Phase II Clinical Trial of Paclitaxel Loaded Polymeric Micelle in Patients with Advanced Pancreatic Cancer

Saif, Muhammad Wasif; Podoltsev, Nikolai A.; Rubin, Mark; Figueroa, José A.; Lee, Minyoung Y.; Kwon, Jin-Won; Rowen, Elin; Yu, Jae-Won; Kerr, Robert O.

doi:10.3109/07357900903179591

Cited by 77 publications

(40 citation statements)

References 26 publications

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“…Genexol-PM, a micellar formulation of paclitaxel consisting of polyethylene glycol-poly(D, L-lactic acid) (PEG-PLA) copolymer, is undergoing phases II and III clinical trials in patients with advanced cancers. Eliminating the use of Cremophor EL and ethanol in the formulation, paclitaxel-loaded PEG-PLA micelles can be administered to cancer patients at significantly higher doses and frequencies than the conventional paclitaxel formulation (Kim et al, 2004; Saif et al, 2010; Kim et al, 2007). Importantly, paclitaxel-loaded PEG-PLA micelles have been shown to elicit partial response in taxane-refractory patients, which most likely results from the elevated drug distribution into tumors (Kim et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Multi-drug delivery to tumor cells via micellar nanocarriers

Katragadda

Teng

Rayaprolu

et al. 2011

International Journal of Pharmaceutics

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The aim of this study was to develop micellar nanocarriers for concomitant delivery of paclitaxel and 17-allylamino-17-demethoxygeldanamycin (17-AAG) for cancer therapy. Paclitaxel and 17-AAG were simultaneously loaded into polymeric micelles by a solvent evaporation method. Two candidate nanocarrier constructs, polyethylene glycol-poly(D, L-lactic acid) (PEG-PLA) micelles and PEG-distearoylphosphatidylethanolamine/tocopheryl polyethylene glycol 1000 (PEG-DSPE/TPGS) mixed micelles, were assessed for the release kinetics of the loaded drugs. Compared to PEG-PLA micelles, entrapment of paclitaxel and 17-AAG into PEG-DSPE/TPGS mixed micelles resulted in significantly prolonged release half-lives. The simultaneous incorporation of paclitaxel and 17-AAG into PEG-DSPE/TPGS mixed micelles was confirmed by 1H NMR analysis. Paclitaxel/17-AAG-loaded PEG-DSPE/TPGS mixed micelles were as effective in blocking the proliferation of human ovarian cancer SKOV-3 cells as the combined free drugs. PEG-DSPE/TPGS mixed micelles may provide a novel and advantageous delivery approach for paclitaxel/17-AAG combination therapy.

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Section: Introductionmentioning

confidence: 99%

Multi-drug delivery to tumor cells via micellar nanocarriers

Katragadda

Teng

Rayaprolu

et al. 2011

International Journal of Pharmaceutics

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“…However, during the study, a prophylaxis for hypersensitivity was routinely recommended, typically hydrocortisone, antihistamine, or an H2 blocker. In addition, several phase II clinical trials conducted in Korea and the US indicated that Genexol-PM was generally well tolerated, and it showed sufficient antitumor activity in patients with metastatic breast cancer, urothelial carcinoma, and progressive pancreatic cancer [132223]. …”

Section: Discussionmentioning

confidence: 99%

An open-label, multicenter, phase I trial of a cremophor-free, polymeric micelle formulation of paclitaxel combined with carboplatin as a first-line treatment for advanced ovarian cancer: a Korean Gynecologic Oncology Group study (KGOG-3016)

Lee

Kim

et al. 2017

J Gynecol Oncol

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ObjectiveThis phase I study aimed to determine the maximum tolerated dose (MTD) of Genexol-PM, when combined with carboplatin, as a first-line treatment in patients with advanced ovarian cancer.MethodsThis open-label, multicenter, phase I, dose-escalation study included 18 patients (median age: 59.0 years, range: 40–75 years) diagnosed with advanced epithelial ovarian cancer. All patients had measurable residual disease after debulking surgery. Patients were assigned to groups (n=6 each group) that received different doses of Genexol-PM (220, 260, and 300 mg/m2, once every 3 weeks) and 5 area under the curve (AUC) carboplatin. Safety and efficacy were analyzed for each dose group.ResultsIn this intention-to-treat population, 3 out of 18 patients dropped out of the study: 1 due to dose-limiting toxicity (DLT), 1 due to hypersensitivity, and 1 was lost during follow-up. DLTs were not reported at 220 mg/m2 or 260 mg/m2, but at 300 mg/m2, 1 patient experienced DLT (grade 3 general pain). The MTD of Genexol-PM was not determined, but a dose of 300 mg/m2 or less could be recommended for the phase II study. Most patients (73.9%) with adverse events recovered without sequelae, and no death occurred that was related to the disease or treatment. The best overall response rate was 94.1%.ConclusionGenexol-PM combined with carboplatin was well tolerated as a first-line treatment, and good responses were observed in patients with advanced ovarian cancer. Based on these results, we recommended a dose of 300 mg/m2 or less for a phase II study.

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“…Despite advantageous properties and excellent preclinical results, only a few polymeric micelles have progressed to clinical trials and only one type of micelles reached the market [19][20][21]. In clinical trials, micellar formulations of doxorubicin (DOX) manifested the same spectrum of side effects as free DOX suggesting a lack of effective tumor targeting [22].…”

Section: Accepted Manuscriptmentioning

confidence: 98%

“…For micellar encapsulated paclitaxel (PTX), a rapid loss of drug from micellar carriers was observed. Despite unfavorable pharmacokinetic parameters [17], the PXT-loaded poly(ethylene oxide)-copoly(D,L-lactide) (PEO 2000 -co-PDLA 1750 ) micelles (Genexol ® -PM) showed promising therapeutic results for breast, lung, and pancreatic cancer in clinical trials [19][20][21].…”

Section: Accepted Manuscriptmentioning

confidence: 99%