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Jack W. Singer - One of the best experts on this subject based on the ideXlab platform.
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Biological and clinical characterization
2016Co-Authors: Stewart D Chipman, Jack W. Singer, Fred B. Oldham, Gabriella Pezzoni, Cell Therapeutics IncAbstract:of Paclitaxel Poliglumex (PPX, CT-2103)
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Procoagulant inhibitory properties of Paclitaxel Poliglumex.
International journal of general medicine, 2010Co-Authors: John Nemunaitis, Jack W. Singer, Neil Senzer, Barry Cooper, Michael Nemunaitis, Cynthia Bedell, Fred B. OldhamAbstract: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/m2. This Phase I, open-label, nonrandomized pilot study was performed to study the effect of the standard dose regimen on blood coagulation.
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Poly- l -Glutamic Acid Anti-cancer Drug Conjugates
Macromolecular Anticancer Therapeutics, 2009Co-Authors: Jack W. Singer, Cecilia Allievi, Patrizia Angiuli, Gabriella Pezzoni, Marc Mckennon, Stefano Di Giovine, Mara Cassin, Paola De Feudis, Marco Natangelo, Enrico VezzaliAbstract:Cytotoxic chemotherapeutic agents are the mainstay of anti-cancer therapy. Improvements in the therapeutic ratio of cytotoxic anti-cancer drugs remain a major unmet need as these agents are limited by toxicity to normal organs and relatively modest anti-tumor efficacy as a result of lack of specificity. Cytotoxic drugs target rapidly dividing cells in normal tissues with similar effects to those in tumor tissue. One approach to overcoming these deficiencies is to chemically conjugate cytotoxic molecules such as Paclitaxel to a macromolecular carrier. This creates new chemical entities that enhance distribution to tumor tissues, render hydrophobic agents water soluble, potentially decrease toxicity to normal organs, and enhance efficacy. Our group has focused on covalently linking cytotoxic agents to a macromolecular peptide polymer, poly-l-glutamic acid (PGA). PGA was selected for its large number of potential binding sites, high aqueous solubility, lack of immunogenicity, and its biodegradability. This chapter focuses on the developmental challenges associated with polymer therapeutics, using as an example, CT-2103, generically named Paclitaxel Poliglumex. Sections are devoted to chemistry, manufacturing, and controls specifically addressing development of characterization methods and release specifications for this complex molecule; preclinical pharmacology and toxicology; pharmacokinetics and metabolism including an interaction with estradiol; and clinical development through Phase III trials. A brief review of a second PGA conjugate with camptothecin, CT-2106, is also included.
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A phase I and pharmacokinetic study of Paclitaxel Poliglumex and cisplatin in patients with advanced solid tumors.
Cancer chemotherapy and pharmacology, 2008Co-Authors: Claire F. Verschraegen, Cecilia Allievi, Jack W. Singer, Keith M. Skubitz, Adil Daud, Andrzej Kudelka, Ian Rabinowitz, Amy J. Eisenfeld, Fred B. OldhamAbstract:Purpose Determine the toxicity, maximum tolerated dose (MTD), and pharmacokinetics of Paclitaxel Poliglumex (PPX; CT-2103) in combination with cisplatin administered every 3 weeks.
