-
1.
MRI assessment of early tumor response in metastatic renal cell carcinoma patients treated with sorafenib.
Kang, HC, Tan, KS, Keefe, SM, Heitjan, DF, Siegelman, ES, Flaherty, KT, O'Dwyer, PJ, Rosen, MA
AJR. American journal of roentgenology. 2013;(1):120-6
Abstract
OBJECTIVE The purpose of this study was to examine early MRI changes in renal cell carcinoma (RCC) treated with the antiangiogenic agent sorafenib and to identify MRI biomarkers of RCC response to sorafenib. MATERIALS AND METHODS Sixteen patients with RCC were evaluated by MRI before and 3-12 weeks after commencing treatment with sorafenib. Two experienced MR radiologists, blinded to treatment status, independently graded tumor appearance on T1-weighted, T2-weighted, and gadolinium-enhanced images. The proportional odds mixed model was used to compare qualitative appearance of tumors before and after therapy. Time-to-progression was correlated with Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 and MR-modified Choi criteria, incorporating changes in both tumor enhancement and size. RESULTS After sorafenib therapy, there was a significant increase in T1 signal intensity of tumors (p < 0.0001) and a significant decrease in degree of tumor enhancement (p < 0.0001). The sum of unidimensional tumor diameters decreased significantly after therapy (p = 0.005). However, the average decrease in size at early follow-up was 13%, and all patients except one had stable disease by RECIST 1.0. Early responders defined by MR-modified Choi criteria had increased time-to-progression compared with nonresponders, whereas early RECIST evaluation did not predict clinical outcome. CONCLUSION Decreased enhancement and T1 shortening of tumors on MRI may be useful biomarkers of RCC response to angiogenesis inhibitors. Response criteria combining early changes in size and enhancement lead to better correlation with clinical outcome compared with size decrease alone.
-
2.
A phase II trial of sorafenib in relapsed and unresectable high-grade osteosarcoma after failure of standard multimodal therapy: an Italian Sarcoma Group study.
Grignani, G, Palmerini, E, Dileo, P, Asaftei, SD, D'Ambrosio, L, Pignochino, Y, Mercuri, M, Picci, P, Fagioli, F, Casali, PG, et al
Annals of oncology : official journal of the European Society for Medical Oncology. 2012;(2):508-16
-
-
Free full text
-
Abstract
PURPOSE After standard multimodal therapy, the prognosis of relapsed and unresectable high-grade osteosarcoma is dismal and unchanged over the last decades. Recently, mitogen-activated protein kinases were shown to be activated in osteosarcoma specimens, suggesting, therefore, they are suitable targets for the multikinase inhibitor sorafenib. Thus, we explored sorafenib activity in patients with relapsed and unresectable osteosarcoma. EXPERIMENTAL DESIGN Patients > 14 years, progressing after standard treatment, were eligible to receive 400 mg of sorafenib twice daily until progression or unacceptable toxicity. The primary end point was progression-free survival (PFS) at 4 months. Secondary objectives were PFS, overall survival (OS), clinical benefit rate (CBR), defined as no progression at 6 months and safety. This nonrandomized phase II study used a Simon two-stage design. PFS and OS at 95% confidence intervals (95% CIs) were calculated by the Kaplan-Meier method. All tests were two sided. RESULTS Thirty-five patients were enrolled. PFS at 4 months was 46% (95% CI 28% to 63%). Median PFS and OS were 4 (95% CI 2-5) and 7 (95% CI 7-8) months, respectively. The CBR was 29% (95% CI 13% to 44%). We observed 3 (8%) partial responses (PRs), 2 (6%) minor responses (< 30% tumor shrinkage) and 12 (34%) stable diseases (SDs). For six patients (17%), PR/SD lasted ≥ 6 months. Noteworthy, tumor density reduction and [(18)F]2-fluoro-2-deoxy-d-glucose-positron emission tomography responses were observed among SD patients. Sorafenib was reduced or briefly interrupted in 16 (46%) patients and permanently discontinued in one (3%) case due to toxicity. CONCLUSIONS Sorafenib demonstrated activity as a second- or third-line treatment in terms of PFS at 4 months with some unprecedented long-lasting responses. Sorafenib, the first targeted therapy showing activity in osteosarcoma patients, deserves further investigations.
-
3.
Phase II escalation study of sorafenib in patients with metastatic renal cell carcinoma who have been previously treated with anti-angiogenic treatment.
