European Journal of Cancer (2015) 51, 595– 603

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Clinical Trial

Phase II study of pazopanib as second-line treatment after sunitinib in patients with metastatic renal cell carcinoma: A Southern China Urology Cancer Consortium Trial Mian Xie a,⇑,1, Chao sheng He b, Jin Kun Huang c,1, Qi zhan Lin d a

Laboratory of translational research, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China Department of Urology, Guangdong General Hospital, Guangzhou, China c Department of Urology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China d Department of Urology, Traditional Chinese Medical Hospital of Guangdong Province, Guangzhou, China b

Received 24 August 2014; received in revised form 16 December 2014; accepted 5 January 2015 Available online 21 January 2015

KEYWORDS Pazopanib Metastatic renal cell carcinoma Phase II Delta-like ligand 4 Hypoxia-inducible factor

Abstract This multicentre, single arm, phase II study was aimed to assess the efficacy and safety of pazopanib as second-line treatment after failure of sunitinib in patients with metastatic renal cell carcinoma (mRCC) and explore biomarkers for pazopanib response. Patients received pazopanib 800 mg per day. The primary end-point was progression-free survival (PFS). Secondary end-points included objective response rate (ORR), overall survival (OS) and safety. Serum proteins (Delta-like ligand (DLL4), Notch1, hypoxia inducible factor-1a (HIF-1a), HIF-2a, vascular endothelial growth factor A (VEGFA) and platelet-derived growth factor receptor b (PDGFRB)) levels were measured using enzyme-linked immunosorbent assay (ELISA). 86 patients with clear cell mRCC were enrolled from December 2009 to March 2012 from three centres in Southern China. Of 85 evaluable patients, the median PFS was 5.6 months (95% confidence interval (CI), 4.1–6.7 months) by independent review. No complete response (CR) was observed in all patients. 13 (15.3%; 95% confidence interval [CI], 11.2–23.9%) patients achieved partial responses (PR) (ORR 15.3%). Median OS was 18.1 months (95% CI, 13.2–19.8 months). The most common adverse events (AEs) were mild to moderate and clinically manageable, including hypertension (37.6%), diarrhoea (36.5%), increased AST (51.8%), and anaemia (60%). AEs resulted in dose reduction in 24.7% of patients. Multivariable analysis showed that higher baseline levels of DLL4 and VEGFA and lower baseline level of HIF-2a were associated with shorter PFS; only lower baseline level of HIF-2a was correlated with shorter OS. The lower expression level of DLL4 after pazopanib treatment was associated with higher response rate probability. In conclusion, pazopanib

⇑ Corresponding author. Tel./fax: +86 20 83062957. 1

E-mail address: [email protected] (M. Xie). These authors contributed equally to this work.

http://dx.doi.org/10.1016/j.ejca.2015.01.005 0959-8049/Ó 2015 Elsevier Ltd. All rights reserved.

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M. Xie et al. / European Journal of Cancer 51 (2015) 595–603

was clinically active and well tolerated as second-line treatment after sunitinib in mRCC patients. Baseline levels of serum DLL4, VEGFA and HIF-2a may have potential utility as biomarkers of clinical efficacy in this setting (chiCTR-TRC-13004016). Ó 2015 Elsevier Ltd. All rights reserved.

