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

Abstract

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)

Off-Target Lapatinib Activity Sensitizes Colon Cancer Cells Through TRAIL Death Receptor Up-Regulation

“…animals survived treatment, and hus, two consecutive daily treatments with high dose lapatinib was a tolerable regimen in our preclinical model. A recent phase clinical trial (25) demonstrated the safety of 2 pulse of dose lapatinib prior to administration of albumin-bound paclitaxel in solid malignancies, further supporting the clinical utility of the treatment paradigm we used in this study.…”

Biodistribution and acute toxicity of naked gold nanoparticles in a rabbit hepatic tumor model

“…These nanoparticles are typically on the order of tens of nanometers to hundreds of micrometers in size (Ibrahim, Desai et al 2002; Wust, Gneveckow et al 2006; Curley, Cherukuri et al 2008; Chien, Illi et al 2009). Of the many forms of nanoparticles, some of the most clinically useful appear to be solid gold nanoparticles (AuNP) because of the presumed but yet unproven safety, the relatively simple and well described chemical reactions with gold, and relative ease of making defined sizes of these nanoparticles (Cherukuri, Glazer et al 2009).…”

Lapatinib Induced Suicidal Death of Human Erythrocytes

“…The concentrations required for those effects are well in the range of lapatinib concentrations determined in patients [61]. Thus, the observed effect of lapatinib on eryptosis may well contribute to or even account for its effect on anemia, a major side effect of the drug [9,11,25,26,61,62]. The sensitivity to lapatinib may be enhanced by clinical conditions known to enhance the susceptibility to triggers of eryptosis, such as dehydration [68], hyperphosphatemia [69], chronic kidney disease (CKD) [70][71][72][73], hemolytic-uremic syndrome [74], diabetes [75], hepatic failure [76], malignancy [63], sepsis [77], sickle-cell disease [63], beta-thalassemia [63], Hb-C and G6PD-deficiency [63], as well as Wilsons disease [78].…”

“…Lapatinib, an inhibitor of human epidermal growth factor receptor (HER) tyrosine kinases [1][2][3][4][5][6][7], is utilized in the treatment of malignancy [1,[8][9][10][11][12], such as breast cancer [2][3][4][5][6][7]. The drug is at least partially effective by triggering suicidal death or apoptosis of tumor cells [46][47][48][49][50][51][52][53][54][55][56][57].…”

“…On the other hand, lapatinib could counteract apoptosis induced by excessive glucose concentrations [58]. Side effects of lapatinib include skin rash, hand foot skin reaction and pruritus [8,9,11,16,23,25,26,30,59], alopecia [9,23], leukopenia [9,16,25,30], diarrhea, nausea and vomiting [9,11,16,23,25,26,30,38,59,60], fatigue [11,23,30], peripheral neuropathy [9,30], and anemia [9,11,25,26,61,62].…”