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F A Greco - One of the best experts on this subject based on the ideXlab platform.
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Clinical studies with Etoposide phosphate.
Seminars in oncology, 1996Co-Authors: F A Greco, J D HainsworthAbstract:Over the past few years we have conducted several clinical studies with Etoposide phosphate (Etopophos; Bristol-Myers Squibb Company, Princeton, NJ). A phase I trial initially was performed to determine the maximum tolerated dose and pharmacokinetics. A brief intravenous infusion for 5 consecutive days was given every 3 weeks. Myelosuppression was the dose-limiting toxicity and other toxicities were quite similar to those associated with Etoposide. The maximum tolerated dose was 100 mg/m2/d for 5 consecutive days. No cytokine support was used in this phase I trial. Pharmacokinetic studies showed very rapid conversion of Etoposide phosphate to Etoposide. The kinetics of Etoposide phosphate were similar to those expected after a comparable Etoposide dose. We subsequently began three additional studies, including a phase II randomized comparison of Etoposide phosphate plus cisplatin versus Etoposide plus cisplatin in patients with small cell lung cancer, a study of low-dose continuous infusion daily Etoposide phosphate, and a high-dose Etoposide phosphate trial to determine the maximum tolerated dose given in concert with granulocyte colony-stimulating factor. The latter two studies are complete; these data are currently being evaluated. The phase II comparative trial was important and showed unequivocally that the response rate and toxicity with Etoposide phosphate plus cisplatin is equivalent to those with Etoposide plus cisplatin in patients with small cell lung cancer. In addition, it appears that there was no survival difference between these two treatment arms in this phase II trial of 120 patients. Etoposide phosphate is easier to administer than Etoposide and, considering all other factors, including total cost of administration, it is preferable to Etoposide for routine clinical use.
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Etoposide phosphate or Etoposide with cisplatin in the treatment of small cell lung cancer: randomized phase II trial.
Lung cancer (Amsterdam Netherlands), 1995Co-Authors: F A Greco, J D HainsworthAbstract:Etoposide phosphate, a water soluble prodrug of Etoposide, has several potential advantages including easier and more rapid administration, avoidance of large fluid loads, and elimination of hypersensitivity reactions and other problems related to the solubilizer. This randomized Phase II study was done to evaluate the efficacy and toxicity of Etoposide phosphate and Etoposide, when used in combination with cisplatin in the treatment of patients with small cell lung cancer. Previously untreated small cell lung cancer patients were randomized to receive cisplatin in combination with molar equivalent does of either Etoposide or Etoposide phosphate. The patients were evaluated with respect to response rate, time to progression, survival, and toxicity. Response rates with Etoposide phosphate and Etoposide were 61% (95% confidence interval 55-67%) and 58% (95% confidence interval 52-64%), respectively (P = 0.85). Median time to progression was 6.9 months for patients who received Etoposide phosphate and 7.0 months for those with Etoposide (P = 0.50). For extensive stage disease patients, median survival with Etoposide phosphate was 9.5 months versus 10 months for Etoposide (P = 0.93). The corresponding median survivals for patients with limited stage disease were > 16 months and 17 months, respectively (P = 0.62). Myelosuppression was the most common toxicity; Grade 3 and 4 leukopenia occurred in 63% of patients receiving Etoposide phosphate compared with 77% receiving Etoposide (P = 0.16). The combination of Etoposide phosphate and cisplatin is effective in the treatment of small cell lung cancer, and can be administered with acceptable toxicity. This study was not designed to be a formal Phase III comparative trial, but the efficacy and toxicity observed with this regimen were found to be similar to a standard Etoposide/cisplatin regimen, using molar equivalent Etoposide doses. Etoposide phosphate is preferable to Etoposide because it is easier to use.
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Phase II randomized study of cisplatin plus Etoposide phosphate or Etoposide in the treatment of small-cell lung cancer.
