A Phase III Randomised Double-blind Study Comparing Sorafenib With Placebo In Patients With Resected Primary Renal Cell Carcinoma at High or Intermediate Risk of Relapse

Research Summary

Annually 208000 new cases and 102000 deaths result each year from renal cellcarcinoma (RCC) throughout the world. The annual incidence in the UK isapproximately 6200 and rising with around 2500 deaths (CRUK figures 2006).Approximately 80% of RCC is clear cell type and 15% is papillary. RCC occurspredominantly in patients over the age of 50 and is more common in men thanwomen. It is associated with risk factors such as cigarette smoking obesity geneticfactors and acquired cystic disease of the kidney.RCC is often asymptomatic (or associated with non-specific symptoms) until diseaseis extensive. The majority of patients (70%) have localised disease at initialdiagnosis. Approximately 30-50% of patients develop metastatic disease after initialnephrectomy with curative intent. At present in primary RCC the only treatmentthat is routinely used is total or partial nephrectomy. However the value of adjuvantimmunotherapy is currently being investigated in the EORTC 30955 / HYDRA study.Methylation or inactivating mutations of the Von Hippel Lindau (VHL) gene arepresent in around 70% of clear cell carcinomas the commonest form of RCC.Inactivation of the VHL gene results in up regulation of vascular endothelial growthfactor (VEGF) and platelet derived growth factor (PDGF). Elevated levels of VEGFare also found in the less common RCC variants such as papillary cell carcinoma.VEGF and PDGF act on cell receptors (VEGFR and PDGFR) to stimulate the formationand stabilisation of new blood vessels which are crucial for the growth of tumours.Recently the oral kinase inhibitor sorafenib (known as Nexavar) has becomeavailable. Sorafenib inhibits several kinases known to be important in thepathobiology of RCC including C-RAF B-RAF VEGFR2 VEGFR3 and PDGFR.Sorafenib is a potent inhibitor of Raf kinase (c-Raf IC 50 = 2nM B-raf wild type IC50= 25nM B-raf mutant = 38nM) in vitro in cells and in vivo with significant dosedependentanti-tumour activity in four different human tumour xenografts.Additionally sorafenib is also a potent inhibitor of VEGF-R2 in vitro (with an IC50 of90nM). Anti-cancer activity was observed in cancers that have Ras mutations aswell as in cancers without Ras mutations. This suggests a potential use of thiscompound in a large spectrum of cancer types including tumours with a variety ofmolecular aetiologies all of which have not yet been defined. Observed anti-canceractivity was cytostatic in nature and was maintained upon continuation of dosing.Sorafenib demonstrated significant anti-tumour activity also against large (400mg-1g) colon and ovarian tumours producing some tumour regressions during thedosing period.Sorafenib as a single agent has been evaluated globally in 6 Phase I trials and 2Phase II trials conducted by Bayer to date as well as the Phase III trial discussed insection 3.3. The Phase I trials had an open-label non-randomised non-controlleddose-escalation design. The phase II trials are ongoing and include an uncontrolledhepatoma study and a randomised discontinuation study. The phase I single agentclinical plan has focused on characterising the safety and pharmacokinetic profilesorafenib in several different dosing regimens. All Phase I patients had a variety ofadvanced refractory solid tumours. Studies 100313 and 100342 were conducted inthe US. In study 100313 low doses were utilized with doses ranging from 50mgonce weekly to 50 mg daily; Study 100313 was discontinued early because otherongoing trials had already explored more intensive drug administration. The other 3trials (100283 100164 and 100277) were conducted outside of the US. Study100283 allowed individual patient titration (e.g. intrapatient dose escalation) as perprotocol. Therefore many patients in this study have been exposed to more thanone dosing regimen In addition this study as per protocol had an initial single dosefor the purpose of pharmacokinetic evaluations one week prior to starting theplanned dosing regimen. Study 100164 has an ongoing extension to exploresorafenib in combination with docetaxel.A database of monitored patients receiving sorafenib has been established. As of 29thMay 2004 there are 182 patients in this database who have been exposed to singleagentsorafenib in the Bayer Phase I program at doses ranging from 50mg onceweekly to 800 mg bid continuously. The 5 most common drug related adverse eventswere hand-foot skin reaction dermatology/skin-other fatigue anorexia anddiarrhoea. There was an increase in the number of SAEs discontinuations due toAes and especially skin toxicities as well as