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Expert Opinion on Investigational Drugs Jun 2011Despite an 80% initial response rate to the standard primary regimen of carboplatin and paclitaxel, most women with ovarian cancer will experience recurrence with... (Review)
Review
INTRODUCTION
Despite an 80% initial response rate to the standard primary regimen of carboplatin and paclitaxel, most women with ovarian cancer will experience recurrence with incurable disease within five years and will be treated with several successive palliative regimens. Consequently, a significant need exists for chemotherapeutic agents, which are not only clinically efficacious, but have acceptable side-effect profiles. Paclitaxel poliglumex (PPX) is a recently developed taxane in which paclitaxel is conjugated to poly(l-glutamic acid), which renders it water soluble, reduces hypersensitivity reactions and preferentially targets it to the tumor.
AREAS COVERED
This review covers pre-clinical pharmacokinetic data and key Phase I and II clinical trial results in ovarian cancer.
EXPERT OPINION
While PPX is active in ovarian cancer, it is unclear at present whether it offers significant benefit in terms of its side-effect profile or outcomes over a standard taxane-based regimen as first-line therapy, or what role it will have in maintenance therapy as studies are ongoing.
Topics: Animals; Antineoplastic Agents, Phytogenic; Drug Delivery Systems; Female; Humans; Neoplasm Recurrence, Local; Ovarian Neoplasms; Paclitaxel; Palliative Care; Polyglutamic Acid; Solubility; Time Factors; Treatment Outcome
PubMed: 21470062
DOI: 10.1517/13543784.2011.576666 -
Anti-cancer Drugs Mar 2005Paclitaxel poliglumex (CT-2103; XYOTAX) is an innovative macromolecular taxane designed to increase the therapeutic index of paclitaxel. This large macromolecule... (Review)
Review
Paclitaxel poliglumex (CT-2103; XYOTAX) is an innovative macromolecular taxane designed to increase the therapeutic index of paclitaxel. This large macromolecule conjugate of paclitaxel and poly-L-glutamic acid accumulates in tumor tissues by taking advantage of the enhanced permeability of tumor vasculature and lack of lymphatic drainage. Paclitaxel poliglumex prolongs exposure to active drug and minimizes systemic exposure. Preclinical studies in animal tumor models demonstrate enhanced safety and efficacy relative to paclitaxel when administered as a single agent or in conjunction with radiation. Clinical pilot studies with paclitaxel poliglumex showed improved outcomes compared to standard taxanes and allowed a more convenient administration schedule. Human pharmacokinetic data are consistent with prolonged tumor exposure to active drug and a limited systemic exposure. Based on these results, three ongoing randomized phase III trials were initiated to test the efficacy of paclitaxel poliglumex in patients with advanced non-small cell lung carcinoma.
Topics: Animals; Antineoplastic Agents; Area Under Curve; Carcinoma, Non-Small-Cell Lung; Drug Synergism; Female; Half-Life; Humans; Lung Neoplasms; Mice; Ovarian Neoplasms; Paclitaxel; Polyglutamic Acid; Randomized Controlled Trials as Topic; Taxoids
PubMed: 15711176
DOI: 10.1097/00001813-200503000-00003 -
Journal of Controlled Release :... Dec 2005Paclitaxel poliglumex (PPX) is an innovative macromolecular taxane designed to increase the therapeutic index of paclitaxel. This large macromolecular conjugate of... (Review)
Review
Paclitaxel poliglumex (PPX) is an innovative macromolecular taxane designed to increase the therapeutic index of paclitaxel. This large macromolecular conjugate of paclitaxel and poly-L-glutamic acid accumulates in tumor tissues by taking advantage of the enhanced permeability of tumor vasculature and lack of lymphatic drainage. Preclinical studies in animal tumor models demonstrate that PPX is more effective than standard paclitaxel and is associated with prolonged tumor exposure to active drug while minimizing systemic exposure. Phase 1 and 2 clinical studies with PPX showed encouraging outcomes compared to standard taxanes with reduced neutropenia and alopecia and allowed a more convenient administration schedule without the need for routine premedications. Human pharmacokinetic data are consistent with prolonged tumor exposure to active drug and a limited systemic exposure. Three phase 3 trials in nonsmall cell lung cancer (STELLAR 2, 3, and 4) have completed enrollment and results are expected in 2005.
Topics: Animals; Antineoplastic Agents, Phytogenic; Humans; Paclitaxel; Polyglutamic Acid; Taxoids
PubMed: 16297482
DOI: 10.1016/j.jconrel.2005.09.033 -
Expert Review of Anticancer Therapy Apr 2007Taxanes, including paclitaxel and docetaxel, are widely used cytotoxic agents for the treatment of solid tumors. Paclitaxel, a small, hydrophobic agent, binds... (Review)
Review
Taxanes, including paclitaxel and docetaxel, are widely used cytotoxic agents for the treatment of solid tumors. Paclitaxel, a small, hydrophobic agent, binds extensively to plasma proteins, and its pharmacokinetic profile is characterized by a short plasma elimination half-life with a broad tissue distribution. These unfavorable pharmacokinetic characteristics are associated with limited tumor exposure and high systemic exposure, reducing the therapeutic index of paclitaxel. Paclitaxel poliglumex (PPX, CT-2103), a polymer-drug conjugate of paclitaxel and poly-L-glutamic acid, was designed to enhance the therapeutic index of paclitaxel by improving its pharmacokinetic profile, and to provide a water-soluble alternative to the standard paclitaxel formulation. Potential advantages of polymer-drug conjugates include delivery of a higher concentration of active drug to tumor tissue and limited exposure of normal tissues. In addition, the slow release of drug from the polymer carrier lowers peak plasma concentrations of the active drug.
