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

Study Overview
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Brief Summary
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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.

Detailed Description
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OBJECTIVES: Primary 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®). Secondary 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).

Official Title
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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

Conditions
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Breast Cancer

Intervention / Treatment
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* Biological: trastuzumab
* Drug: docetaxel
* Drug: lapatinib ditosylate
* Drug: paclitaxel


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed adenocarcinoma of the breast Metastatic (stage IV) disease at primary diagnosis or at relapse after curative intent therapy Local or central laboratory confirmedHER2/neu* overexpressing and/or amplified disease in the invasive component of the primary or metastatic lesion as defined by the following: 3+ overexpression (in > 30% of invasive tumor cells) by immunohistochemistry (IHC) 2+ or 3+ overexpression (in ≤ 30% of invasive tumor cells) by IHC AND demonstrates HER2/neu gene amplification by fluorescence in situ hybridization (FISH) or chromogenic in situ hybridization (CISH) 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) NOTE: *Patients with a negative or equivocal overall result (FISH/CISH ratio of < 2.2, ≤ 6.0 HER2/neu gene copies per nucleus, or staining scores of 0, 1+, 2+, or 3+ [in ≤ 30% of neoplastic cells] by IHC) are not eligible Formalin-fixed paraffin-embedded tumor specimen available No CNS metastases (including leptomeningeal involvement) Hormone receptor status not specified PATIENT CHARACTERISTICS: Menopausal status not specified ECOG performance status 0-2 Life expectancy > 6 months Absolute granulocyte count > 1,500/mm³ Platelet count > 75,000/mm³ Hemoglobin > 10 g/dL Serum creatinine ≤ 2.0 times upper limit of normal (ULN) Total bilirubin ≤ 1.5 times ULN (< 3 times ULN for patients with Gilbert's disease) AST and/or ALT ≤ 2.5 times ULN (< 5 times ULN for patients planning to receive paclitaxel-based therapy) LVEF ≥ 50% by MUGA or ECHO Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception Must be accessible for study treatment and follow-up No history of other malignancies, except adequately treated ductal carcinoma in situ or lobular carcinoma in situ, adequately treated nonmelanoma skin cancer, curatively treated carcinoma in situ of the cervix, or other curatively treated solid tumor (non-breast) with no evidence of disease for ≥ 5 years No serious cardiac illness or condition including, but not limited to, any of the following: History of documented congestive heart failure Systolic dysfunction (LVEF < 50%) High-risk uncontrolled arrhythmias (i.e., ventricular tachycardia, high-grade atrioventricular block, or supraventricular arrhythmias that are not adequately rate-controlled) Unstable angina pectoris requiring anti-anginal medication Clinically significant valvular heart disease Evidence of transmural infarction on ECG Inadequately controlled hypertension (i.e., systolic blood pressure [BP] > 180 mm Hg or diastolic BP > 100 mm Hg) New York Heart Association class III-IV functional status No serious illness or medical condition that would not allow the patient to be managed according to the protocol including, but not limited to, any of the following: History of significant neurologic or psychiatric disorder that would impair the ability to obtain informed consent or limit compliance with study requirements Active uncontrolled infection Serious or nonhealing wound, ulcer, or bone fracture No peripheral neuropathy ≥ grade 2 No gastrointestinal (GI) tract disease resulting in an inability to take oral medication including, but not limited to, any of the following: Malabsorption syndrome Requirement for IV alimentation Uncontrolled inflammatory GI disease (e.g., Crohn's disease or ulcerative colitis) No history of allergic or hypersensitivity reactions to any study drug or their excipients or to compounds with similar chemical composition to any of the study drugs Prior allergic reactions to taxanes are allowed provided they were adequately treated and, according to the treating physician, would not prohibit further treatment with taxanes PRIOR CONCURRENT THERAPY: Recovered from all prior therapy No prior chemotherapy, immunotherapy, biological therapy, or anti-HER2/neu-targeted therapy for recurrent or metastatic breast cancer At least 12 months since prior chemotherapeutic agents, including taxanes, in the neoadjuvant or adjuvant setting At least 12 months since prior anti-HER2/neu-targeted therapy in the neoadjuvant or adjuvant setting Prior treatment with endocrine therapy in the neoadjuvant, adjuvant, or metastatic setting allowed At least 2 weeks since prior radiotherapy in the adjuvant or metastatic setting Prior radiotherapy to a solitary metastatic lesion allowed provided there is documented disease progression after completion of radiotherapy More than 30 days (or 5 half-lives) since prior investigational drugs At least 7 days since prior and no concurrent CYP3A4 inhibitors (6 months for amiodarone) At least 14 days since prior and no concurrent CYP3A4 inducers No prior surgical procedures affecting absorption (e.g., resection of stomach or small bowel) No concurrent palliative radiotherapy No other concurrent anticancer treatment No other concurrent investigational drugs for breast cancer

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Lapatinib<br>Plus taxane based chemotherapy | Drug: docetaxel<br>* 75mg/m2 IV q 3 weekly, day 1 of a 3 week cycle for 8 cycles plus G-CSF (when given together with lapatinib).<br>Drug: lapatinib ditosylate<br>* 1250 mg po daily (while given with taxane). 1500mg PO daily (when given alone after taxane completion).<br>Drug: paclitaxel<br>* 80mg/m2 IV q weekly days 1, 8 and 15 of a 4-week cycle for 6 cycles.<br>|
| Active Comparator: Trastuzumab<br>Plus taxane based chemotherapy. | Biological: trastuzumab<br>* IV q weekly (loading dose 4mg/kg; subsequent doses 2mg/kg) or IV q 3 weekly (loading dose 8mg/kg, subsequent doses 6mg/kg).<br>Drug: docetaxel<br>* 75mg/m2 IV q 3 weekly, day 1 of a 3 week cycle for 8 cycles plus G-CSF (when given together with lapatinib).<br>Drug: paclitaxel<br>* 80mg/m2 IV q weekly days 1, 8 and 15 of a 4-week cycle for 6 cycles.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | 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 | From randomization to RECIST V 1.0 progression or death assessed up to 39 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | OS median follow-up not achieved; estimated with quartile estimates | From randomization to death from any cause, assessed up to 44 months. | 
| Time to CNS Metastases at the Time of First Progression |  | From randomization to CNS metastases at time of first progression, assessed up to 39 months. | 
| CNS Metastases at the Time of Progression (ITT) |  | Incidence rate of CNS metastases at first progression assessed up to 39 months | 
| CNS Metastases at the Time of Progression (HER2+) |  | Incidence rate of CNS mestastes at first progression, assessed up to 39 months | 
| Overall Objective Response Rate (Complete or Partial) ITT | 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). | 4 years | 
| Overall Objective Response Rate (Complete or Partial) HER2/Neu+ | Response determined by RECIST V 1.0 | Median follow-up of 21.5 months. | 
| Clinical Benefit Response Rate (ITT) | Best overall response of CR, PR or stable disease at end of week 24. | 24 weeks | 
| Clinical Benefit Response Rate (HER2/Neu+)) | Best overall response of CR, PR, or stable disease at end of week 24. | 24 weeks | 
| Quality of Life as Measured by the EORTC QLQ-C30 Global Score From Baseline to 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 | 12 weeks | 
| Effects of Changes in Biomarkers on Clinical Outcomes |  | Not available at this time | 
| Economic Evaluation, Including Health Utilities, as Measured by the EQ-5D Questionnaire, and Healthcare Utilization |  | Not available at this time | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent breast cancer, HER2-positive breast cancer, stage IV breast cancer