Phase I study of intermittent high-dose lapatinib alternating with capecitabine for HER2-positive breast cancer patients with central nervous system metastases Journal Article
| Authors: | Morikawa, A.; de Stanchina, E.; Pentsova, E.; Kemeny, M. M.; Li, B. T.; Tang, K.; Patil, S.; Fleisher, M.; Van Poznak, C.; Norton, L.; Seidman, A. D. |
| Article Title: | Phase I study of intermittent high-dose lapatinib alternating with capecitabine for HER2-positive breast cancer patients with central nervous system metastases |
| Abstract: | 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 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 based on our preclinical data and Norton-Simon mathematical modeling. We tested this intermittent, sequential drug schedule in patients with breast cancer with CNS metastasis. Patients and Methods: We conducted a phase I trial using an accelerated dose escalation design in patients with HER2- positive (HER2+) breast cancer with CNS metastasis. Lapatinib was given on 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 1,500 mg BID. Toxicity and efficacy were evaluated. Results: Eleven patients were enrolled: brain only (4 patients, 36%), leptomeningeal (5 patients, 45%), and intramedullary spinal cord (2 patients, 18%). Grade 3 nausea and vomiting were dose-limiting toxicities. The MTD of lapatinib was 1,500 mg BID. Three patients remained on therapy for greater than 6 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 patients with HER2+ breast cancer with CNS metastasis and warrants further investigation. © 2019 American Association for Cancer Research. |
| Journal Title: | Clinical Cancer Research |
| Volume: | 25 |
| Issue: | 13 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2019-07-01 |
| Start Page: | 3784 |
| End Page: | 3792 |
| Language: | English |
| DOI: | 10.1158/1078-0432.Ccr-18-3502 |
| PUBMED: | 30988080 |
| PROVIDER: | scopus |
| PMCID: | PMC6773251 |
| DOI/URL: | |
| Notes: | Source: Scopus |
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