Validated biomarkers of prognosis and response to drug have not been identified for patients with hepatocellular carcinoma (HCC). One of the objectives of the phase III, randomized, controlled ...Sorafenib HCC Assessment Randomized Protocol (SHARP) trial was to explore the ability of plasma biomarkers to predict prognosis and therapeutic efficacy.
In SHARP, 602 patients with advanced HCC were randomized to receive either oral sorafenib 400 mg twice a day per os or matching placebo daily on a continuous basis. Ten plasma biomarkers implicated in the pathogenesis of HCC were measured in 491 patients at baseline and in 305 after 12 weeks of treatment. The candidate biomarkers were analyzed to identify correlates of prognosis or predictors of response to sorafenib.
In both the entire patient population and the placebo cohort, baseline angiopoietin 2 (Ang2) and VEGF concentrations independently predicted survival. Clinical variables such as macroscopic vascular invasion, Eastern Cooperative Oncology Group (ECOG) performance status, and baseline α-fetoprotein and alkaline phosphatase concentrations also independently predicted survival in these groups. In the sorafenib cohort, trends toward enhanced survival benefit from sorafenib were observed in patients with high s-c-KIT or low hepatocyte growth factor concentration at baseline (P of interaction = 0.081 and 0.073, respectively).
The angiogenesis biomarkers Ang2 and VEGF were independent predictors of survival in patients with advanced HCC. In contrast, none of the biomarkers tested significantly predicted response to sorafenib.
Mature survival data and evaluation of vascular endothelial growth factor (VEGF) as a prognostic biomarker from the Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGET) study in ...patients with renal cell carcinoma (RCC) are reported.
Nine hundred three previously treated patients were randomly assigned to receive sorafenib versus placebo. On demonstration of progression-free survival (PFS) benefit with sorafenib, patients assigned to placebo were offered sorafenib. Overall survival (OS) was determined at two planned interim analyses and one final analysis, with a secondary OS analysis conducted by censoring placebo patients who crossed over to sorafenib. The relationships between baseline VEGF level and prognosis and efficacy were evaluated.
The final OS of patients receiving sorafenib was comparable with that of patients receiving placebo (17.8 v 15.2 months, respectively; hazard ratio HR = 0.88; P = .146); however, when post-cross-over placebo survival data were censored, the difference became significant (17.8 v 14.3 months, respectively; HR = 0.78; P = .029). Adverse events at 16 months after cross over were similar to those previously reported. Baseline VEGF levels correlated with Eastern Cooperative Oncology Group performance status (P < .0001), Memorial Sloan-Kettering Cancer Center score (P < .0001), and PFS and OS in univariate (PFS, P = .0013; OS, P = .0009) and multivariate (PFS, P = .0231; OS, P = .0416) analyses of placebo patients and with short OS by multivariate analysis of patients receiving sorafenib (P = .0145). Both high-VEGF (P < .01) and low-VEGF (P < .01) groups benefited from sorafenib.
Although an OS benefit was not seen on a primary intent-to-treat analysis, results of a secondary OS analysis censoring placebo patients demonstrated a survival advantage for those receiving sorafenib, suggesting an important cross-over effect. VEGF levels are prognostic for PFS and OS in RCC. The results of TARGET establish the efficacy and safety of sorafenib in advanced RCC.
This phase II study of sorafenib, an oral multikinase inhibitor that targets Raf kinase and receptor tyrosine kinases, assessed efficacy, toxicity, pharmacokinetics, and biomarkers in advanced ...hepatocellular carcinoma (HCC) patients.
Patients with inoperable HCC, no prior systemic treatment, and Child-Pugh (CP) A or B, received continuous, oral sorafenib 400 mg bid in 4-week cycles. Tumor response was assessed every two cycles using modified WHO criteria. Sorafenib pharmacokinetics were measured in plasma samples. Biomarker analysis included phosphorylated extracellular signal regulated kinase (pERK) in pretreatment biopsies (immunohistochemistry) and blood-cell RNA expression patterns in selected patients.
