Phase II Placebo-Controlled Randomized Discontinuation Trial of Sorafenib in Patients With Metastatic Renal Cell Carcinoma

Ratain, Mark J.; Eisen, Tim; Stadler, Walter M.; Flaherty, Keith T.; Kaye, Stan B.; Rosner, Gary L.; Gore, Martin; Desai, Apurva A.; Patnaik, Amita; Xiong, Henry Q.; Rowinsky, Eric K.; Abbruzzese, James L.; Xia, Chenghua; Simantov, Ronit; Schwartz, Brian; O’Dwyer, Peter J.

doi:10.1200/jco.2005.03.6723

Cited by 970 publications

(565 citation statements)

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“…The design of this RDT, including patients' details and inclusion and exclusion criteria, has been described previously (Ratain et al, 2006). Briefly, eligible patients had histologically or cytologically confirmed, progressive advanced unresectable, or metastatic cancer.…”

Section: Patients' Characteristics and Study Designmentioning

confidence: 99%

“…As described previously (Ratain et al, 2006), the primary end point was the percentage of patients remaining progression free at 12 weeks postrandomisation. Secondary endpoints included PFS after randomisation, overall PFS, tumour response rate and safety (Ratain et al, 2006).…”

Section: Efficacy and Safety Assessmentsmentioning

confidence: 99%

“…Secondary endpoints included PFS after randomisation, overall PFS, tumour response rate and safety (Ratain et al, 2006). This analysis will focus on the changes from baseline in bidimensional tumour measurements after the run-in phase, tumour responses for the entire treatment period, PFS and safety findings for a cohort of patients with advanced melanoma.…”

Section: Efficacy and Safety Assessmentsmentioning

confidence: 99%

“…Sorafenib monotherapy has been shown to have a manageable side effect profile in Phase I/II/III studies (Strumberg et al, 2003Ratain et al, 2004Ratain et al, , 2006Awada et al, 2005;Escudier et al, 2005). The most common toxicities associated with sorafenib are hand-foot skin reaction (HFS), rash and diarrhoea (Strumberg et al, 2003Ratain et al, 2004Ratain et al, , 2006Awada et al, 2005;Escudier et al, 2005).…”

mentioning

confidence: 99%

“…The most common toxicities associated with sorafenib are hand-foot skin reaction (HFS), rash and diarrhoea (Strumberg et al, 2003Ratain et al, 2004Ratain et al, , 2006Awada et al, 2005;Escudier et al, 2005). However, these adverse events are predominantly mild to moderate in severity and easily manageable.…”

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confidence: 99%

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Sorafenib in advanced melanoma: a Phase II randomised discontinuation trial analysis

et al. 2006

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The effects of sorafenib -an oral multikinase inhibitor targeting the tumour and tumour vasculature -were evaluated in patients with advanced melanoma enrolled in a large multidisease Phase II randomised discontinuation trial (RDT). Enrolled patients received a 12-week run-in of sorafenib 400 mg twice daily (b.i.d.). Patients with changes in bi-dimensional tumour measurements o25% from baseline were then randomised to sorafenib or placebo for a further 12 weeks (ie to week 24). Patients with X25% tumour shrinkage after the run-in continued on open-label sorafenib, whereas those with X25% tumour growth discontinued treatment. This analysis focussed on secondary RDT end points: changes in bi-dimensional tumour measurements from baseline after 12 weeks and overall tumour responses (WHO criteria) at week 24, progression-free survival (PFS), safety and biomarkers (BRAF, KRAS and NRAS mutational status). Of 37 melanoma patients treated during the run-in phase, 34 were evaluable for response: one had X25% tumour shrinkage and remained on open-label sorafenib; six (16%) had o25% tumour growth and were randomised (placebo, n ¼ 3; sorafenib, n ¼ 3); and 27 had X25% tumour growth and discontinued. All three randomised sorafenib patients progressed by week 24; one remained on sorafenib for symptomatic relief. All three placebo patients progressed by week-24 and were re-started on sorafenib; one experienced disease re-stabilisation. Overall, the confirmed best responses for each of the 37 melanoma patients who received sorafenib were 19% stable disease (SD) (ie n ¼ 1 open-label; n ¼ 6 randomised), 62% (n ¼ 23) progressive disease (PD) and 19% (n ¼ 7) unevaluable. The overall median PFS was 11 weeks. The six randomised patients with SD had overall PFS values ranging from 16 to 34 weeks. The most common drug-related adverse events were dermatological (eg rash/desquamation, 51%; hand-foot skin reaction, 35%). There was no relationship between V600E BRAF status and disease stability. DNA was extracted from the biopsies of 17/22 patients. Six had V600E-positive tumours (n ¼ 4 had PD; n ¼ 1 had SD; n ¼ 1 unevaluable for response), and 11 had tumours containing wild-type BRAF (n ¼ 9 PD; n ¼ 1 SD; n ¼ 1 unevaluable for response). In conclusion, sorafenib is well tolerated but has little or no antitumour activity in advanced melanoma patients as a single agent at the dose evaluated (400 mg b.i.d.). Ongoing trials in advanced melanoma are evaluating sorafenib combination therapies.

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Section: Patients' Characteristics and Study Designmentioning

confidence: 99%

Section: Efficacy and Safety Assessmentsmentioning

confidence: 99%

Section: Efficacy and Safety Assessmentsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Sorafenib in advanced melanoma: a Phase II randomised discontinuation trial analysis

et al. 2006

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Prospective Study of the Cutaneous Adverse Effects of Sorafenib, a Novel Multikinase Inhibitor

Autier¹,

Escudier²,

Wechsler³

et al. 2008

Arch Dermatol

208

179

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Treatment Interruption

Grund¹

2005

Encyclopedia of Statistical Sciences

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Interruption of active drug treatment in clinical trials can be classified broadly as therapeutic treatment interruption (TI), in which the potential therapeutic benefit of supervised interruption of treatment is investigated, and analytic TI, in which participants are randomized to stopping versus continuing active treatment; the TI arm serves as control group. Design issues for therapeutic TI trials are discussed in the example of a trial in HIV/AIDS. Analytic TIs are used in therapeutic HIV vaccine trials, in randomized discontinuation designs, and in other situations. The use of a randomized discontinuation design for a Phase II drug trial in cancer is discussed.

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Phase II Placebo-Controlled Randomized Discontinuation Trial of Sorafenib in Patients With Metastatic Renal Cell Carcinoma

Abstract: Sorafenib has significant disease-stabilizing activity in metastatic renal cell carcinoma and is tolerable with chronic daily therapy.

Cited by 970 publications

References 30 publications

Sorafenib in advanced melanoma: a Phase II randomised discontinuation trial analysis

Sorafenib in advanced melanoma: a Phase II randomised discontinuation trial analysis

Prospective Study of the Cutaneous Adverse Effects of Sorafenib, a Novel Multikinase Inhibitor

Treatment Interruption

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