1. Introduction Sunitinib is an approved first-line treatment of metastatic renal cell carcinoma (mRCC), but several other tyrosine kinase inhibitors including sorafenib, pazopanib and axitinib are also effective [1]. Sequential therapy with single agent is generally regarded as a viable strategy, since combinations of targeted agents may be poorly tolerated. Strategies have focused on optimal sequencing vascular endothelial growth factor (VEGF)-targeted therapies to maximise their impacts on clinical outcomes. Shifting from one VEGF-targeted therapy to another (i.e. from sunitinib to sorafenib or vice versa) showed some activity, mainly retrospective trials [2–4]. Pazopanib (VotrientÒ, made by GlaxoSmithKline) is an oral angiogenesis inhibitor that targets, among other receptors, vascular endothelial growth factor receptors (VEGFRs), platelet-derived growth factor receptors (PDGFRs) and stem cell factor receptor (c-kit) [5]. Pazopanib has been shown to prolong progression-free survival (PFS) versus placebo in treatment-naive and cytokine-refractory mRCC. Although data from retrospective cohort studies suggest potential benefit for sequencing VEGF-targeted therapies, the activity and safety of pazopanib in mRCC patients with first-line sunitinib treatment remains unknown. Current markers only provide clinicians with risk assessment for patients who received VEGF-targeted therapies on the basis of multiple criteria. Validated molecular markers to identify patients who might benefit from antiangiogenic therapy or to guide drug selection are still unclear [6]. The establishment of biomarkers may help in understanding the biology underlying mRCC and the efficacy of therapies that target the VEGF axis. Blood-based biomarkers have been assessed for several different VEGF inhibitors [7–9]. Further studies should undergo external validation for developing tailored management of mRCC with molecular biomarkers, since individual institutional studies lack the generalisation and consistency required to maintain accuracy among different patient series [10]. The Von Hippel-Lindau (VHL) protein (pVHL) is a component of the ubiquitin-mediated proteolysis pathway that is important for degradation of many cellular proteins, including hypoxia-inducible factors (HIFs). HIFs consist of two subunits hypoxia inducible factor1a (HIF-1a and HIF-2a) and induce the transcription of several genes that regulate angiogenesis, such as VEGF and PDGF [11]. PDGFRs (PDGFR-a

(PDGFRA) and -b (PDGRB) and VEGFRs play an essential role in tumour angiogenesis and growth. VHL–HIF–VEGF pathway is therefore regulated in renal cell carcinoma (RCC) and it represents a reasonable therapeutic target for RCC [12]. Notch signalling is a conserved pathway affecting many biological processes including angiogenesis [13]. Delta-like ligand 4 (DLL4), a ligand for Notch 1, 3 and 4 receptors, is strongly upregulated in tumour vasculature and has a role in tumour angiogenesis (Supplementary Fig. 1) [14]. DLL4-Notch signalling functions as a regulator of angiogenesis downstream of VEGF [15]. VEGF expression may be regulated by HIF-1 and HIF-2 activity and induce DLL4 expression in adjacent endothelial cells (ECs) [16]. Petal et al reported that DLL4 was a hypoxia-regulated gene, which not only received signals from HIF-1a in ECs, but also respond to HIF-VEGF signalling via the hypoxia pathway [17]. Since DLL4Notch and HIF-VEGF have been shown to play an important role during angiogenesis, we focused on the identification of biomarkers involving DLL4-Notch and HIF-VEGF signals which were associated with clinical outcome in mRCC patients with second-line pazopanib treatment. The aim of current phase II study was to assess the activity and toxicity of second-line treatment with pazopanib after failure of first-line sunitinib treatment in patients with clear cell mRCC; to investigate the potential association of DLL4, Notch1, VEGFA, PDGFRB, HIF-1a and HIF-2a with clinical response to pazopanib in mRCC patients. 2. Patients and methods 2.1. Patients The study population consisted of patients aged 18 years or older with clear cell mRCC who had previously received first-line treatment with sunitinib. Common eligibility criteria included adequate hepatic, renal, cardiac and haematological function; absence of symptomatic congestive heart failure, myocardial infarction or coronary artery bypass graft in the previous 6 or 12 months; Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1; at least one measurable target lesion per Response Evaluation Criteria in Solid Tumours (RECIST); life expectancy P12 weeks. Exclusion criteria included: history of another malignancy; brain metastasis; uncontrolled hypertension;