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Serum-free estradiol (E2) levels are prognostic in men with chemotherapy-naive advanced non-small cell lung cancer (NSCLC) and performance status (PS) 2
Journal of Clinical Oncology, 2007Co-Authors: Helen J Ross, Fred B. Oldham, P. Bonomi, B. Bandstra, L. Sandalic, J. Bianco, Jack W. SingerAbstract:7683 Background: In women with advanced NSCLC, premenopausal estradiol levels are associated with a worse survival than postmenopausal levels, suggesting an adverse effect of estradiol on prognosis in NSCLC (JCO 2006, 24(18S):7038; JCO 2006, 24:59–63). Levels of E2, produced from testosterone by aromatase, are often higher in men than in postmenopausal women (Ann Intern Med. 2000, 133:951–63). To investigate the effect of E2 on prognosis in male patients (pts) with advanced NSCLC, total and free E2 levels were assayed in pretreatment samples from men participating in 2 randomized phase III studies, STELLAR 3 and 4. Methods: Free serum E2 levels were measured prior to chemotherapy using a radioimmuno-assay in samples from 289/307 male pts with advanced NSCLC and PS2 enrolled in STELLAR 3 (Paclitaxel + carboplatin (C) v. Paclitaxel Poliglumex (PPX) + C) and STELLAR 4 (vinorelbine or gemcitabine v. PPX). The effect of free E2 levels on survival was evaluated by log rank test. Male pts were categorized as hig...
Mark A Socinski - One of the best experts on this subject based on the ideXlab platform.
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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 naive advanced non small cell lung cancer
Journal of Thoracic Oncology, 2008Co-Authors: Corey J Langer, Kenneth J Obyrne, Mark A Socinski, Sergei M Mikhailov, Krzysztof Leśniewskikmak, M Smakal, Tudor Ciuleanu, Sergey Orlov, Mircea Dediu, David F HeigenerAbstract:Free to read at publisher's site. 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 ≥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. © 2008International Association for the Study of Lung Cancer.
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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 naive advanced non small cell lung cancer
Faculty of Health; Institute of Health and Biomedical Innovation, 2008Co-Authors: Corey J Langer, Kenneth J Obyrne, Mark A Socinski, Sergei M Mikhailov, Krzysztof Leśniewskikmak, M Smakal, Tudor Ciuleanu, Sergey Orlov, Mircea Dediu, David F HeigenerAbstract: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 ≥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. © 2008International Association for the Study of Lung Cancer.
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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-naive advanced non-small cell lung cancer
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, 2008Co-Authors: Mary O'brien, Mark A Socinski, Alexander Y. Popovich, Igor Bondarenko, Antoaneta Tomova, Borys T. Bilynsky˘ı, Yevhen Hotko, Valentin L. Ganul, Ippolit Y. Kostinsky, Amy J. EisenfeldAbstract:Background Patients with advanced non-small cell lung cancer (NSCLC) and impaired performance status (PS ≥ 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 2 ) 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 2 , 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.
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Analysis of prognostic factors in chemo-naïve patients with advanced NSCLC and poor performance status (PS): Cox regression analysis of two phase III trials
Journal of Clinical Oncology, 2006Co-Authors: M. O'brien, Helen J Ross, Mark A Socinski, P. Bonomi, C. J. Langer, Kenneth J. O'byrne, B. Bandstra, Alan Sandler, Luis Paz-aresAbstract:7113 Background: Two phase III trials in chemo-naive PS2 patients with advanced NSCLC compared Paclitaxel Poliglumex (PPX) to either gemcitabine or vinorelbine (STELLAR 4), or PPX/carboplatin to Paclitaxel/carboplatin (STELLAR 3). While overall survival (OS) was similar between treatment arms in both studies, individual patient characteristics may be predictive of benefit. Methods: STELLAR 3 and STELLAR 4 enrolled 400 and 381 chemo-naive PS2 patients, respectively. The impact of pre-defined baseline characteristics on OS was evaluated by univariate and step-wise multivariate Cox regression analysis. Treatment differences between subgroups were also estimated by Cox analysis. Results: Univariate Cox analysis of potential risk factors showed pre-baseline weight loss, extra-thoracic metastasis, and a low lung cancer symptom (LCS) score to be highly significant (p < 0.001). In STELLAR 4, tobacco use was also a highly significant risk factor. Important primary baseline factors predicting survival as determined...
