-
1.
The efficacy and tolerability of MK-0633, a 5-lipoxygenase inhibitor, in chronic asthma.
Wasfi, YS, Villarán, C, de Tilleghem, Cle B, Smugar, SS, Hanley, WD, Reiss, TF, Knorr, BA
Respiratory medicine. 2012;(1):34-46
Abstract
Leukotriene B4 (LTB(4)) is a potent inflammatory mediator in asthma, and is increased in more severe asthma. Targeting LTB(4), in addition to cysteinyl leukotrienes, could be beneficial in asthma. This was a randomized, double-blind trial of once-daily MK-0633, a potent 5-lypoxygenase inhibitor, 10 mg, 50 mg, and 100 mg, and placebo in patients 18-70 years with a history of chronic asthma, and FEV(1) ≥45 and ≤85% predicted. There was a 6-week main period and optional 18-week and 34-week periods (52 weeks total), the latter two comparing only MK-0633 100 mg and placebo. The primary endpoint was the change from baseline in FEV(1) over the last 4 weeks of the 6-week primary treatment period. Secondary endpoints included symptom scores, β-agonist use, peak expiratory flow (PEF), asthma quality of life questionnaire (AQLQ), asthma control questionnaire (ACQ), asthma attacks, exacerbations, days with asthma control, post-β-agonist FEV(1), and blood eosinophils. MK-0633 100 mg was significantly more effective than placebo for the change from baseline in FEV(1) (0.20 L vs. 0.13 L; p = 0.004). The other MK-0633 doses were not significantly more effective than placebo. MK-0633 (at various doses) was also more effective than placebo for β-agonist use, AQLQ, AM and PM PEFR, ACQ, and post-β-agonist FEV(1) (p < 0.05 for all). MK-0633 was associated with a dose-dependent increase in elevated aspartate aminotransferase and alanine aminotransferase. Because of the relative benefit-risk ratio, the optional study periods were terminated after unblinding for the main study period. Overall, the benefit-risk ratio did not support the clinical utility of MK-0633 in asthma.
-
2.
Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma according to baseline status: subset analyses of the phase III Sorafenib Asia-Pacific trial.
Cheng, AL, Guan, Z, Chen, Z, Tsao, CJ, Qin, S, Kim, JS, Yang, TS, Tak, WY, Pan, H, Yu, S, et al
European journal of cancer (Oxford, England : 1990). 2012;(10):1452-65
Abstract
BACKGROUND The phase III Sorafenib Asia-Pacific (AP) trial-conducted in China, Taiwan and South Korea - confirmed that sorafenib improves overall survival (OS) and is safe for patients with advanced hepatocellular carcinoma (HCC). We performed a series of exploratory subset analyses to determine whether baseline status affected response to sorafenib. METHODS In the Sorafenib AP trial, 226 patients with well-preserved liver function (>95% Child-Pugh A) were randomised 2:1 to sorafenib 400mg bid or matching placebo. Subanalyses were based on aetiology (hepatitis B virus present/absent); tumour burden (macroscopic vascular invasion and/or extrahepatic spread present/absent); presence or absence of either lung or lymph node metastasis at baseline, Eastern Cooperative Oncology Group performance status (0, 1-2); serum concentrations of alanine aminotransferase/aspartate aminotransferase (normal, mildly elevated, moderately elevated), alpha-fetoprotein (normal/elevated) and total bilirubin (normal/elevated); and whether or not there was a history of hepatectomy or transarterial chemoembolisation/embolisation. Subgroup assessments included OS, time to progression (TTP), disease control rate and safety. FINDINGS Sorafenib consistently improved both median OS and median TTP, compared with placebo (range of hazard ratios (HR), 0.32-0.87 and 0.31-0.75, respectively). The most common grade 3/4 adverse events were hand-foot skin reaction, diarrhoea and fatigue, the incidence of which was similar between subgroups. INTERPRETATION The efficacy and safety profiles of sorafenib in the subpopulations described were comparable with those in the overall study population. These exploratory analyses suggest that sorafenib is effective for patients from the AP region with advanced HCC, irrespective of baseline status.
-
3.
A double-blind randomized discontinuation phase-II study of sorafenib (BAY 43-9006) in previously treated non-small-cell lung cancer patients: eastern cooperative oncology group study E2501.
