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

Official Title: “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”

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.

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 proteomic and metabonomic 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.

Intervention(s) in this Clinical Trial

• Drug: capecitabine
• Drug: lapatinib ditosylate
• Other: circulating tumor cell analysis
• Other: laboratory biomarker analysis

Primary Measures

• Objective response rate
  • Safety Issue?: No

Secondary Measures

• Toxicity as assessed by NCI CTC v3.0
  • Safety Issue?: Yes
• Time to radiotherapy
  • Safety Issue?: No
• Time to disease progression
  • Safety Issue?: No
• Overall response rate
  • Safety Issue?: No
• Clinical benefit (complete response, partial response, and stable disease for at least 6 months)
  • Safety Issue?: No
• Evaluation of serum proteomic and metabonomic markers as predictors of response
  • Safety Issue?: No
• Evaluation of the predictive value of circulating tumor cells on response
  • Safety Issue?: No

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
• ECOG performance status 0-2
• Life expectancy ≥ 3 months
• 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)
• AST and ALT ≤ 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, 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 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 isoenzyme 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)

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Investigator: Federation Nationale des Centres de Lutte Contre le Cancer Other

Overall Clinical Trial Officials and Contacts

Thomas Bachelot, MD Principal Investigator Centre Leon Berard  

Information obtained from ClinicalTrials.gov on February 09, 2012

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00967031

Study ID Number: CDR0000642631

ClinicalTrials.gov Identifier: NCT00967031

Health Authority: Unspecified

Clinical trial summary from the National Cancer Institute's PDQ® database