 days safety follow-up, assessed up to 40 months

    The total duration of hospitalization in days and average duration of each hospitalization in days were summarized using descriptive statistics.

  22. Reasons for Hospitalization (Canadian and Australian Centers Only)

    Time frame: From date of randomization till 28 days safety follow-up, assessed up to 40 months

    The reasons for hospitalization were categorized: Breast Cancer, Febrile Neutropenia, Infection, Other and Pneumonia.

  23. Type of Ward (Hospital Unit) (Canadian and Australian Centers Only)

    Time frame: From date of randomization till 28 days safety follow-up, assessed up to 40 months

    The type of ward (hospital unit) were categorized: general ward, intensive care unit, oncology ward, rehabilitation unit and other.

  24. Discharge Destinations (Canadian and Australian Centers Only)

    Time frame: From date of randomization till 28 days safety follow-up, assessed up to 40 months

    The discharge destinations were categorized: died, home, rehabilitation facility and transfer to other hospital.

  25. Estrogen Receptor (ER) and Progesterone Receptor (PgR) Status

    Time frame: Up to approximately 39 months

    Immunohistochemistry (IHC) analysis of estrogen receptor (ER) and progesterone receptor (PgR) were performed as part of the mandatory central laboratory testing for protocol-specified biomarkers.

Sponsors and collaborators

Lead sponsor

Novartis Pharmaceuticals

Industry

Collaborators

  • NCIC Clinical Trials Group

Registry information

Official study title

A Randomized, Open-Label, Phase III Study of Taxane Based Chemotherapy With Lapatinib or Trastuzumab as First-Line Therapy for Women With HER2/Neu Positive Metastatic Breast Cancer

Important dates

Study start
2008
Primary completion
2012
Study completion
2022
First posted
Apr 28, 2008
Registry last updated
Mar 21, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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