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Anna Berkenblit - One of the best experts on this subject based on the ideXlab platform.
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drug related pneumonitis in patients with advanced renal cell carcinoma treated with Temsirolimus
Journal of Clinical Oncology, 2011Co-Authors: Jose Pablo Maroto, Mizue Krygowski, Janice P Dutcher, Gary R Hudes, Theodore F Logan, Charles S White, Maria Cincotta, Mark Shapiro, Ignacio Duran, Anna BerkenblitAbstract:Purpose Pneumonitis has occurred in patients treated with inhibitors of the mammalian target of rapamycin (mTOR). In a phase III study of patients with previously untreated, poor-prognosis, advanced renal cell carcinoma (ARCC), the mTOR inhibitor Temsirolimus improved survival compared with interferon. We performed a retrospective, independent, blinded radiographic review of chest computed tomography (CT) images of patients in this study to characterize Temsirolimusrelated pneumonitis. Patients and Methods Patients were treated with intravenous Temsirolimus 25 mg once weekly or subcutaneous interferon alfa 3 million units, with an increase to 18 million units, thrice weekly. Drug-related pneumonitis was identified based on sequential chest CT images, required every 8 weeks, showing changes consistent with pneumonitis and not pneumonia (infection) or disease progression as correlated with clinical data. Cumulative probability of drug-related pneumonitis was estimated using the Kaplan-Meier method. Results Eight (6%) of 138 and 52 (29%) of 178 evaluable patients on interferon and Temsirolimus treatment, respectively, developed radiographically identified drug-related pneumonitis. Time to onset of pneumonitis was significantly shorter on the Temsirolimus arm than on the interferon arm (log-rank P .001). Estimated cumulative probability of pneumonitis at 8 and 16 weeks from first dose was 21% and 31%, respectively, on the Temsirolimus arm and 6% and 8%, respectively, on the interferon arm. Respiratory symptoms were observed around time of onset of radiographically diagnosed Temsirolimus-related pneumonitis in 16 (31%) of 52 patients. Conclusion Patients with ARCC receiving Temsirolimus should be monitored closely for development of pneumonitis, and their management should be altered if clinical symptoms appear.
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analysis of pten and hif 1α and correlation with efficacy in patients with advanced renal cell carcinoma treated with Temsirolimus versus interferon α
Cancer, 2009Co-Authors: Robert A Figlin, Anna Berkenblit, Andrew Strahs, Mizue Krygowski, Janice P Dutcher, David F Mcdermott, Paul De Souza, A. Thiele, J Feingold, Joseph BoniAbstract:BACKGROUND: Exploratory subgroup analyses from the phase 3 global advanced renal cell carcinoma (ARCC) trial were conducted to determine if baseline levels of the tumor molecular markers PTEN and HIF1 α correlated with efficacy in patients treated with Temsirolimus (Torisel) versus interferon-α (IFN). METHODS: Patients in the IFN group received 3 million U (MU) subcutaneously 3x weekly, escalating to 18 MU. Patients in the Temsirolimus group received 25 mg intravenously weekly. PTEN and HIF1 α baseline levels were measured in archived tumor specimens by immunohistochemistry. RESULTS: There was no correlation between baseline PTEN and HIF1 α levels and treatment effect with respect to overall survival (OS), progression-free survival, or objective response rate (ORR) in patients with advanced renal cell carcinoma with poor-risk prognostic factors. CONCLUSIONS: The baseline status of the molecular markers PTEN and HIF1 α did not correlate with efficacy in renal cell carcinoma patients treated with Temsirolimus versus IFN. Patients demonstrated OS and progression-free survival benefit when treated with Temsirolimus regardless of PTEN and HIF1 α status. Thus, baseline PTEN and HIF-1 levels may not predict response to Temsirolimus. Alternatively, the lack of correlation may be due to the variability in tumor specimens that occurred because of the global nature of the clinical trial. Other markers in the phosphoinositide 3-kinase (PI3K)/Akt pathway may be of utility as predictors of response to Temsirolimus in patients with advanced renal cell carcinoma. Cancer 2009. © 2009 American Cancer Society.
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phase iii study to evaluate Temsirolimus compared with investigator s choice therapy for the treatment of relapsed or refractory mantle cell lymphoma
Journal of Clinical Oncology, 2009Co-Authors: Georg Hess, Andrew Strahs, Jorge E Romaguera, Raoul Herbrecht, Gregor Verhoef, Michael Crump, Christian Gisselbrecht, Anna Laurell, Fritz Offner, Anna BerkenblitAbstract:Purpose Temsirolimus, a specific inhibitor of the mammalian target of rapamycin kinase, has shown clinical activity in mantle cell lymphoma (MCL). We evaluated two dose regimens of Temsirolimus in comparison with investigator's choice single-agent therapy in relapsed or refractory disease. Patients and Methods In this multicenter, open-label, phase III study, 162 patients with relapsed or refractory MCL were randomly assigned (1:1:1) to receive one of two Temsirolimus regimens: 175 mg weekly for 3 weeks followed by either 75 mg (175/75-mg) or 25 mg (175/25-mg) weekly, or investigator's choice therapy from prospectively approved options. The primary end point was progression-free survival (PFS) by independent assessment. Results Median PFS was 4.8, 3.4, and 1.9 months for the Temsirolimus 175/75-mg, 175/25-mg, and investigator's choice groups, respectively. Patients treated with Temsirolimus 175/75-mg had significantly longer PFS than those treated with investigator's choice therapy (P = .0009; hazard rati...
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Phase I, pharmacokinetic study of Temsirolimus administered orally to patients with advanced cancer.
