Lapatinib Ditosylate and Capecitabine in Treating Patients With Stage IV Breast Cancer and Brain Metastases

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

Detailed Description
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OBJECTIVES: Primary To assess the objective response rate by volumetric analysis of brain metastasis as assessed by MRI in patients with HER2-positive stage IV breast cancer treated with lapatinib ditosylate and capecitabine. Secondary To document any toxicity evaluated by NCI CTC v3.0. To assess the time to radiotherapy. To document the time to disease progression in the central nervous system (CNS) of these patients. To evaluate the overall response rate for extra-CNS disease. To assess the clinical benefit (complete response, partial response, and stable disease for ≥ 6 months) for both CNS and extra-CNS disease in these patients. Tertiary To evaluate serum proteomics and metabonomics markers as predictors of response. To evaluate the predictive value of circulating tumor cells (CTC) on response. OUTLINE: This is a multicenter study. Patients receive oral lapatinib ditosylate once daily. Patients also receive oral capecitabine twice daily on days 1-14. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed periodically.

Official Title
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A Multicenter Phase II Clinical Trial Assessing the Efficacy of the Combination of Lapatinib and Capecitabine in Patients With Non Pretreated Brain Metastasis From HER2 Positive Breast Cancer

Conditions
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Breast Cancer, Metastatic Cancer

Intervention / Treatment
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* Drug: capecitabine
* Drug: lapatinib ditosylate
* Other: circulating tumor cell analysis
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed invasive breast cancer Stage IV disease At least 1 measurable CNS lesion ≥ 10 mm on T1-weighted gadolinium-enhanced MRI No single brain metastasis that could be treated by surgery HER-2 positive primary tumor as defined as IHC3+ or IHC2+ and FISH-positive Hormone receptor status: not specified PATIENT CHARACTERISTICS: Menopausal status not specified Eastern Cooperative Oncology Group (ECOG) performance status 0-2 Life expectancy ≥ 3 months Absolute Neutrophil Count (ANC) ≥ 1,000/mm^3 Platelet count ≥ 100,000/mm^3 Hemoglobin ≥ 10g/dL Creatinine ≥ 1.5 times upper limit of normal (ULN) Albumin ≥ 2.5 g/dL Serum bilirubin ≤ 1.5 times ULN (unless due to Gilbert's syndrome) ASAT and ALAT ≤ 3 times ULN (≤ 5 times ULN with documented liver metastasis) Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception 2 weeks before, during, and for 28 days after completion of study treatment (female) or for 1 week after completion of treatment (male) Able to swallow and retain oral medication Affiliated to a Social Security System No known contraindication to MRI No prior or active malignancy, unless disease free for ≥ 10 years No other concurrent severe and/or uncontrolled medical disease which could compromise study participation, including any of the following: Infection Cardiac disease (e.g., uncontrolled hypertension, congestive cardiac failure, ventricular arrhythmias, active ischemic heart disease, myocardial infarction within the past year, Left Ventricular EJection Fraction (LVEF) > grade 2) Current active hepatic or biliary disease (except for Gilbert syndrome, asymptomatic gallstones, liver metastasis or stable chronic liver disease per investigator assessment) Renal disease Active gastrointestinal (GI) tract ulceration, malabsorption syndrome, active uncontrolled ulcerative colitis, or disease significantly affecting GI function Severely impaired lung function (e.g., spirometry and diffusion capacity of lung for carbon monoxide (DLCO) ≤ 50% of normal, and O_2 saturation ≤ 88% at rest on room air) No known dihydropyrimidine dehydrogenase deficiency No significantly altered mental status prohibiting the understanding of the study, or with psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow-up schedule Not deprived of liberty or placed under the authority of a tutor PRIOR CONCURRENT THERAPY: At least 2 weeks since prior breast cancer treatment (e.g., trastuzumab, chemotherapy, immunotherapy or biological response modifiers, endocrine therapy, or radiotherapy) More than 30 days since prior investigational drugs More than 14 days since prior and no concurrent strong inhibitors or inducers of the cytochrome P450 isoenzyme 3A4 (CYP3A4) (i.e., clarithromycin, ketoconazole, itraconazole, voriconazole, ritonavir) No prior whole brain radiotherapy (WBRT) or brain stereotactic radiotherapy No prior treatment with capecitabine and/or lapatinib ditosylate No prior resection of the stomach or small bowel No concurrent systemic treatment or radiation therapy for breast cancer (except corticosteroid, bisphosphonates, or mannitol)

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
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lapatinib + capecitabine<br>lapatinib 1250mg/day + capecitabine 2000mg/m2/day | Drug: capecitabine<br> <br> Drug: lapatinib ditosylate<br> <br> Other: circulating tumor cell analysis<br> <br> Other: laboratory biomarker analysis<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate |  | february 2012 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity as assessed by NCI CTC v3.0 |  | february 2012 | 
| Time to radiotherapy |  | february 2012 | 
| Time to disease progression |  | february 2012 | 
| Overall response rate |  | february 2012 | 
| Clinical benefit (complete response, partial response, and stable disease for at least 6 months) |  | february 2012 | 
| Evaluation of serum proteomics and metabonomics markers as predictors of response |  | may 2012 | 
| Evaluation of the predictive value of circulating tumor cells on response |  | february 2012 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HER2-positive breast cancer, male breast cancer, stage IV breast cancer, tumors metastatic to brain