Mancuso, A, Di Paola, ED, Leone, A, Catalano, A, Calabrò, F, Cerbone, L, Zivi, A, Messina, C, Alonso, S, Vigna, L, et al
BJU international. 2012;(2):200-6
Abstract
OBJECTIVE To assess both clinical and biological efficacy and toxicity of sorafenib in patients with metastatic renal cell carcinoma (mRCC) previously treated with an anti-angiogenic vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor. METHODS Sorafenib is an orally active multikinase inhibitor approved for the treatment of mRCC. Drug-focused translational research on tissues (i.e. B-RAF) and plasma (VEGFR-α, circulating endothelial cells, endothelial progenitor cells) was performed to define biological predictive and prognostic markers and their related kinetics. Patients with mRCC pretreated with an anti-angiogenic treatment, an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-2 and adequate organ function were eligible. Patients received sorafenib 400 mg twice a day continuously in 4-week cycles. Patients with no progressive disease at 12 weeks continued to receive sorafenib at the standard dose, whereas progressing patients received an increased dose (600 mg twice a day) with early disease restaging after 4 weeks. Patients who progressed at 600 mg twice a day went off study. Efficacy (overall tumour control) was assessed by Response Evaluation Criteria in Solid Tumors. RESULTS In all, 19 patients were entered. The baseline characteristics were as follows: ECOG PS 0-1 94.8%; median (range) age 62 (41-81) years; nephrectomy 100%; surgery for metastatic disease 26.4%; clear cell 79.1%; papillary cell 15.7%; sarcomatoid/high grade 5.2%; two or more metastatic sites 84%. Overall, 11 patients (58%) had disease control at 6 months without significant correlation between response to prior therapy and hypertension. Progression-free survival (PFS) of 8.3 months was observed. Of six patients for whom the dose was escalated due to early progression, three benefitted with PFS of >3 months. Three (15.7%) of 19 patients had a V600E mutation and one had a K601E mutation; PFS appeared to be substantially shorter in these patients compared with 15 patients with wild-type B-RAF (2.5 vs 9.1 month, P < 0.05). The most common toxicity (National Cancer Institute Common Toxicity Criteria, NCIC 3.0, all patients) was grade ≥1 diarrhoea and grade 2-3 hand-foot syndrome in 11 patients. Grade 3 mucositis was observed in one patient. CONCLUSIONS Sorafenib at doses of 400-600 mg twice a day continuously results in acceptable and well tolerated salvage treatment after VEGFR tyrosine kinase inhibitor failure. In progressive patients, treatment with a higher dose could be a valid option and B-RAF mutations may be an interesting predictive marker to be studied in a larger randomized trial.
-
4.
Selective internal radiation therapy of hepatocellular carcinoma: potential hepatopulmonary shunt reduction after sorafenib administration.
Theysohn, JM, Schlaak, JF, Müller, S, Ertle, J, Schlosser, TW, Bockisch, A, Lauenstein, TC
Journal of vascular and interventional radiology : JVIR. 2012;(7):949-52
Abstract
Sorafenib, a protein kinase inhibitor, is a systemic drug that has been licensed for the treatment of hepatocellular carcinoma (HCC). This retrospective study assessed whether the administration of sorafenib can result in a reduction of the hepatopulmonary shunt (HPS) before selective internal radiation therapy (SIRT). After exclusion from SIRT because of high HPS, computed tomography scan indicated a shunt reduction in seven patients with HCC receiving sorafenib. Repeated measurements revealed HPS reduction (from 26.5% to 7.5% on average), and subsequent SIRT became possible. In conclusion, sorafenib may reduce HPS in patients with advanced HCC in some cases.
-
5.
Intermediate and advanced hepatocellular carcinoma treated with the antiangiogenic agent sorafenib. Evaluation with unenhanced and contrast-enhanced ultrasonography.
