Phase I study of intermittent high dose lapatinib alternating with capecitabine for HER2-positive breast cancer patients with central nervous system metastases
Mené sur 11 patientes atteintes d'un cancer du sein HER2+ présentant des métastases au niveau du système nerveux central, cet essai de phase I évalue l'activité antitumorale, la dose maximale tolérée et la toxicité du lapatinib dispensé de façon intermittente et séquentielle avec la capécitabine
Purpose: Lapatinib and capecitabine cross the blood tumor-barrier in breast cancer brain metastasis but have modest clinical efficacy. Administration of high dose tyrosine kinase inhibitor (TKI) has been evaluated in brain metastases and primary brain tumors as a strategy to improve drug exposure in the central nervous system (CNS).We derived a rational drug scheduling of intermittent high dose lapatinib alternating with capecitabine-basedon our preclinical data and Norton-Simon mathematical modeling. We tested this intermittent, sequential drug schedule in breast cancer patients with CNS metastasis.
Experimental Design: We conducted a phase I trial using an accelerated dose escalation design in HER2-positive breast cancer patients with CNS metastasis. Lapatinib was given Day 1-3 and Day 15-17 with capecitabine on Day 8-14 and Day 22-28 on an every 28-day cycle. Lapatinib dose was escalated, and capecitabine given as a flat dose at 1500mg BID. Toxicity and efficacy were evaluated.
Results: Eleven patients were enrolled: brain only (four patients,36%), leptomeningeal, (five patients,45%), and intramedullary spinal cord (two patients,18%). Grade 3 nausea and vomiting were dose-limiting toxicities. The maximum tolerated dose of lapatinib was 1500mg BID. Three patients remained on therapy for greater than six months.
Conclusions:High dose lapatinib is tolerable when given intermittently and sequentially with capecitabine. Antitumor activity was noted in both CNS and non-CNS sites of disease. This novel administration regimen is feasible and efficacious in HER2-positive breast cancer patients with CNS metastasis and warrants further investigation.
Clinical Cancer Research , résumé, 2018