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

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) 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) One of the significant barriers to the highly effective treatment of patients with metastatic cancer is the failure of chemotherapeutic agents to efficiently reach all the tumor cells and produce their cytotoxic effects on a significant fraction of the whole tumor burden. The lack of access to much of the disease is due to highly abnormal tumor vasculature, characterized by high permeability and very poor architecture resulting in tissue hypertension, hypoxia, acidosis, and absence of osmotic gradients resulting in poor exchange of nutrients and drugs (1). One of the principal challenges in clinical cancer research is to understand the mechanisms underlying this therapeutic barrier and develop adjunctive therapies to overcome it. Measurable progress has been made with therapies that target the vascular endothelial growth factor (VEGF) signaling pathway. The effects of this class of agents on tumor vasculature have been mechanistically defined in preclinical models (2, 3) and their ability to enhance chemotherapeutic efficacy validated in a number of clinical studies (4–6). A role for other vascular targets remains to be defined. The human epidermal growth factor receptor (HER) family of receptor tyrosine kinases are important drivers of tumor endothelial signaling, in particular phosphoinositide 3-kinase/Akt pathway activation (7–10). Upstream signals that activate HER family signaling in tumor endothelial cells include paracrine signaling (11, 12), autocrine signaling (13), and cross-talk from G-protein–coupled receptor activation (14). In preclinical Authors' Affiliations: Departments of Medicine, Obstetrics,Gynecology, and Reproductive Sciences, Dermatology, Radiology, Biopharmaceutical Sciences, and Helen Diller Comprehensive Cancer Center, University of California SanFrancisco, SanFrancisco, California and Clinical PharmacologyModeling and Simulation, GlaxoSmithKline, Research Triangle Park, North Carolina Received 2/27/09; revised 6/25/09; accepted 7/18/09; published OnlineFirst 8/25/09. Grant support: University of California at San Francisco Hellen Diller ComprehensiveCancerCenter,Atwater Foundation.A.J.Chien is supportedbyanAmerican Society of Clinical Oncology Young Investigator Award and an American Cancer Society postdoctoral fellowship. M.M.Moasser is supported by the NIH. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Requests for reprints: Mark M. Moasser, Helen Diller Comprehensive CancerCenter,UniversityofCalifornia, SanFrancisco,Box0875,SanFrancisco, CA 94143-0875. Phone: 415-476-0158; Fax; 415-353-7692; E-mail: mmoasser@ medicine.ucsf.edu. F 2009 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-09-0522 5569 Clin Cancer Res 2009;15(17) September 1, 2009 www.aacrjournals.org Research. on May 3, 2017. © 2009 American Association for Cancer clincancerres.aacrjournals.org Downloaded from Published OnlineFirst August 25, 2009; DOI: 10.1158/1078-0432.CCR-09-0522