Of 137 patients treated (male, 71%; median age, 69 years), 72% had CP A, and 28% had CP B. On the basis of independent assessment, three (2.2%) patients achieved a partial response, eight (5.8%) had a minor response, and 46 (33.6%) had stable disease for at least 16 weeks. Investigator-assessed median time to progression (TTP) was 4.2 months, and median overall survival was 9.2 months. Grade 3/4 drug-related toxicities included fatigue (9.5%), diarrhea (8.0%), and hand-foot skin reaction (5.1%). There were no significant pharmacokinetic differences between CP A and B patients. Pretreatment tumor pERK levels correlated with TTP. A panel of 18 expressed genes was identified that distinguished "nonprogressors" from "progressors" with an estimated 100% accuracy.
Although single-agent sorafenib has modest efficacy in HCC, the manageable toxicity and mechanisms of action support a role for combination regimens with other anticancer agents.
BAY 43-9006, a novel multikinase inhibitor, prevents tumor growth by combining two antitumor activities: inhibition of both tumor cell proliferation and tumor angiogenesis. This phase I, open-label, ...nonrandomized, noncontrolled, single-arm, dose escalation study was done to determine the maximum tolerated dose (MTD), safety profile, pharmacokinetic variables, effect on biomarkers, and tumor response with BAY 43-9006 in 19 patients with advanced, refractory solid tumors.
BAY 43-9006 was given orally in repeated cycles of 1-week on/1-week off. The study comprised five dose levels, ranging from 100 mg twice daily (bid) to 800 mg bid. Treatment of each patient continued until unacceptable toxicity, tumor progression, or death.
Rash and hypertension were the dose-limiting toxicities at the 800 mg bid dose requiring study drug discontinuation; therefore, the MTD of BAY 43-9006 in this study was determined to be 600 mg bid. BAY 43-9006 was generally well tolerated, with mild to moderate toxicities. Pharmacokinetic analysis showed early absorption followed by delayed secondary peaks and slow terminal elimination. Stable disease was achieved in five patients: one patient showed reduced tumor activity (positron emission tomography scan) and reduced mitogen-activated protein kinase signaling (lower phospho-ERK); one patient remained on treatment until study end point.
The results confirm the favorable safety profile of BAY 43-9006 and support the development of this compound for the treatment of solid tumors.
Sorafenib is a novel, small-molecule anticancer compound that inhibits tumor cell proliferation by targeting Raf in the Raf/MEK/ERK signalling pathway, and inhibits angiogenesis by targeting tyrosine ...kinases such as vascular-endothelial growth factor receptor (VEGFR-2 and VEGFR-3) and platelet-derived growth factor receptor (PDGFR). In vitro microsomal data indicate that sorafenib is metabolized by two pathways: phase I oxidation mediated by cytochrome P450 (CYP) 3A4; and phase II conjugation mediated by UGT1A9. Approximately 50% of an orally administered dose is recovered as unchanged drug in the feces, due to either biliary excretion or lack of absorption. The aim of this study was to evaluate the effect of CYP3A inhibition by ketoconazole on sorafenib pharmacokinetics. This was an open-label, non-randomized, 2-period, one-way crossover study in sixteen healthy male subjects. A single 50 mg dose of sorafenib was administered alone (period 1) and in combination with ketoconazole 400 mg once daily (period 2) (ketoconazole was given for 7 days, and a single 50 mg sorafenib dose was administered concomitantly on day 4). No clinically relevant change in pharmacokinetics of sorafenib and no clinically relevant adverse events or laboratory abnormalities were observed in this study upon co-administration of the two drugs. Plasma concentrations of the main CYP3A4 generated metabolite, sorafenib N-oxide, decreased considerably upon ketoconazole co-administration. This effect is in accordance with the in vitro finding that CYP3A4 is the primary enzyme for sorafenib N-oxide formation. Further, these data indicate that blocking sorafenib metabolism by the CYP3A4 pathway will not lead to an increase in sorafenib exposure. This is consistent with data from a clinical mass-balance study that showed 15% of the administered dose was eliminated by glucuronidation, compared to less than 5% eliminated as oxidative metabolites. Since there was no increase in sorafenib exposure following concomitant administration of the highly potent CYP3A4 inhibitor ketoconazole with low dose sorafenib, it is postulated that higher therapeutic doses of sorafenib may be safely co-administered with ketoconazole, as well as with other inhibitors of CYP3A.