Wakelee, HA, Lee, JW, Hanna, NH, Traynor, AM, Carbone, DP, Schiller, JH
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2012;(10):1574-82
-
-
Free full text
-
Abstract
INTRODUCTION Sorafenib is a raf kinase and angiogenesis inhibitor with activity in multiple cancers. This phase-II study in heavily pretreated non-small-cell lung cancer (NSCLC) patients (≥ 2 prior therapies) used a randomized discontinuation design. METHODS Patients received 400 mg of sorafenib orally twice daily for two cycles (2 months) (step 1). Responding patients on step 1 continued on sorafenib; progressing patients went off study, and patients with stable disease were randomized to placebo or sorafenib (step 2), with crossover from placebo allowed upon progression. The primary endpoint of this study was the proportion of patients having stable or responding disease 2 months after randomization. RESULTS There were 299 patients evaluated for step 1; of these, 81 eligible patients were randomized on step 2 and received sorafenib (n = 50) or placebo (n = 31). The 2-month disease control rates after randomization were 54% and 23% for patients initially receiving sorafenib and placebo, respectively, p = 0.005. The hazard ratio for progression on step 2 was 0.51 (95% [confidence interval] CI 0.30, 0.87, p = 0.014) favoring sorafenib. A trend in favor of overall survival with sorafenib was also observed (13.7 versus 9.0 months from time of randomization), hazard ratio 0.67 (95% CI 0.40-1.11), p = 0.117. A dispensing error occurred, which resulted in the unblinding of some patients, but not before completion of the 8-week initial step 2 therapy. Toxicities were manageable and as expected. CONCLUSIONS The results of this randomized discontinuation trial suggest that sorafenib has single-agent activity in a heavily pretreated, enriched patient population with advanced NSCLC. These results support further investigation with sorafenib as a single agent in larger, randomized studies in NSCLC.
-
4.
Phase III study of sorafenib after transarterial chemoembolisation in Japanese and Korean patients with unresectable hepatocellular carcinoma.
Kudo, M, Imanaka, K, Chida, N, Nakachi, K, Tak, WY, Takayama, T, Yoon, JH, Hori, T, Kumada, H, Hayashi, N, et al
European journal of cancer (Oxford, England : 1990). 2011;(14):2117-27
Abstract
BACKGROUND In Japan and South Korea, transarterial chemoembolisation (TACE) is an important locoregional treatment for patients with unresectable hepatocellular carcinoma (HCC). Sorafenib, a multikinase inhibitor, has been shown effective and safe in patients with advanced HCC. This phase III trial assessed the efficacy and safety of sorafenib in Japanese and Korean patients with unresectable HCC who responded to TACE. METHODS Patients (n=458) with unresectable HCC, Child-Pugh class A cirrhosis and ≥25% tumour necrosis/shrinkage 1-3 months after 1 or 2 TACE sessions were randomised 1:1 to sorafenib 400mg bid or placebo and treated until progression/recurrence or unacceptable toxicity. Primary end-point was time to progression/recurrence (TTP). Secondary end-point was overall survival (OS). FINDINGS Baseline characteristics in the two groups were similar; >50% of patients started sorafenib>9 weeks after TACE. Median TTP in the sorafenib and placebo groups was 5.4 and 3.7 months, respectively (hazard ratio (HR), 0.87; 95% confidence interval (CI), 0.70-1.09; P=0.252). HR (sorafenib/placebo) for OS was 1.06 (95% CI, 0.69-1.64; P=0.790). Median daily dose of sorafenib was 386 mg, with 73% of patients having dose reductions and 91% having dose interruptions. Median administration of sorafenib and placebo was 17.1 and 20.1 weeks, respectively. No unexpected adverse events were observed. INTERPRETATION This trial, conducted prior to the reporting of registrational phase III trials, found that sorafenib did not significantly prolong TTP in patients who responded to TACE. This may have been due to delays in starting sorafenib after TACE and/or low daily sorafenib doses.
-
5.
[Randomize trial of cisplatin plus gemcitabine with either sorafenib or placebo as first-line therapy for non-small cell lung cancer].
Wang, Y, Wang, L, Liu, Y, Yu, S, Zhang, X, Shi, Y, Sun, Y
Zhongguo fei ai za zhi = Chinese journal of lung cancer. 2011;(3):239-44
Abstract
BACKGROUND AND OBJECTIVE Platinum-based chemotherapy doublets reached an efficacy plateau in nonsmall-cell lung cancer (NSCLC). This randomized controlled study prospectively assessed the efficacy and safety of cisplatin plus gemcitabine with either Sorafenib or placebo as first-line therapy for NSCLC. METHODS Thirty patients, which were confirmed advanced NSCLC histologically or cytologically, were randomly assigned to receive up to six cycles of cisplatin plus gemcitabine with sorafenib or placebo. The maintenance of sorafenib or placebo after chemotherapy will continued in patients with response or stable disease until disease progression or unacceptable adverse events. RESULTS Overall demographics were balanced between experimental group (sorafenib+chemotherapy) and controlled group (chemotherapy only). Overall response (OS) rate was 55.6% and 41.7% in experimental arm and controlled arm, respectively (P=0.905). Median progressive-free survival (PFS) and median overall survival were similar (5 months vs 4 months, P=0.75; 18 months vs 18 months, P=0.68). Adverse events were tolerable, though the risk of hypertension and diarrhea was increase in experimental arm. Since patients with ECOG PS 0, stage IIIb, no liver metastasis and tyrasine kinasis inhibitor treatment after study had longer survive, these factors seemed to be predictive factors favor of survival in Cox regression analyses. CONCLUSIONS No additional benefit of response rate, PFS or OS were observed from adding targeted agent-sorafenib to regular cisplatin plus gemcitabine chemotherapy. Selecting aproper patients is needed in further study.