Journal of Clinical Oncology, 1995Co-Authors: John D. Hainsworth, N Levitan, G L Wampler, Chandra P. Belani, M S Seyedsadr, J Randolph, L P Schacter, F A GrecoAbstract:PURPOSEThis randomized phase II study evaluated the efficacy and toxicity of Etoposide phosphate when used in combination with cisplatin in the treatment of small-cell lung cancer.PATIENTS AND METHODSPatients with previously untreated small-cell lung cancer were randomized to receive cisplatin in combination with either Etoposide or Etoposide phosphate. Molar-equivalent doses of Etoposide and Etoposide phosphate were used. Response rate, time to progression, survival, and toxicity were compared.RESULTSMajor response rates with Etoposide phosphate and Etoposide were 61% (95% confidence interval, 55% to 67%) and 58% (95% confidence interval, 52% to 64%), respectively (P = .85). No significant differences in median time to progression or survival were observed in patients who received Etoposide phosphate versus Etoposide. Grade 3 and 4 leukopenia occurred in 63% of patients who received Etoposide phosphate compared with 77% who received Etoposide (P = .16).CONCLUSIONThe combination of Etoposide phosphate and...
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Bioavailability of low-dose oral Etoposide.
Journal of Clinical Oncology, 1993Co-Authors: Kenneth R. Hande, M G Krozely, F A Greco, John D. Hainsworth, David H. JohnsonAbstract:PURPOSETo determine the bioavailability of oral Etoposide capsules administered at doses of 100 mg and 400 mg.PATIENTS AND METHODSThe bioavailability of oral Etoposide was determined by measuring the area under the Etoposide plasma concentration versus time curve (AUC) following intravenous (IV) Etoposide administration and comparing that value to the AUC achieved following an oral dose administered 1 day later to the same patient. The bioavailability of a 100-mg oral dose of Etoposide was measured on 16 occasions in 11 patients. The bioavailability of a 400-mg dose was determined on 12 occasions in six patients.RESULTSThe mean (+/- SD) bioavailability following a 100-mg dose of oral Etoposide was 76% +/- 22%, which was significantly greater (P < .01) than the mean bioavailability of 48% +/- 18% following a 400-mg oral dose. The coefficient of variation in oral Etoposide bioavailability was significant: 29% with a 100-mg oral dose and 37% with a 400-mg dose.CONCLUSIONBioavailability of a 100-mg oral etopo...
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Etoposide kinetics in patients with obstructive jaundice.
Journal of Clinical Oncology, 1990Co-Authors: Kenneth R. Hande, F A Greco, John D. Hainsworth, Steven N. Wolff, G Reed, David H. JohnsonAbstract:The kinetics and urinary excretion of Etoposide and Etoposide glucuronide were determined in 11 patients with obstructive jaundice (bilirubin greater than 2.0 mg/dL) and in 23 patients with normal renal and hepatic function. Mean (+/- SE) measurements of clearance (24.5 +/- 2.06 v 26.5 +/- 2.05 mL/min/m2), half-life (5.7 +/- 0.5 v 6.4 +/- 0.5 hours), and volume of distribution (12.4 +/- 1.1 v 13.7 +/- 1.6 L/m2) were not significantly different in patients with jaundice when compared with controls. Similarly, Etoposide kinetics in three patients determined during a period of hyperbilirubinemia were not different from measurements made in the same patients following resolution of their obstructive jaundice. In patients with jaundice, 46% of an administered Etoposide dose was excreted in the urine as Etoposide compared with 35% in controls (P = .15). Urinary excretion of Etoposide glucuronide accounted for 29% of an administered Etoposide dose in control patients and 15% in those with hepatic obstruction (P = .03). Biliary Etoposide excretion measured in four patients with T-tubes was insignificant (less than 2.0% of an administered dose). The calculated renal clearance of Etoposide was 11.5 mL/min/m2 in patients with jaundice and 10.4 mL/min/m2 in controls (P = .53). Respective metabolic clearance was 4.9 and 6.9 mL/min/m2 in these two study groups (P = .13). Although hepatic metabolism of Etoposide may be slightly decreased in patients with obstructive jaundice, a modest increase in renal Etoposide excretion appears to compensate for this change, so that total clearance is similar in the patients with jaundice when compared with controls. No Etoposide dose reductions appear to be needed in treating patients with obstructive jaundice who have normal renal function.
