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Cora N Sternberg - One of the best experts on this subject based on the ideXlab platform.

  • comparz post hoc analysis characterizing Pazopanib responders with advanced renal cell carcinoma
    Clinical Genitourinary Cancer, 2019
    Co-Authors: Cora N Sternberg, R J Motzer, Toni K Choueiri, Thomas E Hutson, Paul Nathan, C Kollmannsberger, Georg A Bjarnason, Camillo Porta, Viktor Grunwald, Luca Dezzani
    Abstract:

    Abstract Background The phase 3 COMPARZ study demonstrated non-inferior efficacy of Pazopanib versus sunitinib in advanced renal cell carcinoma (RCC). This COMPARZ post hoc analysis characterized Pazopanib responders, patient subgroups who achieved better outcomes, and the effect of dose modification on efficacy and safety. Patients and Methods Patients were randomized to Pazopanib 800 mg/day (N = 557) or sunitinib 50 mg/day, 4 weeks on/2 weeks off (N = 553). Secondary end-points include time to complete response [CR]/partial response [PR]; the proportion of patients with CR/PR ≥10 months and progression-free survival (PFS) ≥10 months; efficacy in patients with baseline metastasis; and logistic regression analyses of patient characteristics associated with CR/PR ≥10 months. Median PFS, objective response rate (ORR), and safety were evaluated in patients with or without dose reductions or interruptions lasting ≥7 days. Results Median time to response was numerically shorter for Pazopanib versus sunitinib (11.9 versus 17.4 weeks). A similar percentage of Pazopanib and sunitinib patients had CR/PR ≥10 months (14% and 13%, respectively), and PFS ≥10 months (31% and 34%, respectively). Within both arms, patients with adverse event (AE)-related dose modifications had higher cumulative doses, longer time on treatment, improved PFS and ORR, and more frequent AEs versus patients with no dose modification. Logistic regression analyses did not identify baseline characteristics associated with response in either arm. Conclusion These results support similar efficacy of Pazopanib and sunitinib. Dose modifications when required due to AEs can be implemented safely without compromising Pazopanib or sunitinib efficacy.

  • genome wide association study gwas of efficacy and safety endpoints in Pazopanib or sunitinib treated patients with renal cell carcinoma rcc
    Journal of Clinical Oncology, 2014
    Co-Authors: Toby Johnson, Cora N Sternberg, Toni K Choueiri, Chunfang Xu, Robert A Figlin, Karen S King, Sandy Stinnett, Keith C Deen, Christopher Carpenter, Colin F Spraggs
    Abstract:

    4503 Background: Pazopanib and sunitinib are angiogenesis inhibitors approved for treatment of advanced RCC, but there is substantial heterogeneity in response to either treatment. We hypothesized that patient’s germline genetic variation may affect treatment efficacy or safety endpoints. Methods: N=1099 patients, from the COMPARZ study (NCT00720941, NCT01147822, N=374 Pazopanib, N=355 sunitinib) and three other phase II/III Pazopanib studies (NCT00244764, NCT00334282, NCT00387764, N=370), provided consent for pharmacogenetic research. GWAS analyses used normal, ordinal, and Cox regression models to test 30M genetic variants (genotyped or imputed) for association with progression free survival (PFS), overall survival (OS), and best response (BR) in Pazopanib or sunitinib treated patients, and with safety endpoints in Pazopanib treated patients (bilirubin elevation, transaminase elevation, blood pressure change, hand foot syndrome [HFS], diarrhoea, fatigue, cardiotoxicity, hypothyroidism, proteinuria). Res...

  • a randomised double blind phase iii study of Pazopanib in patients with advanced and or metastatic renal cell carcinoma final overall survival results and safety update
    European Journal of Cancer, 2013
    Co-Authors: Cora N Sternberg, Robert E Hawkins, John Wagstaff, Pamela Salman, Jozef Mardiak, Carlos H Barrios, J J Zarba, Oleg Gladkov, Cezary Szczylik, Lauren Mccann
    Abstract:

    Abstract Background In this randomised phase III study (VEG105192; NCT00334282 ), Pazopanib previously demonstrated statistically and clinically meaningful improvement of progression-free survival versus placebo in patients with advanced/metastatic renal cell carcinoma (mRCC). Final overall survival (OS) and updated safety results are now reported. Methods Treatment-naive or cytokine-pretreated mRCC patients ( n  = 435) stratified and randomised (2:1) to Pazopanib 800 mg daily or placebo, were treated until disease progression, death or unacceptable toxicity. Upon progression, placebo patients could receive Pazopanib through an open-label study. Final OS in the intent-to-treat population was analysed using a stratified log-rank test. Rank-preserving structural failure time (RPSFT) and inverse probability of censoring weighted (IPCW) analyses were performed post-hoc to adjust for crossover. Findings The difference in final OS between Pazopanib- and placebo-treated patients was not statistically significant (22.9 versus 20.5 months, respectively; hazard ratio [HR] = 0.91; 95% confidence interval [CI], 0.71–1.16; one-sided P  = .224). Early and frequent crossover from placebo to Pazopanib and prolonged duration of crossover treatment confounded the OS analysis. In IPCW analyses, Pazopanib decreased mortality (HR = 0.504; 95% CI, 0.315–0.762; two-sided P  = .002). Similar, albeit non-significant, results were obtained in RPSFT analyses (HR = 0.43; 95% CI, 0.215–1.388; two-sided P  = .172). Since the last cutoff, cumulative exposure to Pazopanib increased by 30%. The Pazopanib safety profile showed no new safety signals or changes in the type, frequency and severity of adverse events. Interpretation Although no significant difference in OS was observed in this study, extensive crossover from placebo to Pazopanib confounded final OS analysis. Post-hoc analyses adjusting for crossover suggest OS benefit with Pazopanib treatment for mRCC patients.

  • Safety and tolerability of Pazopanib in the treatment of renal cell carcinoma
    Expert Opinion on Drug Safety, 2012
    Co-Authors: Andrea Zivi, Linda Cerbone, Federica Recine, Cora N Sternberg
    Abstract:

    Introduction: Renal cell carcinoma (RCC) is still a challenging disease. Over the last 6 years, the use of novel targeted therapies interfering with vascularization and inhibition of other downstream pathways has revolutionized the therapy of this disease, leading to an improvement of patient outcomes. In particular, dysregulation of the vascular endothelial growth factor (VEGF) pathway and VEGF protein overexpression have proved important, as they result in increased tumor angiogenesis and RCC growth and development. Areas covered: This review briefly discusses the mechanisms of action and clinical applications of Pazopanib. It mainly outlines the safety and tolerability of Pazopanib for locally advanced/metastatic RCC. Phase III Pazopanib safety data are also indirectly compared with other standard, antiangiogenic receptor tyrosine kinase inhibitors currently used in the management of RCC. Expert opinion: Pazopanib is a new drug available in the oncology portfolio to treat patients with predominantly cl...

  • Pazopanib clinical development of a potent anti angiogenic drug
    Critical Reviews in Oncology Hematology, 2011
    Co-Authors: Fabio A B Schutz, Toni K Choueiri, Cora N Sternberg
    Abstract:

    Pazopanib is an oral, multi-targeted, tyrosine kinase inhibitor (TKI) that binds to the vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR) and several other key proteins responsible for angiogenesis, tumor growth and cell survival. Pazopanib exhibited in vivo and in vitro activity against tumor growth and, in early clinical trials, was well tolerated with the main side effects being hypertension, fatigue and gastrointestinal disorders. Pazopanib showed clinical activity in several tumors including renal cell cancer (RCC), breast cancer, soft tissue sarcoma, thyroid cancer, hepatocellular cancer and cervical cancer. A phase III clinical trial in metastatic RCC patients showed a significant improvement in progression-free survival, leading to its approval in the US. In metastatic breast cancer, the combination of Pazopanib with lapatinib was more effective than lapatinib alone. At the time of the current publication, Pazopanib is being evaluated in more than 35 phase II and III trials.

R J Motzer - One of the best experts on this subject based on the ideXlab platform.

  • comparz post hoc analysis characterizing Pazopanib responders with advanced renal cell carcinoma
    Clinical Genitourinary Cancer, 2019
    Co-Authors: Cora N Sternberg, R J Motzer, Toni K Choueiri, Thomas E Hutson, Paul Nathan, C Kollmannsberger, Georg A Bjarnason, Camillo Porta, Viktor Grunwald, Luca Dezzani
    Abstract:

    Abstract Background The phase 3 COMPARZ study demonstrated non-inferior efficacy of Pazopanib versus sunitinib in advanced renal cell carcinoma (RCC). This COMPARZ post hoc analysis characterized Pazopanib responders, patient subgroups who achieved better outcomes, and the effect of dose modification on efficacy and safety. Patients and Methods Patients were randomized to Pazopanib 800 mg/day (N = 557) or sunitinib 50 mg/day, 4 weeks on/2 weeks off (N = 553). Secondary end-points include time to complete response [CR]/partial response [PR]; the proportion of patients with CR/PR ≥10 months and progression-free survival (PFS) ≥10 months; efficacy in patients with baseline metastasis; and logistic regression analyses of patient characteristics associated with CR/PR ≥10 months. Median PFS, objective response rate (ORR), and safety were evaluated in patients with or without dose reductions or interruptions lasting ≥7 days. Results Median time to response was numerically shorter for Pazopanib versus sunitinib (11.9 versus 17.4 weeks). A similar percentage of Pazopanib and sunitinib patients had CR/PR ≥10 months (14% and 13%, respectively), and PFS ≥10 months (31% and 34%, respectively). Within both arms, patients with adverse event (AE)-related dose modifications had higher cumulative doses, longer time on treatment, improved PFS and ORR, and more frequent AEs versus patients with no dose modification. Logistic regression analyses did not identify baseline characteristics associated with response in either arm. Conclusion These results support similar efficacy of Pazopanib and sunitinib. Dose modifications when required due to AEs can be implemented safely without compromising Pazopanib or sunitinib efficacy.