-
6.
Evaluation of KRAS mutations, angiogenic biomarkers, and DCE-MRI in patients with advanced non-small-cell lung cancer receiving sorafenib.
Kelly, RJ, Rajan, A, Force, J, Lopez-Chavez, A, Keen, C, Cao, L, Yu, Y, Choyke, P, Turkbey, B, Raffeld, M, et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2011;(5):1190-9
-
-
Free full text
-
Abstract
PURPOSE Sorafenib, a multikinase inhibitor targeting Raf and VEGFR, has shown activity in unselected patients with non-small-cell lung cancer (NSCLC). At present there are no validated biomarkers indicative of sorafenib activity. EXPERIMENTAL DESIGN Patients received sorafenib 400 mg BID daily to determine activity and tolerability and to measure its biological effects. KRAS mutation status (N = 34), angiogenesis markers (VEGF, bFGF, FLT-1, PLGF-1) and imaging with DCE-MRI (dynamic contrast enhanced MRI) to determine early changes in tumor vascular characteristics were evaluated. Three parameters K(trans), K(ep), and V(e) were measured by DCE-MRI at baseline and day 14 of cycle 1. Cytokine analysis was done on days 0, 14, 28, and 54. RESULTS Thirty-seven patients with previously treated stage IV NSCLC were enrolled in this single-center phase II trial. In 34 evaluable patients, 2 had partial responses and 20 had stable disease for 3 to 17 months, a disease control rate of 65%. The median progression-free survival (PFS) was 3.4 months, and median overall survival (OS) was 11.6 months. Toxicity was consistent with the known side effects of sorafenib. KRAS (32%) and EGFR mutations (22%) showed no correlation with response, PFS, or OS. K(ep), was significant in predicting an improvement in OS (P = 0.035) and PFS (P = 0.029). Cytokine analysis demonstrated an improved OS for bFGF day 0 (<6 vs. >6 pg/mL; P = 0.042), whereas a PFS benefit was seen with bFGF at day 28 (<6 vs. >6; P = 0.028). CONCLUSIONS KRAS and EGFR mutational status showed no correlation with response, PFS, or OS. Radiologic and cytokine changes may act as biomarkers indicative of early angiogenesis inhibition.
-
7.
Anti-adrenergic medications and edema development after intracerebral hemorrhage.
Sansing, LH, Messe, SR, Cucchiara, BL, Lyden, PD, Kasner, SE
Neurocritical care. 2011;(3):395-400
Abstract
BACKGROUND Use of antihypertensive medications is common after intracerebral hemorrhage (ICH). Medications that block adrenergic activation (e.g., beta-blockers and the alpha(2)-agonist, clonidine) may reduce the inflammatory response and therefore have secondary benefit after ICH. METHODS The patients with acute ICH enrolled in the placebo arm of the CHANT trial were included. Univariate and multivariate analyses were undertaken for factors associated with blood pressure medication use, edema at 72 h, and clinical outcome at 90 days. RESULTS Of the 303 patients, 87.8% received some antihypertensive treatment during the first 72 h of hospitalization. Edema volume on neuroimaging at 72 h was independently associated with clinical outcome. Use of anti-adrenergic medications was associated with less edema after controlling for hemorrhage volume and blood pressure. CONCLUSIONS Antihypertensive medications that antagonize the sympathetic nervous system may reduce perihematomal edema after ICH.
-
8.
Long-term safety of sorafenib in advanced renal cell carcinoma: follow-up of patients from phase III TARGET.
