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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 -
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 -
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 -
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 -
Clinical Lung Cancer Nov 2005The objectives of this open-labeled, multicenter, phase II trial were to evaluate response, survival, and tolerability in patients at high risk (Eastern Cooperative...
Efficacy and safety of paclitaxel poliglumex as first-line chemotherapy in patients at high risk with advanced-stage non-small-cell lung cancer: results of a phase II study.
BACKGROUND
The objectives of this open-labeled, multicenter, phase II trial were to evaluate response, survival, and tolerability in patients at high risk (Eastern Cooperative Oncology Group performance status [PS] of 2 or age >or= 70 years) with advanced-stage non-small-cell lung cancer (NSCLC) receiving single-agent paclitaxel poliglumex as first-line monotherapy.
PATIENTS AND METHODS
Paclitaxel poliglumex was administered as a 10-20-minute infusion on day 1 of each 3-week cycle. Thirty patients were enrolled: 28 received paclitaxel poliglumex 175 mg/m2, and 2 received 235 mg/m2. Patients exhibiting a partial response (PR; by Response Evaluation Criteria in Solid Tumors) or stable disease (SD) continued uninterrupted treatment with paclitaxel poliglumex for
RESULTS
Neither patient treated at the 235 mg/m2 dose was evaluable for response. The overall response rate was 7% (PR in 2 patients), and 16 patients (57%) experienced SD. Of the 20 patients with stage IV disease, 2 exhibited a PR, and 13 exhibited SD. Median duration of response in patients with SD or better was 9 weeks. Overall median survival was 6 months. Median survival for patients with a PS of 0/1 or 2 was 7.8 months and 5.7 months, respectively; median survival for patients aged >or= 70 years was 7.8 months. No grade 4 nonhematologic toxicities were reported. Three patients experienced grade 3 neuropathy. Weekly hematologic assessments showed grade 3 anemia in 2 patients, grade 3 neutropenia (not associated with neutropenic fever) in 3 patients, and grade 4 neutropenia in 2 patients. No patient required growth factor support.
CONCLUSION
The results of this study indicate that paclitaxel poliglumex is generally well tolerated and has activity at a dose level of 175 mg/m2 as first-line monotherapy in patients at high risk with advanced NSCLC.
Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Phytogenic; Carcinoma, Non-Small-Cell Lung; Disease Progression; Female; Humans; Infusions, Intravenous; Lung Neoplasms; Male; Middle Aged; Paclitaxel; Survival Analysis
PubMed: 16354318
DOI: 10.3816/CLC.2005.n.039 -
American Journal of Clinical Oncology Feb 2012To evaluate the pathologic complete response (CR) rate and safety of paclitaxel poliglumex (PPX), cisplatin, and concurrent radiation for patients with esophageal cancer.
PURPOSE
To evaluate the pathologic complete response (CR) rate and safety of paclitaxel poliglumex (PPX), cisplatin, and concurrent radiation for patients with esophageal cancer.
PATIENTS AND METHODS
Patients with adenocarcinoma or squamous cell carcinoma of the esophagus or gastroesophageal junction with no evidence of distant metastasis received PPX (50 mg/m(2)/wk) and cisplatin (25 mg/m(2)/wk) for 6 weeks with 50.4 Gy concurrent radiation. Six to eight weeks after completion of chemoradiotherapy, patients underwent surgical resection.
RESULTS
Forty patients were enrolled, 37 patients with adenocarcinoma and 3 patients with squamous cell cancer. The treatment-related grade 3 nonhematologic toxicities included esophagitis (7%), nausea (7%), and fatigue (5%). Three patients with clinical endoscopic CR (2 with squamous cell cancer) refused surgery. Twelve of the remaining 37 patients (32%) had a pathologic CR. The 12 patients with pathologic CR all had adenocarcinoma.
CONCLUSION
PPX, cisplatin, and concurrent radiation are well tolerated, easily administered regimen for esophageal cancer with a low incidence of significant esophagitis and a high pathologic CR rate consistent with the preclinical data of PPX and radiation.
Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Chemoradiotherapy, Adjuvant; Cisplatin; Dose Fractionation, Radiation; Drug Administration Schedule; Esophageal Neoplasms; Esophagectomy; Esophagitis; Esophagogastric Junction; Fatigue; Female; Humans; Male; Middle Aged; Nausea; Neoadjuvant Therapy; Paclitaxel; Polyglutamic Acid; Treatment Outcome
PubMed: 21297434
DOI: 10.1097/COC.0b013e318201a126 -
Cancer Chemotherapy and Pharmacology Jul 2009Paclitaxel poliglumex (PPX, also called Xyotax or CT-2103) is a water soluble macromolecular drug conjugate that links paclitaxel with a biodegradable polymer,...
BACKGROUND
Paclitaxel poliglumex (PPX, also called Xyotax or CT-2103) is a water soluble macromolecular drug conjugate that links paclitaxel with a biodegradable polymer, poly-L-glutamic acid. The recommended phase II dose of PPX every 3 week is 235 mg/m(2) administered over a 10-min infusion without premedication. This study was designed to determine the MTD and pharmacology of PPX administered weekly to patients with solid malignancies.
METHODS
The starting dose of weekly PPX was 20 mg/m(2). Each cycle consists of 6 weekly treatments with pharmacokinetics of PPX (the conjugated paclitaxel) and unconjugated paclitaxel obtained after the first and sixth dose. Three to six patients were enrolled at each dose level. Toxicity and response were assessed by the NCI Common Toxicity criteria version 2 and RECIST criteria, respectively.
RESULTS
Twenty-six patients were treated with PPX at the following dose levels: 20 mg/m(2) (five patients), 40 mg/m(2) (four patients), 60 mg/m(2) (four patients), 70 mg/m(2) (eight patients) and 80 mg/m(2) (five patients). Dose-limiting toxicities, consisting of grade 3 neutropenia, occurred in the 80 mg/m(2) cohort during cycle 1. Therefore, the dose recommended for phase II studies was 70 mg/m(2). In this cohort, a single dose-limiting event, consisting of diarrhea, was seen. Neuropathy and fatigue were the most common toxicities. No objective responses were noted. Pharmacokinetics was dose-proportional, and the degree of neutropenia related to drug exposure, but not to peak plasma concentration. There was no significant accumulation of conjugated or unconjugated paclitaxel with this dosing schedule.
CONCLUSIONS
The recommended dose of PPX for subsequent disease-directed studies is 70 mg/m(2) weekly.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Phytogenic; Drug Resistance, Neoplasm; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Staging; Neoplasms; Paclitaxel; Polyglutamic Acid; Prognosis; Salvage Therapy; Survival Rate; Treatment Outcome
PubMed: 19034451
DOI: 10.1007/s00280-008-0869-5 -
Cancer Chemotherapy and Pharmacology Mar 2007The efficacy and tolerability of paclitaxel is limited by its low solubility, high systemic exposure, and a lack of selective tumor uptake. Paclitaxel poliglumex (PPX;...
BACKGROUND
The efficacy and tolerability of paclitaxel is limited by its low solubility, high systemic exposure, and a lack of selective tumor uptake. Paclitaxel poliglumex (PPX; XYOTAX) is a macromolecular drug conjugate that was developed to overcome these limitations; the 2' hydroxyl group of paclitaxel is linked to a biodegradable polymer, poly-L: -glutamic acid, to form an inactive polymeric conjugate. PPX was previously shown to accumulate in tumor tissue, presumably by taking advantage of the hyperpermeable tumor vasculature and suppressed lymphatic clearance in tumor tissue.
METHODS
Because anti-tumor activity requires the release of paclitaxel from the polymer-drug conjugate, the current report characterizes PPX biodegradation and release of paclitaxel as determined by quantitative HPLC/mass spectral analysis.
RESULTS
The identification of monoglutamyl-paclitaxel metabolites in tumor tissue confirmed the in vivo metabolism of PPX in a panel of mouse tumor models. In vitro characterization of the metabolic pathway suggests that PPX can enter tumor cells, and is metabolized to form both mono- and diglutamyl-paclitaxel cleavage products. The intracellular formation of these intermediate metabolites is at least partially dependent on the proteolytic activity of the lysosomal enzyme cathepsin B; PPX metabolism is inhibited by a highly selective inhibitor of cathepsin B, CA-074. Reduced metabolism of PPX in livers and spleens from cathepsin B deficient mice confirms that cathepsin B is an important mediator of PPX metabolism in vivo; however, other proteolytic enzymes may contribute as well.