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Analysis of prognostic factors in patients with advanced relapsed/refractory NSCLC: Cox regression analysis of a randomized phase III trial comparing docetaxel and Paclitaxel Poliglumex (PPX)
Journal of Clinical Oncology, 2006Co-Authors: P. Bonomi, Helen J Ross, Luis Paz-ares, M. O'brien, C. J. Langer, Kenneth J. O'byrne, B. Bandstra, Alan Sandler, Mark A SocinskiAbstract:7040 Background: A phase III trial compared PPX to docetaxel as 2nd-line treatment in pts with relapsed/refractory advanced NSCLC (STELLAR 2). While overall survival was similar between arms, the need for supportive measures to manage the effects of myelosuppression was significantly reduced in the PPX arm. The current analysis was performed to evaluate determinants of survival in the 2nd-line treatment of NSCLC. Methods: STELLAR 2 enrolled 849 pts, 427 on PPX and 422 on docetaxel; all patients were included in the analysis. Randomization between the study arms was stratified by tumor stage, performance status (PS), start of frontline chemotherapy (< 4 mo vs more than 4 mo), gender, and prior taxane therapy. Univariate and multivariate Cox regression analyses were performed to evaluate the impact of baseline characteristics on overall survival (OS). Results: At randomization, 29% of pts had received prior taxane, 14% were PS2, 80% had stage IV disease, and 31% had started frontline therapy within the prio...
P. Bonomi - One of the best experts on this subject based on the ideXlab platform.
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Phase II trial of Paclitaxel Poliglumex (CT-2103) in pre- and post-menopausal women on hormonal replacement therapy (HRT) with non-small cell lung cancer (NSCLC).
Journal of Clinical Oncology, 2011Co-Authors: Marta Batus, R. Mohajer, D. Pach, Sanjib Basu, Mary J. Fidler, P. BonomiAbstract:e18047 Background: Relationship of estrogen use, smoking, and NSCLC has been reported in several studies. Capthesin B is expressed on most NSCLC and is the major metabolizing enzyme for CT-2103. It...
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Serum-free estradiol (E2) levels are prognostic in men with chemotherapy-naive advanced non-small cell lung cancer (NSCLC) and performance status (PS) 2
Journal of Clinical Oncology, 2007Co-Authors: Helen J Ross, Fred B. Oldham, P. Bonomi, B. Bandstra, L. Sandalic, J. Bianco, Jack W. SingerAbstract:7683 Background: In women with advanced NSCLC, premenopausal estradiol levels are associated with a worse survival than postmenopausal levels, suggesting an adverse effect of estradiol on prognosis in NSCLC (JCO 2006, 24(18S):7038; JCO 2006, 24:59–63). Levels of E2, produced from testosterone by aromatase, are often higher in men than in postmenopausal women (Ann Intern Med. 2000, 133:951–63). To investigate the effect of E2 on prognosis in male patients (pts) with advanced NSCLC, total and free E2 levels were assayed in pretreatment samples from men participating in 2 randomized phase III studies, STELLAR 3 and 4. Methods: Free serum E2 levels were measured prior to chemotherapy using a radioimmuno-assay in samples from 289/307 male pts with advanced NSCLC and PS2 enrolled in STELLAR 3 (Paclitaxel + carboplatin (C) v. Paclitaxel Poliglumex (PPX) + C) and STELLAR 4 (vinorelbine or gemcitabine v. PPX). The effect of free E2 levels on survival was evaluated by log rank test. Male pts were categorized as hig...
