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

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