title: Polymeric nanoparticle-docetaxel for the treatment of advanced solid tumors: phase I clinical trial and preclinical data from an orthotopic pancreatic cancer model.
abstract: We assessed the efficacy of the polymeric nanoparticle containing docetaxel (PNP-DTX) in preclinical mouse models and determined the maximum tolerated dose (MTD) through clinical study. Subcutaneous and orthotopic mouse models were dedicated. Tumor growth delay in orthotopic model and quantification of in vivo imaging in orthotopic model were evaluated. Phase I clinical study was a single-center, prospective, open-label trial in advanced solid tumors. PNP-DTX was injected intravenously and the starting dose was 20 mg/m2 escalated to 35 mg/m2, 45 mg/m2, 60 mg/m2 and 75 mg/m2. Pharmacokinetics, tumor response, toxicities were evaluated. Preclinical result revealed the more potent cytotoxic effect of PNP-DTX than docetaxel (DTX). However, there was no difference between PNP-DTX and DTX in subcutaneous model. Tubulin polymerization assay showed that PNP-DTX preserved original mode of action of DTX. For phase I clinical trial, 18 patients were analyzed. The dose of 75 mg/m2 was tentatively determined as the MTD and the most common toxicity was grade 4 neutropenia not lasting over 7days. The Cmax of 60 mg/m2 PNP-DTX and AUClast of 45 mg/m2 PNP-DTX were measured to be comparable to those of 75 mg/m2 DTX. Partial remission (PR) was achieved in 4 (22%) patients. The potency of PNP-DTX was revealed especially in orthotopic mouse model. The MTD of PNP-DTX could not be confirmed, but 75 mg/m2 was tentatively determined. The PNP-DTX of 45 mg/m2 had the same pharmacokinetic profile with that of 75 mg/m2 DTX.
authors.affiliation: Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.|Institute for Innovative Cancer Research, Asan Medical Center, Seoul, Korea.
authors.forename: Si Yeol
authors.initials: SY
authors.lastname: Song
authors.affiliation: Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Kyu-Pyo
authors.initials: KP
authors.lastname: Kim
authors.affiliation: Institute for Innovative Cancer Research, Asan Medical Center, Seoul, Korea.|Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Seong-Yun
authors.initials: SY
authors.lastname: Jeong
authors.affiliation: Institute for Innovative Cancer Research, Asan Medical Center, Seoul, Korea.|Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Jin
authors.initials: J
authors.lastname: Park
authors.affiliation: Institute for Innovative Cancer Research, Asan Medical Center, Seoul, Korea.|Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Jaesook
authors.initials: J
authors.lastname: Park
authors.affiliation: College of Pharmacy, Duksung Women's University, Seoul, Korea.
authors.forename: Joohee
authors.initials: J
authors.lastname: Jung
authors.affiliation: Korea Institute of Radiological and Medical Sciences, National Project to Establish Platform to Develop The New Concept Therapy, Seoul, Korea.
authors.forename: Hye Kyung
authors.initials: HK
authors.lastname: Chung
authors.affiliation: Department of Parenteral Delivery Program, Samyang Pharmaceuticals R&D, Daejeon, Korea.
authors.forename: Sa-Won
authors.initials: SW
authors.lastname: Lee
authors.affiliation: Department of Parenteral Delivery Program, Samyang Pharmaceuticals R&D, Daejeon, Korea.
authors.forename: Min Hyo
authors.initials: MH
authors.lastname: Seo
authors.affiliation: Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.|Institute for Innovative Cancer Research, Asan Medical Center, Seoul, Korea.
authors.forename: Jung-Shin
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Kyung Hae
authors.initials: KH
authors.lastname: Jung
authors.affiliation: Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.|Institute for Innovative Cancer Research, Asan Medical Center, Seoul, Korea.
authors.forename: Eun Kyung
authors.initials: EK
authors.lastname: Choi
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D051379:Mice; D008875:Middle Aged; D053758:Nanoparticles; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000473:pathology; D011108:Polymers; D043823:Taxoids / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D016896:Treatment Outcome; D050257:Tubulin Modulators / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D011108:Polymers; D043823:Taxoids; D050257:Tubulin Modulators; D000077143:Docetaxel
keywords: MTD; PNP-DTX; efficacy; pancreas; phase I