Phase II study of liposomal doxorubicin in refractory ovarian cancer: antitumor activity and toxicity modification by liposomal encapsulation.

Fm, Muggia; Hainsworth, John D.; Jeffers, Susan; Pj, Miller; Groshen, Susan; Tan, Matthew; Roman, L. A.; Uziely, Beatrice; Muderspach, Laila I.; Garcia, Agustin; Burnett, Alexander; Greco, Filippo; Morrow, C. Paul; Paradiso, Linda J.; Liang, Leyi

doi:10.1200/jco.1997.15.3.987

Cited by 590 publications

(281 citation statements)

References 16 publications

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“…Mucositis was also rare and mild. No infusionrelated reactions, which are sometimes seen in cases of liposomal drug administration (Uziely et al, 1995;Muggia et al, 1996;Stewart et al, 1998;Gordon et al, 2001), occurred in this trial. Ultimately, this phase I study showed that the recommended dosage of NK911 (50 mg m À2 ) using a 3-week schedule was similar to the recommended dosage of free DXR (40 -60 mg m À2 ).…”

Section: Discussionmentioning

confidence: 66%

“…Doxil is comprised of doxorubicin (DXR) encapsulated in STEALTHt liposomes, which are composed of a phospholipid bilayer with surface-bound methoxypolyethyleneglycol. Doxil recently received the US Food and Drug Administration's (FDA) approval for use in the treatment of Kaposi sarcoma or ovarian cancer after the clinical benefits of this drug were clearly shown in recent clinical trials (Muggia et al, 1996;Stewart et al, 1998;Gordon et al, 2001).…”

mentioning

confidence: 99%

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Phase I clinical trial and pharmacokinetic evaluation of NK911, a micelle-encapsulated doxorubicin

Matsumura

Hamaguchi²,

Umemura³

et al. 2004

Br J Cancer

579

283

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NK911 is a novel supramolecular nanocarrier designed for the enhanced delivery of doxorubicin (DXR) and is one of the successful polymer micelle systems to exhibit an efficient accumulation in solid tumours in mice. The purpose of this study was to define the maximum-tolerated dose (MTD) and dose-limiting toxicities (DLTs) of NK911 and to evaluate its pharmacokinetic profile in man. NK911 was given intravenously to patients with solid tumours every 3 weeks using an infusion pump at a rate of 10 mg DXR equivalent min À1 . The starting dose was 6 mg DXR equivalent m À2 , and the dose was escalated according to the accelerated titration method. A total of 23 patients participated in this study. Neutropenia was the predominant haematological toxicity, and grade 3 or 4 neutropenia was observed at doses of 50 and 67 mg m À2 . Common nonhaematological toxicities were mild alopecia, stomatitis, and anorexia. In the dose identification part of the study, DLTs were observed at a dose of 67 mg m À2 (grade 4 neutropenia lasting more than 5 days). Thus, this dosage level was determined to be the MTD. Infusion-related reactions were not observed in any cases. The C 5 min and area under the concentration curve parameters of NK911 exhibited dose-dependent characteristics. Among the 23 patients, a partial response was obtained in one patient with metastatic pancreatic cancer. NK911 was well tolerated and produced only moderate nausea and vomiting at myelosuppressive dosages. The recommended phase II dose was determined to be 50 mg m À2 every 3 weeks.

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Section: Discussionmentioning

confidence: 66%

mentioning

confidence: 99%

Phase I clinical trial and pharmacokinetic evaluation of NK911, a micelle-encapsulated doxorubicin

Matsumura

Hamaguchi²,

Umemura³

et al. 2004

Br J Cancer

579

283

View full text Add to dashboard Cite

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“…Liposomal drug delivery systems with doxorubicin have been extensively investigated in relapsed ovarian cancer (Muggia et al, 1997), breast cancer (Ranson et al, 1997) and others (Law et al, 1994;Schwartz and Caspar, 1995;Ellerhorst et al, 1999;Harrington et al, 2001;Judson et al, 2001). A number of trials have been performed with polymer -doxorubicin conjugate where there is covalent linkage of polymer to doxorubicin.…”