Investigational new drugs, 2009Co-Authors: Jan C. Buckner, Anna Berkenblit, Joseph Boni, Bahram Forouzesh, Charles Erlichman, Manuel Hidalgo, Gary Dukart, Eric K. RowinskyAbstract:An oral formulation of Temsirolimus (Torisel®), an inhibitor of the mammalian target of rapamycin, was evaluated on an intermittent schedule (once daily for 5 days every 2 weeks) in patients with advanced cancer. The maximum tolerated dose was determined to be 75 mg after dose-limiting toxicities of grade 3 elevated aminotransferases (1 patient) and grade 3 rash (1 patient) occurred with a 100-mg dose. The most common Temsirolimus-related adverse events were mucositis, rash/maculopapular rash, and asthenia. Six of 12 patients who received the 75-mg dose required dose reductions due to Temsirolimus-related adverse events. Two patients who received 75-mg Temsirolimus and did not have dose reductions had minor tumor responses. Relative exposure from contributions of both Temsirolimus and sirolimus, the principal metabolite, was 17.9% of the 75-mg dose. Thus, oral Temsirolimus, 75 mg administered once daily for 5 days every 2 weeks, was further evaluated in patients with metastatic breast cancer.
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Effect of Temsirolimus versus interferon-α on outcome of patients with advanced renal cell carcinoma of different tumor histologies
Medical Oncology, 2009Co-Authors: Janice P Dutcher, Anna Berkenblit, Andrew Strahs, Mizue Krygowski, Robert A Figlin, Jay Marshall Feingold, David F Mcdermott, Paul De Souza, A. Thiele, Gary R HudesAbstract:Purpose Exploratory subgroup analyses from the phase 3 global advanced renal cell carcinoma (ARCC) trial were conducted to assess the influence of tumor histology on outcome of patients treated with Temsirolimus (Torisel™) or interferon-α (IFN). Patients and methods Patients with ARCC including clear cell and other types such as papillary and chromophobe histologies received either IFN (3 million units [MU] subcutaneously three times weekly, escalating to 18 MU) or Temsirolimus (25 mg intravenously weekly). Results Approximately 80% of patients had clear cell and 20% of patients had other histologies, the majority of which were papillary. Patients with clear cell and other RCC histologies, treated with Temsirolimus, demonstrated comparable median overall and progression-free survival. In contrast, patients with other RCC histologies, treated with IFN, demonstrated shorter median overall and progression-free survival than patients with clear cell RCC. Hazard ratios for death for treatment with Temsirolimus versus IFN were less than 1 for patients regardless of tumor histology. For patients treated with Temsirolimus, 59% with clear cell and 68% with other RCC histologies experienced tumor reductions. For patients treated with IFN, 35% with clear cell and 14% with other RCC histologies had tumor reductions. However, Temsirolimus did not appear to improve the objective response rate compared to IFN. Temsirolimus resulted in a superior clinical benefit rate compared with IFN, regardless of tumor histology. Conclusion Temsirolimus appears to be efficacious in patients with clear cell and non-clear cell histologies and can, therefore, be used for the treatment of all types of RCC.
Gary R Hudes - One of the best experts on this subject based on the ideXlab platform.
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Increase in Cholesterol Predicts Survival Advantage in Renal Cell Carcinoma Patients Treated with Temsirolimus
Clinical cancer research : an official journal of the American Association for Cancer Research, 2012Co-Authors: Chee Khoon Lee, Gary R Hudes, Ian C. Marschner, R. John Simes, Merryn Voysey, Brian L. Egleston, Paul De SouzaAbstract:Purpose: Temsirolimus is an effective treatment for renal cell carcinoma. It is associated with increases in serum cholesterol, triglyceride, and glucose. We investigated whether changes of these biomarkers could predict its efficacy. Experimental Design: We examined serial measurements of cholesterol, triglycerides, and glucose from patients randomized to IFN or Temsirolimus in the Global Advanced Renal Cell Carcinoma Trial. Using time-dependent proportional hazards models, we quantified the association between changes in these biomarkers from baseline with overall survival (OS) and progression-free survival (PFS). We also assess the extent to which changes of these biomarkers predict the effects of Temsirolimus on survival. Results: Temsirolimus was associated with larger mean increases in cholesterol (1.02 mmol/L; P < 0.0001), triglycerides (0.32 mmol/L; P = 0.0008), and glucose (1.28 mmol/L; P < 0.0001) compared with IFN and improved survival rate (OS: HR = 0.76, P = 0.02; PFS: HR = 0.70, P = 0.001). Cholesterol increase during study was associated with longer survival (OS: HR=0.77 per mmol/L, P < 0.0001; PFS: HR= 0.81 per mmol/L; P < 0.0001). Temsirolimus effect on cholesterol predicted its effect on survival with no additional survival advantage observed after adjusting for cholesterol change during study (OS: HR = 1.14, P = 0.37; PFS: HR = 0.88, P = 0.35). Temsirolimus effect on triglycerides or glucose did not predict its effect on survival, with survival advantage in favor of Temsirolimus still observed after adjusting for these factors (P = 0.003 and P = 0.002). Conclusion: Cholesterol increase is a potential predictor for Temsirolimus efficacy. Longer survival in patients treated with Temsirolimus was observed in those with larger increases in cholesterol. Prospectively designed biomarker studies of Temsirolimus or other mTOR inhibitors are recommended. ©2012 AACR.
