lapatinib and temozolomide for the treatment of progressive brain disease in her-2 positive breast cancer

Conditions: Metastatic Breast Cancer; Brain Metastases; HER2 Positive

Summary: objectives: primary - determine the maximum tolerated dose (mtd) and evaluate the dose limiting toxicities (dlt) of combining lapatinib and temozolomidesecondary - obtain preliminary information on the clinical anti-tumor activity of lapatinib plus temozolomide on brain metastases secondary to her-2 positive breast cancer including objective response rate (orr), clinical benefit (cb) and duration of response (dr) methodology: phase i, single-centre, open-label, dose-escalation study of combining lapatinib and temozolomide in her-2 positive breast cancer patients with progressive brain metastases after surgery or radiotherapy or radiosurgery treatment: temozolomide will be given orally for 5 days of every 28 days, at doses of either 100mg/m2/day or 150mg/m2/day or 200mg/m2/day and lapatinib will be given orally every day at either 1000mg/day or 1250mg/day or 1500mg/day.sequential cohorts will be escalated in increments according to the dose escalation scheme, and determined by dose limiting toxicities.

patients selection criteria: * age 18 - 70 years * women with cytologically or histologically proven metastatic breast cancer with recurrent / progressive brain metastases evaluable by mri, after standard treatment with surgery (at least 3 weeks prior) or wbrt (at least 3 weeks prior) or stereotactic rt (at least 1 week prior); or otherwise deemed as unsuitable for standard treatment in the first instance * known her-2 positive status (immunohistochemistry (ihc) 3+ fluorescence in situ hybridization (fish) positive ) * previous chemotherapy (adjuvant and metastatic regimens) allowed * previous treatment with trastuzumab allowed (trastuzumab to be discontinued prior to study entry) * at least one measurable lesion in the brain, defined as any lesion \>5mm in longest dimension on t1-weighted, gadolinium-enhanced mri * expected life-expectancy of more than 3 months * ecog performance status of 0, 1 or 2 * adequate bone marrow, renal and hepatic functionslvef * lvef 50% measured by echocardiography or muga scan * concomitant corticosteroids and anti-convulsants for symptomatic brain metastases are allowed

Eligibility criteria:
inclusion criteria: * 18 - 70 years * women with cytologically or histologically proven metastatic breast cancer with recurrent / progressive brain metastases evaluable by mri, after standard treatment with surgery (at least 3 weeks prior) or wbrt (at least 3 weeks prior) or stereotactic rt (at least 1 week prior); or otherwise deemed as unsuitable for standard treatment in the first instance * known her-2 positive status (immunohistochemistry (ihc) 3+ fluorescence in situ hybridization (fish) positive ) * previous chemotherapy (adjuvant and metastatic regimens) allowed * previous treatment with trastuzumab allowed (trastuzumab to be discontinued prior to study entry) * at least one measurable lesion in the brain, defined as any lesion \>5mm in longest dimension on t1-weighted, gadolinium-enhanced mri * expected life-expectancy of more than 3 months * ecog performance status of 0, 1 or 2 * adequate bone marrow, renal and hepatic functionslvef * lvef \>50% measured by echocardiography or muga scan * concomitant corticosteroids and anti-convulsants for symptomatic brain metastases are allowed

Keywords: her-2 positive; brain metastases