John D. Hainsworth - One of the best experts on this subject based on the ideXlab platform.
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Etoposide phosphate or Etoposide with cisplatin in the treatment of small cell lung cancer: Randomized Phase II trial
Lung Cancer, 1995Co-Authors: F. Anthony Greco, John D. HainsworthAbstract:Abstract Etoposide phosphate, a water soluble prodrug of Etoposide, has several potential advantages including easier and more rapid administration, avoidance of large fluid loads, and elimination of hypersensitivity reactions and other problems related to the solubilizer. This randomized Phase II study was done to evaluate the efficacy and toxicity of Etoposide phosphate and Etoposide, when used in combination with cisplatin in the treatment of patients with small cell lung cancer. Previously untreated small cell lung cancer patients were randomized to receive cisplatin in combination with molar equivalent doses of either Etoposide or Etoposide phosphate. The patients were evaluated with respect to response rate, time to progression, survival, and toxicity. Response rates with Etoposide phosphate and Etoposide were 61% (95% confidence interval 55–67%) and 58% (95% confidence interval 52–64%), respectively (P = 0.85). Median time to progression was 6.9 months for patients who received Etoposide phosphate and 7.0 months for those with Etoposide (P = 0.50). For extensive stage disease patients, median survival with Etoposide phosphate was 9.5 months versus 10 months for Etoposide (P = 0.93). The corresponding median survivals for patients with limited stage disease were > 16 months and 17 months, respectively (P = 0.62). Myelosuppression was the most common toxicity; Grade 3 and 4 leukopenia occurred in 63% of patients receiving Etoposide phosphate compared with 77% receiving Etoposide (P = 0.16). The combination of Etoposide phosphate and cisplatin is effective in the treatment of small cell lung cancer, and can be administered with acceptable toxicity. This study was not designed to be a formal Phase III comparative trial, but the efficacy and toxicity observed with this regimen were found to be similar to a standard Etoposide/cisplatin regimen, using
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Phase II randomized study of cisplatin plus Etoposide phosphate or Etoposide in the treatment of small-cell lung cancer.
Journal of Clinical Oncology, 1995Co-Authors: John D. Hainsworth, N Levitan, G L Wampler, Chandra P. Belani, M S Seyedsadr, J Randolph, L P Schacter, F A GrecoAbstract:PURPOSEThis randomized phase II study evaluated the efficacy and toxicity of Etoposide phosphate when used in combination with cisplatin in the treatment of small-cell lung cancer.PATIENTS AND METHODSPatients with previously untreated small-cell lung cancer were randomized to receive cisplatin in combination with either Etoposide or Etoposide phosphate. Molar-equivalent doses of Etoposide and Etoposide phosphate were used. Response rate, time to progression, survival, and toxicity were compared.RESULTSMajor response rates with Etoposide phosphate and Etoposide were 61% (95% confidence interval, 55% to 67%) and 58% (95% confidence interval, 52% to 64%), respectively (P = .85). No significant differences in median time to progression or survival were observed in patients who received Etoposide phosphate versus Etoposide. Grade 3 and 4 leukopenia occurred in 63% of patients who received Etoposide phosphate compared with 77% who received Etoposide (P = .16).CONCLUSIONThe combination of Etoposide phosphate and...
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Bioavailability of low-dose oral Etoposide.