  • randomized phase iii trial of adjuvant Pazopanib versus placebo after nephrectomy in patients with localized or locally advanced renal cell carcinoma
    Journal of Clinical Oncology, 2017
    Co-Authors: R J Motzer, Naomi B Haas, Frede Donskov, Marine Grossgoupil, Sergei Varlamov, Evgeny Kopyltsov, Bohuslav Melichar, Brian I Rini, Toni K Choueiri, Milada Zemanova
    Abstract:

    PurposeThis phase III trial evaluated the efficacy and safety of Pazopanib versus placebo in patients with locally advanced renal cell carcinoma (RCC) at high risk for relapse after nephrectomy.Patients and MethodsA total of 1,538 patients with resected pT2 (high grade) or ≥ pT3, including N1, clear cell RCC were randomly assigned to Pazopanib or placebo for 1 year; 403 patients received a starting dose of 800 mg or placebo. To address toxicity attrition, the 800-mg starting dose was lowered to 600 mg, and the primary end point analysis was changed to disease-free survival (DFS) for Pazopanib 600 mg versus placebo (n = 1,135). Primary analysis was performed after 350 DFS events in the intent-to-treat (ITT) Pazopanib 600 mg group (ITT600mg), and DFS follow-up analysis was performed 12 months later. Secondary end point analyses included DFS with ITT Pazopanib 800 mg (ITT800mg) and safety.ResultsThe primary analysis results of DFS ITT600mg favored Pazopanib but did not show a significant improvement over pla...

  • overall survival in renal cell carcinoma with Pazopanib versus sunitinib
    The New England Journal of Medicine, 2014
    Co-Authors: R J Motzer, Lauren Mccann, Keith C Deen, Thomas E Hutson, Toni K Choueiri
    Abstract:

    Survival results are now mature for a noninferiority trial comparing Pazopanib with sunitinib in renal-cell carcinoma. Median survival was 42.5 months with Pazopanib and 43.6 months with sunitinib,...

  • Pazopanib versus sunitinib in metastatic renal cell carcinoma
    The New England Journal of Medicine, 2013
    Co-Authors: R J Motzer, Robert E Hawkins, David Cella, Thomas E Hutson, James A Reeves, Paul Nathan, Michael Staehler, Paul De Souza, Jaime R Merchan, Ekaterini Boleti
    Abstract:

    Background Pazopanib and sunitinib provided a progression-free survival benefit, as compared with placebo or interferon, in previous phase 3 studies involving patients with metastatic renal-cell carcinoma. This phase 3, randomized trial compared the efficacy and safety of Pazopanib and sunitinib as first-line therapy. Methods We randomly assigned 1110 patients with clear-cell, metastatic renal-cell carcinoma, in a 1:1 ratio, to receive a continuous dose of Pazopanib (800 mg once daily; 557 patients) or sunitinib in 6-week cycles (50 mg once daily for 4 weeks, followed by 2 weeks without treatment; 553 patients). The primary end point was progression-free survival as assessed by independent review, and the study was powered to show the noninferiority of Pazopanib versus sunitinib. Secondary end points included overall survival, safety, and quality of life. Results Pazopanib was noninferior to sunitinib with respect to progression-free survival (hazard ratio for progression of disease or death from any caus...

  • association of il8 polymorphisms with overall survival in patients with renal cell carcinoma in comparz Pazopanib versus sunitinib phase iii study
    Journal of Clinical Oncology, 2013
    Co-Authors: Chunfang Xu, Toni K Choueiri, Toby Johnson, Keith C Deen, Christopher Carpenter, Colin F Spraggs, Arundathy N Bartlettpandite, R J Motzer
    Abstract:

    4519 Background: Pazopanib and sunitinib are angiogenesis inhibitors approved for treatment of advanced renal cell carcinoma (RCC). COMPARZ, a phase III randomized clinical trial comparing Pazopanib vs sunitinib for RCC, demonstrated similar efficacies for the two therapies but safety profiles differed. Our genetic analyses of previous Pazopanib clinical trials found that IL8 polymorphisms may be associated with progression-free survival (PFS) and overall survival (OS). We attempted to validate these associations in the COMPARZ study. Methods: Of the 1110 participants in COMPARZ, 724 (65%) provided consent and DNA for pharmacogenetic analyses (Pazopanib, N = 371; sunitinib, N = 353).Associations of IL8 polymorphisms (rs1126647 and rs4073) with PFS and OS were tested using the Cox proportional hazards model with baseline factors as covariates in a combined analysis of all patients and also separately in Pazopanib-treated and sunitinib-treated patients. One-tailed P values were calculated for effects in the...