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drug related pneumonitis in patients with advanced renal cell carcinoma treated with Temsirolimus
Journal of Clinical Oncology, 2011Co-Authors: Jose Pablo Maroto, Mizue Krygowski, Janice P Dutcher, Gary R Hudes, Theodore F Logan, Charles S White, Maria Cincotta, Mark Shapiro, Ignacio Duran, Anna BerkenblitAbstract:Purpose Pneumonitis has occurred in patients treated with inhibitors of the mammalian target of rapamycin (mTOR). In a phase III study of patients with previously untreated, poor-prognosis, advanced renal cell carcinoma (ARCC), the mTOR inhibitor Temsirolimus improved survival compared with interferon. We performed a retrospective, independent, blinded radiographic review of chest computed tomography (CT) images of patients in this study to characterize Temsirolimusrelated pneumonitis. Patients and Methods Patients were treated with intravenous Temsirolimus 25 mg once weekly or subcutaneous interferon alfa 3 million units, with an increase to 18 million units, thrice weekly. Drug-related pneumonitis was identified based on sequential chest CT images, required every 8 weeks, showing changes consistent with pneumonitis and not pneumonia (infection) or disease progression as correlated with clinical data. Cumulative probability of drug-related pneumonitis was estimated using the Kaplan-Meier method. Results Eight (6%) of 138 and 52 (29%) of 178 evaluable patients on interferon and Temsirolimus treatment, respectively, developed radiographically identified drug-related pneumonitis. Time to onset of pneumonitis was significantly shorter on the Temsirolimus arm than on the interferon arm (log-rank P .001). Estimated cumulative probability of pneumonitis at 8 and 16 weeks from first dose was 21% and 31%, respectively, on the Temsirolimus arm and 6% and 8%, respectively, on the interferon arm. Respiratory symptoms were observed around time of onset of radiographically diagnosed Temsirolimus-related pneumonitis in 16 (31%) of 52 patients. Conclusion Patients with ARCC receiving Temsirolimus should be monitored closely for development of pneumonitis, and their management should be altered if clinical symptoms appear.
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Effect of Temsirolimus versus interferon-α on outcome of patients with advanced renal cell carcinoma of different tumor histologies
Medical Oncology, 2009Co-Authors: Janice P Dutcher, Anna Berkenblit, Andrew Strahs, Mizue Krygowski, Robert A Figlin, Jay Marshall Feingold, David F Mcdermott, Paul De Souza, A. Thiele, Gary R HudesAbstract:Purpose Exploratory subgroup analyses from the phase 3 global advanced renal cell carcinoma (ARCC) trial were conducted to assess the influence of tumor histology on outcome of patients treated with Temsirolimus (Torisel™) or interferon-α (IFN). Patients and methods Patients with ARCC including clear cell and other types such as papillary and chromophobe histologies received either IFN (3 million units [MU] subcutaneously three times weekly, escalating to 18 MU) or Temsirolimus (25 mg intravenously weekly). Results Approximately 80% of patients had clear cell and 20% of patients had other histologies, the majority of which were papillary. Patients with clear cell and other RCC histologies, treated with Temsirolimus, demonstrated comparable median overall and progression-free survival. In contrast, patients with other RCC histologies, treated with IFN, demonstrated shorter median overall and progression-free survival than patients with clear cell RCC. Hazard ratios for death for treatment with Temsirolimus versus IFN were less than 1 for patients regardless of tumor histology. For patients treated with Temsirolimus, 59% with clear cell and 68% with other RCC histologies experienced tumor reductions. For patients treated with IFN, 35% with clear cell and 14% with other RCC histologies had tumor reductions. However, Temsirolimus did not appear to improve the objective response rate compared to IFN. Temsirolimus resulted in a superior clinical benefit rate compared with IFN, regardless of tumor histology. Conclusion Temsirolimus appears to be efficacious in patients with clear cell and non-clear cell histologies and can, therefore, be used for the treatment of all types of RCC.
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Phase I/II Trial of Temsirolimus Combined With Interferon Alfa for Advanced Renal Cell Carcinoma
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2007Co-Authors: Robert J. Motzer, David F Mcdermott, Gary R Hudes, Bernard J. Escudier, Laurence Moore, Brendan D. Curti, Sylvie Negrier, Brigitte Duclos, Timothy O'toole, Joseph BoniAbstract:Purpose Temsirolimus, an inhibitor of the mammalian target of rapamycin, has single-agent activity against advanced renal cell carcinoma (RCC). A recommended dose and safety profile for the combination of Temsirolimus and interferon alfa (IFN) were determined in patients with advanced RCC. Patients and Methods Patients were enrolled onto a multicenter, ascending-dose study of Temsirolimus (5, 10, 15, 20, or 25 mg) administered intravenously once a week combined with IFN (6 or 9 million units [MU]) administered subcutaneously three times per week. An expanded cohort was treated at the recommended dose to obtain additional safety and efficacy information. Results Seventy-one patients were entered to receive one of six dose levels. The recommended dose was Temsirolimus 15 mg/IFN 6 MU based on dose-limiting toxicities of stomatitis, fatigue, and nausea/vomiting, which were observed at higher doses of Temsirolimus and IFN. The most frequent grade 3 or 4 toxicities occurring in any cycle included leukopenia, hy...
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Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma.
The New England journal of medicine, 2007Co-Authors: Gary R Hudes, Robert A Figlin, Janice P Dutcher, David F Mcdermott, Michael A. Carducci, Piotr Tomczak, Anil Kapoor, Elzbieta Staroslawska, Jeffrey A. Sosman, Istvan BodrogiAbstract:Background Interferon alfa is widely used for metastatic renal-cell carcinoma but has limited efficacy and tolerability. Temsirolimus, a specific inhibitor of the mammalian target of rapamycin kinase, may benefit patients with this disease. Methods In this multicenter, phase 3 trial, we randomly assigned 626 patients with previously untreated, poor-prognosis metastatic renal-cell carcinoma to receive 25 mg of intravenous Temsirolimus weekly, 3 million U of interferon alfa (with an increase to 18 million U) subcutaneously three times weekly, or combination therapy with 15 mg of Temsirolimus weekly plus 6 million U of interferon alfa three times weekly. The primary end point was overall survival in comparisons of the Temsirolimus group and the combination-therapy group with the interferon group. Results Patients who received Temsirolimus alone had longer overall survival (hazard ratio for death, 0.73; 95% confidence interval [CI], 0.58 to 0.92; P=0.008) and progression-free survival (P
Joseph Boni - One of the best experts on this subject based on the ideXlab platform.