CONCLUSIONS
The cathepsin B-mediated release of paclitaxel may have therapeutic implications as cathepsin B is upregulated in malignant cells, particularly during tumor progression.
Topics: Animals; Antineoplastic Agents; Cathepsin B; Cell Line; Chromatography, High Pressure Liquid; Female; Male; Mass Spectrometry; Mice; Mice, Inbred C57BL; Mice, Knockout; Paclitaxel; Polyglutamic Acid
PubMed: 16924498
DOI: 10.1007/s00280-006-0296-4 -
Wiley Interdisciplinary Reviews.... May 2018Chemotherapy for cancer treatment is limited by the excessive toxicity to normal tissues. The design of chemodrug-loaded nanoformulations provides a unique approach to... (Review)
Review
Chemotherapy for cancer treatment is limited by the excessive toxicity to normal tissues. The design of chemodrug-loaded nanoformulations provides a unique approach to improve the treatment efficacy while minimizing toxicity. Despite the numerous publications of nanomedicine for the last several decades, however, only a small fraction of the developed nanoformulations have entered clinical trials, with even fewer being approved for clinical application. Poly(l-glutamic acid)-paclitaxel (PG-TXL) belongs to the few formulations that reached phase III clinical trials. Unfortunately, the development of PG-TXL stopped in 2016 due to the inability to show significant improvement over current standard care. This review will provide an overview of the preclinical and clinical evaluations of PG-TXL, and discuss lessons to be learned from this ordeal. The precise identification of suitable patients for clinical trial studies, deep understanding of the mechanisms of action, and an effective academic-industry partnership throughout all phases of drug development are important for the successful bench-to-bedside translation of new nanoformulations. This article is categorized under: Implantable Materials and Surgical Technologies > Nanomaterials and Implants Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Biology-Inspired Nanomaterials > Peptide-Based Structures.
Topics: Animals; Breast Neoplasms; Cell Line, Tumor; Clinical Trials as Topic; Drug Discovery; Drug Evaluation, Preclinical; Humans; Mice; Nanomedicine; Paclitaxel; Polyglutamic Acid; Research Design
PubMed: 28895304
DOI: 10.1002/wnan.1497 -
Anti-cancer Drugs Apr 2010Taxanes remain the only agents to extend survival in castration-resistant metastatic prostate cancer, but their impact on the natural history of this disease is modest....
A phase II study of paclitaxel poliglumex in combination with transdermal estradiol for the treatment of metastatic castration-resistant prostate cancer after docetaxel chemotherapy.
Taxanes remain the only agents to extend survival in castration-resistant metastatic prostate cancer, but their impact on the natural history of this disease is modest. We sought to test the hypothesis that increased delivery of taxane chemotherapy to the tumor through the use of a macromolecular polymer-drug conjugate of paclitaxel modulated by estradiol could extend the utility of this class of drugs. Patients with metastatic adenocarcinoma of the prostate who progressed despite standard hormonal therapy and after docetaxel-containing chemotherapy were treated with transdermal estradiol (0.2 mg/24 h) for 4 weeks followed by the same dose of transdermal estradiol and paclitaxel poliglumex (PPX; 150 mg/m intravenous) every 28 days. The primary objective was to determine the level of activity of the regimen measured using a fraction of patients who experienced a confirmed decline in serum prostate-specific antigen (PSA) of 50% or more. A two-stage phase II study designed to identify a response rate of > or =25% required three responders among 21 patients in the first stage. Twenty-one patients who received a median of two earlier chemotherapy regimens were enrolled in the trial between March 2007 and May 2008. During the estradiol-only treatment phase, no patient had a PSA decline in excess of 50% and lesser PSA declines that ranged from 8.8 to 34.1% were seen in five patients. No patients achieved a > or =50% PSA decline following the addition of PPX and there were no responses in measurable disease. The median time to progression was 4 weeks. In conclusion, this regimen of low-dose transdermal estradiol induction followed by PPX does not have activity in taxane pretreated patients with castration-resistant prostate cancer.
Topics: Administration, Cutaneous; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Dose-Response Relationship, Drug; Estradiol; Humans; Male; Middle Aged; Neoplasm Metastasis; Orchiectomy; Paclitaxel; Polyglutamic Acid; Prostatic Neoplasms; Taxoids
PubMed: 20016365
DOI: 10.1097/CAD.0b013e3283355211