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Serum cathepsin B (CB) levels are prognostic in chemotherapy-naive patients (pts) with advanced non-small cell lung cancer (NSCLC) and performance status (PS) of 2
Journal of Clinical Oncology, 2007Co-Authors: Jack W. Singer, Fred B. Oldham, P. Bonomi, B. Bandstra, L. Sandalic, J. Bianco, Helen J RossAbstract:18036 Background: CB is an estrogen-influenced lysosomal cysteine protease produced by tumor cells and tumor-associated macrophages; tumor tissue CB protein levels and proteolytic activity are prognostic in NSCLC (Anticancer Res. 2004; 24:4147–61). The prognostic value of serum CB has not previously been evaluated in NSCLC. Here we evaluate the impact of pretreatment CB levels on survival in pts from 2 phase III trials in advanced NSCLC, STELLAR 3 and 4. These trials compared Paclitaxel Poliglumex (PPX) against commonly used regimens. As the intratumoral metabolic pathway of PPX is characterized by the CB-mediated release of Paclitaxel (P) from a polymeric backbone (Ca Chemother Pharm. 2006. Epub ahead of print), correlation of CB levels with PPX efficacy was assessed as well. Methods: Pretreatment serum samples from 450 chemo-naive pts with advanced NSCLC and PS 2 enrolled in STELLAR 3 (P + carboplatin (C) v. PPX + C) (N=315) and STELLAR 4 (vinorelbine or gemcitabine v. PPX) (N=135) were assayed for CB b...
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Analysis of prognostic factors in chemo-naïve patients with advanced NSCLC and poor performance status (PS): Cox regression analysis of two phase III trials
Journal of Clinical Oncology, 2006Co-Authors: M. O'brien, Helen J Ross, Mark A Socinski, P. Bonomi, C. J. Langer, Kenneth J. O'byrne, B. Bandstra, Alan Sandler, Luis Paz-aresAbstract:7113 Background: Two phase III trials in chemo-naive PS2 patients with advanced NSCLC compared Paclitaxel Poliglumex (PPX) to either gemcitabine or vinorelbine (STELLAR 4), or PPX/carboplatin to Paclitaxel/carboplatin (STELLAR 3). While overall survival (OS) was similar between treatment arms in both studies, individual patient characteristics may be predictive of benefit. Methods: STELLAR 3 and STELLAR 4 enrolled 400 and 381 chemo-naive PS2 patients, respectively. The impact of pre-defined baseline characteristics on OS was evaluated by univariate and step-wise multivariate Cox regression analysis. Treatment differences between subgroups were also estimated by Cox analysis. Results: Univariate Cox analysis of potential risk factors showed pre-baseline weight loss, extra-thoracic metastasis, and a low lung cancer symptom (LCS) score to be highly significant (p < 0.001). In STELLAR 4, tobacco use was also a highly significant risk factor. Important primary baseline factors predicting survival as determined...
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Analysis of prognostic factors in patients with advanced relapsed/refractory NSCLC: Cox regression analysis of a randomized phase III trial comparing docetaxel and Paclitaxel Poliglumex (PPX)
Journal of Clinical Oncology, 2006Co-Authors: P. Bonomi, Helen J Ross, Luis Paz-ares, M. O'brien, C. J. Langer, Kenneth J. O'byrne, B. Bandstra, Alan Sandler, Mark A SocinskiAbstract:7040 Background: A phase III trial compared PPX to docetaxel as 2nd-line treatment in pts with relapsed/refractory advanced NSCLC (STELLAR 2). While overall survival was similar between arms, the need for supportive measures to manage the effects of myelosuppression was significantly reduced in the PPX arm. The current analysis was performed to evaluate determinants of survival in the 2nd-line treatment of NSCLC. Methods: STELLAR 2 enrolled 849 pts, 427 on PPX and 422 on docetaxel; all patients were included in the analysis. Randomization between the study arms was stratified by tumor stage, performance status (PS), start of frontline chemotherapy (< 4 mo vs more than 4 mo), gender, and prior taxane therapy. Univariate and multivariate Cox regression analyses were performed to evaluate the impact of baseline characteristics on overall survival (OS). Results: At randomization, 29% of pts had received prior taxane, 14% were PS2, 80% had stage IV disease, and 31% had started frontline therapy within the prio...
Helen J Ross - One of the best experts on this subject based on the ideXlab platform.
