A Study Of Pazopanib In Chinese Patients With Metastatic Renal Cell Carcinoma

BACKGROUND:Renal cell carcinoma(RCC)is the most common cancer of the kidney.Current analyses estimate more than 50,000 new cases and12,890 deaths in the United States in 2007.Relapse rates are 20%-30%in patients with localized high-grade tumors and post-radical nephrectomy,usually within 3 years. RCC is highly resistant to chemotherapy,generally cytokines have response rates of 5%to 20%and median overall survival of 12 months,but use is limited by toxicity.No data thus far demonstrating adjuvant systemic therapy is effective in reducing risk of relapse.Therapies targeted to vascular endothelial growth factor (VEGF)and platelet-derived growth-factor(PDGF)receptors are the new standard of care(e.g.,sunitinib and sorafenib).Pazopanib is an new oral angiogenesis inhibitor of VEGF receptors-1,-2 and -3;platelet-derived growth-factor receptor-α/βand c-kit etc,PhaseⅠtesting revealed an acceptable toxicity profile and activity in metastatic RCC.Due to a very heterogenous disease with a highly variable natural history,even when patients have apparently similar tumor morphology,the clinical course of their cancers may differ profoundly.So we need to evaluate the efficacy and safety of pazopanib in Chinese patients with advanced or metastatic renal clear-cell carcinoma and attempt to find some factors relating to the underlying tumor molecular biology, host factors,and iterative decision pathways based on responses to treatment in clinical trials.OBJECTIVES:1.To evaluate the efficacy and safety of pazopanib in patients with advanced or metastatic clear-cell RCC in China.2.To evaluate toxicity-efficacy interactions by comparing progression free survival(PFS)in patients who experienced different grades skin toxicity with those who did not retrospectively.Skin toxicity comprised hand-foot skin reaction(HFS)and rash etc.3.To evaluate the relationship between serum biomarkers' level and metastatic tumor burden in the Pazopanib treatment of metastatic renal cell cancer (mRCC).4.To evaluate expression of some genes in tumor and Pazopanib's efficacy interactions by comparing progression-free survival(PFS)and best response in patients who have different genes expression level in primary renal carcinoma tissues.PATIENTS AND METHODS:Patients:In China,fifteen Patients with metastatic renal clear-cell carcinoma who are identified progression whether first-line cytokine therapy or not were enrolled onto an pazopanib single-arm phaseⅡtrial in Jun～Oct 2006,and six Patients with locally advanced and/or metastatic renal clear-cell carcinoma were enrolled onto a randomized, double-blind,placebo-controlled phaseⅢtrial in Nov～Dec 2006 respectively.Six patients who have progressed on the placebo arm may receive pazopanib through an open-label study(analog phaseⅡtrial)at the discretion of the investigator and the patient.Pazopanib or placebo was administered 800mg or less daily oral therapy according to the trial's demand.Methods:1.Objective clinical response was assessed by Response Evaluation Criteria in Solid Tumors(RECIST)using computed tomography or magnetic resonance imaging scan and bone scan(if bone metastases were present at baseline)every 6～8weeks thereafter until the end of treatment.PE,blood and urine related lab profiles in outpatient were obtained every month throughout the study.2.Objective clinical response include subjects' PFS and Interim analysis Complete response(CR),partial response(PR)and stable disease(SD)rates at 12 weeks after pazopanib therapy.·Safety of drug was assessed by the investigator based on Common Terminology Criteria for Adverse Events(NCI-CTC v3.0).·Primary tumor immunohistochemical stains using antibodies to VEGF,EGFR,VEGFR-2 and HER-2 the biomarkers were used to study the relationship between genes expression,tumor cell proliferation, and prognosis in metastatic RCC.·Monitoring serum soluble VEGF,VEGFR-2 and bFGF levels by ELISA in some subjects at some timepoint for disease progression as well as assessing efficacy and activity of pazopanib.RESULTS:Efficacy:All 21 patients received pazopanib in two trials and were included in the analysis of efficacy.Partial responses(PR)determined by RECIST were achieved in 11 patients(52.4%)after 3 months therapy.Six patients(28.6%) had stable disease(SD)and no patient had CR.The majority of patients had a reduction in measurable disease at the time of analysis achieved during treatment with pazopanib.The meam of progression-free survival(PFS)in pazopanib group and placebo group was 10.8 months and 4.5 months respectively.Safety: the mean of pazopanib treatment duration was 10months.The most common adverse event was hypopigmentation of hair and hand-food syndrome,which was categorized as grade 3 severity in 2 patients(9.4%).The most frequently occurring laboratory abnormalities included leukopenia without infection,liver dysfunction(G3:1,4.7%)without clinical signs or symptoms and mild proteinuria. No patient developed renal insufficiency associated with pazopanib treatment. One patient was discontinued by investigator for pneumothorax associated with pazopanib;Dose reductions were performed in 8 patients(38.5%)from 800 to 600～200 mg/d,and dose suspension were performed in six patients.Common reasons for dose reductions and suspension included hand-food syndrome, diarrhea and asymptomatic laboratory abnormalities.The dose was escalated to 800 mg/d with toxicity relief.Assessment of serum biomarkers'levels and metastatic tumor burden:As putative biomarkers,serum VEGF,sVEGF-R2, and bFGF levels were serially measured in some patients on study.In the majority of cases,VEGF levels increased and sVEGF-R2 levels decreased during treatment, but our results show no linear relationship between the levels of the three biomarkers and tumor burden in all patients.There are some unknown factors that affect the levels of three biomarkers.Assessment of primary tumor protain expression and clinical outcome of pazopanib:VEGF,EGFR,VEGFR-2 and HER-2 levels assessed by immunohistochemistry(IHC)in 17 tumor and graded according to staining intensity(negative,1+,2+,3+).All primary tumors(100%) expressed strong cell membrane immunoreactivity for EGFR,but none for HER-2. VEGF expression(＞1+)was in 12 tumors(71%)and VEGFR-2 expression was in 13(77%).Partial responses(PR)were achieved in all 6 patients(VEGF2+)after 3 months therapy.There was a tendency toward a rapid reduction of metastatic sites for high grade VEGF-positive primary tumors during pazopanib therapy. But the high grade VEGF-positive primary tumors don't predicted a longer PFS. The VEGFR2 and EGFR couldn't predict the clinical outcome in this trials.CONCLUSIONS:It is the first clinical trial about pazopanib in Chinese patient with locally advanced and/or metastatic renal clear-cell carcinoma.In two trials of pazopanib as single agents,we reviewed an good result of disease control rate at Week 12 and also an longer PFS in most patients who were failure of previous cytokines treatment compared with placebo.Most common pazopanib -related AEs:hand-foot syndrome,diarrhea,hair color changes,hypertension,nausea, etc.and some laboratory abnormalities without clinical signs or symptoms such as leukopenia,liver dysfunction and mild proteinuria etc.There are more skin toxicity in china although acceptable.It seem that pazopanib has a high incidence and grade of hand-foot syndrome in patients with longer PFS.Now trials are ongoing and 4 subjects remain on study.In all subjects we can't fend linear relationship between the levels of before presumptive serum biomarkers(such as VEGF,sVEGF-R2,and bFGF)and metastatic tumor burden.But there seem to be a tendency toward a rapid reduction of metastatic sites for high-grade VEGF expression in primary tumors during pazopanib therapy,So pazopanib as single agents is safe and effective in Chinese patients with metastatic RCC,and may be first or second line therapy for advanced RCC in the future.