With its potent inhibitory effects against Raf-1 kinase and vascular endothelial growth factor receptor-2, sorafenib is a novel oral anticancer agent targeting signal transduction and angiogenic ...pathways. This study is designed to combine sorafenib and gemcitabine due to their compatibility in preclinical models and nonoverlapping clinical toxicities.
An initial dose-escalation part of the study enrolled patients with advanced solid tumors, followed by an expanded cohort at the recommended dose for patients with advanced unresectable or metastatic pancreatic cancer. Sorafenib is administered continuously, whereas gemcitabine is given at 1,000 mg/m2 weekly x 7 followed by 1 rest week, then weekly x 3 every 4 weeks.
Forty-two patients have been enrolled overall, including 19 in the dose-escalation part and 23 in the extended pancreatic cancer cohort. Demographics were as follows: male-to-female ratio = 26:16; median age = 61 years (range 39-83 years); Eastern Cooperative Oncology Group performance status 0:1:2 ratio = 16:21:5. The recommended dose of this combination is sorafenib 400 mg twice daily and gemcitabine 1,000 mg/m2. The most frequent grade 3 or 4 adverse events of all causalities were thrombocytopenia (28.6%), lymphopenia (21.4%), lipase elevation (19%), neutropenia (16.7%), and fatigue (14.3%). Antitumor activity was observed in both groups, with 2 (10.5%) confirmed partial responses in ovarian cancer and 12 patients (63.2%) with disease stabilization in the dose-escalation part; 13 patients (56.5%) achieved disease stabilization in the pancreatic cohort. There was no consistent pharmacokinetic drug-to-drug interaction between sorafenib and gemcitabine.
Sorafenib and gemcitabine are well tolerated in combination; further evaluations in pancreatic and ovarian cancers are warranted.
This study evaluated the safety, maximum tolerated dose, pharmacokinetics, and antitumor activity of sorafenib, a multikinase inhibitor, combined with paclitaxel and carboplatin in patients with ...solid tumors.
Thirty-nine patients with advanced cancer (24 with melanoma) received oral sorafenib 100, 200, or 400 mg twice daily on days 2 to 19 of a 21-day cycle. All patients received carboplatin corresponding to AUC6 and 225 mg/m(2) paclitaxel on day 1. Pharmacokinetic analyses were done for sorafenib on days 2 and 19 of cycle 1 and for paclitaxel on day 1 of cycles 1 and 2. Pretreatment tumor samples from 17 melanoma patients were analyzed for BRAF mutations.
Sorafenib was well tolerated at the doses evaluated. The most frequent severe adverse events were hematologic toxicities (grade 3 or 4 in 33 patients, 85%). Twenty-seven (69%) patients had sorafenib-related adverse events, the most frequent of which were dermatologic events (26 patients, 67%). Exposure to paclitaxel was not altered by intervening treatment with sorafenib. Treatment with sorafenib, paclitaxel, and carboplatin resulted in one complete response and nine partial responses, all among patients with melanoma. There was no correlation between BRAF mutational status and treatment responses in patients with melanoma.
The recommended phase II doses are oral 400 mg twice daily sorafenib, carboplatin at an AUC6 dose, and 225 mg/m(2) paclitaxel. The tumor responses observed with this combined regimen in patients with melanoma warrant further investigation.
