A Phase I and Pharmacokinetic Study of Paclitaxel Poliglumex (XYOTAX), Investigating Both 3-Weekly and 2-Weekly Schedules

Boddy, Alan V.; Plummer, ER; Todd, R; Sludden, Julieann; Griffin, MJ; Robson, L; Cassidy, James T.; Bissett, Donald; Bernareggi, A.; Verrill, M.; Calvert, A. H.

doi:10.1158/1078-0432.ccr-05-0803

Cited by 100 publications

(65 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Design and synthesis of PGG-PTX PGA-PTX (also known as CT-2103) was reported to produce complete regression of established tumors in mice 6 and has demonstrated activity in Phase I 19,20 and Phase II 21 clinical trials. However, the combination of CT-2103 and carboplatin was not superior to PTX and carboplatin in a randomized Phase III trial in patients with lung cancer.…”

Section: Resultsmentioning

confidence: 99%

Synthesis, characterization, and biological evaluation of poly(L-γ-glutamyl-glutamine)-paclitaxel nanoconjugate

van¹

2010

IJN

View full text Add to dashboard Cite

Abstract:The purpose of this study was to develop a novel, highly water-soluble poly(L-γ-glutamyl-glutamine)-paclitaxel nanoconjugate (PGG-PTX) that would improve the therapeutic index of paclitaxel (PTX). PGG-PTX is a modification of poly(L-glutamic acid)-paclitaxel conjugate (PGA-PTX) in which an additional glutamic acid has been added to each glutamic side chain in the polymer. PGG-PTX has higher water-solubility and faster dissolution than PGA-PTX. Unlike PGA-PTX, PGG-PTX self-assembles into nanoparticles, whose size remains in the range of 12-15 nm over the concentration range from 25 to 2,000 µg/mL in saline. Its critical micellar concentration in saline was found to be ∼25 µg/mL. The potency of PGG-PTX when tested in vitro against the human lung cancer H460 cell line was comparable to other known polymer-PTX conjugates. However, PGG-PTX possesses lower toxicity compared with PGA-PTX in mice. The maximum tolerated dose of PGG-PTX was found to be 350 mg PTX/kg, which is 2.2-fold higher than the maximum tolerated dose of 160 mg PTX/kg reported for the PGA-PTX. This result indicates that PGG-PTX was substantially less toxic in vivo than PGA-PTX.

show abstract

Section: Resultsmentioning

confidence: 99%

Synthesis, characterization, and biological evaluation of poly(L-γ-glutamyl-glutamine)-paclitaxel nanoconjugate

van¹

2010

IJN

View full text Add to dashboard Cite

show abstract

“…Careful tuning of NP size, especially in the 10-100 nm range, enables control of circulation time, 6,7 as well as passive tumor accumulation due to the "enhanced permeability and retention" effect. 8 Particle size also affects NP cellular uptake.…”

mentioning

confidence: 99%

Targeted Cytosolic Delivery of Cell-Impermeable Compounds by Nanoparticle-Mediated, Light-Triggered Endosome Disruption

Febvay

Marini

Belcher³

et al. 2010

Nano Lett.

110

View full text Add to dashboard Cite

Nanoparticle (NP)-mediated drug delivery typically relies on cargo release to occur passively or in response to environmental stimuli. Here we present a delivery method based on light-activated disruption of intracellular vesicles after internalization of biofunctionalized mesoporous silica nanoparticles loaded with cargo. This method combines the power of targeted delivery with the spatiotemporal control of light activation. As an example, we delivered a cell-impermeable fluorescent compound exclusively to the cytosol of multidrug resistant cancer cells in a mixed population. KeywordsMesoporous silica; nanoparticles; P-glycoprotein; drug delivery; photodynamic therapy; endosomeThe potential of nanomaterials for drug delivery has been extensively explored in recent years. [1][2][3][4] Such efforts have been driven to a large extent by the need to reduce side effects in anticancer drugs (such as doxorubicin's severe cardiotoxicity) via tissue-specific targeting. 5 Beyond enhanced targetability, NP-encapsulation of drugs may also provide protection against premature degradation and enable efficient delivery of substances with poor inherent solubility or membrane permeability. Important determinants of the success of NP-mediated drug delivery are biocompatibility, circulation time, immunogenicity, specific targeting, © 2010 American Chemical Society * To whom correspondence should be addressed. dclapham@enders.tch.harvard.edu. HHMI Author Manuscript HHMI Author Manuscript HHMI Author Manuscripttiming of cargo release and, ideally, access to intracellular compartments. Careful tuning of NP size, especially in the 10-100 nm range, enables control of circulation time, 6,7 as well as passive tumor accumulation due to the "enhanced permeability and retention" effect. 8 Particle size also affects NP cellular uptake. 9 A highly desirable feature of NP-based delivery platforms is precise temporal control of compound release. This can be regulated by incorporating release mechanisms triggered by environmental stimuli such as pH, 10 temperature, 11 or enzymatic reactions. 12 Another important way to control payload delivery for membrane-impermeable drugs is to regulate access to the cytosol, which usually requires escape from the endolysosomal compartment where particles are clustered following receptor-mediated endocytosis. Here we present a method for precise spatial and temporal control over cytosolic delivery of compounds that would otherwise be cell-impermeable by incorporating a light-triggered endosomal escape mechanism within a cell targetable mesoporous silica carrier.Among potential nanocarriers, mesoporous silicate materials 13-15 have demonstrated great potential for biomedical applications due to their biocompatibility, ease of functionalization, and large surface-to-volume ratio. 16 They have been successfully used to deliver drugs, 17,18 proteins 19 and nucleic acids. 20,21 Most recent efforts have been focused on their biological targeting in order to achieve site-specific delivery. 16,22 Size contro...