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phase iii trial comparing Paclitaxel Poliglumex vs docetaxel in the second line treatment of non small cell lung cancer
British Journal of Cancer, 2008Co-Authors: L Pazares, Helen J Ross, Mary Obrien, A Riviere, U Gatzemeier, J Von Pawel, E Kaukel, Lutz Freitag, W Digel, H G BischoffAbstract: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.
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Phase III trial comparing Paclitaxel Poliglumex vs docetaxel in the second-line treatment of non-small-cell lung cancer
British journal of cancer, 2008Co-Authors: Luis Paz-ares, Helen J Ross, A Riviere, U Gatzemeier, J Von Pawel, E Kaukel, Lutz Freitag, W Digel, Mary O'brien, Helge BischoffAbstract: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
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Serum-free estradiol (E2) levels are prognostic in men with chemotherapy-naive advanced non-small cell lung cancer (NSCLC) and performance status (PS) 2
Journal of Clinical Oncology, 2007Co-Authors: Helen J Ross, Fred B. Oldham, P. Bonomi, B. Bandstra, L. Sandalic, J. Bianco, Jack W. SingerAbstract:7683 Background: In women with advanced NSCLC, premenopausal estradiol levels are associated with a worse survival than postmenopausal levels, suggesting an adverse effect of estradiol on prognosis in NSCLC (JCO 2006, 24(18S):7038; JCO 2006, 24:59–63). Levels of E2, produced from testosterone by aromatase, are often higher in men than in postmenopausal women (Ann Intern Med. 2000, 133:951–63). To investigate the effect of E2 on prognosis in male patients (pts) with advanced NSCLC, total and free E2 levels were assayed in pretreatment samples from men participating in 2 randomized phase III studies, STELLAR 3 and 4. Methods: Free serum E2 levels were measured prior to chemotherapy using a radioimmuno-assay in samples from 289/307 male pts with advanced NSCLC and PS2 enrolled in STELLAR 3 (Paclitaxel + carboplatin (C) v. Paclitaxel Poliglumex (PPX) + C) and STELLAR 4 (vinorelbine or gemcitabine v. PPX). The effect of free E2 levels on survival was evaluated by log rank test. Male pts were categorized as hig...
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Serum cathepsin B (CB) levels are prognostic in chemotherapy-naive patients (pts) with advanced non-small cell lung cancer (NSCLC) and performance status (PS) of 2
Journal of Clinical Oncology, 2007Co-Authors: Jack W. Singer, Fred B. Oldham, P. Bonomi, B. Bandstra, L. Sandalic, J. Bianco, Helen J RossAbstract:18036 Background: CB is an estrogen-influenced lysosomal cysteine protease produced by tumor cells and tumor-associated macrophages; tumor tissue CB protein levels and proteolytic activity are prognostic in NSCLC (Anticancer Res. 2004; 24:4147–61). The prognostic value of serum CB has not previously been evaluated in NSCLC. Here we evaluate the impact of pretreatment CB levels on survival in pts from 2 phase III trials in advanced NSCLC, STELLAR 3 and 4. These trials compared Paclitaxel Poliglumex (PPX) against commonly used regimens. As the intratumoral metabolic pathway of PPX is characterized by the CB-mediated release of Paclitaxel (P) from a polymeric backbone (Ca Chemother Pharm. 2006. Epub ahead of print), correlation of CB levels with PPX efficacy was assessed as well. Methods: Pretreatment serum samples from 450 chemo-naive pts with advanced NSCLC and PS 2 enrolled in STELLAR 3 (P + carboplatin (C) v. PPX + C) (N=315) and STELLAR 4 (vinorelbine or gemcitabine v. PPX) (N=135) were assayed for CB b...