Journal of Clinical Oncology, 1993Co-Authors: Kenneth R. Hande, M G Krozely, F A Greco, John D. Hainsworth, David H. JohnsonAbstract:PURPOSETo determine the bioavailability of oral Etoposide capsules administered at doses of 100 mg and 400 mg.PATIENTS AND METHODSThe bioavailability of oral Etoposide was determined by measuring the area under the Etoposide plasma concentration versus time curve (AUC) following intravenous (IV) Etoposide administration and comparing that value to the AUC achieved following an oral dose administered 1 day later to the same patient. The bioavailability of a 100-mg oral dose of Etoposide was measured on 16 occasions in 11 patients. The bioavailability of a 400-mg dose was determined on 12 occasions in six patients.RESULTSThe mean (+/- SD) bioavailability following a 100-mg dose of oral Etoposide was 76% +/- 22%, which was significantly greater (P < .01) than the mean bioavailability of 48% +/- 18% following a 400-mg oral dose. The coefficient of variation in oral Etoposide bioavailability was significant: 29% with a 100-mg oral dose and 37% with a 400-mg dose.CONCLUSIONBioavailability of a 100-mg oral etopo...
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Etoposide kinetics in patients with obstructive jaundice.
Journal of Clinical Oncology, 1990Co-Authors: Kenneth R. Hande, F A Greco, John D. Hainsworth, Steven N. Wolff, G Reed, David H. JohnsonAbstract:The kinetics and urinary excretion of Etoposide and Etoposide glucuronide were determined in 11 patients with obstructive jaundice (bilirubin greater than 2.0 mg/dL) and in 23 patients with normal renal and hepatic function. Mean (+/- SE) measurements of clearance (24.5 +/- 2.06 v 26.5 +/- 2.05 mL/min/m2), half-life (5.7 +/- 0.5 v 6.4 +/- 0.5 hours), and volume of distribution (12.4 +/- 1.1 v 13.7 +/- 1.6 L/m2) were not significantly different in patients with jaundice when compared with controls. Similarly, Etoposide kinetics in three patients determined during a period of hyperbilirubinemia were not different from measurements made in the same patients following resolution of their obstructive jaundice. In patients with jaundice, 46% of an administered Etoposide dose was excreted in the urine as Etoposide compared with 35% in controls (P = .15). Urinary excretion of Etoposide glucuronide accounted for 29% of an administered Etoposide dose in control patients and 15% in those with hepatic obstruction (P = .03). Biliary Etoposide excretion measured in four patients with T-tubes was insignificant (less than 2.0% of an administered dose). The calculated renal clearance of Etoposide was 11.5 mL/min/m2 in patients with jaundice and 10.4 mL/min/m2 in controls (P = .53). Respective metabolic clearance was 4.9 and 6.9 mL/min/m2 in these two study groups (P = .13). Although hepatic metabolism of Etoposide may be slightly decreased in patients with obstructive jaundice, a modest increase in renal Etoposide excretion appears to compensate for this change, so that total clearance is similar in the patients with jaundice when compared with controls. No Etoposide dose reductions appear to be needed in treating patients with obstructive jaundice who have normal renal function.
Marie-odile Jauberteau-marchan - One of the best experts on this subject based on the ideXlab platform.
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In vitro apoptotic induction of human glioblastoma cells by Fas ligand plus Etoposide and in vivo antitumour activity of combined drugs in xenografted nude rats
International Journal of Oncology, 2007Co-Authors: Stéphane Giraud, Caroline Boda, Barbara Bessette, Daniel Petit, Fabrice Lalloué, Muriel Mathonnet, Marie-odile Jauberteau-marchanAbstract:Human glioblastomas that express Fas/CD95 receptor are highly resistant to conventional brain tumour therapies. The aim of this study is to evaluate anti-tumour properties of a combination of Fas ligand (FasL) plus Etoposide with or without dexamethasone on intracerebral experimental glioblastomas. The human Fas-expressing glioblastoma cell line, U-87 MG, was firstly studied in vitro for apoptosis and proliferation assays in the presence of FasL and Etoposide, separately or associated, in order to detect a supra-additive effect on FasL or Etoposide-induced apoptosis. The tumourigenicity of the U-87 MG cell line and therapeutic effects of FasL-Etoposide alone or combined with dexamethasone were next studied on U-87 MG cells xenografted to nude-rat brain and tumour size was hence examined by histological and immunohistochemical stainings. We demonstrated in vitro that the combination of both molecules strongly inhibited the proliferation rate and increased the sensitivity of glioblastoma cells to Fas or Etoposide-mediated apoptosis. Moreover, analysis of rat brains was performed 30 days after xenograft of glioblastoma cells. These data show that the combination of FasL and Etoposide could reduce significantly the tumour size and that the addition of dexamethasone enhanced the inhibiting effect of FasL and Etoposide on tumour growth in vivo.
