Long-term safety of sorafenib (SOR) for the treatment (tx) of advanced clear-cell renal-cell carcinoma (RCC): Data analysis from patients (pts) treated for over 1 year in the phase III TARGET study

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e16057-e16057
Author(s):  
T. E. Hutson ◽  
J. Bellmunt ◽  
C. Porta ◽  
M. Staehler ◽  
C. Szczylik ◽  
...  
Keyword(s):  
Clear Cell ◽  
Descriptive Analysis ◽  
Phase Iii ◽  
Controlled Study ◽  
Cell Renal Cell Carcinoma ◽  
Double Blind ◽  
Clear Cell Rcc ◽  
Prior Systemic Therapy ◽  
Ecog Ps

e16057 Background: Results of the phase III multicenter TARGET study, a randomized, double-blind, placebo (PBO)- controlled study of tx with SOR in pts with clear-cell RCC in whom 1 prior systemic therapy had failed, indicated that SOR is effective (PFS 5.5 vs 2.8 mo, HR=0.44, P<0.000001, and 39% increase in survival for SOR vs PBO, HR=0.71, P=0.015) and safe in pts with advanced RCC (Escudier et al. N Engl J Med. 2007). With a database cut-off of Sept 8, 2006, we analyzed the safety of long-term use of SOR in pts in TARGET (study start Nov 2003). Methods: Pts (N=903) with advanced metastatic clear-cell RCC that had progressed after 1 systemic tx, ECOG PS 0–2, and low- or intermediate-risk MSKCC score were randomized 1:1 to SOR 400 mg BID or PBO. End points included OS, PFS, and safety. A single planned analysis of PFS showed a significant benefit of SOR over PBO; consequently, pts assigned to PBO were offered SOR. Descriptive analysis of safety and efficacy of pts treated >1 year (y) was conducted. Results: 169/903 pts were randomized to SOR and treated >1 y and 27 pts treated >2 y. Due to crossover of PBO to SOR, only 6 pts randomized to PBO were treated with SOR >1 y. Pts treated with SOR >1 y had median PFS of 10.9 months and a response rate of 22.5%. Median tx duration was 20 months. Drug-related adverse events (AEs) were mainly grades 1 and 2 and occurred early during tx (see Table ); 31% and 22% of pts required dose interruption and reduction, respectively, because of AEs. Conclusions: Long-term tx with SOR did not result in new toxicities or an increase in overall incidence of tx-related AEs. Toxicity was not cumulative and no increase in grades 3/4 AEs was observed. Pts with preexisting cardiac disease or hypertension tolerated long-term tx with SOR; no dose reduction was required. No increase in cardiovascular toxicity was observed in this pt population. Long-term tx of pts with advanced RCC with SOR is medically manageable, with a predictable AE profile. [Table: see text] [Table: see text]

Efficacy and safety of sorafenib in patients with advanced clear-cell renal cell carcinoma (RCC) with diabetes: Results from the phase III TARGET study

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e16099-e16099
Author(s):  
S. Oudard ◽  
T. Eisen ◽  
C. Szczylik ◽  
M. Siebels ◽  
S. Negrier ◽  
...  
Keyword(s):  
Clear Cell ◽  
Formal Analysis ◽  
Phase Iii ◽  
Controlled Study ◽  
Efficacy And Safety ◽  
Cell Renal Cell Carcinoma ◽  
Double Blind ◽  
Diabetes Status ◽  
Study Population ◽  
Clear Cell Rcc

e16099 Background: Results of the phase III TARGET trial, a randomized, double-blind, placebo-controlled study of sorafenib (SOR) treatment in pts with clear-cell RCC in whom 1 prior systemic therapy had failed, indicated that SOR is effective and safe for pts with advanced RCC, leading to the approval of SOR for the treatment of advanced RCC. Diabetes can be associated with increased morbidity during treatment in a variety of malignancies. Therefore, an exploratory subset analysis was performed to evaluate the efficacy and safety of SOR in pts enrolled in TARGET with or without diabetes at baseline. Methods: Pts (N=903) with advanced clear-cell RCC, ECOG PS 0–2, and low- or intermediate-risk MSKCC score were randomized 1:1 to SOR 400 mg BID or placebo (PBO). End points included OS, PFS, and safety. A planned independently-assessed formal analysis of PFS showed significant benefit for SOR over PBO; consequently, pts assigned to PBO were able to cross over to SOR. Results: Pt demographics were similar for all subsets. Pre- crossover data by subset are shown in the table . The incidence of drug-related adverse events (AEs) across subgroups was consistent with that for the overall population. In pts with vs without diabetes, treatment with SOR was not associated with increased hyperglycemia (1 pt/arm in the without diabetes subgroups only) or hypertension. Conclusions: The safety profile of SOR in pts with diabetes was comparable with that for the overall study population. SOR was well tolerated and AEs were manageable. Trends in improved PFS were observed for SOR regardless of baseline diabetes status; however, the small diabetic subset limits interpretation of a SOR OS benefit in this subpopulation. *Final PFS of overall study population based on independent review from Jan 2005; all other data from May 2005 database [Table: see text] [Table: see text]

