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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 -
British Journal of Cancer May 2008Paclitaxel poliglumex (PPX), a macromolecule drug conjugate linking paclitaxel to polyglutamic acid, reduces systemic exposure to peak concentrations of free paclitaxel.... (Comparative Study)
Comparative Study Randomized Controlled Trial
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(-2) PPX or 75 mg m(-2) docetaxel. The study enrolled 849 previously treated NSCLC patients with advanced disease. Median survival (6.9 months in both arms, hazard ratio=1.09, P=0.257), 1-year survival (PPX=25%, docetaxel=29%, P=0.134), and time to progression (PPX=2 months, docetaxel=2.6 months, P=0.075) were similar between treatment arms. Paclitaxel poliglumex was associated with significantly less grade 3 or 4 neutropenia (P<0.001) and febrile neutropenia (P=0.006). Grade 3 or 4 neuropathy (P<0.001) 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%, P<0.001). 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(-2) resulted in increased neurotoxicity compared with docetaxel.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Carcinoma, Non-Small-Cell Lung; Docetaxel; Drug Administration Schedule; Female; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Paclitaxel; Patient Selection; Polyglutamic Acid; Quality of Life; Taxoids; Treatment Outcome
PubMed: 18475293
DOI: 10.1038/sj.bjc.6604372 -
Gynecologic Oncology Sep 2008To estimate the maximum tolerated dose (MTD) of paclitaxel poliglumex (PPX) in combination with carboplatin in patients with chemotherapy-naive ovarian, primary...
Paclitaxel poliglumex and carboplatin as first-line therapy in ovarian, peritoneal or fallopian tube cancer: a phase I and feasibility trial of the Gynecologic Oncology Group.
PURPOSE
To estimate the maximum tolerated dose (MTD) of paclitaxel poliglumex (PPX) in combination with carboplatin in patients with chemotherapy-naive ovarian, primary peritoneal or fallopian tube cancer, and to assess the feasibility of administering multiple cycles of this regimen.
METHODS
The first 11 patients were treated in a standard 3 + 3 dose-seeking design, with carboplatin held constant at area under the curve (AUC) of 6 and PPX at 225, 175 or 135 mg/m(2). Pharmacokinetics of PPX and carboplatin were evaluated during this dose-seeking component of the trial. MTD was defined by acute dose-limiting toxicities (DLT) in the first cycle. Twenty additional evaluable patients were treated at the estimated MTD to assess the feasibility of this regimen over >or=4cycles.
RESULTS
PPX at 225 mg/m(2) resulted in DLT in 2/3 patients, and was de-escalated first to 175 mg/m(2) and then to 135 mg/m(2). PPX slowly hydrolyzed to paclitaxel and did not alter the pharmacokinetics of carboplatin. DLT within the first 4-cycles were observed in 3 patients (15%) treated at the MTD: neutropenia > 2weeks (2), febrile neutropenia (1). Nineteen patients (95%) experienced grade 4 neutropenia. Sixteen patients (80%) had at least one episode of grade 3 thrombocytopenia. Three patients (15%) had grade 2 and one had grade 3 peripheral neuropathy. Complete response by CA-125 was 75%.
CONCLUSIONS
The recommended dose of PPX of 135 mg/m(2) with carboplatin (AUC = 6) in newly diagnosed ovarian cancer was feasible for multiple cycles, but hematologic toxicity was greater compared with standard carboplatin and 3-hour paclitaxel.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Cohort Studies; Drug Interactions; Fallopian Tube Neoplasms; Feasibility Studies; Female; Humans; Middle Aged; Ovarian Neoplasms; Paclitaxel; Peritoneal Neoplasms; Polyglutamic Acid
PubMed: 18597837
DOI: 10.1016/j.ygyno.2008.05.008 -
Journal of Thoracic Oncology : Official... Jun 2008Performance status (PS) 2 patients with non-small cell lung cancer (NSCLC) experience more toxicity, lower response rates, and shorter survival times than healthier... (Comparative Study)
Comparative Study Randomized Controlled Trial
Phase III trial comparing paclitaxel poliglumex (CT-2103, PPX) in combination with carboplatin versus standard paclitaxel and carboplatin in the treatment of PS 2 patients with chemotherapy-naïve advanced non-small cell lung cancer.
