Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Investigational New Drugs
Published in: Investigational New Drugs 2/2018

01-04-2018 | PHASE I STUDIES

Phase I dose escalation and pharmacokinetic study on the nanoparticle formulation of polymeric micellar paclitaxel for injection in patients with advanced solid malignancies

Authors: Meiqi Shi, Jing Sun, Jinsong Zhou, Hao Yu, Shaorong Yu, Guohao Xia, Li Wang, Yue Teng, Gangyi Liu, Chen Yu, Jifeng Feng, Yaling Shen

Published in: Investigational New Drugs | Issue 2/2018

Login to get access

Summary

Background Polymeric micellar paclitaxel (PM-paclitaxel) is a novel Cremophor EL-free, nanoparticle-encapsulated paclitaxel formulation administered through intravenous injection. The primary objective of this phase I trial was to determine the first cycle dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of PM-paclitaxel. Secondary objectives included the evaluation of the safety, antitumor activity, and pharmacokinetic (PK) profile of PM-paclitaxel in patients with advanced malignancies. Methods The PM-paclitaxel dose was escalated from 175 mg/m2 (level 1) to 435 mg/m2 (level 5). PM-paclitaxel was intravenously administered to patients for 3 h without premedication on day 1 of a 21-day cycle. Results Eighteen patients with confirmed advanced malignancies received PM-paclitaxel. DLT included grade 4 neutropenia (four patients) and grade 3 numbness (one patient), which occurred in one of the six patients who received 300 mg/m2 (level 3) PM-paclitaxel and all three patients who were treated with 435 mg/m2 PM-paclitaxel. Thus, the MTD of PM-paclitaxel was determined as 390 mg/m2 (level 4). Acute hypersensitive reactions were not observed. Partial response was observed in six of 18 patients (33.3%), three of whom had prior exposure to paclitaxel chemotherapy. The peak concentration and area under the curve values of paclitaxel increased with increasing dosage, indicating that PM-paclitaxel exhibits linear PKs. Conclusions PM-paclitaxel showed high MTD without additional toxicity, and exhibited desirable antitumor activity. The recommended dose of PM paclitaxel for phase II study is 300 mg/m2.
Literature
1.
2.
Gelderblom H, Verweij J, Nooter K, Sparreboom A (2001) Cremophor EL: the drawbacks and advantages of vehicle selection for drug formulation. Eur J Cancer 37:1590–1598CrossRefPubMed
3.
Szebeni J, Alving CR, Savay S, Barenholz Y, Priev A, Danino D et al (2001) Formation of complement-activating particles in aqueous solutions of Taxol: possible role in hypersensitivity reactions. Int Immunopharmacol 1:721–735CrossRefPubMed
4.
Liebmann J, Cook JA, Lipschultz C, Teague D, Fisher J, Mitchell JB (1994) The influence of Cremophor EL on the cell cycle effects of paclitaxel (Taxol) in human tumor cell lines. Cancer Chemother Pharmacol 33:331–339CrossRefPubMed
5.
Nannan Panday VR, Huizing MT, Ten Bokkel Huinink WW, Vermorken JB, Beijnen JH (1997) Hypersensitivity reactions to the taxanes paclitaxel and docetaxel. Clin Drug Invest 14:418–427CrossRef
6.
Sparreboom A, van Zuylen L, Brouwer E, Loos WJ, de Bruijn P, Gelderblom H et al (1999) Cremophor EL-mediated alteration of paclitaxel distribution in human blood: clinical pharmacokinetic implications. Cancer Res 59:1457–1467
7.
Henningsson A, Karlsson MO, Vigano L, Gianni L, Verweij J, Sparreboom A (2001) Mechanism-based pharmacokinetic model for paclitaxel. J Clin Oncol 19:4065–4073CrossRefPubMed
8.
Nuijen B, Bouma M, Schellens JH, Beijnen JH (2001) Progress in the development of alternative pharmaceutical formulations of taxanes. Investig New Drugs 19:143–153CrossRef
9.
Oerlemans C, Bult W, Bos M, Storm JG, Nijsen FWJ, Hennink WE (2010) Polymeric micelles in anticancer therapy: targeting, imaging and triggered release. Pharm Res 27:2569–2589CrossRefPubMedPubMedCentral
10.
11.
Straubinger RM, Arrmold RD, Zhou R, Mazurchuk R, Slack JE (2004) Antivascular and antitumor activities of liposome-associated drugs. Anticancer Res 24:397–404PubMed
12.
Ibrahim NK, Desai N, Legha S, Soon-Shiong P, Theriault RL, Rivera E et al (2002) Phase I and pharmacokinetic study of ABI-007, a Cremophor-free, protein-stabilized, nanoparticle formulation of paclitaxel. Clin Cancer Res 8:1038–1044PubMed
13.
