Chemotherapy and Lapatinib or Trastuzumab in Treating Women With HER2/Neu-Positive Metastatic Breast Cancer
RATIONALE: HER2/neu is a receptor (protein) which is found in unusually high amounts in approximately 1 in 5 cancer patients. Scientific evidence suggests that having high amounts of the HER2/neu receptor is important for breast cancer to grow and spread. Women with previously untreated metastatic breast cancer (breast cancer that has spread to other organs) and with high levels of the HER2/neu receptor receive as their usual treatment chemotherapy with one of the approved chemotherapy drugs paclitaxel or docetaxel (called "taxanes") together with another approved drug called "trastuzumab". Chemotherapy drugs, such as paclitaxel and docetaxel, work either by killing tumour cells or by stopping them from dividing. Trastuzumab is an antibody that is given through a vein in the arm and it works by specifically "targeting" the HER2/neu i.e. it attaches to it and "turns it off". Although some of the patients who receive this taxane plus trastuzumab treatment feel better for some months, the cancer usually starts to grow again. Lapatinib is a new drug. Like trastuzumab, it also works by specifically "targeting" the HER2/neu receptor, but it does so in a different way. Lapatinib is not an antibody. It is a pill that is taken daily by mouth. Because lapatinib works in a different way than trastuzumab, it may be worse, as good as or better than trastuzumab in keeping metastatic HER/neu positive cancer from growing. However, this is not known.
Purpose: This randomized Phase III trial is comparing chemotherapy (a taxane) given together with lapatinib with chemotherapy (a taxane) given together with trastuzumab in women with HER2/neu positive breast cancer.
Drug: lapatinib ditosylate
|Study Design:||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official 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|
- Progression-free Survival [ Time Frame: From randomization to RECIST V 1.0 progression or death assessed up to 39 months. ]Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions
- Overall Survival [ Time Frame: From randomization to death from any cause, assessed up to 44 months. ]OS median follow-up not achieved; estimated with quartile estimates
- Time to CNS Metastases at the Time of First Progression [ Time Frame: From randomization to CNS metastases at time of first progression, assessed up to 39 months. ]
- CNS Metastases at the Time of Progression (ITT) [ Time Frame: Incidence rate of CNS metastases at first progression assessed up to 39 months ]
- CNS Metastases at the Time of Progression (HER2+) [ Time Frame: Incidence rate of CNS mestastes at first progression, assessed up to 39 months ]
- Overall Objective Response Rate (Complete or Partial) ITT [ Time Frame: 4 years ]
Patients included in this assessment must have had at least one measurable lesion at baseline, and had at least one RECIST re-evaluation after baseline while on protocol therapy, prior to, or on, date of progression.
Best overall response was classified to be Complete Response (CR) or Partial Response (PR).
- Overall Objective Response Rate (Complete or Partial) HER2/Neu+ [ Time Frame: Median follow-up of 21.5 months. ]Response determined by RECIST V 1.0
- Clinical Benefit Response Rate (ITT) [ Time Frame: 24 weeks ]Best overall response of CR, PR or stable disease at end of week 24.
- Clinical Benefit Response Rate (HER2/Neu+)) [ Time Frame: 24 weeks ]Best overall response of CR, PR, or stable disease at end of week 24.
- Quality of Life as Measured by the EORTC QLQ-C30 Global Score From Baseline to 12 Weeks [ Time Frame: 12 weeks ]
The EORTC QLQ-C30 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.
At 12 weeks: Group mean difference between arms
- Effects of Changes in Biomarkers on Clinical Outcomes [ Time Frame: Not available at this time ]
- Economic Evaluation, Including Health Utilities, as Measured by the EQ-5D Questionnaire, and Healthcare Utilization [ Time Frame: Not available at this time ]
|Study Start Date:||October 2008|
|Estimated Study Completion Date:||December 2016|
|Primary Completion Date:||August 2012 (Final data collection date for primary outcome measure)|
Active Comparator: Lapatinib
Plus taxane based chemotherapy
75mg/m2 IV q 3 weekly, day 1 of a 3 week cycle for 8 cycles plus G-CSF (when given together with lapatinib).Drug: lapatinib ditosylate
1250 mg po daily (while given with taxane). 1500mg PO daily (when given alone after taxane completion).Drug: paclitaxel
80mg/m2 IV q weekly days 1, 8 and 15 of a 4-week cycle for 6 cycles.