Hutson, TE, Bellmunt, J, Porta, C, Szczylik, C, Staehler, M, Nadel, A, Anderson, S, Bukowski, R, Eisen, T, Escudier, B, et al
European journal of cancer (Oxford, England : 1990). 2010;(13):2432-40
Abstract
BACKGROUND The phase III Treatment Approaches in Renal cancer Global Evaluation Trial (TARGET) indicated that sorafenib is effective and well tolerated in advanced renal cell carcinoma patients. However, few data have been published on the safety of long-term sorafenib treatment. A retrospective subgroup analysis was performed to evaluate the efficacy and safety of sorafenib in patients in TARGET who received treatment for >1 year. METHODS The present subgroup analysis (based on the September 2006 database with updated safety analysis) evaluated the efficacy and safety of sorafenib in all patients in the sorafenib arm of TARGET who were treated for >1 year. The assessments included the overall survival, progression-free survival (PFS), disease control rate (DCR), and safety. The patients remained on therapy post-progression at the discretion of the investigator. RESULTS In TARGET, 169 patients received treatment with sorafenib for >1 year. The median PFS of patients in this subpopulation was 10.9 months from the date of randomisation, with a DCR of 92%. The most commonly reported treatment-related adverse events of any grade were diarrhoea (74%), rash/desquamation (51%), hand-foot skin reaction (49%), alopecia (39%), and fatigue (38%). Adverse events were mild to moderate, and presented early in the course of the treatment; there were no unexpected toxicities associated with the long-term administration of sorafenib. CONCLUSIONS Results of this subgroup analysis of patients enrolled in TARGET who received treatment for >1 year indicate that long-term treatment with sorafenib is associated with continued efficacy and a well-tolerated safety profile.
-
9.
Incidence of brain metastases in renal cell carcinoma treated with sorafenib.
Massard, C, Zonierek, J, Gross-Goupil, M, Fizazi, K, Szczylik, C, Escudier, B
Annals of oncology : official journal of the European Society for Medical Oncology. 2010;(5):1027-31
-
-
Free full text
-
Abstract
BACKGROUND This retrospective study evaluated the incidence of brain metastases in a subgroup of patients with metastatic renal cell carcinoma (RCC) who were randomly assigned to receive sorafenib, an oral multikinase inhibitor (400 mg b.i.d.), versus placebo in the phase III Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGET). PATIENTS AND METHODS Patients enrolled in TARGET at two centres (Institut Gustave Roussy, Villejuif, France, n = 85; Central Clinical Hospital of Military Medical Academy, Warsaw, Poland, n = 54) made up the current subgroup, who were retrospectively evaluated for the incidence of brain metastases during follow-up. The association between treatment (sorafenib versus placebo) and occurrence of brain metastases was evaluated by univariate analysis. RESULTS The overall incidence of brain metastases in patients receiving sorafenib was 3% (2 of 70 patients) compared with 12% (8 of 69 patients) in patients receiving placebo (P < 0.05). The incidence of brain metastases was also significantly lower in the sorafenib group after 1 (P = 0.0447) and 2 years (P = 0.005) of treatment compared with the placebo group. CONCLUSIONS In this subpopulation, sorafenib may reduce the occurrence of brain metastases. Antiangiogenic therapy, such as sorafenib, could be an effective preventive therapy for brain metastases in advanced RCC.
-
10.
Design and rationale for the non-interventional Global Investigation of Therapeutic DEcisions in Hepatocellular Carcinoma and Of its Treatment with Sorafenib (GIDEON) study.
Lencioni, R, Marrero, J, Venook, A, Ye, SL, Kudo, M
International journal of clinical practice. 2010;(8):1034-41
-
-
Free full text
-
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a complicated condition influenced by multiple confounding factors, making optimum patient management extremely challenging. Ethnicity, stage at diagnosis, comorbidities and tumour morphology affect outcomes and vary from region to region, and there is no common language to assess patient prognosis and make treatment recommendations. Despite recent efforts to reduce the incidence of HCC, most patients present with unresectable disease. Non-surgical treatments include ablation, transarterial chemoembolisation and the multikinase inhibitor, sorafenib, but their effects in all patient subgroups are not known and further information is needed to optimise the use of these treatments. AIMS The Global Investigation of Therapeutic DEcisions in Hepatocellular Carcinoma and Of its Treatment with SorafeNib (GIDEON) study (ClinicalTrials.gov identifier NCT00812175; http://clinicaltrials.gov/) is an ongoing global, prospective, non-interventional study of patients with unresectable HCC who are eligible for systemic therapy and for whom the decision has been taken to treat with sorafenib under real-life practice conditions. The aim of this study is to evaluate the safety and efficacy of sorafenib in different subgroups, especially Child-Pugh B where data are limited. DISCUSSION This study will recruit 3000 patients from > 40 countries and follow them for approximately 5 years to compile a large and robust database of information that will be used to analyse local, regional and global differences in baseline characteristics, disease aetiology, treatment practice patterns and treatment outcomes, with a view to improve the knowledge base used to guide physician treatment decisions and to improve patient outcomes.