lapatinib before NAB Paclitaxel for advanced malignancies
 

A Phase I Study of a 2-Day Lapatinib Chemosensitization Pulse Preceding Nanoparticle Albumin-Bound Paclitaxel for Advanced Solid Malignancies

<nobr>Amy J. Chien¹^,6</nobr>, <nobr>Julie A. Illi⁶</nobr>, <nobr>Andrew H. Ko¹^,6</nobr>, <nobr>Wolfgang M. Korn¹^,6</nobr>, <nobr>Lawrence Fong¹^,6</nobr>, <nobr>Lee-may Chen²^,6</nobr>, <nobr>Mohammed Kashani-Sabet³^,6</nobr>, <nobr>Charles J. Ryan¹^,6</nobr>, <nobr>Jonathan E. Rosenberg¹^,6</nobr>, <nobr>Sarita Dubey¹^,6</nobr>, <nobr>Eric J. Small¹^,6</nobr>, <nobr>Thierry M. Jahan¹^,6</nobr>, <nobr>Nola M. Hylton⁴^,6</nobr>, <nobr>Benjamin M. Yeh⁴^,6</nobr>, <nobr>Yong Huang⁵</nobr>, <nobr>Kevin M. Koch⁷</nobr> and <nobr>Mark M. Moasser¹^,6</nobr> 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<script type="text/javascript"><!-- var u = "mmoasser", d = "medicine.ucsf.edu"; document.getElementById("em0").innerHTML = '<a href="mailto:' + u + '@' + d + '">' + u + '@' + d + '<\/a>'//--></script>.
<!-- ABS --> Purpose: Systemic chemotherapy fails to access much of the tumorburden in patients with advanced cancer, significantly limitingits efficacy. In preclinical studies, brief high doses of tyrosinekinase inhibitors (TKI) targeting the human epidermal growthfactor receptor (HER) family can prime tumor vasculature foroptimal chemotherapeutic delivery and efficacy. This study investigatesthe clinical relevance of this approach.
Experimental Design: A phase I clinical study of escalatingdoses of the HER TKI lapatinib given as a 2-day pulse beforea weekly infusion of nab-paclitaxel (100 mg/m²) was conductedin patients with advanced solid tumors.
Results: Twenty-five patients were treated. Treatment was associatedwith grade 1 to 2 toxicities including diarrhea, nausea, rash,neutropenia, neuropathy, fatigue, alopecia, and anemia. Thetwo dose-limiting toxicities were grade 3 vomiting and grade4 neutropenia, and the maximum tolerated dose of lapatinib wasdefined as 5250 mg/day in divided doses. Lapatinib concentrationsincreased with increasing dose. Dynamic Contrast Enhanced MagneticResonance Imaging studies in a subset of patients confirmeda decrease in tumor vascular permeability immediately followinga lapatinib pulse. Sixty-five percent of evaluable patientsexperienced 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 beforeweekly nab-paclitaxel is a feasible and tolerable clinical regimen,suitable for testing this novel vascular-priming chemosensitizationhypothesis developed in preclinical models. (Clin Cancer Res2009;15(17):5569–75)