Abstract Aim The safety, pharmacokinetics and efficacy of sorafenib plus docetaxel in patients with advanced refractory cancer were investigated in a Phase I, dose-escalation trial. Methods ...Twenty-seven patients in four Cohorts received docetaxel on Day 1 (Cohorts 1 and 4: 75 mg/m2 ; Cohorts 2 and 3: 100 mg/m2 ) plus sorafenib on Days 2–19 (Cohorts 1 and 2: 200 mg twice-daily (bid); Cohorts 3 and 4: 400 mg bid) in 21-day cycles. Results Most common adverse events (AEs) (Grade 3–5) included neutropenia (89%), leucopaenia (81%), hand–foot skin reaction (30%) and fatigue (30%). The most common drug-related AEs leading to dose reduction/interruption or permanent discontinuation were dermatologic (41%), gastrointestinal (26%) and constitutional (22%). Coadministration of sorafenib altered the pharmacokinetics of docetaxel. On average, docetaxel area under the concentration–time curve (AUC)0–24 increased by 5% (Cohort 1), 54% (Cohort 2), 36% (Cohort 3) and 80% (Cohort 4) with docetaxel plus sorafenib, while Cmax increased by 16–32%, independent of sorafenib/docetaxel doses. Three of 25 evaluable patients (11%) had partial responses; 14 (52%) had stable disease. Conclusion Dose-limiting dermatologic AEs were more common than expected for either therapy alone. A starting dose of docetaxel 75 mg/m2 plus sorafenib 400 mg bid (with dose reductions for dermatological toxicities) is proposed for Phase II.
Sorafenib and erlotinib are potent, orally administered receptor tyrosine kinase inhibitors with antiproliferative and antiangiogenic activities. Given their inhibitory target profile and efficacy as ...single agents, the combination of these drugs is of considerable interest in solid malignancies. This study aimed to determine the recommended phase II dose of this targeted combination, their toxicity profile, pharmacokinetic interaction, and preliminary clinical activities.
Sorafenib was administered alone for a 1-week run-in period, and then both drugs were given together continuously, with every 28 days considered as a cycle. Three dose levels were assessed.
Seventeen patients with advanced solid tumors received 75 cycles of treatment. The most frequent adverse events of all grades were constitutional and gastrointestinal in nature followed by electrolytes and dermatologic toxicities. Fatigue was the most common adverse event (17 patients; 100%) followed by diarrhea (15 patients; 88%), hypophosphatemia (13 patients; 76%), and acneiform rash (12 patients; 71%). These adverse events were predominantly mild to moderate. The recommended phase II dose of this combination was determined as 400 mg twice daily sorafenib and 150 mg daily erlotinib. Pharmacokinetic analysis revealed no significant effect of erlotinib on the pharmacokinetic profile of sorafenib. Among 15 evaluable patients, 3 (20%) achieved a confirmed partial response and 9 (60%) had stable disease as best response.
Sorafenib and erlotinib are well tolerated and seem to have no pharmacokinetic interactions when administered in combination at their full single-agent recommended doses. This well tolerated combination resulted in promising activity that needs further validation in phase II studies.
To evaluate the combination of sorafenib and gefitinib in patients with advanced non-small cell lung cancer.
In this dose-escalation trial, patients received oral sorafenib (200-400 mg) twice daily ...with gefitinib (250 mg orally) once daily to identify the recommended dose for phase II trials (RDP; part A). The pharmacokinetics of the RDP were characterized further in additional patients (part B) receiving single-agent gefitinib or sorafenib for 21 days followed by a 7-day washout with crossover to the other agent for an additional 21 days. Patients then received the combination of sorafenib plus gefitinib in 28-day cycles. Safety, pharmacokinetics, and antitumor efficacy were evaluated. Potential drug-drug interactions and the relationship between pharmacokinetics and toxicity were also assessed.
Thirty-one patients were treated (n=12, part A; n=19, part B). Most adverse events were grade 1/2. The most frequent grade 3/4 events included diarrhea and elevated alanine aminotransferase (both 9.7%). One dose-limiting toxicity occurred (part A: elevated alanine aminotransferase at 400 mg twice daily). Gefitinib had no effect on sorafenib pharmacokinetics. However, gefitinib C(max) (26%) and area under the curve (38%) were reduced by concomitant sorafenib. One patient had a partial response; 20 (65%; n=8, part A; n=12, part B) had stable disease >or=4 months. The RDP was sorafenib 400 mg twice daily with gefitinib 250 mg once daily.
Sorafenib combined with gefitinib is well tolerated, with promising efficacy in patients with advanced non-small cell lung cancer. Studies to further investigate the significance of the reduction in gefitinib exposure by sorafenib are warranted.
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