Toni K Choueiri - One of the best experts on this subject based on the ideXlab platform.

  • comparz post hoc analysis characterizing Pazopanib responders with advanced renal cell carcinoma
    Clinical Genitourinary Cancer, 2019
    Co-Authors: Cora N Sternberg, R J Motzer, Toni K Choueiri, Thomas E Hutson, Paul Nathan, C Kollmannsberger, Georg A Bjarnason, Camillo Porta, Viktor Grunwald, Luca Dezzani
    Abstract:

    Abstract Background The phase 3 COMPARZ study demonstrated non-inferior efficacy of Pazopanib versus sunitinib in advanced renal cell carcinoma (RCC). This COMPARZ post hoc analysis characterized Pazopanib responders, patient subgroups who achieved better outcomes, and the effect of dose modification on efficacy and safety. Patients and Methods Patients were randomized to Pazopanib 800 mg/day (N = 557) or sunitinib 50 mg/day, 4 weeks on/2 weeks off (N = 553). Secondary end-points include time to complete response [CR]/partial response [PR]; the proportion of patients with CR/PR ≥10 months and progression-free survival (PFS) ≥10 months; efficacy in patients with baseline metastasis; and logistic regression analyses of patient characteristics associated with CR/PR ≥10 months. Median PFS, objective response rate (ORR), and safety were evaluated in patients with or without dose reductions or interruptions lasting ≥7 days. Results Median time to response was numerically shorter for Pazopanib versus sunitinib (11.9 versus 17.4 weeks). A similar percentage of Pazopanib and sunitinib patients had CR/PR ≥10 months (14% and 13%, respectively), and PFS ≥10 months (31% and 34%, respectively). Within both arms, patients with adverse event (AE)-related dose modifications had higher cumulative doses, longer time on treatment, improved PFS and ORR, and more frequent AEs versus patients with no dose modification. Logistic regression analyses did not identify baseline characteristics associated with response in either arm. Conclusion These results support similar efficacy of Pazopanib and sunitinib. Dose modifications when required due to AEs can be implemented safely without compromising Pazopanib or sunitinib efficacy.

  • randomized phase iii trial of adjuvant Pazopanib versus placebo after nephrectomy in patients with localized or locally advanced renal cell carcinoma
    Journal of Clinical Oncology, 2017
    Co-Authors: R J Motzer, Naomi B Haas, Frede Donskov, Marine Grossgoupil, Sergei Varlamov, Evgeny Kopyltsov, Bohuslav Melichar, Brian I Rini, Toni K Choueiri, Milada Zemanova
    Abstract:

    PurposeThis phase III trial evaluated the efficacy and safety of Pazopanib versus placebo in patients with locally advanced renal cell carcinoma (RCC) at high risk for relapse after nephrectomy.Patients and MethodsA total of 1,538 patients with resected pT2 (high grade) or ≥ pT3, including N1, clear cell RCC were randomly assigned to Pazopanib or placebo for 1 year; 403 patients received a starting dose of 800 mg or placebo. To address toxicity attrition, the 800-mg starting dose was lowered to 600 mg, and the primary end point analysis was changed to disease-free survival (DFS) for Pazopanib 600 mg versus placebo (n = 1,135). Primary analysis was performed after 350 DFS events in the intent-to-treat (ITT) Pazopanib 600 mg group (ITT600mg), and DFS follow-up analysis was performed 12 months later. Secondary end point analyses included DFS with ITT Pazopanib 800 mg (ITT800mg) and safety.ResultsThe primary analysis results of DFS ITT600mg favored Pazopanib but did not show a significant improvement over pla...