Socinski MA, Bondarenko I, Karaseva NA, Makhson AM, Vynnychenko I, Okamoto I et al (2012) Weekly nab-paclitaxel in combination with carboplatin versus solvent-based paclitaxel plus carboplatin as first-line therapy in patients with advanced non-small-cell lung cancer: final results of a phase III trial. J Clin Oncol 30:2055–2062CrossRefPubMed
14.
Gupta N, Hatoum H, Dy GK (2014) First line treatment of advanced non-small-cell lung cancer – specific focus on albumin bound paclitaxel. Int J Nanomedicine 9:209–921PubMed
15.
Lee KS, Chung HC, Im SA, Park YH, Kim CS, Kim SB et al (2008) Multicenter phase II trial of Genexol-PM, a Cremophor-free, polymeric micelle-formulated paclitaxel, in patients with metastatic breast cancer. Breast Cancer Res Treat 108:241–250CrossRefPubMed
16.
Kim DW, Kim SY, Kim SW, Shin SW, Shin SW, Kim JS et al (2007) Multicenter phase II trial of Genexol-PM, a novel Cremophor-free, polymeric micelle-formulated paclitaxel, with cisplatin in patients with advanced non-small-cell lung cancer. Ann Oncol 18:2009–2014CrossRefPubMed
17.
Kim TY, Kim DW, Chung JY, Shin SG, Kim SC, Heo DS et al (2004) Phase I and pharmacokinetic study of Genexol-PM, a Cremophor-free, polymeric micelle-formulated paclitaxel, in patients with advanced malignancies. Clin Cancer Res 10:3706–3716
18.
Zhang Q, Huang X, Gao L (2009) A clinical study on the premedication of paclitaxel liposome in the treatment of solid tumors. Biomed Pharmacother 63:603–607CrossRefPubMed
19.
Xu X, Wang L, Xu HQ, Huang XE, Qian YD, Xiang J (2013) Clinical comparison between paclitaxel liposome (Lipusu®) and paclitaxel for treatment of patients with metastic gastric cancer. Asian Pac J Cancer P 14:2591–2594CrossRef
20.
Zhou GL, Han B, Song YS, Sun J, Zhou JS, Jiang XG et al (2014) Anti-tumor effects of paclitaxel micelle for injection in vivo. Chin J of New Drugs Clin Rem 33:582–587
21.
Han B, Liu X, Sun J, Zhou GL, Zhang LL, You ZQ et al (2011) Tissue distribution of paclitaxel micelle and paclitaxel injection in tumor-bearing mice. Chin J of New Drugs Clin Rem 30:603–608
22.
Mao XY, Zhang MX, Zhou QY, Dong CX, Shen WW, Liu GY, Jia JY et al (2015) A pharmacokinetic study of paclitaxel- loaded micelle in patients with advanced solid carcinoma by LC-MS/MS. Chin J of New Drugs Clin Rem 34:869–873
23.
Gianni L, Kearns CM, Giani A, Capri G, Vigano L, Locatelli A et al (1995) Nonlinear pharmacokinetics and metabolism of paclitaxel and its pharmacokinetic/ pharmacodynamics relationships in humans. J Clin Oncol 13:180–190CrossRefPubMed
24.
Ohtsu T, Sasaki Y, Tamura T, Miyata Y, Nakanomyo H, Nishiwaki Y et al (1995) Clinical pharmacokinetics and pharmacodynamics of paclitaxel: a 3-hour infusion versus a 24-hour infusion. Clin Cancer Res 6:599–606
Metadata
Title
Phase I dose escalation and pharmacokinetic study on the nanoparticle formulation of polymeric micellar paclitaxel for injection in patients with advanced solid malignancies
Authors
Meiqi Shi
Jing Sun
Jinsong Zhou
Hao Yu
Shaorong Yu
Guohao Xia
Li Wang
Yue Teng
Gangyi Liu
Chen Yu
Jifeng Feng
Yaling Shen
Publication date
01-04-2018
Publisher
Springer US
Published in
Investigational New Drugs / Issue 2/2018
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI
https://doi.org/10.1007/s10637-017-0506-4

Other articles of this Issue 2/2018

Investigational New Drugs 2/2018 Go to the issue

PHASE III STUDIES

Phase III study of dulanermin (recombinant human tumor necrosis factor-related apoptosis-inducing ligand/Apo2 ligand) combined with vinorelbine and cisplatin in patients with advanced non-small-cell lung cancer

PHASE II STUDIES

A phase IIa study of HA-irinotecan, formulation of hyaluronic acid and irinotecan targeting CD44 in extensive-stage small cell lung cancer

SHORT REPORT

Characteristics of patients with sorafenib-treated advanced hepatocellular carcinoma eligible for second-line treatment

SHORT REPORT

Gastrointestinal perforation related to lenvatinib, an anti-angiogenic inhibitor that targets multiple receptor tyrosine kinases, in a patient with metastatic thyroid cancer

PRECLINICAL STUDIES

Systematic analysis reveals a lncRNA-mRNA co-expression network associated with platinum resistance in high-grade serous ovarian cancer

PHASE I STUDIES

Effect of alisertib, an investigational aurora a kinase inhibitor on the QTc interval in patients with advanced malignancies
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits