OT2-05-01: An Open-Label Positron Emission Tomography Study To Investigate and Quantify Brain and Tumor Penetration of Carbon-11-Labeled Lapatinib in Patients with HER2−Overexpressing Advanced or Metastatic Breast Cancer.

Abstract

Abstract Background: Patients with HER2−overexpressing (HER2+) breast cancer tend to develop visceral metastases. About a third will develop brain metastases in the course of their disease. Several anticancer agents including trastuzumab are not believed to readily cross the blood-brain barrier (BBB); therefore, central nervous system (CNS) disease progression is emerging as an important clinical problem in this patient population. Although preclinical data indicate that lapatinib brain concentrations are low in healthy animals, probably due to the BBB efflux transporters, observations from clinical studies suggest lapatinib treatment might be associated with reduced CNS tumor growth. One hypothesis is that disruption of the BBB by tumors circumvents the usual protective function of transporters. Alternatively, inhibition of efflux transporters by lapatinib enhances its own accumulation with repeat dosing. The role of lapatinib in prevention of brain metastases is currently being explored in a phase III trial, EGF 111438 (CEREBEL). Methods: To directly assess if lapatinib penetrates the brain and brain metastases, an open-label non-randomized study using carbon-11-labeled [11C] lapatinib is enrolling patients with HER2+ metastatic breast cancer. A minimum of 10 patients with an ECOG of <3 are grouped into 2 cohorts: with at least one 1-cm diameter brain metastasis or without brain metastases. Two positron emission tomography (PET) scans will be performed in each patient following intravenous administration of a microdose of [11C] lapatinib: in lapatinib-naïve patients and at steady-state lapatinib, after treatment with unlabelled oral lapatinib 1500 mg once daily for 8 days. [11C] lapatinib time-activity curves will be generated for normal brain and brain metastases, the PET volume of distribution in the brain calculated and penetration of [11C] lapatinib into the brain quantified. Analysis of brain PET data is explorative as [11C] lapatinib is a new tracer. Therefore, this study investigates both the difference in lapatinib brain penetration between patients with and without brain metastases, as well as the effect of low and high concentrations of lapatinib on the BBB efflux system. The study is currently recruiting in one center in the United Kingdom. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr OT2-05-01.