A phase III, randomized, controlled study to compare tivozanib with sorafenib in patients (pts) with advanced renal cell carcinoma (RCC).

2011 ◽  
Vol 29 (7_suppl) ◽  
pp. 310-310 ◽  
Author(s):  
R. J. Motzer ◽  
P. Bhargava ◽  
B. Esteves ◽  
M. Al-Adhami ◽  
W. Slichenmyer ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Clear Cell ◽  
Objective Response ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Controlled Study ◽  
Vegf Receptor ◽  
Randomized Controlled ◽  
Long Term Treatment ◽  
Clear Cell Rcc

310 Background: Drugs that block vascular endothelial growth factor (VEGF) pathway signaling, such as the tyrosine kinase inhibitor sorafenib, have become standard treatment for pts with RCC. Tivozanib (AV-951) is a potent, selective small-molecule pan-VEGF receptor (VEGFR) inhibitor, with activity against the VEGFR-1, -2, and -3 kinases at subnanomolar concentrations. Preliminary results from a phase II randomized discontinuation trial of tivozanib (1.5 mg/d; 3 wks on, 1 wk off) in pts with RCC demonstrated an objective response rate (ORR) of 27% and a median progression-free survival (PFS) of 11.8 mo by independent radiology review, with a favorable safety profile. Patients with clear cell RCC who had undergone nephrectomy had an ORR of 32% and median PFS of 14.8 mo (Bhargava, et al. ASCO 2010. Abstract 4599). Based on this antitumor activity a phase III, randomized, controlled, global, multicenter trial is currently in progress to compare tivozanib with sorafenib in pts with advanced RCC. Methods: Approximately 500 adults with clear cell RCC who have undergone nephrectomy and received ≤ 1 prior systemic treatment (no prior VEGF-targeted therapy) were randomized 1:1 to treatment with tivozanib or sorafenib. Pts are receiving 1.5 mg/d tivozanib orally in 4-week cycles (3 wks on, 1 wk off) or continuous 400 mg sorafenib orally twice daily. The primary endpoint will be PFS by independent radiology review; secondary endpoints will include overall survival, ORR, and duration of response. Safety is being monitored through adverse event reporting and laboratory analyses; toxicities are graded using the NCI Common Terminology Criteria for Adverse Events, version 3.0. The effect of therapy on health-related quality of life will be compared between arms using kidney cancer-specific (FKSI-DRS), oncology (FACT-G), and general (EQ-5D) assessments. Pharmacokinetics and biomarker analyses will be performed. Results: Pending. Conclusions: Enrollment completed in August 2010. An ongoing extension study will allow access to tivozanib for pts who demonstrate progressive disease on sorafenib, as well as long-term treatment with tivozanib or sorafenib for pts who demonstrate clinical benefit. [Table: see text]

scholarly journals Secukinumab for Long-Term Treatment of Psoriatic Arthritis: A Two-Year Followup From a Phase III, Randomized, Double-Blind Placebo-Controlled Study

2017 ◽  
Vol 69 (3) ◽  
pp. 347-355 ◽  
Author(s):  
Arthur Kavanaugh ◽  
Philip J. Mease ◽  
Andreas M. Reimold ◽  
Hasan Tahir ◽  
Jürgen Rech ◽  
...  
Keyword(s):  
Psoriatic Arthritis ◽  
Term Treatment ◽  
Phase Iii ◽  
Controlled Study ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Long Term Treatment

A randomized phase II study of nivolumab plus ipilimumab versus standard of care in previously untreated and advanced non-clear cell renal cell carcinoma (SUNIFORECAST).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS5103-TPS5103
Author(s):  
Marit Ahrens ◽  
Bernard Escudier ◽  
Ekaterini Boleti ◽  
Marc-Oliver Grimm ◽  
Marine Gross-Goupil ◽  
...  
Keyword(s):  
Phase Ii ◽  
Renal Cell ◽  
Clear Cell ◽  
Treatment Strategies ◽  
Standard Of Care ◽  
Phase Iii ◽  
Fixed Dose ◽  
Cell Renal Cell Carcinoma ◽  
Randomized Phase Ii ◽  
Prior Systemic Therapy