  • genome wide association study gwas of efficacy and safety endpoints in Pazopanib or sunitinib treated patients with renal cell carcinoma rcc
    Journal of Clinical Oncology, 2014
    Co-Authors: Toby Johnson, Cora N Sternberg, Toni K Choueiri, Chunfang Xu, Robert A Figlin, Karen S King, Sandy Stinnett, Keith C Deen, Christopher Carpenter, Colin F Spraggs
    Abstract:

    4503 Background: Pazopanib and sunitinib are angiogenesis inhibitors approved for treatment of advanced RCC, but there is substantial heterogeneity in response to either treatment. We hypothesized that patient’s germline genetic variation may affect treatment efficacy or safety endpoints. Methods: N=1099 patients, from the COMPARZ study (NCT00720941, NCT01147822, N=374 Pazopanib, N=355 sunitinib) and three other phase II/III Pazopanib studies (NCT00244764, NCT00334282, NCT00387764, N=370), provided consent for pharmacogenetic research. GWAS analyses used normal, ordinal, and Cox regression models to test 30M genetic variants (genotyped or imputed) for association with progression free survival (PFS), overall survival (OS), and best response (BR) in Pazopanib or sunitinib treated patients, and with safety endpoints in Pazopanib treated patients (bilirubin elevation, transaminase elevation, blood pressure change, hand foot syndrome [HFS], diarrhoea, fatigue, cardiotoxicity, hypothyroidism, proteinuria). Res...

  • overall survival in renal cell carcinoma with Pazopanib versus sunitinib
    The New England Journal of Medicine, 2014
    Co-Authors: R J Motzer, Lauren Mccann, Keith C Deen, Thomas E Hutson, Toni K Choueiri
    Abstract:

    Survival results are now mature for a noninferiority trial comparing Pazopanib with sunitinib in renal-cell carcinoma. Median survival was 42.5 months with Pazopanib and 43.6 months with sunitinib,...

  • association of il8 polymorphisms with overall survival in patients with renal cell carcinoma in comparz Pazopanib versus sunitinib phase iii study
    Journal of Clinical Oncology, 2013
    Co-Authors: Chunfang Xu, Toni K Choueiri, Toby Johnson, Keith C Deen, Christopher Carpenter, Colin F Spraggs, Arundathy N Bartlettpandite, R J Motzer
    Abstract:

    4519 Background: Pazopanib and sunitinib are angiogenesis inhibitors approved for treatment of advanced renal cell carcinoma (RCC). COMPARZ, a phase III randomized clinical trial comparing Pazopanib vs sunitinib for RCC, demonstrated similar efficacies for the two therapies but safety profiles differed. Our genetic analyses of previous Pazopanib clinical trials found that IL8 polymorphisms may be associated with progression-free survival (PFS) and overall survival (OS). We attempted to validate these associations in the COMPARZ study. Methods: Of the 1110 participants in COMPARZ, 724 (65%) provided consent and DNA for pharmacogenetic analyses (Pazopanib, N = 371; sunitinib, N = 353).Associations of IL8 polymorphisms (rs1126647 and rs4073) with PFS and OS were tested using the Cox proportional hazards model with baseline factors as covariates in a combined analysis of all patients and also separately in Pazopanib-treated and sunitinib-treated patients. One-tailed P values were calculated for effects in the...

Thomas E Hutson - One of the best experts on this subject based on the ideXlab platform.

  • comparz post hoc analysis characterizing Pazopanib responders with advanced renal cell carcinoma
    Clinical Genitourinary Cancer, 2019
    Co-Authors: Cora N Sternberg, R J Motzer, Toni K Choueiri, Thomas E Hutson, Paul Nathan, C Kollmannsberger, Georg A Bjarnason, Camillo Porta, Viktor Grunwald, Luca Dezzani
    Abstract:

    Abstract Background The phase 3 COMPARZ study demonstrated non-inferior efficacy of Pazopanib versus sunitinib in advanced renal cell carcinoma (RCC). This COMPARZ post hoc analysis characterized Pazopanib responders, patient subgroups who achieved better outcomes, and the effect of dose modification on efficacy and safety. Patients and Methods Patients were randomized to Pazopanib 800 mg/day (N = 557) or sunitinib 50 mg/day, 4 weeks on/2 weeks off (N = 553). Secondary end-points include time to complete response [CR]/partial response [PR]; the proportion of patients with CR/PR ≥10 months and progression-free survival (PFS) ≥10 months; efficacy in patients with baseline metastasis; and logistic regression analyses of patient characteristics associated with CR/PR ≥10 months. Median PFS, objective response rate (ORR), and safety were evaluated in patients with or without dose reductions or interruptions lasting ≥7 days. Results Median time to response was numerically shorter for Pazopanib versus sunitinib (11.9 versus 17.4 weeks). A similar percentage of Pazopanib and sunitinib patients had CR/PR ≥10 months (14% and 13%, respectively), and PFS ≥10 months (31% and 34%, respectively). Within both arms, patients with adverse event (AE)-related dose modifications had higher cumulative doses, longer time on treatment, improved PFS and ORR, and more frequent AEs versus patients with no dose modification. Logistic regression analyses did not identify baseline characteristics associated with response in either arm. Conclusion These results support similar efficacy of Pazopanib and sunitinib. Dose modifications when required due to AEs can be implemented safely without compromising Pazopanib or sunitinib efficacy.