Topics: Antineoplastic Agents, Phytogenic; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Macromolecular Substances; Paclitaxel; Polyglutamic Acid; Taxoids
PubMed: 17428162
DOI: 10.1586/14737140.7.4.415 -
IDrugs : the Investigational Drugs... Sep 2005Cell Therapeutics Inc, under license from the MD Anderson Cancer Center and in collaboration with Chugai Pharmaceutical Co Ltd (the Japanese subsidiary of Roche), is... (Review)
Review
Cell Therapeutics Inc, under license from the MD Anderson Cancer Center and in collaboration with Chugai Pharmaceutical Co Ltd (the Japanese subsidiary of Roche), is developing paclitaxel poliglumex, an intravenous poly-(alpha-L-glutamic acid) conjugate of paclitaxel for the potential treatment of solid tumors.
Topics: Animals; Antineoplastic Agents; Clinical Trials as Topic; Humans; Neoplasms; Paclitaxel; Polyglutamic Acid; Structure-Activity Relationship; Taxoids
PubMed: 16118697
DOI: No ID Found -
International Journal of Nanomedicine 2006Paclitaxel is a widely used chemotherapeutic agent; however, its therapeutic index is limited by low tumor exposure and high systemic exposure. Paclitaxel poliglumex... (Review)
Review
Paclitaxel is a widely used chemotherapeutic agent; however, its therapeutic index is limited by low tumor exposure and high systemic exposure. Paclitaxel poliglumex (PPX) is macromolecular drug conjugate that links paclitaxel with a biodegradable polymer, poly-L-glutamic acid. PPX enhances tumor exposure by taking advantage of the hyperpermeable vasculature and suppressed lymphatic clearance characteristic of tumor tissue. The release of paclitaxel from the polymeric backbone is, at least in part, dependent on the metabolism of PPX by the lysosomal protease cathepsin B, which is upregulated in many tumor types. Retrospective analysis of clinical data from two phase III trials in advanced lung cancer suggests that PPX activity may be modulated by estradiol: a trend toward improved survival in the PPX arm compared with the control arm was observed in female, but not in male patients. Estrogens are known to induce cathepsin B activity; cathepsin B-mediated proteolysis is a key enzymatic processing step in PPX metabolism. The association between estrogens and PPX activity is being further explored in ongoing preclinical studies. An additional phase III trial will enroll women with advanced NSCLC to prospectively evaluate the efficacy of PPX in relation to pre- and post-menopausal estrogen levels.
Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Drug Carriers; Estradiol; Humans; Macromolecular Substances; Neoplasms; Paclitaxel; Polyglutamic Acid; Tubulin
PubMed: 17722272
DOI: 10.2147/nano.2006.1.4.375 -
Current Pharmaceutical Design 2021Background and Introduction: Peripheral neuropathy is one of the most common dose-limiting side effects of solvent-based paclitaxel. Paclitaxel poliglumex (PPX) and... (Meta-Analysis)
Meta-Analysis
UNLABELLED
Background and Introduction: Peripheral neuropathy is one of the most common dose-limiting side effects of solvent-based paclitaxel. Paclitaxel poliglumex (PPX) and NK105 were developed to overcome the paclitaxel induced peripheral neuropathy. However, the incidence of peripheral neuropathy induced by PPX and NK105 was reported higher than solvent-based paclitaxel, but evidence remains inconsistent.
METHODS
The article was reported in accordance with PRISMA Guidelines (Registration number: CRD42021245313). We conducted a meta-analysis to compare the incidence and severity of peripheral neuropathy between solvent-based paclitaxel, PPX and NK105 mono-chemotherapy.
RESULTS
Results revealed that no significant difference exists between the incidence of all grade peripheral neuropathy among the solvent-based paclitaxel, PPX and NK105 treated groups. While, the incidence of high grade peripheral neuropathy induced by NK105 was lower than two other groups. Moreover, the overall survival was not improved in PPX compared with other groups. However, NK105 demonstrated significant longer overall survival in patients with cancer.
CONCLUSION
Current evidence suggests more attention should be paid to the paclitaxel poliglumex re-formulation.
