Summary
Purpose This study investigated the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetic (PK) profiles of DHP107, a novel oral paclitaxel containing neither Cremophor EL nor P-glycoprotein (P-gp) inhibitor. Patients and methods Patients with advanced solid tumors refractory to all standard treatments were administered a single oral dose of DHP107 on a dose-escalating schedule (60–600 mg/m2) during the first chemotherapy cycle, and intravenous paclitaxel 175 mg/m2 during subsequent cycles. Cohorts of 3 patients were treated at each dose level provided no DLTs were observed. The pharmacokinetics of paclitaxel and its metabolites were investigated for oral DHP107 and intravenous paclitaxel. Results Thirty-four patients were enrolled. Dose-limiting toxicities were not observed, even at the highest dose level (600 mg/m2). Further dose escalation was not performed because pharmacokinetics did not increase proportionally at doses above 250 mg/m2. The coefficient of variance of AUClast DHP107 ranged from 11.8 % to 34.0 %, comparable to 24.4 % of intravenous paclitaxel 175 mg/m2. There were no grade 4 toxicities, whereas grade 3 toxicities included diarrhea (12.1 %), neutropenia (6.1 %) and fatigue (3.0 %). While no objective responses were observed, 11 patients (33.3 %) showed stable disease. Conclusions DHP107 was safe and feasible in patients with advanced malignancies. As exposure of paclitaxel plateau among patients receiving more than 250 mg/m2 of DHP107, the dose escalation of DHP107 may be limited to 250 mg/m2 in further clinical trials.
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Acknowledgment
This study was supported by a grant from DAE HWA Pharmaceutical Co. and Gangwon Leading Industry Office by Korean government
Conflict of Interest
Hyeyoun Kim works for DAE HWA Pharmaceutical Co., Ltd. as a commissioner, and has a leadership position to disclose.
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Yong Sang Hong and Kyu-pyo Kim are equally contributed to this work.
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Hong, Y.S., Kim, Kp., Lim, HS. et al. A phase I study of DHP107, a mucoadhesive lipid form of oral paclitaxel, in patients with advanced solid tumors: Crossover comparisons with intravenous paclitaxel. Invest New Drugs 31, 616–622 (2013). https://doi.org/10.1007/s10637-012-9841-7
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DOI: https://doi.org/10.1007/s10637-012-9841-7