TPS5103 Background: Non-clear cell renal cell carcinomas (nccRCC) are a heterogeneous group of tumors accounting for approximately 25% of RCC patients (pts.). Since most clinical trials focus on clear-cell RCC (ccRCC) only, data on treatment strategies for nccRCC are limited. The combination of Nivolumab and Ipilimumab (IO/IO) has recently been approved for treatment in RCC showing a significant improvement in overall response rate (ORR), progression free (PFS), and overall survival (OS) in intermediate and high-risk pts. compared to sunitinib in a phase-III trial. Furthermore retrospective analysis in nccRCC patients have shown promising results for IO/IO as well in these entities. Methods: In this prospective randomized phase-II multicenter European trial adults with advanced or metastatic nccRCC without prior systemic therapy are eligible. Other key inclusion criteria include: available tumor tissue, Karnofsky > 70% and measurable disease per RECIST 1.1. All histological diagnoses are reviewed by a central pathologist. The study plans to randomize ~306 pts. stratified for papillary or non-papillary non-clear cell histology and by the International Metastatic RCC Database Consortium (IMDC) risk score. Pts. will be randomized 1:1 to either i) Nivolumab 3mg/kg intravenously (IV) plus Ipilimumab 1mg/kg IV every 3 weeks for 4 doses followed by Nivolumab fixed dose 240mg IV every 2 weeks or ii) standard of care therapy according to the approved schedule. Treatment will be discontinued in case of unacceptable toxicity or withdrawal of informed consent. Pts may continue treatment beyond progression, if clinical benefit is achieved and treatment is well tolerated. Primary endpoint is the OS rate at 12 months. Secondary endpoints include OS rate at 6 and 18 months, median OS, PFS, ORR and quality of life. The trial is in progress and 122 patients (78 pts with papillary, 37 pts with non-papillary histology) have been enrolled until now. Clinical trial information: NCT03075423 .

RENAVIV: A randomized phase III, double-blind, placebo-controlled study of pazopanib with or without abexinostat in patients with locally advanced or metastatic renal cell carcinoma.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. TPS681-TPS681 ◽  
Author(s):  
Rahul Raj Aggarwal ◽  
Scott Thomas ◽  
Ralph J. Hauke ◽  
Luke T. Nordquist ◽  
Pamela N. Munster
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Histone Acetylation ◽  
Renal Cell ◽  
Clear Cell ◽  
Locally Advanced ◽  
Phase Iii ◽  
Controlled Study ◽  
Double Blind ◽  
Double Blind Placebo

TPS681 Background: Abexinostat is a pan-histone deacetylase (HDAC) inhibitor that has shown promising activity in prior pre-clinical studies and early phase clinical trials. A phase 1b study of pazopanib plus abexinostat (Aggarwal et al. J Clin Oncol 2017) demonstrated strikingly durable responses in patients (pts) with clear cell renal cell carcinoma (RCC), including one patient with previously refractory disease with ongoing response for > 5 years’ duration. Induction of histone acetylation in peripheral blood mononuclear cells (PBMCs) was associated with durable treatment response. We hypothesize that the addition of abexinostat to pazopanib will significantly improve outcomes in patients with clear cell RCC. Methods: RENAVIV is a global, randomized, double-blind, placebo-controlled, two arm phase 3 study of pazopanib plus abexinostat versus pazopanib plus placebo, in pts with locally advanced or metastatic RCC with clear cell component. Up to one prior line of immunotherapy is allowed. Prior VEGF-targeting tyrosine kinase inhibitor treatment is prohibited. Stratification factors include: 1) Prior immunotherapy (yes/no) and 2) prognostic group (good, intermediate, poor). Pts randomized to pazopanib + placebo have the option of crossing over to receive pazopanib plus abexinostat at the time of disease progression. The primary endpoint is PFS by independent review committee. Secondary endpoints include PFS by investigator assessment, overall survival, safety, objective response rate (ORR), duration of response, patient-reported quality of life, and outcomes in cross-over population. Planned correlative studies include association between histone acetylation and HDAC expression in PBMCs with clinical outcomes. The total planned accrual is 413 pts, estimated to provide 90% power to detect a hazard ratio of 0.67 in the comparison of PFS between experimental versus control arms, with an overall two-sided type I error rate of 0.025. A pre-specified minimum of 50% of patients are required to have received prior immunotherapy. The first patient was enrolled in October 2018. Clinical trial information: NCT03592472.

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