J D Hainsworth - One of the best experts on this subject based on the ideXlab platform.
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Clinical studies with Etoposide phosphate.
Seminars in oncology, 1996Co-Authors: F A Greco, J D HainsworthAbstract:Over the past few years we have conducted several clinical studies with Etoposide phosphate (Etopophos; Bristol-Myers Squibb Company, Princeton, NJ). A phase I trial initially was performed to determine the maximum tolerated dose and pharmacokinetics. A brief intravenous infusion for 5 consecutive days was given every 3 weeks. Myelosuppression was the dose-limiting toxicity and other toxicities were quite similar to those associated with Etoposide. The maximum tolerated dose was 100 mg/m2/d for 5 consecutive days. No cytokine support was used in this phase I trial. Pharmacokinetic studies showed very rapid conversion of Etoposide phosphate to Etoposide. The kinetics of Etoposide phosphate were similar to those expected after a comparable Etoposide dose. We subsequently began three additional studies, including a phase II randomized comparison of Etoposide phosphate plus cisplatin versus Etoposide plus cisplatin in patients with small cell lung cancer, a study of low-dose continuous infusion daily Etoposide phosphate, and a high-dose Etoposide phosphate trial to determine the maximum tolerated dose given in concert with granulocyte colony-stimulating factor. The latter two studies are complete; these data are currently being evaluated. The phase II comparative trial was important and showed unequivocally that the response rate and toxicity with Etoposide phosphate plus cisplatin is equivalent to those with Etoposide plus cisplatin in patients with small cell lung cancer. In addition, it appears that there was no survival difference between these two treatment arms in this phase II trial of 120 patients. Etoposide phosphate is easier to administer than Etoposide and, considering all other factors, including total cost of administration, it is preferable to Etoposide for routine clinical use.
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Etoposide phosphate or Etoposide with cisplatin in the treatment of small cell lung cancer: randomized phase II trial.
Lung cancer (Amsterdam Netherlands), 1995Co-Authors: F A Greco, J D HainsworthAbstract:Etoposide phosphate, a water soluble prodrug of Etoposide, has several potential advantages including easier and more rapid administration, avoidance of large fluid loads, and elimination of hypersensitivity reactions and other problems related to the solubilizer. This randomized Phase II study was done to evaluate the efficacy and toxicity of Etoposide phosphate and Etoposide, when used in combination with cisplatin in the treatment of patients with small cell lung cancer. Previously untreated small cell lung cancer patients were randomized to receive cisplatin in combination with molar equivalent does of either Etoposide or Etoposide phosphate. The patients were evaluated with respect to response rate, time to progression, survival, and toxicity. Response rates with Etoposide phosphate and Etoposide were 61% (95% confidence interval 55-67%) and 58% (95% confidence interval 52-64%), respectively (P = 0.85). Median time to progression was 6.9 months for patients who received Etoposide phosphate and 7.0 months for those with Etoposide (P = 0.50). For extensive stage disease patients, median survival with Etoposide phosphate was 9.5 months versus 10 months for Etoposide (P = 0.93). The corresponding median survivals for patients with limited stage disease were > 16 months and 17 months, respectively (P = 0.62). Myelosuppression was the most common toxicity; Grade 3 and 4 leukopenia occurred in 63% of patients receiving Etoposide phosphate compared with 77% receiving Etoposide (P = 0.16). The combination of Etoposide phosphate and cisplatin is effective in the treatment of small cell lung cancer, and can be administered with acceptable toxicity. This study was not designed to be a formal Phase III comparative trial, but the efficacy and toxicity observed with this regimen were found to be similar to a standard Etoposide/cisplatin regimen, using molar equivalent Etoposide doses. Etoposide phosphate is preferable to Etoposide because it is easier to use.