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Analysis of prognostic factors in chemo-naïve patients with advanced NSCLC and poor performance status (PS): Cox regression analysis of two phase III trials
Journal of Clinical Oncology, 2006Co-Authors: M. O'brien, Helen J Ross, Mark A Socinski, P. Bonomi, C. J. Langer, Kenneth J. O'byrne, B. Bandstra, Alan Sandler, Luis Paz-aresAbstract:7113 Background: Two phase III trials in chemo-naive PS2 patients with advanced NSCLC compared Paclitaxel Poliglumex (PPX) to either gemcitabine or vinorelbine (STELLAR 4), or PPX/carboplatin to Paclitaxel/carboplatin (STELLAR 3). While overall survival (OS) was similar between treatment arms in both studies, individual patient characteristics may be predictive of benefit. Methods: STELLAR 3 and STELLAR 4 enrolled 400 and 381 chemo-naive PS2 patients, respectively. The impact of pre-defined baseline characteristics on OS was evaluated by univariate and step-wise multivariate Cox regression analysis. Treatment differences between subgroups were also estimated by Cox analysis. Results: Univariate Cox analysis of potential risk factors showed pre-baseline weight loss, extra-thoracic metastasis, and a low lung cancer symptom (LCS) score to be highly significant (p < 0.001). In STELLAR 4, tobacco use was also a highly significant risk factor. Important primary baseline factors predicting survival as determined...
F. B. Oldham - One of the best experts on this subject based on the ideXlab platform.
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Medical resource utilization (MRU) and costs associated with Paclitaxel Poliglumex (PPX) compared to gemcitabine (Gem) or vinorelbine (Vin) in non-small cell lung cancer (NSCLC) patients
Journal of Clinical Oncology, 2007Co-Authors: F. B. Oldham, K. P. Anastassopoulos, K. O'byrne, M. S. Maxon, C. P. SchaeferAbstract:18172 Background: NSCLC accounts for 80% of lung cancer cases and is commonly treated with taxanes. PPX is a phase III, biologically-enhanced, investigational, chemotherapeutic for treatment of NSC...
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Paclitaxel Poliglumex (PPX), cisplatin and concurrent radiation for esophageal and gastric cancer: A phase I study
Journal of Clinical Oncology, 2007Co-Authors: T. Dipetrillo, F. B. Oldham, Paul A. Akerman, Thomas J. Miner, Devon Evans, R. Millis, Maureen Jean, D. Henderson, A. Eisenfeld, Howard SafranAbstract:15130 Background: PPX is a conjugate of Paclitaxel to a polyglutamate polymer. Preclinically, PPX demonstrated a radiation enhancement factor (REF) >7.0, versus 1.5–2.0 for Paclitaxel. (Milas et al Int J Rad Onc 55:2003, Li et al. Clin Cancer Res 6:2000). The maximally tolerated dose (MTD) of PPX was determined previously to be 70 mg/m2 /week with concurrent radiation. We initiated a phase I study of PPX, cisplatin, and concurrent radiation with patients with esophageal and gastric cancer. Methods: Patients with esophageal or gastric cancer receiving chemoradiation for locoregional control, adjuvant, or neoadjuvant treatment were eligible. All patients received radiation at a dose of 50.4 Gy delivered in 28 fractions (5 fractions per week for 5 1/2 weeks), and cisplatin (25 mg/m2) on days 1, 8, 15, 22, 29, and 36. PPX was given as a 10 minute infusion in escalating dosages prior to each cisplatin dose. Dose limiting toxicities (DLTs) were defined as grade 4 hematologic toxicity, esophagitis, nausea/vomiting, or dehydration, or any other grade 3/4 non-hematologic toxicity. Patients were enrolled in successive cohorts of three. The MTD was defined as the dose level at which no more than 2 of 6 patients have DLTs. Results: Eleven patients have been entered over 2 dose levels of PPX: 50 mg/m2 (six patients, dose level 1), and 60mg/m2 (5 patients, dose level 2). Five patients had esophageal cancer and six had gastric cancer. All histologies were adenocarcinomas. One of six patients treated at dose level had a DLT (esophagitis). Three of five patients had DLTs at dose level 2, including esophagitis, nausea, vomiting, and dehydration. Conclusions: PPX is a novel radiation sensitizer for patients with esophageal and gastric cancer. The MTD for PPX is 50 mg/m2 /week in combination with cisplatin 25mg/ m2 /week for 6 weeks, and 50.4 Gy concurrent radiation for patients with esophagogastric cancer. A phase II study of PPX/cisplatin and radiation will be initiated. No significant financial relationships to disclose.
