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Published on: December 1, 2016
A phase I study of a 2-day lapatinib chemosensitization pulse preceding nanoparticle albumin-bound Paclitaxel for
Amy J Chien1, Julie A Illi, Andrew H Ko
1Department of Medicine, University of California San Francisco, San Francisco, California 94143-0875, USA.
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.
Insights
High-dose lapatinib pulses before nab-paclitaxel chemotherapy improved tumor vascular delivery in advanced cancer patients. This combination therapy showed promising response rates, especially in taxane-refractory cases.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Systemic chemotherapy has limited efficacy in advanced cancers due to poor tumor penetration.
- Preclinical studies suggest human epidermal growth factor receptor (HER) tyrosine kinase inhibitors (TKIs) can enhance chemotherapy delivery by priming tumor vasculature.
- This study aimed to evaluate the clinical applicability of this vascular-priming strategy.
Purpose of the Study:
- To assess the feasibility and tolerability of a novel combination regimen.
- To investigate the clinical relevance of vascular priming using HER TKI lapatinib before nab-paclitaxel chemotherapy.
- To determine the maximum tolerated dose (MTD) of lapatinib in this pulsed regimen.
Main Methods:
- A Phase I clinical trial involving escalating doses of lapatinib administered as a 2-day pulse prior to weekly nab-paclitaxel (100 mg/m(2)).
- Patient population included individuals with advanced solid tumors.
- Tumor vascular permeability was assessed using Dynamic Contrast Enhanced Magnetic Resonance Imaging (DCE-MRI).
Main Results:
- Twenty-five patients were enrolled; the MTD of lapatinib was determined to be 5250 mg/day.
- Common toxicities included diarrhea, nausea, and rash; dose-limiting toxicities were vomiting and neutropenia.
- DCE-MRI confirmed reduced tumor vascular permeability post-lapatinib pulse.
- A partial or stable response was observed in 65% of evaluable patients, with 72% being previously taxane-refractory.
Conclusions:
- A 2-day pulse of high-dose lapatinib followed by weekly nab-paclitaxel is a feasible and tolerable regimen.
- This approach supports the hypothesis of vascular-priming chemosensitization in a clinical setting.
- The regimen warrants further investigation in larger trials for advanced cancer patients.