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analysis of pten and hif 1α and correlation with efficacy in patients with advanced renal cell carcinoma treated with Temsirolimus versus interferon α
Cancer, 2009Co-Authors: Robert A Figlin, Anna Berkenblit, Andrew Strahs, Mizue Krygowski, Janice P Dutcher, David F Mcdermott, Paul De Souza, A. Thiele, J Feingold, Joseph BoniAbstract:BACKGROUND: Exploratory subgroup analyses from the phase 3 global advanced renal cell carcinoma (ARCC) trial were conducted to determine if baseline levels of the tumor molecular markers PTEN and HIF1 α correlated with efficacy in patients treated with Temsirolimus (Torisel) versus interferon-α (IFN). METHODS: Patients in the IFN group received 3 million U (MU) subcutaneously 3x weekly, escalating to 18 MU. Patients in the Temsirolimus group received 25 mg intravenously weekly. PTEN and HIF1 α baseline levels were measured in archived tumor specimens by immunohistochemistry. RESULTS: There was no correlation between baseline PTEN and HIF1 α levels and treatment effect with respect to overall survival (OS), progression-free survival, or objective response rate (ORR) in patients with advanced renal cell carcinoma with poor-risk prognostic factors. CONCLUSIONS: The baseline status of the molecular markers PTEN and HIF1 α did not correlate with efficacy in renal cell carcinoma patients treated with Temsirolimus versus IFN. Patients demonstrated OS and progression-free survival benefit when treated with Temsirolimus regardless of PTEN and HIF1 α status. Thus, baseline PTEN and HIF-1 levels may not predict response to Temsirolimus. Alternatively, the lack of correlation may be due to the variability in tumor specimens that occurred because of the global nature of the clinical trial. Other markers in the phosphoinositide 3-kinase (PI3K)/Akt pathway may be of utility as predictors of response to Temsirolimus in patients with advanced renal cell carcinoma. Cancer 2009. © 2009 American Cancer Society.
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Phase I, pharmacokinetic study of Temsirolimus administered orally to patients with advanced cancer.
Investigational new drugs, 2009Co-Authors: Jan C. Buckner, Anna Berkenblit, Joseph Boni, Bahram Forouzesh, Charles Erlichman, Manuel Hidalgo, Gary Dukart, Eric K. RowinskyAbstract:An oral formulation of Temsirolimus (Torisel®), an inhibitor of the mammalian target of rapamycin, was evaluated on an intermittent schedule (once daily for 5 days every 2 weeks) in patients with advanced cancer. The maximum tolerated dose was determined to be 75 mg after dose-limiting toxicities of grade 3 elevated aminotransferases (1 patient) and grade 3 rash (1 patient) occurred with a 100-mg dose. The most common Temsirolimus-related adverse events were mucositis, rash/maculopapular rash, and asthenia. Six of 12 patients who received the 75-mg dose required dose reductions due to Temsirolimus-related adverse events. Two patients who received 75-mg Temsirolimus and did not have dose reductions had minor tumor responses. Relative exposure from contributions of both Temsirolimus and sirolimus, the principal metabolite, was 17.9% of the 75-mg dose. Thus, oral Temsirolimus, 75 mg administered once daily for 5 days every 2 weeks, was further evaluated in patients with metastatic breast cancer.
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Effect of ketoconazole, a potent CYP3A4 inhibitor, on the pharmacokinetics of Temsirolimus administered by intravenous infusion
Molecular Cancer Therapeutics, 2007Co-Authors: Joseph Boni, Cathie Leister, Jaime Burns, Bruce HugAbstract:B95 Background: Intravenous (IV) Temsirolimus, a novel inhibitor of the mammalian target of rapamycin (mTOR), has been approved by the US Food and Drug Administration for the treatment of advanced renal cell carcinoma. Intravenous Temsirolimus also is being studied in patients with other solid tumors and hematologic malignancies. Representative pharmacokinetics (PK) for Temsirolimus in patients with cancer and healthy subjects are available. Both Temsirolimus and its metabolite sirolimus are substrates for cytochrome P450 (CYP) 3A4. Orally administered sirolimus-structural analogs are CYP3A4 substrates and exhibit substantial drug interaction with ketoconazole (KETO), a potent CYP3A4 inhibitor. The objective of this study was to characterize the effect of ketoconazole (KETO), a potent CYP3A4 inhibitor, on the PK profile of IV Temsirolimus. Methods: This was an open-label, nonrandomized, 2-period, sequential study in healthy adult subjects. A 5-mg dose of Temsirolimus was chosen for combination with KETO to mitigate safety concerns of the Temsirolimus 25-mg clinical dosage. On day 1, a single 5-mg dose of Temsirolimus was administered via 30-minute IV infusion. After a 14-day washout period, oral 400 mg KETO was administered once daily for 7 consecutive days (days 15-21). A 5-mg IV dose of Temsirolimus was administered 2 hours after the KETO dose on day 15. Concentrations of Temsirolimus and sirolimus in whole blood were measured using a validated, dual, LC/MS/MS bioanalytic assay. PK analyses utilized a noncompartmental model. Least squares geometric mean (LSGM) ratios of test to reference treatments and their 90% confidence intervals for Cmax, AUCT, and AUC were determined. Results: 17 subjects (mean age, 34 years) were enrolled. PK profiles were available for 16 subjects who received Temsirolimus alone and for 14 subjects who received concomitant KETO with IV Temsirolimus. Coadministration of KETO with IV 5-mg Temsirolimus resulted in no meaningful change in mean Temsirolimus Cmax or AUC. However, coadministration of KETO with IV 5-mg Temsirolimus resulted in large increases in sirolimus PK parameters, a 2.2-fold increase in mean Cmax, anda3.2-fold increasein mean AUC. The 90% confidence intervals for LSGM ratios of Cmax, AUCT, and AUC for Temsirolimus were within 80% to 125%. In this regimen, KETO coadministration with Temsirolimus was well tolerated and there were no unexpected safety results in these healthy subjects. Conclusion: Concomitant administration of KETO with Temsirolimus resulted in a 3.2-fold increase in mean AUC for sirolimus compared with Temsirolimus administration alone.