show abstract

“…. The single-cycle, maximum tolerated dose of PPX in phase Ia study was 233 mg m À2 every 3 weeks, with neutropenia being the dose-limiting toxicity (Boddy et al, 2005). In the phase Ib portion of the trial, in which CT-2103 was administered every 2 weeks, the maximum tolerated dose was 177 mg m À2 , with neuropathy being the dose-limiting side effect.…”

mentioning

confidence: 99%

Phase III trial comparing paclitaxel poliglumex vs docetaxel in the second-line treatment of non-small-cell lung cancer

et al. 2008

View full text Add to dashboard Cite

Paclitaxel poliglumex (PPX), a macromolecule drug conjugate linking paclitaxel to polyglutamic acid, reduces systemic exposure to peak concentrations of free paclitaxel. Patients with non-small-cell lung cancer (NSCLC) who had received one prior platinum-based chemotherapy received 175 or 210 mg m À2 PPX or 75 mg m À2 docetaxel. The study enrolled 849 previously treated NSCLC patients with advanced disease. Median survival (6.9 months in both arms, hazard ratio ¼ 1.09, P ¼ 0.257), 1-year survival (PPX ¼ 25%, docetaxel ¼ 29%, P ¼ 0.134), and time to progression (PPX ¼ 2 months, docetaxel ¼ 2.6 months, P ¼ 0.075) were similar between treatment arms. Paclitaxel poliglumex was associated with significantly less grade 3 or 4 neutropenia (Po0.001) and febrile neutropenia (P ¼ 0.006). Grade 3 or 4 neuropathy (Po0.001) was more common in the PPX arm. Patients receiving PPX had less alopecia and did not receive routine premedications. More patients discontinued due to adverse events in the PPX arm compared to the docetaxel arm (34 vs 16%, Po0.001). Paclitaxel poliglumex and docetaxel produced similar survival results but had different toxicity profiles. Compared with docetaxel, PPX had less febrile neutropenia and less alopecia, shorter infusion times, and elimination of routine use of medications to prevent hypersensitivity reactions. Paclitaxel poliglumex at a dose of 210 mg m À2 resulted in increased neurotoxicity compared with docetaxel. (Jemal et al, 2007). For patients who present with advanced-stage disease (IIIb or IV), platinum-based multi-agent chemotherapy modestly improves survival compared with best supportive care or singleagent therapy (Pfister et al, 2004). However, nearly all patients relapse, and only 10 -20% survive 2 years. Three agents are currently approved for second-line therapy in advanced nonsmall-cell lung cancer (NSCLC). Docetaxel and erlotinib were approved on the basis of improved survival compared with best supportive care (Shepherd et al, 2000(Shepherd et al, , 2005. Pemetrexed received approval as second-line therapy due to its similarity in survival and response rates with lower toxicity than that of docetaxel, although statistical noninferiority was not achieved (Hanna et al, 2004). Despite response rates of approximately 10%, second-line treatment improves survival by approximately 2 months compared with best supportive care.Owing to the palliative nature of second-line therapy in NSCLC and its relatively modest effect on survival, minimising the toxicity of therapy is an important consideration. Additional effective therapies that achieve that goal are needed.Paclitaxel poliglumex (PPX) is a macromolecular polymer -drug conjugate that links paclitaxel to a biodegradable polymeric backbone consisting of L-glutamic acid residues. Because the conjugation site is through the 2 0 hydroxyl of paclitaxel, a site crucial for tubulin binding, conjugated paclitaxel does not interact with b-tubulin and is biologically inactive . Paclitaxel poliglumex is relatively stable in circulation; the ar...

show abstract

A Phase I and Pharmacokinetic Study of Paclitaxel Poliglumex (XYOTAX), Investigating Both 3-Weekly and 2-Weekly Schedules

Cited by 100 publications

References 20 publications

Synthesis, characterization, and biological evaluation of poly(L-γ-glutamyl-glutamine)-paclitaxel nanoconjugate

Synthesis, characterization, and biological evaluation of poly(L-γ-glutamyl-glutamine)-paclitaxel nanoconjugate

Targeted Cytosolic Delivery of Cell-Impermeable Compounds by Nanoparticle-Mediated, Light-Triggered Endosome Disruption

Phase III trial comparing paclitaxel poliglumex vs docetaxel in the second-line treatment of non-small-cell lung cancer

Contact Info

Product

Resources

About

A Phase I and Pharmacokinetic Study of Paclitaxel Poliglumex (XYOTAX), Investigating Both 3-Weekly and 2-Weekly Schedules

Cited by 100 publications

References 20 publications

Synthesis, characterization, and biological evaluation of poly(L-&gamma;-glutamyl-glutamine)-paclitaxel nanoconjugate

Synthesis, characterization, and biological evaluation of poly(L-&gamma;-glutamyl-glutamine)-paclitaxel nanoconjugate

Targeted Cytosolic Delivery of Cell-Impermeable Compounds by Nanoparticle-Mediated, Light-Triggered Endosome Disruption

Phase III trial comparing paclitaxel poliglumex vs docetaxel in the second-line treatment of non-small-cell lung cancer

Contact Info

Product

Resources

About

Synthesis, characterization, and biological evaluation of poly(L-γ-glutamyl-glutamine)-paclitaxel nanoconjugate

Synthesis, characterization, and biological evaluation of poly(L-γ-glutamyl-glutamine)-paclitaxel nanoconjugate