INTRODUCTION
Performance status (PS) 2 patients with non-small cell lung cancer (NSCLC) experience more toxicity, lower response rates, and shorter survival times than healthier patients treated with standard chemotherapy. Paclitaxel poliglumex (PPX), a macromolecule drug conjugate of paclitaxel and polyglutamic acid, reduces systemic exposure to peak concentrations of free paclitaxel and may lead to increased concentrations in tumors due to enhanced vascular permeability.
METHODS
Chemotherapy-naive PS 2 patients with advanced NSCLC were randomized to receive carboplatin (area under the curve = 6) and either PPX (210 mg/m/10 min without routine steroid premedication) or paclitaxel (225 mg/m/3 h with standard premedication) every 3 weeks. The primary end point was overall survival.
RESULTS
A total of 400 patients were enrolled. Alopecia, arthralgias/myalgias, and cardiac events were significantly less frequent with PPX/carboplatin, whereas grade > or =3 neutropenia and grade 3 neuropathy showed a trend of worsening. There was no significant difference in the incidence of hypersensitivity reactions despite the absence of routine premedication in the PPX arm. Overall survival was similar between treatment arms (hazard ratio, 0.97; log rank p = 0.769). Median and 1-year survival rates were 7.9 months and 31%, for PPX versus 8 months and 31% for paclitaxel. Disease control rates were 64% and 69% for PPX and paclitaxel, respectively. Time to progression was similar: 3.9 months for PPX/carboplatin versus 4.6 months for paclitaxel/carboplatin (p = 0.210).
CONCLUSION
PPX/carboplatin failed to provide superior survival compared with paclitaxel/carboplatin in the first-line treatment of PS 2 patients with NSCLC, but the results with respect to progression-free survival and overall survival were comparable and the PPX regimen was more convenient.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carboplatin; Carcinoma, Non-Small-Cell Lung; Disease-Free Survival; Female; Follow-Up Studies; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Paclitaxel; Polyglutamic Acid; Quality of Life; Retrospective Studies; Survival Rate; Treatment Outcome; United States
PubMed: 18520802
DOI: 10.1097/JTO.0b013e3181753b4b -
Annals of Oncology : Official Journal... Mar 2012Despite current trend of targeted therapy development, cytotoxic agents are a mainstay of treatment of patients with breast cancer. We reviewed recent advances in... (Review)
Review
BACKGROUND
Despite current trend of targeted therapy development, cytotoxic agents are a mainstay of treatment of patients with breast cancer. We reviewed recent advances in cytotoxic therapy for patients with metastatic breast cancer (MBC).
MATERIALS AND METHODS
Medline searches were conducted for English language studies using the term 'MBC' and 'cytotoxic drugs'. The data search was restricted to the period 2000-2011.
RESULTS
Several novel cytotoxic compounds, all microtubule inhibitors, have been approved for clinical use in MBC: (i) nab-paclitaxel, reported to improve tumour response and decrease hypersensitivity reactions in comparison with other taxanes; (ii) ixabepilone, shown to have clinical benefit in taxane- and anthracycline-resistant disease and (iii) eribulin, shown to improve overall survival in heavily pre-treated patients, when compared with best available standard treatment. Agents, such as larotaxel, vinflunine, trabectidin and formulations, including cationic liposomal paclitaxel or paclitaxel poliglumex, are currently under evaluation in phase II/III trials.
CONCLUSION
Toxicity and chemotherapy resistance are still major limitations in the treatment of patients with MBC. Further research into new cytotoxic compounds is needed in order to maximise benefit, whilst minimising toxicity.
Topics: Antineoplastic Agents; Breast Neoplasms; Clinical Trials as Topic; Cytotoxins; Female; Humans
PubMed: 21896541
DOI: 10.1093/annonc/mdr382 -
Methods and Findings in Experimental... 2010A-3309, Abobotulinumtoxin A, Adalimumab, AIDSVAX gp120 B/E, ALVAC E120TMG, Atorvastatin calcium; Bepridil, Bevacizumab; Candesartan cilexetil, Capecitabine, Cetuximab,...