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Lack of pharmacokinetic interaction between intravenous Temsirolimus and the cytochrome P450 2D6 substrate desipramine
Molecular Cancer Therapeutics, 2007Co-Authors: Joseph Boni, Cathie Leister, Jaime Burns, Bruce HugAbstract:B96 Background: Intravenous (IV) Temsirolimus is a novel inhibitor of mammalian target of rapamycin (mTOR) and recently has been approved by the US Food and Drug Administration for the treatment of patients with advanced renal cell carcinoma. Intravenous Temsirolimus is also being evaluated for the treatment of patients with mantle cell lymphoma. In studies with pooled human liver microsomes, the cytochrome P450 (CYP) 2D6 was inhibited by Temsirolimus with Ki=1.5µM and was associated with a moderate Cmax/Ki ≈0.38 of the anticipated peak Temsirolimus concentration following IV dosing. This study investigated whether Temsirolimus inhibited the activity of CYP2D6 in humans. The effect of IV Temsirolimus on the pharmacokinetic (PK) profile of desipramine (DES), a substrate of CYP2D6 was evaluated. Methods: In this open-label, nonrandomized, 2-period, sequential study, healthy adults were genotyped for CYP2D6 polymorphisms. In period 1, subjects received 1 DES 50-mg tablet. In period 2, subjects received 1 oral DES 50-mg tablet coadministered with 1 Temsirolimus 25-mg dose given via 30-minute IV infusion. Plasma and urine samples for PK analyses were collected in both periods. DES and its metabolite 2-hydroxy-DES were measured using a validated LC/MS/MS assay. PK analyses utilized a noncompartmental model. Least squares geometric mean (LSGM) ratios of test to reference treatments and their 90% confidence intervals (CIs) for Cmax, AUCT, and AUC were determined. Results: 26 subjects (mean age 34 y; n=25 men) received oral DES and 23 of these received DES coadministered with IV Temsirolimus. One subject had a poor metabolizer CYP2D6 genotype. Mean DES Cmax and AUC were 13% and 4% lower and mean 2-hydroxy-DES Cmax and AUC were 9% and 5% lower, respectively, with Temsirolimus coadministration. Although Temsirolimus coadministration resulted in statistically significant pharmacokinetic effects for DES (CmaxP=.001; AUCTP=.043; Vz/F P
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mTOR inhibition following a single intravenous infusion of Temsirolimus in healthy individuals
Molecular Cancer Therapeutics, 2007Co-Authors: Joseph Boni, Jaime Burns, Bruce Hug, Daryl SonnichsenAbstract:C144 Background: Temsirolimus is a selective inhibitor of the mammalian target of rapamycin (mTOR), which has been approved by the US Food and Drug Administration for the treatment of patients with advanced renal cell carcinoma. Temsirolimus binds to intracellular FKBP-12 and the complex inhibits mTOR kinase activity, resulting in inhibition of phosphorylation of proteins downstream of mTOR and subsequent G1 phase cell cycle arrest. The objectives of this study were to define the structure of pharmacokinetic (PK) disposition of Temsirolimus and to characterize its pharmacokinetic (PK) and pharmacodynamic (PD) relationship after a single intravenous (IV) dose. Methods: In this open-label, inpatient/outpatient, nonrandomized, sequential group study, healthy adults received single Temsirolimus doses of 1, 3, 10, 15, or 25 mg IV over 30 minutes. Venous blood samples were collected over 14 days to measure concentrations of Temsirolimus and sirolimus (a major metabolite) in blood and levels of phosphorylated S6 ribosomal protein (S6RP), a cytosolic distal substrate of p70S6 kinase in the mTOR pathway, in CD3+ lymphocytes. A nonlinear compartmental PK model described the maximal binding capacity (Bmax) and dissociation constant (Kd) of binding in red blood cells and peripheral tissues. An indirect response PK/PD model was used to quantify temporal effects of drug concentration on PD response. Results: The study included 30 subjects; 6 received each dose of Temsirolimus. In red blood cells, specific Temsirolimus binding was dose-dependent, with mean maximal receptor occupancy observed with doses of 3 mg or higher. The mean (10th, 90th percentile) Bmax in red blood cells and tissues was 1.4 (0.47, 2.5) mg and 5.0 (0.94, 9.9) mg, respectively, and 6.4 [1.4, 12.4] mg for whole body. The mean (10th, 90th percentile) Kd was 5.1 (1.3, 8.7) ng/mL and was comparable to active concentrations in preclinical models for tumor growth inhibition. Inhibition of phosphorylation of S6RP was rapid, and extent and duration were dose dependent with median IC50 that ranged from 0.31 ng/mL (1 mg dose) to 5.1 ng/mL (25 mg dose). The duration of 50% maximal inhibition of S6RP phosphorylation was 82 hours.Conclusions: Temsirolimus IV doses greater than 6.4 mg may be required to optimize drug distribution and exposure to maximize clinical benefit. The PK/PD response profile of phosphorylation of S6RP demonstrated substantial modulation and confirmed that a single 25-mg IV dose of Temsirolimus suppressed mTOR-mediated signaling for a long duration.