  • characterisation of liver chemistry abnormalities associated with Pazopanib monotherapy a systematic review and meta analysis of clinical trials in advanced cancer patients
    European Journal of Cancer, 2015
    Co-Authors: Thomas Powles, Christopher Carpenter, Thomas E Hutson, Sergio Bracarda, Mei Chen, Elliot Norry, Natalie Compton, Mark A Heise, Philipp Harter, Lini Pandite
    Abstract:

    Abstract Drug-induced liver chemistry abnormalities, primarily transaminase elevations, are commonly observed in Pazopanib-treated patients. This meta-analysis characterises liver chemistry abnormalities associated with Pazopanib. Data of Pazopanib-treated patients from nine prospective trials were integrated ( N  = 2080). Laboratory datasets were used to characterise the incidence, timing, recovery and patterns of liver events, and subsequent rechallenge with Pazopanib. Severe cases of liver chemistry abnormalities were clinically reviewed. Multivariate analyses identified predisposing factors. Twenty percent of patients developed elevated alanine aminotransferase (ALT) >3×ULN. Incidence of peak ALT >3–5×ULN, >5–8×ULN, >8–20×ULN and >20×ULN was 8%, 5%, 5% and 1%, respectively. Median time to onset for all events was 42 days; 91% of events were observed within 18 weeks. Recovery rates based on peak ALT >3–5×ULN, >5–8×ULN, >8-20×ULN and >20×ULN were 91%, 90%, 90% and 64%, respectively. Median time from onset to recovery was 30 days, but longer in patients without dose interruption. Based on clinical review, no deaths were associated with drug-induced liver injury. Overall, 38% of rechallenged patients had ALT elevation recurrence, with 9-day median time to recurrence. Multivariate analysis showed that older age was associated with development of ALT >8×ULN. There was no correlation between hypertension and transaminitis. Our data support the current guidelines on regular liver chemistry tests after initiation of Pazopanib, especially during the first 9 or 10 weeks, and also demonstrate the safety of rechallenge with Pazopanib.

  • overall survival in renal cell carcinoma with Pazopanib versus sunitinib
    The New England Journal of Medicine, 2014
    Co-Authors: R J Motzer, Lauren Mccann, Keith C Deen, Thomas E Hutson, Toni K Choueiri
    Abstract:

    Survival results are now mature for a noninferiority trial comparing Pazopanib with sunitinib in renal-cell carcinoma. Median survival was 42.5 months with Pazopanib and 43.6 months with sunitinib,...

  • Pazopanib versus sunitinib in metastatic renal cell carcinoma
    The New England Journal of Medicine, 2013
    Co-Authors: R J Motzer, Robert E Hawkins, David Cella, Thomas E Hutson, James A Reeves, Paul Nathan, Michael Staehler, Paul De Souza, Jaime R Merchan, Ekaterini Boleti
    Abstract:

    Background Pazopanib and sunitinib provided a progression-free survival benefit, as compared with placebo or interferon, in previous phase 3 studies involving patients with metastatic renal-cell carcinoma. This phase 3, randomized trial compared the efficacy and safety of Pazopanib and sunitinib as first-line therapy. Methods We randomly assigned 1110 patients with clear-cell, metastatic renal-cell carcinoma, in a 1:1 ratio, to receive a continuous dose of Pazopanib (800 mg once daily; 557 patients) or sunitinib in 6-week cycles (50 mg once daily for 4 weeks, followed by 2 weeks without treatment; 553 patients). The primary end point was progression-free survival as assessed by independent review, and the study was powered to show the noninferiority of Pazopanib versus sunitinib. Secondary end points included overall survival, safety, and quality of life. Results Pazopanib was noninferior to sunitinib with respect to progression-free survival (hazard ratio for progression of disease or death from any caus...

  • efficacy and safety of Pazopanib in patients with metastatic renal cell carcinoma
    Journal of Clinical Oncology, 2010
    Co-Authors: Thomas E Hutson, Lauren Mccann, Ian D Davis, Paul De Souza, Jeanpascal Machiels, Sylvie Rottey, B F Hong, Richard J Epstein, Katherine Baker, Thomas Crofts
    Abstract:

    PURPOSE: Inactivation of the von Hippel-Lindau gene in clear-cell renal cell carcinomas (RCC) leads to overexpression of hypoxia inducible factor, a transcription factor regulating vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) gene expression. Pazopanib, an angiogenesis inhibitor targeting VEGF receptor, PDGF receptor, and c-KIT, was evaluated in patients with RCC. PATIENTS AND METHODS: This phase II study was designed as a randomized discontinuation study but was revised to an open-label study on the recommendation of the data monitoring committee (based on week 12 response rate [RR] of 38% in the first 60 patients). The primary end point was changed from progressive disease rate at 16 weeks postrandomization to RR. Pazopanib 800 mg was administered orally once daily. Pazopanib 800 mg was administered orally once daily. RESULTS: The study enrolled 225 patients with metastatic RCC; 155 patients (69%) were treatment naive, and 70 patients (31%) had received one prior cytokine- or bevacizumab-containing regimen. Overall RR was 35%; median duration of response was 68 weeks. Median progression-free survival (PFS) was 52 weeks. Eastern Cooperative Oncology Group performance status of 0 and time from diagnosis to treatment of more than 1 year were correlated with prolonged PFS. Pazopanib was generally well tolerated. The most common adverse events were diarrhea, fatigue, and hair depigmentation. The most common laboratory abnormalities were elevated AST and ALT. CONCLUSION: Pazopanib demonstrated durable activity in patients with advanced RCC and was generally well tolerated in this population. These findings support the further development of Pazopanib in advanced RCC.

Axel Le Cesne - One of the best experts on this subject based on the ideXlab platform.

  • safety and efficacy of Pazopanib in advanced soft tissue sarcoma palette eortc 62072 subgroup analyses
    BMC Cancer, 2019
    Co-Authors: Axel Le Cesne, Jeanyves Blay, Patrick Schoffski, Massimo Aglietta, Sebastian Bauer, George D Demetri, Luca Dezzani, Qasim Ahmad, I Judson, P Hohenberger
    Abstract:

    PALETTE is a phase 3 trial that demonstrated single-agent activity of Pazopanib in advanced soft tissue sarcomas (aSTS). We performed retrospective subgroup analyses to explore potential relationships between patient characteristics, prior lines of therapy, dose intensity, and dose modifications on safety and efficacy of Pazopanib in aSTS. PALETTE compared Pazopanib with placebo in patients with aSTS (age ≥ 18 years) whose disease had progressed during or following prior chemotherapy. In these subgroup analyses, median progression-free survival (mPFS) among patients receiving Pazopanib was the efficacy outcome of interest. Adverse events (AEs) were also compared within subgroups. All analyses were descriptive and exploratory. A total of 246 patients received Pazopanib in the PALETTE study. The mPFS was longer in patients who had only 1 prior line versus 2+ prior lines of therapy (24.7 vs 18.9 weeks, respectively); AE rates were similar regardless of number of prior lines of therapy. The mPFS was similar in patients aged < 65 and ≥ 65 y (20.0 and 20.1 weeks, respectively). Although AEs leading to study discontinuation were higher in older patients (≥65 y, 30%; < 65 y, 17%), rates of dose reductions, dose interruptions, and serious AEs were similar between the 2 age groups. No reduction in mPFS was noted in patients requiring dose reductions or dose interruptions to manage toxicities. Longer mPFS was observed in patients receiving Pazopanib following only 1 line of therapy. Additionally, mPFS with Pazopanib was maintained regardless of patient age or dose modifications used to manage toxicity. NCT00753688 , first posted September 16, 2008 (registered prospectively).

  • Pazopanib plus best supportive care versus best supportive care alone in advanced gastrointestinal stromal tumours resistant to imatinib and sunitinib pazogist a randomised multicentre open label phase 2 trial
    Lancet Oncology, 2016
    Co-Authors: Claire Cropet, Maud Toulmonde, Axel Le Cesne, Mathieu Molimard, Emmanuelle Bompas, Philippe Cassier, Isabelle Raycoquard, M Rios, Antoine Adenis, Antoine Italiano
    Abstract:

