Abraxane and Lapatinib in Treating Patients With Stage I, Stage II, or Stage III Breast Cancer

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as Abraxane, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Lapatinib may stop the growth of tumor cells by blocking some of the enzymes needed for their growth. Giving Abraxane together with lapatinib may kill more tumor cells. PURPOSE: This phase II trial is studying how well giving Abraxane together with lapatinib works in treating patients with stage I, stage II, or stage III breast cancer.

Detailed Description
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OBJECTIVES: Primary Determine the clinical response rate, as measured by clinical exam and imaging studies, in patients with stage I-III breast cancer treated with neoadjuvant Abraxane in combination with lapatinib. Secondary Determine the pathologic complete response rate in patients treated with this regimen. Correlate proliferation (Ki67), apoptosis (cleaved caspase-3), and angiogenesis (vW, CD34) markers, measured before and after treatment, with tumor response in these patients. Conduct other correlative studies, including epidermal growth factor receptor (EGFR), HER2/neu, matrix metalloproteinases (MMPs), and transforming growth factor (TGF-β), before and after treatment with this regimen to assess tumor response in these patients. Determine the toxicity of this regimen in these patients. OUTLINE: This is a pilot study. Patients are assigned to 1 of 2 treatment groups. Group 1: The first 10 patients receive Abraxane IV over 30 minutes on day 1 and oral lapatinib once daily on days 1-21. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Group 2: The next 20 patients receive Abraxane and lapatinib (at a higher dose) as in group 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients undergo blood collection and tumor biopsies periodically for correlative biomarker studies. PROJECTED ACCRUAL: A total of 30 patients will be accrued to this study.

Official Title
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Pilot Neoadjuvant Trial in Breast Cancer With Combination of ABI-007 (Abraxane) and GW572016 (Lapatinib)

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: lapatinib ditosylate
* Drug: paclitaxel albumin-stabilized nanoparticle formulation


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed breast cancer Clinical stage I-III disease Measurable disease defined as ≥ 1 unidimensionally measurable lesion ≥ 20 mm by conventional techniques OR ≥ 10 mm with spiral CT scan HER2/neu 3+ by immunohistochemistry or positive by fluorescent in situ hybridization No known brain metastases Hormone receptor status unspecified PATIENT CHARACTERISTICS: Menopausal status not specified Male or female Life expectancy > 12 weeks ECOG performance status (PS) 0-1 OR Karnofsky PS 80-100% WBC ≥ 3,000/mm^3 Absolute neutrophil count ≥ 1,500 mm^3 Platelet count ≥ 100,000/mm^3 Total bilirubin normal AST and ALT ≤ 2.5 times upper limit of normal Creatinine normal OR creatinine clearance ≥ 60 mL/min LVEF ≥ 50% as measured by echocardiogram or MUGA scan No other malignancy within the past year Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception Able to swallow and retain oral medication No history of allergic reactions attributed to compounds of similar chemical or biologic composition to lapatinib No ongoing or active infection No symptomatic congestive heart failure No unstable angina pectoris No cardiac arrhythmia No psychiatric illness or social situation that would preclude study compliance No other uncontrolled illness No gastrointestinal (GI) tract disease that would preclude ability to take oral medication No malabsorption syndrome No requirement for IV alimentation No uncontrolled inflammatory GI disease (e.g., Crohn's disease or ulcerative colitis) PRIOR CONCURRENT THERAPY: No prior chemotherapy, immunotherapy, radiotherapy, or hormonal therapy for breast cancer No prior treatment with epidermal growth factor receptor targeting therapies No prior surgical procedures affecting absorption No prior surgery for breast cancer At least 14 days since prior and no concurrent CYP3A4 inducers, including any of the following: Dexamethasone or dexamethasone equivalent dose ≥ 1.5 mg/day, including any of the following: Cortisone (≥ 50 mg/day) Hydrocortisone (≥ 40 mg/day) Prednisone (≥ 10 mg/day) Methylprednisolone (≥ 8 mg/day) Phenytoin Carbamazepine Phenobarbital Efavirenz Nevirapine Rifampin Rifabutin Rifapentine Hypericum perforatum (St. John's wort) Modafinil At least 7 days since prior and no concurrent CYP3A4 inhibitors, including any of the following: Clarithromycin Erythromycin Troleandomycin Delavirdine Ritonavir Indinavir Saquinavir Nelfinavir Amprenavir Lopinavir Itraconazole Ketoconazole Voriconazole Fluconazole (doses up to 150 mg/day are permitted) Nefazodone Fluvoxamine Verapamil Diltiazem Cimetidine Aprepitant Grapefruit or its juice At least 6 months since prior and no concurrent amiodarone At least 2 days since prior and no concurrent gastric pH modifiers*, including any of the following: Cimetidine Ranitidine Nizatidine Famotidine Omeprazole Esomeprazole Rabeprazole Pantoprazole Lansoprazole NOTE: *Antacids are allowed within 1 hour before and after administration of study drug No other concurrent investigational agents No other concurrent anticancer therapy, including chemotherapy, radiotherapy, immunotherapy, or antitumor hormonal therapy No concurrent herbal (alternative) medicines No concurrent combination antiretroviral therapy for HIV-positive patients Concurrent bisphosphonates allowed

