Polymeric nanoparticle-docetaxel for the treatment of advanced solid tumors: phase I clinical trial and preclinical data from an orthotopic pancreatic cancer model

Autor: Min Hyo Seo, Sa-Won Lee, Eun Kyung Choi, Jin Park, Jaesook Park, Kyu-Pyo Kim, Hye Kyung Chung, Joohee Jung, Seong-Yun Jeong, Si Yeol Song, Kyung Hae Jung, Jung-shin Lee
Rok vydání: 2016
Předmět:
Male
0301 basic medicine
Oncology
Polymers
efficacy
Drug Evaluation
Preclinical
Phases of clinical research
Docetaxel
Mice
0302 clinical medicine
Neoplasms
heterocyclic compounds
pancreas
Middle Aged
Tubulin Modulators
Tumor Burden
Treatment Outcome
030220 oncology & carcinogenesis
Female
Taxoids
Research Paper
medicine.drug
inorganic chemicals
Adult
medicine.medical_specialty
Maximum Tolerated Dose
Antineoplastic Agents
Neutropenia
03 medical and health sciences
Pharmacokinetics
Cell Line
Tumor
Internal medicine
Pancreatic cancer
medicine
Animals
Humans
Potency
Aged
Neoplasm Staging
Dose-Response Relationship
Drug
business.industry
phase I
medicine.disease
Polymeric nanoparticles
Xenograft Model Antitumor Assays
MTD
Pancreatic Neoplasms
enzymes and coenzymes (carbohydrates)
Disease Models
Animal
030104 developmental biology
Maximum tolerated dose
Nanoparticles
business
PNP-DTX
Zdroj: Oncotarget
ISSN: 1949-2553
DOI: 10.18632/oncotarget.12668
Popis: // Si Yeol Song 1, 3 , Kyu-pyo Kim 2 , Seong-Yun Jeong 3, 4 , Jin Park 3, 4 , Jaesook Park 3, 4 , Joohee Jung 5 , Hye Kyung Chung 6 , Sa-Won Lee 7 , Min Hyo Seo 7 , Jung-shin Lee 2, 3 , Kyung Hae Jung 2 , Eun Kyung Choi 1, 3 1 Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea 2 Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea 3 Institute for Innovative Cancer Research, Asan Medical Center, Seoul, Korea 4 Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea 5 College of Pharmacy, Duksung Women’s University, Seoul, Korea 6 Korea Institute of Radiological and Medical Sciences, National Project to Establish Platform to Develop The New Concept Therapy, Seoul, Korea 7 Department of Parenteral Delivery Program, Samyang Pharmaceuticals R&D, Daejeon, Korea Correspondence to: Eun Kyung Choi, email: ekchoi@amc.seoul.kr Kyung Hae Jung, email: khjung@amc.seoul.kr Keywords: PNP-DTX, phase I, MTD, efficacy, pancreas Received: March 27, 2016 Accepted: September 25, 2016 Published: October 14, 2016 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/m 2 escalated to 35 mg/m 2 , 45 mg/m 2 , 60 mg/m 2 and 75 mg/m 2 . 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/m 2 was tentatively determined as the MTD and the most common toxicity was grade 4 neutropenia not lasting over 7days. The C max of 60 mg/m 2 PNP-DTX and AUC last of 45 mg/m 2 PNP-DTX were measured to be comparable to those of 75 mg/m 2 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/m 2 was tentatively determined. The PNP-DTX of 45 mg/m 2 had the same pharmacokinetic profile with that of 75 mg/m 2 DTX.
Databáze: OpenAIRE
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