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phase ii study of Paclitaxel Poliglumex ppx carboplatin c for 1st line induction and maintenance therapy of stage iii iv ovarian or primary peritoneal carcinoma
Journal of Clinical Oncology, 2005Co-Authors: T. Herzog, R. J. Barret, R. Edwards, F. B. OldhamAbstract:5012 Background: C/Paclitaxel (P) treatment, with a 70% complete response rate based on CA 125, is standard induction therapy for ovarian cancer. PPX (XYOTAX), a macromolecular drug conjugate that links P with a biodegradable polymer, poly-L-glutamic acid, is water soluble and can be administered as a 10 min infusion. Eliminating the need for CremophorEL reduces the risk of hypersensitivity reactions, even without premedication. The safety and efficacy of PPX/C for induction therapy followed by single agent PPX for maintenance therapy were evaluated. Methods: 82 patients (pts) with newly diagnosed stage III/IV ovarian or primary peritoneal carcinoma who had standard debulking surgery for their disease were enrolled. Pts received induction therapy of C (AUC 6) + 175 (62 pts) or 210 mg/m2 (20 pts) PPX as a 10 min IV infusion Q3 weeks. Pts with ≥stable disease after 4–6 cycles receive single-agent maintenance therapy (175 mg/m2 PPX, Q4 weeks X 12). NCI CTC (v 2) is used to assess safety. Response is based on...
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Phase II study of Paclitaxel Poliglumex (PPX) /carboplatin (C) for 1st line induction and maintenance therapy of stage III/IV ovarian or primary peritoneal carcinoma
Journal of Clinical Oncology, 2005Co-Authors: T. Herzog, R. J. Barret, R. Edwards, F. B. OldhamAbstract:5012 Background: C/Paclitaxel (P) treatment, with a 70% complete response rate based on CA 125, is standard induction therapy for ovarian cancer. PPX (XYOTAX), a macromolecular drug conjugate that links P with a biodegradable polymer, poly-L-glutamic acid, is water soluble and can be administered as a 10 min infusion. Eliminating the need for CremophorEL reduces the risk of hypersensitivity reactions, even without premedication. The safety and efficacy of PPX/C for induction therapy followed by single agent PPX for maintenance therapy were evaluated. Methods: 82 patients (pts) with newly diagnosed stage III/IV ovarian or primary peritoneal carcinoma who had standard debulking surgery for their disease were enrolled. Pts received induction therapy of C (AUC 6) + 175 (62 pts) or 210 mg/m2 (20 pts) PPX as a 10 min IV infusion Q3 weeks. Pts with ≥stable disease after 4–6 cycles receive single-agent maintenance therapy (175 mg/m2 PPX, Q4 weeks X 12). NCI CTC (v 2) is used to assess safety. Response is based on...
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Paclitaxel Poliglumex (PPX) and concurrent radiation for treatment of patients with esophageal or gastric cancer: A dose-ranging study
Journal of Clinical Oncology, 2005Co-Authors: T. Dipetrillo, F. B. Oldham, Paul A. Akerman, B. Chauhan, Thomas J. Miner, D. Cruff, Tyvin A. Rich, A. Countouriotis, Howard SafranAbstract:4065 Background: Paclitaxel Poliglumex (XYOTAX) is a drug conjugate that links Paclitaxel to a biodegradable polymer, poly-L-glutamic acid. PPX is water-soluble and can be given as a 10-minute infu...