A-3309, Abobotulinumtoxin A, Adalimumab, AIDSVAX gp120 B/E, ALVAC E120TMG, Atorvastatin calcium; Bepridil, Bevacizumab; Candesartan cilexetil, Capecitabine, Cetuximab, Clopidogrel; Dapagliflozin, Dasatinib, Denosumab, Dexmedetomidine hydrochloride, Diacetylmorphine, Diannexin, Docetaxel, Dutasteride; Entecavir, Eplerenone, Erlotinib hydrochloride, Escitalopram oxalate, Everolimus, Ezetimibe; Fesoterodine fumarate, Flagellin.HuM2e, Fluzone; Glimepiride/rosiglitazone maleate; Hyaluronic acid-paclitaxel bioconjugate; IDX-184, Imatinib mesylate, Infliximab, Insulin glargine, Irbesartan; JX-594; Landiolol, Latrunculin B, Levocetirizine dihydrochloride, Liraglutide, Lyprinol; Metformin, Metronidazole/tetracycline hydrochloride/bismuth biskalcitrate, Mipomersen sodium, Mycophenolic acid sodium salt; Nalfurafine hydrochloride, Nilotinib hydrochloride monohydrate; Paclitaxel nanoparticles, Paclitaxel poliglumex, Peginterferon alfa-2a, Peginterferon alfa-2b, Perospirone hydrochloride, Pimavanserin tartrate, Pirfenidone, Pitavastatin calcium, Prasterone, Prasugrel, Pregabalin, Ranelic acid distrontium salt, Ranibizumab, Remimazolam, Risedronate, Rosuvastatin calcium; Silodosin, Silybin phosphatidylcholine complex, Sirolimus-eluting stent, Sitagliptin phosphate monohydrate, Sorafenib, Sunitinib malate; Tadalafil, Tamsulosin hydrochloride, Technosphere/insulin, Telmisartan, Temsirolimus, Teriparatide, Thymalfasin, Ticagrelor, Toltedorine-XR, Tramadol-XR, Triphosadenine, Trospium-XR; Val8-GLP-1(7-37)OH, Valsartan, Vardenafil hydrochloride hydrate, Varenicline tartrate, Velaglucerase alfa; Zoledronic acid monohydrate.
Topics: Clinical Trials as Topic; Humans
PubMed: 20852754
DOI: 10.1358/mf.2010.32.6.1538165 -
International Journal of General... Dec 2010In Phase I evaluation of CT-2103 (paclitaxel poliglumex), prolongation of prothrombin time (PT) and activated thromboplastin time (aPTT) was observed, without clinical...
BACKGROUND
In Phase I evaluation of CT-2103 (paclitaxel poliglumex), prolongation of prothrombin time (PT) and activated thromboplastin time (aPTT) was observed, without clinical consequence, with doses 1.3-1.5 times higher than the current clinical dose of 175 mg/m(2). This Phase I, open-label, nonrandomized pilot study was performed to study the effect of the standard dose regimen on blood coagulation.
METHODS
Seven previously treated solid tumor patients received CT-2103 175 mg/m(2) intravenously on day 1 of 21-day cycles for a mean of 5.4 cycles (median 4, range 2-14). Plasma samples were collected for cycle 1 predose and at hours 1, 24, 48, and 72 after the end of administration for drug levels, and for PT and aPTT assays.
RESULTS
No coagulopathy-related adverse events were documented. Bleeding time remained normal in the six patients tested, with transient increases in PT and aPTT noted but resolving within 72 hours. Titration studies at 100 μg/mL of CT-2103 (corresponding to the standard clinical dose) prolonged PT and aPTT clotting times, produced a modest dose-dependent reduction of thrombin and factor Xa, and no significant changes in factors IXa, XIa, or XIIa. Two patients achieved stable disease for ≥10 cycles.
CONCLUSION
CT-2103 is associated with transient prolongation of PT and aPTT without clinical sequelae.
PubMed: 21403785
DOI: 10.2147/IJGM.S12170 -
Journal of Thoracic Oncology : Official... Jul 2008Patients with advanced non-small cell lung cancer (NSCLC) and impaired performance status (PS >or= 2) have limited life expectancies and decreased tolerance for... (Comparative Study)
Comparative Study Randomized Controlled Trial
Randomized phase III trial comparing single-agent paclitaxel Poliglumex (CT-2103, PPX) with single-agent gemcitabine or vinorelbine for the treatment of PS 2 patients with chemotherapy-naïve advanced non-small cell lung cancer.
