Abstract
BackgroundVascular endothelial growth factor (VEGF) directed therapies are being used in a large number of advanced tumors. Metastatic renal cell carcinoma (mRCC) is highly dependent on the VEGF pathway; VEGF receptor (VEGFR) tyrosine kinase inhibitors (TKI) and humanized VEGF monoclonal antibody have been registered for clinical use in advanced renal cell carcinoma. The VEGFR TKI, pazopanib, with a rather manageable toxicity profile, was preferred to sunitinib by mRCC patients. We investigate the combination of pazopanib and bevacizumab to determine the maximum tolerated dose (MTD) in mRCC and other advanced solid tumors.MethodsIn this bicentric phase I trial with a 3 + 3 + 3 dose-escalation design, patients received oral pazopanib once daily plus intravenous infusion of bevacizumab every 2 weeks from D15, at one of the four dose levels (DL) planned according to the occurrence of dose limiting toxicities (DLT). 400 and 600 mg pazopanib were respectively combined with 7.5 mg/kg bevacizumab in DL1 and DL2, and 600 and 800 mg pazopanib with 10 mg/kg bevacizumab in DL3 and DL4. Tumor response was evaluated every 8 weeks. Blood samples were assayed to investigate pazopanib pharmacokinetics.ResultsTwenty five patients including seven mRCC were enrolled. Nine patients received the DL1, ten received the DL2. No DLT were observed at DL1, five DLT at DL2, and 3 DLT in the six additional patients who received the DL1. A grade 3 microangiopathic hemolytic anemia syndrome was observed in four (16%) patients. Five (22%) patients achieved a partial response. The mean (range) plasmatic concentrations of 400 and 600 pazopanib were respectively 283 (139–427) and 494 (227–761) μg.h/mL at Day 1, and 738 (487–989) and 1071 (678–1464) μg.h/mL at Day 15 i.e. higher than those previously reported with pazopanib, and were not directly influenced by bevacizumab infusion.ConclusionsThe combination of pazopanib and bevacizumab induces angiogenic toxicity in patients without any pre-existing renal or vascular damage. Even if a marginal efficacy was reported with five (22%) patients in partial response in different tumor types, the toxicity profile compromises the development of this combination.Trial registrationThe study was retrospectively registered on ClinicalTrials.gov (number NCT01202032) on 2010, Sept 14th.
Highlights
Vascular endothelial growth factor (VEGF) directed therapies are being used in a large number of advanced tumors
A rather strong rational supports the combination of bevacizumab known to induce a rapid clearance of circulating VEGF, with VEGF receptor (VEGFR) tyrosine kinase inhibitors (TKI) that mostly induce an increase of the circulating VEGF levels
Additional inclusion criteria were Eastern Cooperative Oncology Group performance status (ECOG-PS) of 0 or 1, adequate vital functions defined as absolute neutrophil count ≥1500 cells/μL, hemoglobin ≥9.0 g/dL, and platelets ≥100,000 cells/μL, Prothrombine time (PT) ≤1.2xupper limit of normal [Upper limit of normal [ULN] (ULN)] and APTT ≤1.2xULN, hepatic aspartate aminotransferase (AST) / alanine aminotransferase (ALT) ≤2.5xULN, total bilirubin ≤1.5xULN, and serum creatinine ≤1.5 mg/dL or creatinine clearance ≥50 mL/min
Summary
Vascular endothelial growth factor (VEGF) directed therapies are being used in a large number of advanced tumors. Metastatic renal cell carcinoma (mRCC) is highly dependent on the VEGF pathway; VEGF receptor (VEGFR) tyrosine kinase inhibitors (TKI) and humanized VEGF monoclonal antibody have been registered for clinical use in advanced renal cell carcinoma. Treatments have evolved from known therapies using exclusively cytokines to therapies targeting angiogenesis, cell proliferation, and tumor growth. These recent developments have enabled tangible clinical benefits in different solid tumor types [2,3,4,5], especially in renal cell cancer, and supported subsequent development of VEGF inhibitors, mainly tyrosine kinase inhibitors (TKI) directed against VEGF receptors (VEGFR). Some of these combinations have been attempted and reported promising results in terms of efficacy but their feasibility remains as a matter of debate [14, 25,26,27,28]
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