Abstract
Background: ABC-03 was a randomized phase II trial of cediranib (C; AZD2171) [inhibitor of VEGFR-1, -2 and -3 tyrosine kinase and VEGF-induced signaling] or placebo (P) in combination with cisplatin/gemcitabine for pts with ABC. Changes in plasma biomarkers including angiogenic proteins and a marker of cell death (CK18) have not been reported in ABC.Methods: ELISA was performed for 15 angiogenesis or inflammatory-related proteins and CK18 in plasma of pts with repeated sampling during treatment and at disease progression. Tumor markers were also evaluated. Overall survival (OS) was analyzed using Cox model for baseline (BL) biomarkers and time-varying covariate Cox model (TVC) for biomarkers with serial measurements.Results: Plasma samples were available from 117 of 124 pts (59 in C arm, 58 in P). After adjusting for treatment and pt characteristics, higher BL VEGFR2 (p = 0.02), CK18 (p = 0.005), CEA (p < 0.001), CA19-9 (p = 0.03) and CA125 (p = 0.001) correlated with shorter OS, as did incremental increases in CK18 (HR 1.08, 95%CI 1.05-1.11, p < 0.001) and IL-6 (HR 1.02, 95%CI 1.00-1.03, p = 0.008) using TVC. There was evidence for interaction between treatment and BL CA19-9 and PDGFbb for OS: incremental increases in CA19-9 were associated with an increased risk of death (C: HR 1.44, 95%CI 1.16-1.80; P: HR 1.03, 95%CI 1.00-1.05, p = 0.001) and higher values of PDGFbb were associated with a decreased risk of death with C (HR 0.82, 95%CI 0.68-1.00) and an increased risk of death with P (HR 1.15, 95%CI 0.99-1.34, p = 0.01). In TVC, there was evidence of interaction between treatment and VEGFA (p = 0.03), PDGFbb (p = 0.08), VEGFC (p = 0.06) and SDF1b (p = 0.06). Higher values of VEGFA were associated with increased risk of death with P (HR 1.31, 95%CI 1.06-1.62) but not with C (HR 0.99, 95%CI 0.86-1.15) (p = 0.03).Conclusions: High BL VEGFR2, CK18 and tumor markers are associated with a poor outcome in pts with ABC. Increasing levels of CA19-9 and PDGFbb from BL were associated with increased and decreased risk of death, respectively, in C-treated pts. Changes in VEGFA correlated with OS for pts on P but not C. These findings may inform future clinical trial stratification and design. Clinical trial information: NCT00939848
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