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.

Figures

Figure 1

Incidence of diarrhea in relation to lapatinib dose

Figure 2

Lapatinib and paclitaxel pharmacokinetic studies A) 48 hour lapatinib plasma concentrations in individual patients (red dots). Historical data from previous lapatinib studies employing twice daily, continuous dosing (blue dots). B) Plasma paclitaxel concentrations with or without a preceding two day lapatinib 5250 mg/day pulse (n = 3 patients).

Figure 2

Lapatinib and paclitaxel pharmacokinetic studies A) 48 hour lapatinib plasma concentrations in individual patients (red dots). Historical data from previous lapatinib studies employing twice daily, continuous dosing (blue dots). B) Plasma paclitaxel concentrations with or without a preceding two day lapatinib 5250 mg/day pulse (n = 3 patients).

Figure 3

DCE-MRI studies A) Tumor vascular permeability (Ktrans) values in individual patients. Scans 1 and 2 were pre- and post- first lapatinib pulse (baseline and day 3 of first cycle), respectively. Scans 3 and 4 were pre- and post- third lapatinib pulse (days 15 and 17 of first cycle), respectively. B) Tumor vascular perfusion volume (Vp) values in individual patients.

Figure 3

DCE-MRI studies A) Tumor vascular permeability (Ktrans) values in individual patients. Scans 1 and 2 were pre- and post- first lapatinib pulse (baseline and day 3 of first cycle), respectively. Scans 3 and 4 were pre- and post- third lapatinib pulse (days 15 and 17 of first cycle), respectively. B) Tumor vascular perfusion volume (Vp) values in individual patients.