BACKGROUND
Patients with advanced non-small cell lung cancer (NSCLC) and impaired performance status (PS >or= 2) have limited life expectancies and decreased tolerance for drug-induced toxicities. Current treatment guidelines indicate that PS 2 patients benefit from systemic therapy. Further refinement of treatment in these patients requires reduction of treatment-associated toxicities while maintaining or improving efficacy. Paclitaxel poliglumex (PPX), a macromolecular polymer-drug conjugate of paclitaxel and poly-l-glutamic acid, may enhance the therapeutic index of paclitaxel.
METHODS
Chemotherapy-naive PS 2 patients with advanced NSCLC randomly received single-agent PPX (175 mg/m) or a comparator (single-agent vinorelbine or gemcitabine). The primary end point of this study was overall survival.
RESULTS
Overall survival was similar between treatment arms (hazard ratio [HR] = 0.95; log-rank p = 0.686). Median and 1-year survival were 7.3 months and 26%, respectively, for PPX versus 6.6 months and 26% for the control arm. There was a nonsignificant trend toward improved survival in women in the PPX arm compared with standard single agents (HR = 0.65; p = 0.069). The most frequent grade 3/4 adverse events in the treatment versus control arm were dyspnea (13% versus 17%, respectively) and fatigue (10% versus 9%). Grade 3/4 neutropenia and anemia were reduced in the PPX arm (2% versus 8% and 3% versus 9%, respectively). Neuropathy, a taxane-specific toxicity, was more common in the PPX arm; grade 3 neuropathy was limited to 3%.
CONCLUSIONS
Single-agent PPX, dosed at 175 mg/m, is active and well tolerated in PS 2 patients with advanced NSCLC. Patients on PPX required fewer red blood cell transfusions, hematopoietic growth factors, opioid analgesics, and clinic visits than patients receiving gemcitabine or vinorelbine.
Topics: Antimetabolites, Antineoplastic; Antineoplastic Agents, Phytogenic; Carcinoma, Non-Small-Cell Lung; Deoxycytidine; Female; Humans; Lung Neoplasms; Male; Middle Aged; Paclitaxel; Polyglutamic Acid; Survival Rate; Gemcitabine
PubMed: 18594318
DOI: 10.1097/JTO.0b013e31817c6b68 -
American Journal of Clinical Oncology Apr 2014Capecitabine and paclitaxel are established effective treatments, alone and combined with other cytotoxic and targeted agents, for metastatic breast cancer (MBC)....
BACKGROUND
Capecitabine and paclitaxel are established effective treatments, alone and combined with other cytotoxic and targeted agents, for metastatic breast cancer (MBC). Paclitaxel polyglumex (a macromolecular conjugate of paclitaxel bound to poly-L-glutamic acid) has potential advantages over conventional paclitaxel, including little alopecia, short infusion time with no premedication, enhanced tumor permeability/retention effect, and improved tolerability. We therefore examined tolerability and efficacy of paclitaxel polyglumex with capecitabine in patients with MBC.
PATIENTS AND METHODS
This was a single-stage phase 2 study, with interim analysis conducted with endpoints of tumor response, adverse events (toxicities), time to progression, and overall survival. The main eligibility criteria were: age >18 years, no prior MBC chemotherapy, Eastern Cooperative Oncology Group performance score <2, disease measurable by RECIST criteria, no HER2 overexpression or amplification, no brain metastases or peripheral sensory neuropathy. Treatment consisted of paclitaxel polyglumex (135 mg/m) by intravenous infusion on day 1+capecitabine (825 mg/m) orally twice daily on days 1 to 14, repeated on a 3-week cycle. Forty-one evaluable patients were required to test the null hypothesis that the complete and partial tumor response rate (CR+PR) was at the most 40% against the alternative of at least 60%. Paclitaxel polyglumex+capecitabine would be considered promising in this population if ≥21 responses were observed among first 41 evaluable patients.