Section: Discussionmentioning

confidence: 99%

Phase I dose escalation and pharmacokinetic study of pluronic polymer-bound doxorubicin (SP1049C) in patients with advanced cancer

et al. 2004

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SP1049C is a novel anticancer agent containing doxorubicin and two nonionic pluronic block copolymers. In preclinical studies, SP1049C demonstrated increased efficacy compared to doxorubicin. The objectives of this first phase I study were to determine the toxicity profile, dose-limiting toxicity, maximum tolerated dose and pharmacokinetic profile of SP1049C, and to document any antitumour activity. The starting dose was 5 mg m À2 (doxorubicin content) as an intravenous infusion once every 3 weeks for up to six cycles. A total of 26 patients received 78 courses at seven dose levels. The dose-limiting toxicity was myelosuppression and DLT was reached at 90 mg m À2 . The maximum tolerated dose was 70 mg m À2 and is recommended for future trials. The pharmacokinetic profile of SP1049C showed a slower clearance than has been reported for conventional doxorubicin. Evidence of antitumour activity was seen in some patients with advanced resistant solid tumours. Phase II trials with this agent are now warranted to further define its antitumour activity and safety profile.

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“…Recent successes in this area of clinical research include the efficacy of liposomal doxorubicin in AIDS-related Kaposi's sarcoma and patients with refractory ovarian cancer (Muggia et al, 1997;Northfelt et al, 1997). Although the precise mechanisms by which liposomes selectively enter tumours and release drug are not completely understood, their successful application with doxorubicin has led to a resurgence of interest in this area.…”

Section: Discussionmentioning

confidence: 99%

“…Using this approach it is feasible that high plasma levels of free cisplatin, which are associated with the side effects of the drug, may be reduced whilst at the same time allowing more specific targeting of cisplatin to the tumour. This type of liposome delivery system has previously been used successfully for the delivery of doxorubicin in both animal and patient studies (Papahadjopoulous et al, 1991;Vaage et al, 1992;Uziely et al, 1995;Muggia et al, 1997).…”

mentioning

confidence: 99%

A phase I study in paediatric patients to evaluate the safety and pharmacokinetics of SPI-77, a liposome encapsulated formulation of cisplatin

et al. 2001

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Summary Pre-clinical studies indicate that cisplatin encapsulated in STEALTH ® liposomes (SPI-77) retains anti-tumour activity, but has a much reduced toxicity, compared to native cisplatin. A phase I study was conducted to determine the toxicity and pharmacokinetics of SPI-77 administered to children with advanced cancer not amenable to other treatment. Paediatric patients were treated at doses ranging from 40 to 320 mg m -2 by intravenous infusion every 4 weeks. Blood samples taken during, and up to 3 weeks after, administration and plasma and ultrafiltrate were prepared immediately. Urine was collected, when possible, for 3 days after administration. SPI-77 administration was well tolerated with the major toxicity being an infusion reaction which responded to modification of the initial infusion rate of SPI-77. Limited haematological toxicity and no nephrotoxicity were observed. No responses to treatment were seen during the course of this phase I study. Measurement of total plasma platinum showed that cisplatin was retained in the circulation with a half life of up to 134 h, with maximum plasma concentrations approximately 100-fold higher than those reported following comparable doses of cisplatin. Comparison of plasma and whole blood indicated that cisplatin was retained in the liposomes and there was no free platinum measurable in the ultrafiltrate. Urine recovery was less than 4% of the dose administered over 72 h. Results from this phase I study indicate that high doses of liposomal cisplatin can safely be given to patients, but further studies are required to address the issue of reformulation of liposomally bound cisplatin.

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Phase II study of liposomal doxorubicin in refractory ovarian cancer: antitumor activity and toxicity modification by liposomal encapsulation.

Cited by 590 publications

References 16 publications

Phase I clinical trial and pharmacokinetic evaluation of NK911, a micelle-encapsulated doxorubicin

Phase I clinical trial and pharmacokinetic evaluation of NK911, a micelle-encapsulated doxorubicin

Phase I dose escalation and pharmacokinetic study of pluronic polymer-bound doxorubicin (SP1049C) in patients with advanced cancer

A phase I study in paediatric patients to evaluate the safety and pharmacokinetics of SPI-77, a liposome encapsulated formulation of cisplatin

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