Grades 3 and 4 toxicities at the higherdose levels (= 600 mg bid). Hence 400 mg bid was selected as the recommendeddose for Phase II. Currently the Phase II program includes 2 completed studies.The phase II program was designed to explore anti-tumour efficacy in certaintumour types as well as gain additional experience with pharmacokinetics and safety.Study 10874 is a multicentre uncontrolled trial in advanced hepatocellular carcinomapatients. There are 137 patients treated to date. Study 100391 is a randomiseddiscontinuation (RD) study and was designed to evaluate advanced refractorytumour types primarily colorectal carcinoma but at the same time explore othertumour types. Thus far the study has enrolled 501 patients composed of 139colorectal 30 renal 34 melanoma 4 pancreatic 3 thyroid and variety of lesscommon tumour types. This study has a unique design. The course of therapy canbe categorised by 2 periods: an induction phase followed by a randomisation phase.During the induction phase all patients are treated with sorafenib at 400 mg twicedaily for 12 weeks. Subsequently patients with stable disease are randomised toeither continuous dosing with sorafenib or placebo. The responders are maintainedon therapy while those with progressive disease are discontinued from study drug.This design is to compare the rates of stable disease 12 weeks after randomisation.In general available information from the ongoing Phase II studies reveal toxicitiesthat are similar to Phase I data. Again the 5 most frequent drug-related toxicitiesobserved are hand-foot skin reaction dermatology/skin-other anorexia diarrhoeaand fatigue. Anti-tumour activity was observed in both Phase I and Phase II studies.Two partial responses were observed in the Phase I studies one each inhepatocellular carcinoma and renal cell carcinoma. Preliminary anti-tumour activitywas also reported in both Phase II studies with tumour shrinkage in hepatoma CRCmelanoma thyroid sarcoma pancreatic cancer and RCC.Data from the clinical mass-balance study have shown that on average less than20% of the administered dose is excreted in the urine. This is in contrast to preclinicaldata showing that less than 10% of sorafenib is excreted by the kidneys.Thus even in the presence of complete shutdown of renal clearance of the drug it isexpected that a small increase in the exposure may be observed; one which is in therealms of the sizeable inter-patient variability that has been observed in Phase Itrials.Rationale for SORCE903 patients with renal-cell carcinoma that was resistant to standard therapy wererandomised to receive either continuous treatment with oral sorafenib (at a dose of400 mg twice daily) or placebo; 451 patients received sorafenib and 452 receivedplacebo. The primary end point was overall survival. A single planned analysis ofprogression-free survival in January 2005 showed a statistically significant benefit ofsorafenib over placebo. Consequently crossover was permitted from placebo tosorafenib beginning in May 2005. At the January 2005 cutoff the medianprogression-free survival was 5.5 months in the sorafenib group and 2.8 months inthe placebo group (hazard ratio for disease progression in the sorafenib group 0.44;95% confidence interval [CI] 0.35 to 0.55; P<0.01)5. The first interim analysis ofoverall survival in May 2005 showed that Sorafenib reduced the risk of death ascompared with placebo (hazard ratio 0.72; 95% CI 0.54 to 0.94; P=0.02) althoughthis benefit was not statistically significant according to the O'Brien-Flemingthreshold. Partial responses were reported as the best response in 10% of patientsreceiving sorafenib and in 2% of those receiving placebo (P<0.001).In view of the promising results of sorafenib when used in the advanced diseasesetting a trial in the adjuvant setting is both timely and worthwhile.A recent analysis by Leibovich of 1671 patients who underwent radical nephrectomyfor clinically localised RCC between 1970 and 2000 demonstrated that by using asimple scoring system involving TNM staging nuclear grade and presence ofnecrosis it was possible to identify a high risk cohort (374 patients or 22% of thesample) who had a 3-year metastasis-free survival (MFS) of only 37% and anintermediate risk cohort (608 patients or 36% of the sample) with a 3-yearmetastasis-free survival of 80%7. One important benefit of this scoring system isthat it represents very little extra work for the reporting pathologist in addition toraising awareness of these factors and their definitions. Hence the decision to usethis score in the SORCE study.

Research Overview
PI Name Zarkar - A
Sponsor Medical Research Council
Project Status Open
Proposed End Date 01/09/2014
Study Run through CRF? Yes
Recruitment so far 2