RESULTS
Forty-eight patients were enrolled between April 2006 and April 2007; all patients were evaluable. The median number of treatment cycles administered was 6. Eighteen patients [38%; 95% confidence interval (CI), 24%-53%] had a confirmed tumor response (2 CR, 16 PR) by RECIST criteria. Fifteen (38%; 95% CI, 23%-53%) responses occurred in first 41 patients, falling short of prespecified goal of 21 responses. Median duration of tumor response was 13.2 months. Three of the responders were progression free at last follow-up with a median follow-up of 43 months. Median progression-free survival was 5.1 months (95% CI, 4.0-7.6 mo). Six-month progression-free survival was 42% (95% CI, 30%-58%). Median dose level administered was paclitaxel polyglumex (135 mg/m) and capecitabine (825 mg/m) for cycles 1 to 7. Most common severe (grade 3/4) toxicities (at least possibly related to study drug) were: leukopenia 9 (19%), neutropenia 8 (17%), neurosensory 4 (8%), skin reaction-hand/foot 4 (8%), and dyspnea 2 (4%). Forty-six percent (22/47) of patients experienced grade ≥3 toxicity and 8% (4/48) experienced grade ≥4 toxicity. No alopecia was reported.
CONCLUSIONS
Although the trial failed to reach goal of 21 confirmed tumor responses among the first 41 evaluable patients, paclitaxel polyglumex and capecitabine is well tolerated and effective in MBC.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Capecitabine; Deoxycytidine; Disease-Free Survival; Drug Administration Schedule; Female; Fluorouracil; Follow-Up Studies; Humans; Leukopenia; Middle Aged; Neutropenia; Paclitaxel; Polyglutamic Acid; Proportional Hazards Models; Treatment Outcome
PubMed: 23211220
DOI: 10.1097/COC.0b013e31826e0550 -
Journal of Clinical Oncology : Official... Dec 2022To compare taxane maintenance chemotherapy, paclitaxel (P) and paclitaxel poliglumex (PP), with surveillance (S) in women with ovarian, peritoneal, or fallopian tube... (Randomized Controlled Trial)
Randomized Controlled Trial
Phase III Randomized Trial of Maintenance Taxanes Versus Surveillance in Women With Advanced Ovarian/Tubal/Peritoneal Cancer: A Gynecologic Oncology Group 0212:NRG Oncology Study.
PURPOSE
To compare taxane maintenance chemotherapy, paclitaxel (P) and paclitaxel poliglumex (PP), with surveillance (S) in women with ovarian, peritoneal, or fallopian tube (O/PC/FT) cancer who attained clinical complete response after first-line platinum-taxane therapy.
METHODS
Women diagnosed with O/PC/FT cancer who attained clinical complete response after first-line platinum-taxane-based chemotherapy were randomly allocated 1:1:1 to S or maintenance, P 135 mg/m once every 28 days for 12 cycles, or PP at the same dose and schedule. Overall survival (OS) was the primary efficacy end point.
RESULTS
Between March 2005 and January 2014, 1,157 individuals were enrolled. Grade 2 or worse GI adverse events were more frequent among those treated with taxane (PP: 20%, P: 27% S: 11%). Grade 2 or worse neurologic adverse events occurred more often with taxane treatment (PP: 46%, P: 36% S: 14%). At the fourth scheduled interim analysis, both taxane regimens passed the OS futility boundary and the Data Monitoring Committee approved an early release of results. With a median follow-up of 8.1 years, 653 deaths were reported; none were attributed to the study treatment. Median survival durations were 58.3, 56.8, and 60.0 months for S, P, and PP, respectively. Relative to S, the hazard of death for P was 1.091 (95% CI, 0.911 to 1.31; = .343) and for PP, it was 1.033 (95% CI, 0.862 to 1.24; = .725). The median times to first progression or death (PFS) were 13.4, 18.9, and 16.3 months for S, P, and PP, respectively. Hazard ratio = 0.801; 95% CI, 0.684 to 0.938; = .006 for P and hazard ratio = 0.854; 95% CI, 0.729 to 1.00; = .055 for PP.
CONCLUSION
Maintenance therapy with P and PP did not improve OS among patients with newly diagnosed O/tubal/peritoneal cancer, but may modestly increase PFS. GI and neurologic toxicities were more frequent in the taxane treatment arms.
Topics: Female; Humans; Platinum; Medical Futility; Neoplasms
PubMed: 35759733
DOI: 10.1200/JCO.22.00146