David F Mcdermott - One of the best experts on this subject based on the ideXlab platform.
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analysis of pten and hif 1α and correlation with efficacy in patients with advanced renal cell carcinoma treated with Temsirolimus versus interferon α
Cancer, 2009Co-Authors: Robert A Figlin, Anna Berkenblit, Andrew Strahs, Mizue Krygowski, Janice P Dutcher, David F Mcdermott, Paul De Souza, A. Thiele, J Feingold, Joseph BoniAbstract:BACKGROUND: Exploratory subgroup analyses from the phase 3 global advanced renal cell carcinoma (ARCC) trial were conducted to determine if baseline levels of the tumor molecular markers PTEN and HIF1 α correlated with efficacy in patients treated with Temsirolimus (Torisel) versus interferon-α (IFN). METHODS: Patients in the IFN group received 3 million U (MU) subcutaneously 3x weekly, escalating to 18 MU. Patients in the Temsirolimus group received 25 mg intravenously weekly. PTEN and HIF1 α baseline levels were measured in archived tumor specimens by immunohistochemistry. RESULTS: There was no correlation between baseline PTEN and HIF1 α levels and treatment effect with respect to overall survival (OS), progression-free survival, or objective response rate (ORR) in patients with advanced renal cell carcinoma with poor-risk prognostic factors. CONCLUSIONS: The baseline status of the molecular markers PTEN and HIF1 α did not correlate with efficacy in renal cell carcinoma patients treated with Temsirolimus versus IFN. Patients demonstrated OS and progression-free survival benefit when treated with Temsirolimus regardless of PTEN and HIF1 α status. Thus, baseline PTEN and HIF-1 levels may not predict response to Temsirolimus. Alternatively, the lack of correlation may be due to the variability in tumor specimens that occurred because of the global nature of the clinical trial. Other markers in the phosphoinositide 3-kinase (PI3K)/Akt pathway may be of utility as predictors of response to Temsirolimus in patients with advanced renal cell carcinoma. Cancer 2009. © 2009 American Cancer Society.
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Effect of Temsirolimus versus interferon-α on outcome of patients with advanced renal cell carcinoma of different tumor histologies
Medical Oncology, 2009Co-Authors: Janice P Dutcher, Anna Berkenblit, Andrew Strahs, Mizue Krygowski, Robert A Figlin, Jay Marshall Feingold, David F Mcdermott, Paul De Souza, A. Thiele, Gary R HudesAbstract:Purpose Exploratory subgroup analyses from the phase 3 global advanced renal cell carcinoma (ARCC) trial were conducted to assess the influence of tumor histology on outcome of patients treated with Temsirolimus (Torisel™) or interferon-α (IFN). Patients and methods Patients with ARCC including clear cell and other types such as papillary and chromophobe histologies received either IFN (3 million units [MU] subcutaneously three times weekly, escalating to 18 MU) or Temsirolimus (25 mg intravenously weekly). Results Approximately 80% of patients had clear cell and 20% of patients had other histologies, the majority of which were papillary. Patients with clear cell and other RCC histologies, treated with Temsirolimus, demonstrated comparable median overall and progression-free survival. In contrast, patients with other RCC histologies, treated with IFN, demonstrated shorter median overall and progression-free survival than patients with clear cell RCC. Hazard ratios for death for treatment with Temsirolimus versus IFN were less than 1 for patients regardless of tumor histology. For patients treated with Temsirolimus, 59% with clear cell and 68% with other RCC histologies experienced tumor reductions. For patients treated with IFN, 35% with clear cell and 14% with other RCC histologies had tumor reductions. However, Temsirolimus did not appear to improve the objective response rate compared to IFN. Temsirolimus resulted in a superior clinical benefit rate compared with IFN, regardless of tumor histology. Conclusion Temsirolimus appears to be efficacious in patients with clear cell and non-clear cell histologies and can, therefore, be used for the treatment of all types of RCC.
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potential histologic and molecular predictors of response to Temsirolimus in patients with advanced renal cell carcinoma
Clinical Genitourinary Cancer, 2007Co-Authors: Daniel Cho, Sabina Signoretti, Sandra L. Dabora, Meredith M. Regan, Apryle Seeley, Mauro Mariotti, Amanda Youmans, Adam Polivy, Lucy Mandato, David F McdermottAbstract:Abstract Purpose Similar to other molecularly targeted agents, Temsirolimus, an inhibitor of mammalian target of rapamycin, has shown promising activity in advanced renal cell carcinoma. However, only a subset of patients appears to derive significant tumor responses. In an effort to identify potential predictors of response to Temsirolimus, tumor samples from a subset of patients within a randomized phase II trial of Temsirolimus in advanced renal cell carcinoma were studied. Patients and Methods Paraffinembedded tissue sections from patients who had received Temsirolimus were immunostained with antibodies to carbonic anhydrase IX, phospho- S6, phospho-Akt (pAkt), and phosphotase and tensin homologue. Expression levels were correlated with objective response (partial response [PR], minor response [MR]) and clinical benefit (PR, MR, SD ≤ 4 cycles) to Temsirolimus. In addition, von Hippel–Lindau ( VHL ) mutational analysis was performed and correlated with response. Results Tissue specimens were obtained from 20 patients who were evaluable for both tumor response and staining for phospho-S6 and carbonic anhydrase IX. In addition, 19 specimens were evaluable for pAkt, and 18 for phosphotase and tensin homologue. VHL mutational analysis was performed on 16 samples. Five patients achieved an objective response (1 PR/4 MRs) to Temsirolimus. There was a positive association of phospho-S6 expression ( P = .02) and a trend toward positive expression of pAkt ( P = .07) with response to Temsirolimus. No patient without high expression of either phospho-S6 or pAkt experienced an objective tumor response. There was no correlation of carbonic anhydrase IX and phosphotase and tensin homologue expression or VHL status with response to Temsirolimus. Conclusion These results suggest that phospho-S6 and pAkt expression are promising predictive biomarkers for response to Temsirolimus that are worthy of further exploration for use in patient selection models for mammalian target of rapamycin inhibitors.
