A Phase I Study of a 2-Day Lapatinib Chemosensitization Pulse Preceding Nanoparticle Albumin-Bound Paclitaxel for Advanced Solid Malignancies
Amy J. Chien1,6, Julie A. Illi6, Andrew H. Ko1,6, Wolfgang M. Korn1,6, Lawrence Fong1,6, Lee-may Chen2,6, Mohammed Kashani-Sabet3,6, Charles J. Ryan1,6, Jonathan E. Rosenberg1,6, Sarita Dubey1,6, Eric J. Small1,6, Thierry M. Jahan1,6, Nola M. Hylton4,6, Benjamin M. Yeh4,6, Yong Huang5, Kevin M. Koch7 and Mark M. Moasser1,6 Authors' Affiliations: Departments of 1 Medicine, 2 Obstetrics, Gynecology, and Reproductive Sciences, 3 Dermatology, 4 Radiology, 5 Biopharmaceutical Sciences, and 6 Helen Diller Comprehensive Cancer Center, University of California San Francisco, San Francisco, California and 7 Clinical Pharmacology Modeling and Simulation, GlaxoSmithKline, Research Triangle Park, North Carolina
Requests for reprints: Mark M. Moasser, Helen Diller Comprehensive Cancer Center, University of California, San Francisco, Box 0875, San Francisco, CA 94143-0875. Phone: 415-476-0158; Fax; 415-353-7692; E-mail: mmoasser@medicine.ucsf.edu.
Purpose: Systemic chemotherapy fails to access much of the tumor
burden in patients with advanced cancer, significantly limiting
its efficacy. In preclinical studies, brief high doses of tyrosine
kinase inhibitors (TKI) targeting the human epidermal growth
factor receptor (HER) family can prime tumor vasculature for
optimal chemotherapeutic delivery and efficacy. This study investigates
the clinical relevance of this approach.
Experimental Design: A phase I clinical study of escalating
doses of the HER TKI lapatinib given as a 2-day pulse before
a weekly infusion of nab-paclitaxel (100 mg/m
2) was conducted
in patients with advanced solid tumors.
Results: Twenty-five patients were treated. Treatment was associated
with grade 1 to 2 toxicities including diarrhea, nausea, rash,
neutropenia, neuropathy, fatigue, alopecia, and anemia. The
two dose-limiting toxicities were grade 3 vomiting and grade
4 neutropenia, and the maximum tolerated dose of lapatinib was
defined as 5250 mg/day in divided doses. Lapatinib concentrations
increased with increasing dose.
Dynamic Contrast Enhanced Magnetic Resonance Imaging studies in a subset of patients confirmed a decrease in tumor vascular permeability immediately following a lapatinib pulse.
Sixty-five percent of evaluable patients experienced a partial or stable response on this therapy, 72% of whom were previously taxane-refractory.
Conclusion: A 2-day pulse of high-dose lapatinib given before
weekly nab-paclitaxel is a feasible and tolerable clinical regimen,
suitable for testing this novel vascular-priming chemosensitization
hypothesis developed in preclinical models. (Clin Cancer Res
2009;15(17):5569–75)