Active Comparator: Trastuzumab
Plus taxane based chemotherapy.
IV q weekly (loading dose 4mg/kg; subsequent doses 2mg/kg) or IV q 3 weekly (loading dose 8mg/kg, subsequent doses 6mg/kg).Drug: docetaxel
75mg/m2 IV q 3 weekly, day 1 of a 3 week cycle for 8 cycles plus G-CSF (when given together with lapatinib).Drug: paclitaxel
80mg/m2 IV q weekly days 1, 8 and 15 of a 4-week cycle for 6 cycles.
- To compare the progression-free survival of women with HER2/neu-positive metastatic breast cancer treated with taxane-based chemotherapy in combination with lapatinib ditosylate or trastuzumab (Herceptin®).
- To compare the overall survival.
- To compare the time to CNS metastases at the time of first progression.
- To compare the incidence rates of CNS metastases at the time of progression.
- To compare the overall objective response rate (complete or partial response), time to response, and duration of response in patients with measurable disease at baseline.
- To compare the clinical benefit response rate.
- To compare the adverse event profile.
- To compare the quality of life.
- To compare clinical outcomes using biomarker changes in biological samples.
- To compare health economics, including healthcare utilization and health utilities.
OUTLINE: This is a multicenter study. Patients are stratified according to prior neoadjuvant/adjuvant anti-HER2/neu-targeted therapy (yes vs no), prior neoadjuvant/adjuvant taxane chemotherapy (yes vs no), planned taxane therapy (paclitaxel vs docetaxel), and liver metastasis (yes vs no). Patients are randomized to 1 of 2 treatment arms.
- Arm I: Patients receive either paclitaxel IV on days 1, 8, and 15; treatment with paclitaxel repeats every 4 weeks for 6 courses in the absence of disease progression or unacceptable toxicity. Alternatively, patients may receive docetaxel IV on day 1; treatment with docetaxel repeats every 3 weeks for 8 courses in the absence of disease progression or unacceptable toxicity. Patients on docetaxel also receive filgrastim (G-CSF) according to institutional standard. All patients receive oral lapatinib ditosylate once daily during taxane treatment and continue after completion of taxane treatment, in the absence of disease progression or unacceptable toxicity.
- Arm II: Patients receive paclitaxel IV on days 1, 8, and 15 and trastuzumab (Herceptin®) IV on days 1, 8, 15, and 22. Treatment repeats every 4 weeks for 6 courses in the absence of disease progression or unacceptable toxicity. Alternatively, patients may receive docetaxel IV and trastuzumab IV on day 1. Treatment repeats every 3 weeks for 8 courses in the absence of disease progression or unacceptable toxicity. After completion of taxane chemotherapy and trastuzumab, all patients receive trastuzumab alone IV once every 3 weeks in the absence of disease progression or unacceptable toxicity.
Formalin-fixed paraffin-embedded tissue samples are analyzed for ER, PgR, EGFR, CK5/6, Ki67, and other molecular biomarkers by tissue microarray and immunohistochemistry.
Patients complete quality of life questionnaires (EORTC QLQ-C30 and a Trial Specific Checklist) at baseline, every 12 weeks for 96 weeks, and then every 24 weeks until disease progression.
After completion of study treatment, patients are followed at 4 weeks post treatment, and then every 12 weeks thereafter (counting from the beginning of study therapy).
Please refer to this study by its ClinicalTrials.gov identifier: NCT00667251
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|Study Director:||Novartis pharmaceuticals||Novartis Pharmaceuticals|