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Phase I/II Trial of Temsirolimus Combined With Interferon Alfa for Advanced Renal Cell Carcinoma
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2007Co-Authors: Robert J. Motzer, David F Mcdermott, Gary R Hudes, Bernard J. Escudier, Laurence Moore, Brendan D. Curti, Sylvie Negrier, Brigitte Duclos, Timothy O'toole, Joseph BoniAbstract:Purpose Temsirolimus, an inhibitor of the mammalian target of rapamycin, has single-agent activity against advanced renal cell carcinoma (RCC). A recommended dose and safety profile for the combination of Temsirolimus and interferon alfa (IFN) were determined in patients with advanced RCC. Patients and Methods Patients were enrolled onto a multicenter, ascending-dose study of Temsirolimus (5, 10, 15, 20, or 25 mg) administered intravenously once a week combined with IFN (6 or 9 million units [MU]) administered subcutaneously three times per week. An expanded cohort was treated at the recommended dose to obtain additional safety and efficacy information. Results Seventy-one patients were entered to receive one of six dose levels. The recommended dose was Temsirolimus 15 mg/IFN 6 MU based on dose-limiting toxicities of stomatitis, fatigue, and nausea/vomiting, which were observed at higher doses of Temsirolimus and IFN. The most frequent grade 3 or 4 toxicities occurring in any cycle included leukopenia, hy...
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Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma.
The New England journal of medicine, 2007Co-Authors: Gary R Hudes, Robert A Figlin, Janice P Dutcher, David F Mcdermott, Michael A. Carducci, Piotr Tomczak, Anil Kapoor, Elzbieta Staroslawska, Jeffrey A. Sosman, Istvan BodrogiAbstract:Background Interferon alfa is widely used for metastatic renal-cell carcinoma but has limited efficacy and tolerability. Temsirolimus, a specific inhibitor of the mammalian target of rapamycin kinase, may benefit patients with this disease. Methods In this multicenter, phase 3 trial, we randomly assigned 626 patients with previously untreated, poor-prognosis metastatic renal-cell carcinoma to receive 25 mg of intravenous Temsirolimus weekly, 3 million U of interferon alfa (with an increase to 18 million U) subcutaneously three times weekly, or combination therapy with 15 mg of Temsirolimus weekly plus 6 million U of interferon alfa three times weekly. The primary end point was overall survival in comparisons of the Temsirolimus group and the combination-therapy group with the interferon group. Results Patients who received Temsirolimus alone had longer overall survival (hazard ratio for death, 0.73; 95% confidence interval [CI], 0.58 to 0.92; P=0.008) and progression-free survival (P
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drug related pneumonitis in patients with advanced renal cell carcinoma treated with Temsirolimus
Journal of Clinical Oncology, 2011Co-Authors: Jose Pablo Maroto, Mizue Krygowski, Janice P Dutcher, Gary R Hudes, Theodore F Logan, Charles S White, Maria Cincotta, Mark Shapiro, Ignacio Duran, Anna BerkenblitAbstract:Purpose Pneumonitis has occurred in patients treated with inhibitors of the mammalian target of rapamycin (mTOR). In a phase III study of patients with previously untreated, poor-prognosis, advanced renal cell carcinoma (ARCC), the mTOR inhibitor Temsirolimus improved survival compared with interferon. We performed a retrospective, independent, blinded radiographic review of chest computed tomography (CT) images of patients in this study to characterize Temsirolimusrelated pneumonitis. Patients and Methods Patients were treated with intravenous Temsirolimus 25 mg once weekly or subcutaneous interferon alfa 3 million units, with an increase to 18 million units, thrice weekly. Drug-related pneumonitis was identified based on sequential chest CT images, required every 8 weeks, showing changes consistent with pneumonitis and not pneumonia (infection) or disease progression as correlated with clinical data. Cumulative probability of drug-related pneumonitis was estimated using the Kaplan-Meier method. Results Eight (6%) of 138 and 52 (29%) of 178 evaluable patients on interferon and Temsirolimus treatment, respectively, developed radiographically identified drug-related pneumonitis. Time to onset of pneumonitis was significantly shorter on the Temsirolimus arm than on the interferon arm (log-rank P .001). Estimated cumulative probability of pneumonitis at 8 and 16 weeks from first dose was 21% and 31%, respectively, on the Temsirolimus arm and 6% and 8%, respectively, on the interferon arm. Respiratory symptoms were observed around time of onset of radiographically diagnosed Temsirolimus-related pneumonitis in 16 (31%) of 52 patients. Conclusion Patients with ARCC receiving Temsirolimus should be monitored closely for development of pneumonitis, and their management should be altered if clinical symptoms appear.