M. Xie et al. / European Journal of Cancer 51 (2015) 595–603

clinically significant cardiovascular disease during the preceding 12 months; proteinuria exceeding 1 g/24 h; coagulopathy. 2.2. Study design and treatment This is a prospective, open-label, single-arm, multicentre, phase II trial. Patients received continuous treatment of 800 mg pazopanib once daily until disease progression, unacceptable toxicity or withdrawal of consent occurred. Dose reductions by 400 mg to a lowest dose of 200 mg daily were allowed on the basis of tolerability and according to protocol-defined guidelines. The study was approved by the institutional review boards of all participating centres and was conducted in agreement with the Declaration of Helsinki and the International Conference on Harmonization of Good Clinical Practice guidelines. All patients gave written informed consent. The primary end-point was progression-free survival (PFS). Secondary end-points were overall survival (OS), objective response rate (ORR) and safety. We assessed the tumour response according to the RECIST 1.1. Efficacy was evaluated by computed tomography with contrast of the chest, abdomen and pelvis. We performed tumour assessments with the use of imaging studies at baseline and every six weeks until the end of treatment. We also used such assessments to confirm a response (at least 4 weeks after initial documentation) and whenever disease progression was suspected. All imaging scans were evaluated by an independent imaging-review committee (IRC) blinded to study treatment. Patients who had inadequate data for study assessment was regarded as non-evaluable. Adverse events (AEs) were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Safety was assessed by physical examination and laboratory tests. Electrocardiograms (ECGs) were performed at baseline and every six weeks until the end of treatment. Follow-up for OS was performed every three months after disease progression until death or study withdrawal. 2.3. Sample collection and analysis Patients provided written Institutional Review Board—approved informed consent to collect blood samples for biomarker analysis. Serum samples were prepared from venous blood samples collected at baseline (day 7 to pretreatment on day 1) (T0) and after six weeks of treatment (T1), frozen, and stored at 70 °C to 80 °C until analysis. Before analysis, serum samples were thawed overnight at 4 °C (first thaw), centrifuged at 1500g to remove debris, and aliquoted to multiple tubes for the same day analysis or stored at 70 °C to 80 °C for future studies. The samples for

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enzyme-linked immunosorbent assay (ELISA) were conducted using these aliquots, which were thawed (second thaw) and prepared in the same manner. We analysed the serum samples blinded to clinical outcome. Serum concentrations of DLL4, Notch1, HIF-1a, HIF-2a, VEGFA and PDGFRB were determined using validated enzyme-linked immunosorbent assay (ELISA) kit (R&D Systems, Minneapolis, MN). Concentrations of these biomarkers were measured in duplicated. 2.4. Statistical analyses This study defined objective response according to RECIST 1.1, and PFS and OS as previously described [18]. All data were considered for patients who had received at least one dose of study drug (intent-to-treat, ITT). Patients alive and progression-free were censored at the date of the last follow-up, death or last patient contact [9]. PFS and OS were estimated by Kaplan–Meier method. Patients with biomarker data available for at least one time point were included in statistical analysis. Patients missing biomarker value for given time point were excluded from the exploratory analysis. Changes in expression levels of DLL4 and markers of hypoxia at baseline (T0) and after six weeks of treatment (T1) were tested by means of paired Student’s t-tests. To investigate whether T1 concentrations were associated with tumour response (RECIST), covariance analysis was adopted, which are known as the most efficient approach for the analysis of pre-post design [20]. Patients were categorised as responders (complete response (CR), partial response (PR), including stable disease (SD)) or non-responders for exploratory study. We tested the concentrations of all the biomarkers as independent variable to predict response status by logistic regression. Evaluation of the prognostic value of the biomarker was done initially using univariable Cox and Kaplan–Meier analysis, followed by multivariable Cox proportional hazard models [21]. The impact of all variables (previous nephrectomy, six IMDC (International Metastatic RCC Database Consortium) risk factors (anaemia, neutrophilia, Karnofski performance status (KPS)

Phase II study of pazopanib as second-line treatment after sunitinib in patients with metastatic renal cell carcinoma: a Southern China Urology Cancer Consortium Trial.

This multicentre, single arm, phase II study was aimed to assess the efficacy and safety of pazopanib as second-line treatment after failure of suniti...
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