Jun Ho Ji - One of the best experts on this subject based on the ideXlab platform.
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durvalumab plus platinum Etoposide versus platinum Etoposide in first line treatment of extensive stage small cell lung cancer caspian a randomised controlled open label phase 3 trial
The Lancet, 2019Co-Authors: Luis Pazares, Mikhail Dvorkin, Yuanbin Chen, Niels Reinmuth, Katsuyuki Hotta, D V Trukhin, Galina Statsenko, Maximilian Hochmair, Mustafa Ozguroglu, Jun Ho JiAbstract:Summary Background Most patients with small-cell lung cancer (SCLC) have extensive-stage disease at presentation, and prognosis remains poor. Recently, immunotherapy has demonstrated clinical activity in extensive-stage SCLC (ES-SCLC). The CASPIAN trial assessed durvalumab, with or without tremelimumab, in combination with Etoposide plus either cisplatin or carboplatin (platinum–Etoposide) in treatment-naive patients with ES-SCLC. Methods This randomised, open-label, phase 3 trial was done at 209 sites across 23 countries. Eligible patients were adults with untreated ES-SCLC, with WHO performance status 0 or 1 and measurable disease as per Response Evaluation Criteria in Solid Tumors, version 1.1. Patients were randomly assigned (in a 1:1:1 ratio) to durvalumab plus platinum–Etoposide; durvalumab plus tremelimumab plus platinum–Etoposide; or platinum–Etoposide alone. All drugs were administered intravenously. Platinum–Etoposide consisted of Etoposide 80–100 mg/m2 on days 1–3 of each cycle with investigator's choice of either carboplatin area under the curve 5–6 mg/mL per min or cisplatin 75–80 mg/m2 (administered on day 1 of each cycle). Patients received up to four cycles of platinum–Etoposide plus durvalumab 1500 mg with or without tremelimumab 75 mg every 3 weeks followed by maintenance durvalumab 1500 mg every 4 weeks in the immunotherapy groups and up to six cycles of platinum–Etoposide every 3 weeks plus prophylactic cranial irradiation (investigator's discretion) in the platinum–Etoposide group. The primary endpoint was overall survival in the intention-to-treat population. We report results for the durvalumab plus platinum–Etoposide group versus the platinum–Etoposide group from a planned interim analysis. Safety was assessed in all patients who received at least one dose of their assigned study treatment. This study is registered at ClinicalTrials.gov, NCT03043872, and is ongoing. Findings Patients were enrolled between March 27, 2017, and May 29, 2018. 268 patients were allocated to the durvalumab plus platinum–Etoposide group and 269 to the platinum–Etoposide group. Durvalumab plus platinum–Etoposide was associated with a significant improvement in overall survival, with a hazard ratio of 0·73 (95% CI 0·59–0·91; p=0·0047]); median overall survival was 13·0 months (95% CI 11·5–14·8) in the durvalumab plus platinum–Etoposide group versus 10·3 months (9·3–11·2) in the platinum–Etoposide group, with 34% (26·9–41·0) versus 25% (18·4–31·6) of patients alive at 18 months. Any-cause adverse events of grade 3 or 4 occurred in 163 (62%) of 265 treated patients in the durvalumab plus platinum–Etoposide group and 166 (62%) of 266 in the platinum–Etoposide group; adverse events leading to death occurred in 13 (5%) and 15 (6%) patients. Interpretation First-line durvalumab plus platinum–Etoposide significantly improved overall survival in patients with ES-SCLC versus a clinically relevant control group. Safety findings were consistent with the known safety profiles of all drugs received. Funding AstraZeneca.