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analysis of pten and hif 1α and correlation with efficacy in patients with advanced renal cell carcinoma treated with Temsirolimus versus interferon α
Cancer, 2009Co-Authors: Robert A Figlin, Anna Berkenblit, Andrew Strahs, Mizue Krygowski, Janice P Dutcher, David F Mcdermott, Paul De Souza, A. Thiele, J Feingold, Joseph BoniAbstract:BACKGROUND: Exploratory subgroup analyses from the phase 3 global advanced renal cell carcinoma (ARCC) trial were conducted to determine if baseline levels of the tumor molecular markers PTEN and HIF1 α correlated with efficacy in patients treated with Temsirolimus (Torisel) versus interferon-α (IFN). METHODS: Patients in the IFN group received 3 million U (MU) subcutaneously 3x weekly, escalating to 18 MU. Patients in the Temsirolimus group received 25 mg intravenously weekly. PTEN and HIF1 α baseline levels were measured in archived tumor specimens by immunohistochemistry. RESULTS: There was no correlation between baseline PTEN and HIF1 α levels and treatment effect with respect to overall survival (OS), progression-free survival, or objective response rate (ORR) in patients with advanced renal cell carcinoma with poor-risk prognostic factors. CONCLUSIONS: The baseline status of the molecular markers PTEN and HIF1 α did not correlate with efficacy in renal cell carcinoma patients treated with Temsirolimus versus IFN. Patients demonstrated OS and progression-free survival benefit when treated with Temsirolimus regardless of PTEN and HIF1 α status. Thus, baseline PTEN and HIF-1 levels may not predict response to Temsirolimus. Alternatively, the lack of correlation may be due to the variability in tumor specimens that occurred because of the global nature of the clinical trial. Other markers in the phosphoinositide 3-kinase (PI3K)/Akt pathway may be of utility as predictors of response to Temsirolimus in patients with advanced renal cell carcinoma. Cancer 2009. © 2009 American Cancer Society.
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Effect of Temsirolimus versus interferon-α on outcome of patients with advanced renal cell carcinoma of different tumor histologies
Medical Oncology, 2009Co-Authors: Janice P Dutcher, Anna Berkenblit, Andrew Strahs, Mizue Krygowski, Robert A Figlin, Jay Marshall Feingold, David F Mcdermott, Paul De Souza, A. Thiele, Gary R HudesAbstract:Purpose Exploratory subgroup analyses from the phase 3 global advanced renal cell carcinoma (ARCC) trial were conducted to assess the influence of tumor histology on outcome of patients treated with Temsirolimus (Torisel™) or interferon-α (IFN). Patients and methods Patients with ARCC including clear cell and other types such as papillary and chromophobe histologies received either IFN (3 million units [MU] subcutaneously three times weekly, escalating to 18 MU) or Temsirolimus (25 mg intravenously weekly). Results Approximately 80% of patients had clear cell and 20% of patients had other histologies, the majority of which were papillary. Patients with clear cell and other RCC histologies, treated with Temsirolimus, demonstrated comparable median overall and progression-free survival. In contrast, patients with other RCC histologies, treated with IFN, demonstrated shorter median overall and progression-free survival than patients with clear cell RCC. Hazard ratios for death for treatment with Temsirolimus versus IFN were less than 1 for patients regardless of tumor histology. For patients treated with Temsirolimus, 59% with clear cell and 68% with other RCC histologies experienced tumor reductions. For patients treated with IFN, 35% with clear cell and 14% with other RCC histologies had tumor reductions. However, Temsirolimus did not appear to improve the objective response rate compared to IFN. Temsirolimus resulted in a superior clinical benefit rate compared with IFN, regardless of tumor histology. Conclusion Temsirolimus appears to be efficacious in patients with clear cell and non-clear cell histologies and can, therefore, be used for the treatment of all types of RCC.
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Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma.
The New England journal of medicine, 2007Co-Authors: Gary R Hudes, Robert A Figlin, Janice P Dutcher, David F Mcdermott, Michael A. Carducci, Piotr Tomczak, Anil Kapoor, Elzbieta Staroslawska, Jeffrey A. Sosman, Istvan BodrogiAbstract:Background Interferon alfa is widely used for metastatic renal-cell carcinoma but has limited efficacy and tolerability. Temsirolimus, a specific inhibitor of the mammalian target of rapamycin kinase, may benefit patients with this disease. Methods In this multicenter, phase 3 trial, we randomly assigned 626 patients with previously untreated, poor-prognosis metastatic renal-cell carcinoma to receive 25 mg of intravenous Temsirolimus weekly, 3 million U of interferon alfa (with an increase to 18 million U) subcutaneously three times weekly, or combination therapy with 15 mg of Temsirolimus weekly plus 6 million U of interferon alfa three times weekly. The primary end point was overall survival in comparisons of the Temsirolimus group and the combination-therapy group with the interferon group. Results Patients who received Temsirolimus alone had longer overall survival (hazard ratio for death, 0.73; 95% confidence interval [CI], 0.58 to 0.92; P=0.008) and progression-free survival (P
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Temsirolimus interferon alfa or both for advanced renal cell carcinoma
The New England Journal of Medicine, 2007Co-Authors: Gary R Hudes, Robert A Figlin, Janice P Dutcher, David F Mcdermott, Michael A. Carducci, Piotr Tomczak, Anil Kapoor, Elzbieta Staroslawska, Jeffrey A. Sosman, Istvan BodrogiAbstract:Background Interferon alfa is widely used for metastatic renal-cell carcinoma but has limited efficacy and tolerability. Temsirolimus, a specific inhibitor of the mammalian target of rapamycin kinase, may benefit patients with this disease. Methods In this multicenter, phase 3 trial, we randomly assigned 626 patients with previously untreated, poor-prognosis metastatic renal-cell carcinoma to receive 25 mg of intravenous Temsirolimus weekly, 3 million U of interferon alfa (with an increase to 18 million U) subcutaneously three times weekly, or combination therapy with 15 mg of Temsirolimus weekly plus 6 million U of interferon alfa three times weekly. The primary end point was overall survival in comparisons of the Temsirolimus group and the combination-therapy group with the interferon group. Results Patients who received Temsirolimus alone had longer overall survival (hazard ratio for death, 0.73; 95% confidence interval [CI], 0.58 to 0.92; P=0.008) and progression-free survival (P<0.001) than did patie...