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment arm<br>30 patients receive Abraxane IV over 30 minutes on day 1 and oral lapatinib once daily on days 1-21. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. | Drug: lapatinib ditosylate<br>* Oral lapatinib is taken once daily on days 1-21 of each treatment cycle. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.<br>* Other names: Tyverb;Drug: paclitaxel albumin-stabilized nanoparticle formulation<br>* 30 patients receive Abraxane IV over 30 minutes on day 1 each of each treatment cycle. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.<br>* Other names: ABI-007;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Response Rate (cRR) | cRR measured by RECIST for target lesions assessed by clinical exam+ mammogram+ ultrasound (US). cRR is defined as number of patients who's best response in any of the assessments (clinical exam/mammogram/US) is CR+PR. Response will be defined as one of the following in either clinical exam, mammogram or US: Complete Response (CR)-Disappearance of all target lesions. Partial Response (PR)>=30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum. Stable Disease-neither sufficient shrinkage to qualify for Partial disease nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum LD while on study. Progressive Disease <=20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. | At Baseline, then before each treatment cycle begins and after 4 cycles of study treatment (1 cycle = 21 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathologic Complete Response (pCR) | Pathologic Complete Response (pCR) will be assessed by breast biopsy at baseline and after 4 cycles of study treatment (1 cycle = 21 days) and at surgery. This will be defined as the number of patients that show a pCR after surgery. pCR is defined as the absence of histologic evidence of invasive tumor cells in the surgical breast specimen and axillary lymph nodes. | At baseline, then after 4 cycles of study treatment (1 cycle = 21 days ) and at surgery | 
| Proliferation (Ki67) Measured at Baseline and After Completion of Study Treatment | Correlation of proliferation (Ki67) will be assessed by breast biopsy at baseline and after 4 cycles of study treatment (1 cycle = 21 days). Ki67 scoring was performed based on degree of staining (0= no staining, 1=weak nuclear staining, 2=moderate nuclear staining, 3=strong nuclear staining). Ki67 scores were counted on a maximum of 10 randomly selected x40 high-power fields with an eyepiece grid of 10x10 squares containing representative sections of tumor and calculated as percentage of positively stained cells to total tumor cells (Percent Score method) Ki67 labeling Index (LI) as assessed by counting a maximum of 1,000 malignant cells at x400 magnification. | At baseline, then after 4 cycles of study treatment (1 cycle = 21 days ) | 
| Apoptosis (Cleaved Caspase-3) Measured at Baseline and After Completion of Study Treatment | Apoptosis/cleaved caspase-3 (CC3) will be assessed by breast biopsy at baseline and after 4 cycles of study treatment (1 cycle = 21 days). Scoring was based on the degree of staining (0=more than 90% of tumor cells with no staining, 1= more than 90% of tumor cells have weak staining, 2= more than 90% of tumor cells have moderate staining, 3= more than 90% of tumor cells have strong staining). CC3 scores were counted on a maximum of 10 randomly selected x40 high-power fields with an eyepiece grid of 10x10 squares containing representative sections of tumor and calculated as percentage of positively stained cells to total tumor cells (Percent Score method) CC3 labeling Index (LI) as assessed by counting a maximum of 1,000 malignant cells at x400 magnification. | At baseline, then after 4 cycles of study treatment (1 cycle = 21 days ) | 
| Angiogenesis (vW, CD34) Markers as Measured at Baseline and After Completion of Study Treatment | Angiogenesis (vW, CD34) markers will be assessed by breast biopsy at baseline and after 4 cycles of study treatment (1 cycle = 21 days). Expressions were analyzed by light microscopy in invasive breast cancer regions. Tumor cells were assigned a score: 0 = no staining weak staining less than 1% of tumor cells = medium staining in 1-10% of tumor cells/weak staining in less than 1% of tumor cells = medium or strong staining in more than 10% of the tumor cells. Capillary density was assessed in breast sections stained for CD34 at a x200 magnification by counting the number of capillaries per field with five fields per slide and results expressed as the average number of capillaries per field. | At baseline, then after 4 cycles of study treatment (1 cycle = 21 days ) | 
| Epidermal Growth Factor Receptor (EGFR), and Matrix Metalloproteinases (MMPs), Measured at Baseline and After Completion of Study Treatment | Epidermal growth factor receptor (EGFR), HER2/neu, matrix metalloproteinases (MMPs), and transforming growth factor (TGF-β) will be assessed by breast biopsy at baseline and after 4 cycles of study treatment (1 cycle = 21 days) with expressions analyzed by light microscopy in invasive breast cancer regions. MMP2 cytoplasmic staining intensity was assigned a score: 0=no reactivity, =1-10% of tumor cells reactive, =11-25% of tumor cells reactive, = 26-50% of cells reactive, = more than 50% of cells reactive Greater than or equal to 2+ score was considered positive for expression. EGFR membrane staining was assigned a score: 0 = no staining or faint staining in less than 10% of cells = faint incomplete membrane staining in more than 10% of cells = weak to moderate complete membrane staining of more than 10% of cells = strong complete membrane staining in more than 10% of tumor cells | At baseline, then after 4 cycles of study treatment (1 cycle = 21 days ) | 
| Side Effects From the Combination of Abraxane and Lapatinib | Side effects from the combination of Abraxane and Lapatinib will be assessed using CTCAE 3.0. Side effects that were related to study treatment and grade 3 or higher were collected where: Grade 1= Mild Grade 2 = Moderate Grade 3 = Severe Grade 4 = Life-threatening Grade 5 = Death | At baseline, then before the start of each study treatment cycle (1 cycle = 21 days) begins | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage I breast cancer, stage II breast cancer, stage IIIA breast cancer, stage IIIB breast cancer, stage IIIC breast cancer