Topics: Antineoplastic Agents, Phytogenic; Humans; Paclitaxel; Peripheral Nervous System Diseases; Polyglutamic Acid; Solvents
PubMed: 32940171
DOI: 10.2174/1381612826666200917145551 -
Anti-cancer Drugs May 2014Since their addition to paclitaxel in the oncologists' armamentarium in the early 1990s, several new taxane formulations have been developed. Besides docetaxel and... (Review)
Review
Since their addition to paclitaxel in the oncologists' armamentarium in the early 1990s, several new taxane formulations have been developed. Besides docetaxel and nab-paclitaxel, new analogs with better therapeutic profiles are being investigated. The goals of this next generation of taxanes are to improve the toxicity profile and efficacy, and to overcome resistance patterns. Several new taxanes, including cabazitaxel, paclitaxel poliglumex, paclitaxel+endotag, and polymeric-micellar paclitaxel, have shown clinical efficacy. These chemotherapeutics are part of many ongoing phase II and III studies on various cancer types. In addition, there are immunotoxins that link key antibodies to mitotic spindle inhibitors (trastuzumab emtansine and brentuximab vedotin). Through this mechanism, novel formulations increase cytotoxicity, improve specificity, and create possibilities for drug enhancement.
Topics: Antineoplastic Agents, Phytogenic; Drug Therapy, Combination; Humans; Immunotoxins; Neoplasms; Taxoids
PubMed: 24374330
DOI: 10.1097/CAD.0000000000000053 -
American Journal of Clinical Oncology Oct 2014Paclitaxel poliglumex (PPX), a drug conjugate that links paclitaxel to poly-L-glutamic acid, is a potent radiation sensitizer. Prior studies in esophageal cancer have...
OBJECTIVES
Paclitaxel poliglumex (PPX), a drug conjugate that links paclitaxel to poly-L-glutamic acid, is a potent radiation sensitizer. Prior studies in esophageal cancer have demonstrated that PPX (50 mg/m/wk) can be administered with concurrent radiation with acceptable toxicity. The primary objective of this study was to determine the safety of the combination of PPX with temozolomide and concurrent radiation for high-grade gliomas.
METHODS
Eligible patients were required to have WHO grade 3 or 4 gliomas. Patients received weekly PPX (50 mg/m/wk) combined with standard daily temozolomide (75 mg/m) for 6 weeks with concomitant radiation (2.0 Gy, 5 d/wk for a total dose of 60 Gy).
RESULTS
Twenty-five patients were enrolled, 17 with glioblastoma and 8 with grade 3 gliomas. Seven of 25 patients had grade 4 myelosuppression. Hematologic toxicity lasted up to 5 months suggesting a drug interaction between PPX and temozolomide. For patients with glioblastoma, the median progression-free survival was 11.5 months and the median overall survival was 18 months.
CONCLUSIONS
PPX could not be safely combined with temozolomide due to grade 4 hematologic toxicity. However, the favorable progression-free and overall survival suggest that PPX may enhance radiation for glioblastoma. A randomized study of single agent PPX/radiation versus temozolomide/radiation for glioblastoma without MGMT methylation is underway.
Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Brachytherapy; Brain Neoplasms; Chemoradiotherapy; Combined Modality Therapy; Dacarbazine; Disease-Free Survival; Female; Glioma; Humans; Male; Middle Aged; Paclitaxel; Polyglutamic Acid; Survival Analysis; Temozolomide
PubMed: 23388562
DOI: 10.1097/COC.0b013e31827de92b -
American Journal of Clinical Oncology Aug 2006To determine the maximal tolerated dose (MTD) and dose limiting toxicities of poly(l-glutamic acid)-paclitaxel (PPX) and concurrent radiation (PPX/RT) for patients with...
OBJECTIVES
To determine the maximal tolerated dose (MTD) and dose limiting toxicities of poly(l-glutamic acid)-paclitaxel (PPX) and concurrent radiation (PPX/RT) for patients with esophageal and gastric cancer.
METHODS
Patients with esophageal or gastric cancer receiving chemoradiation for loco-regional, adjuvant, or palliative intent were eligible. The initial dose of PPX was 40 mg/m2/wk, for 6 weeks with 50.4 Gy radiation. Dose levels were increased in increments of 10 mg/m2/wk of PPX.
RESULTS
Twenty-one patients were enrolled over 5 dose levels. Sixteen patients had esophageal cancer and 5 had gastric cancer. Twelve patients received PPX/RT as definitive loco-regional therapy, 4 patients had undergone resection and received adjuvant PPX/RT, and 5 patients had metastatic disease and received PPX/RT for palliation of dysphagia. Dose limiting toxicities of gastritis, esophagitis, neutropenia, and dehydration developed in 3 of 4 patients treated at the 80 mg/m2 dose level. Four of 12 patients (33%) with loco-regional disease had a complete clinical response.
CONCLUSIONS
The maximally tolerated dose of PPX with concurrent radiotherapy is 70 mg/m2/wk for patients with esophageal and gastric cancer.
Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Squamous Cell; Combined Modality Therapy; Esophageal Neoplasms; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Paclitaxel; Polyglutamic Acid; Radiation-Sensitizing Agents; Radiotherapy, Conformal; Stomach Neoplasms
PubMed: 16891865
DOI: 10.1097/01.coc.0000224494.07907.4e