Moschouris, H, Malagari, K, Gkoutzios, P, Kalokairinou, M, Stamatiou, K, Chatzimichail, K, Kornezos, I, Karagiannis, E, Kiltenis, M, Papadaki, MG
Medical ultrasonography. 2012;(2):87-94
Abstract
AIMS: To evaluate the sonographic changes observed in hepatocellular carcinoma (HCC) post antiangiogenic treatment with sorafenib. PATIENTS AND METHODS Twenty one intermediate or advanced HCC patients (19 men, 2 women; mean age: 66.8 years; 32 target tumors-TTs) received sorafenib as monotherapy and were studied with unenhanced ultrasonography (US) and contrast-enhanced ultrasonography (CEUS) with a second generation echo-enhancer (SonoVue) at bimonthly intervals. Changes in lesional size, echotexture and enhancement were evaluated. Response was classified according to RECIST (Response Evaluation Criteria In Solid Tumors) and modified (m) RECIST. RESULTS Cystic changes were detected on US in 4 patients (7 lesions); CEUS showed a significant (51-100%) decrease of viable, enhancing TTs in the aforementioned patients. Four additional patients (5 lesions) showed a 73-87% decrease of their viable TTs on CEUS, but no changes on US. 13/21 patients showed less than 30% decrease, no change, or increase of their viable TTs. Based on the last sonographic evaluation, response was as follows: RECIST- Complete Response, CR (n=0), Partial Response, PR (n=1), Stable Disease, SD (n=16), Progressive Disease, PD (n=4); mRECIST- CR (n=2), PR (n=6), SD (n=11), PD (n=2). The 8 responders (CR+PR) according to mRECIST had significantly longer mean overall survival (OS) compared to the 13 non-responders (21.5 vs 12.2 months, p=0.018, Kaplan-Meier method). However, statistical significance was reduced (p=0.065) after adjustment for BCLC and Child's class. CONCLUSION US may occasionally detect changes indicative of the effect of sorafenib on HCC, but CEUS is required to evaluate and grade post-therapeutic reduction of tumoral enhancement. The latter is likely to correlate with OS.
-
6.
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.
-
7.
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.
-
8.
Phase I study investigating the safety and feasibility of combining imatinib mesylate (Gleevec) with sorafenib in patients with refractory castration-resistant prostate cancer.
Nabhan, C, Villines, D, Valdez, TV, Tolzien, K, Lestingi, TM, Bitran, JD, Christner, SM, Egorin, MJ, Beumer, JH
British journal of cancer. 2012;(4):592-7
-
-
Free full text
-
Abstract
BACKGROUND Determining the maximum tolerated dose (MTD) and the dose-limiting toxicity (DLT) of sorafenib (S) plus imatinib (IM) in castration-resistant prostate cancer (CRPC) patients. METHODS Refractory CRPC patients were enrolled onto this 3+3 dose escalation designed study. Imatinib pharmacokinetics (PK) were determined on day 15, 4 h post dose with a validated LC-MS assay. RESULTS Seventeen patients were enrolled; 10 evaluable (6 at 400 mg S qd with 300 mg IM qd (DL0) and 4 at 400 mg S bid with 300 mg IM qd (DL1)); inevaluable patients received <1 cycle. The median age was 73 (57-89); median prostatic serum antigen was 284 ng ml(-1) (11.7-9027). Median number of prior non-hormonal therapies was 3 (1-12). Dose-limiting toxicities were diarrhoea and hand-foot syndrome. Maximum tolerated dose was 400 mg S and 300 mg IM both daily. No biochemical responses were observed. Two patients had stable disease by RECIST. Median time to progression was 2 months (1-5). Median OS was 6 months (1-30+) with 3/17 patients (17%) alive at 21 months median follow-up. Ten patients had PK data suggesting that S reduced IM clearance by 55%, resulting in 77% increased exposure (P=0.005; compared with historical data). CONCLUSION This is the first report showing that S+IM can be administered in CRPC at a dose of 400 mg S and 300 mg IM, daily.
-
9.
Phase 2 Southwest Oncology Group-directed intergroup trial (S0505) of sorafenib in advanced soft tissue sarcomas.
von Mehren, M, Rankin, C, Goldblum, JR, Demetri, GD, Bramwell, V, Ryan, CW, Borden, E
Cancer. 2012;(3):770-6
-
-
Free full text
-
Abstract
BACKGROUND Patients with advanced soft tissue sarcomas (STS) have limited therapeutic options. Sorafenib (BAY 43-9006) is a multitargeted tyrosine kinase inhibitor of raf, vascular endothelial growth factor receptors 1 (VEGFR1) through 3, platelet-derived growth factor B, fms-like tyrosine kinase 3, and c-kit, and some of these may be relevant in STS. METHODS The authors tested sorafenib at a dose of 400 mg twice daily in patients with advanced vascular sarcoma (VS), high-grade liposarcomas, and leiomyosarcomas who had received 0 or 1 previous regimens for advanced disease. RESULTS Fifty-one patients were accrued to the study, and 37 were evaluable for toxicity and response. There were no unexpected side effects and no confirmed responses. The median progression-free survival was 3 months, and the median overall survival was 17 months. Six of 8 patients in the VS cohort had prolonged clinical benefit (stable disease or better), resulting in a median progression-free survival of 5 months compared with 2 to 3 months for the patients who had liposarcoma and leiomyosarcomas. CONCLUSIONS Sorafenib at the dose and schedule studied did not result in any responses in the VS, liposarcoma, or leiomyosarcoma cohort according to Response Evaluation Criteria in Solid Tumors.
-
10.
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.