    Summary Background Gastrointestinal stromal tumours (GIST) are the most common mesenchymal neoplasms of the gastrointestinal tract. Imatinib followed by sunitinib and regorafenib is the standard sequence of treatment for advanced disease. Pazopanib is effective in soft tissue sarcomas but has never been assessed in advanced GIST in a randomised trial. We aimed to assess the efficacy and safety of Pazopanib in patients with previously treated advanced GIST. Methods In this randomised, open-label phase 2 study, we enrolled adults (aged ≥18 years) with advanced GIST resistant to imatinib and sunitinib from 12 comprehensive cancer centres or university hospitals in France and randomly assigned them 1:1 using an interactive web-based centralised platform to 800 mg oral Pazopanib once daily in 4-week cycles plus best supportive care or best supportive care alone. Randomisation was stratified by the number of previous treatment regimens (2 vs ≥3); no-one was masked to treatment group allocation. Upon disease progression, patients in the best supportive care group were allowed to switch to Pazopanib as compassionate treatment. The primary endpoint was investigator-assessed progression-free survival, analysed by intention-to-treat. All randomised participants who received at least one dose of Pazopanib were included in the safety analysis. This study is registered with ClinicalTrials.gov, number NCT01323400. Findings Between April 12, 2011, and Dec 9, 2013, 81 patients were enrolled and randomly assigned to Pazopanib plus best supportive care (n=40) or best supportive care alone (n=41). The median follow-up was 26·4 months (IQR 22·0–37·8) in the Pazopanib plus best supportive care group and 28·9 months (22·0–35·2) in the best supportive care group. 4-month investigator-assessed progression-free survival was 45·2% (95% CI 29·1–60·0) in the Pazopanib plus best supportive care group versus 17·6% (7·8–30·8) in the best supportive care group (hazard ratio [HR] 0·59, 95% CI 0·37–0·96; p=0·029). Median progression-free survival was 3·4 months (95% CI 2·4–5·6) with Pazopanib plus best supportive care and 2·3 months (2·1–3·3) with best supportive care alone (HR 0·59 [0·37–0·96], p=0·03). 36 (88%) of the patients originally assigned to the best supportive care group switched to Pazopanib following investigator-assessed disease progression; these patients had a median progression-free survival from Pazopanib initiation of 3·5 months (95% CI 2·2–5·2). 55 (72%) of the 76 Pazopanib-treated patients had Pazopanib-related grade 3 or worse adverse events, the most common of which was hypertension (15 [38%] in the Pazopanib plus best supportive care group and 13 [36%] in the best supportive care group). 20 (26%) patients had Pazopanib-related serious adverse events (14 [35%] in the Pazopanib plus best supportive care group and six [17%] in the best supportive care group), including pulmonary embolism in eight (9%) patients (five [13%] in the Pazopanib plus best supportive care group and three [7%] in the best supportive care group). Three Pazopanib-related deaths occurred (two pulmonary embolisms [one in each group] and one hepatic cytolysis [in the best supportive care group]). Three adverse event-related but not Pazopanib-related deaths occurred in the best supportive care group after switch to Pazopanib; these deaths were from hyperammonaemic encephalopathy, pneumopathy, and respiratory failure. Interpretation Pazopanib plus best supportive care improves progression-free survival compared with best supportive care alone in patients with advanced GIST resistant to imatinib and sunitinib, with a toxicity profile similar to that reported for other sarcomas. This trial provides reference outcome data for future studies of targeted inhibitors in the third-line setting for these patients. Funding GlaxoSmithKline, French National Cancer Institute, EuroSARC (FP7-278742), Centre Leon Berard.

  • Pazopanib for metastatic soft tissue sarcoma palette a randomised double blind placebo controlled phase 3 trial
    The Lancet, 2012
    Co-Authors: Winette T.a. Van Der Graaf, Jeanyves Blay, Sant P Chawla, B Buinguyen, P G Casali, Patrick Schoffski, Massimo Aglietta, Arthur P Staddon, Yasuo Beppu, Axel Le Cesne
    Abstract:

    Summary Background Pazopanib, a multitargeted tyrosine kinase inhibitor, has single-agent activity in patients with advanced non-adipocytic soft-tissue sarcoma. We investigated the effect of Pazopanib on progression-free survival in patients with metastatic non-adipocytic soft-tissue sarcoma after failure of standard chemotherapy. Methods This phase 3 study was done in 72 institutions, across 13 countries. Patients with angiogenesis inhibitor-naive, metastatic soft-tissue sarcoma, progressing despite previous standard chemotherapy, were randomly assigned by an interactive voice randomisation system in a 2:1 ratio in permuted blocks (with block sizes of six) to receive either Pazopanib 800 mg once daily or placebo, with no subsequent cross-over. Patients, investigators who gave the treatment, those assessing outcomes, and those who did the analysis were masked to the allocation. The primary endpoint was progression-free survival. Efficacy analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00753688. Findings 372 patients were registered and 369 were randomly assigned to receive Pazopanib (n=246) or placebo (n=123). Median progression-free survival was 4·6 months (95% CI 3·7–4·8) for Pazopanib compared with 1·6 months (0·9–1·8) for placebo (hazard ratio [HR] 0·31, 95% CI 0·24–0·40; p vs 155 in the Pazopanib group [65%]), diarrhoea (20 [16%] vs 138 [58%]), nausea (34 [28%] vs 129 [54%]), weight loss (25 [20%] vs 115 [48%]), and hypertension (8 [7%] vs 99 [41%]). The median relative dose intensity was 100% for placebo and 96% for Pazopanib. Interpretation Pazopanib is a new treatment option for patients with metastatic non-adipocytic soft-tissue sarcoma after previous chemotherapy. Funding GlaxoSmithKline.