Gordon, M. S. et al. Phase I safety and pharmacokinetic study of recombinant human anti-vascular endothelial growth factor in patients with advanced cancer. J. Clin. Oncol. 19, 843-850

Indiana University School of Medicine, Indianapolis, IN, USA.
Journal of Clinical Oncology (Impact Factor: 18.43). 02/2001; 19(3):843-50.
Source: PubMed

ABSTRACT We investigated the safety and pharmacokinetics of a recombinant human monoclonal antibody to vascular endothelial growth factor (rhuMAb VEGF) in patients with cancer.
Cohorts of patients with metastatic cancer having failed prior therapy entered a phase I trial of rhuMAb VEGF administered by a 90-minute intravenous infusion at doses from 0.1 to 10.0 mg/kg on days 0, 28, 35, and 42. Patients underwent pharmacokinetic sampling on day 0 and had serum samples obtained during the subsequent 28 days. Response assessment was carried out on days 49 and 72.
Twenty-five patients with a median Eastern Cooperative Oncology Group performance status of 0 were accrued. There were no grade III or IV adverse events definitely related to the antibody. There were three episodes of tumor-related bleeding. Infusions of rhuMAb VEGF were well tolerated without significant toxicity. Grades I and II adverse events possibly or probably related to study drug included asthenia, headache, and nausea. Pharmacokinetics revealed a linear profile with a half-life of 21 days. There were no objective responses, though 12 patients experienced stable disease over the duration of the study.
rhuMAb VEGF was safely administered without dose-limiting toxicity at doses ranging up to 10 mg/kg. Multiple doses of rhuMAb VEGF were well tolerated, and pharmacokinetic studies indicate that doses of > or = 0.3 mg/kg have a half-life similar to that of other humanized antibodies. Subsequent trials will explore rhuMAb VEGF alone and in combination chemotherapy.

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    • "This study explored how bevacizumab modulates the so called 'angiogenic balance', by following plasma variations of some proteins, related to the angiogenic process. First of all, our study definitively proved and confirmed the preliminary results obtained both from our (Loupakis et al, 2007) and other laboratories (Gordon et al, 2001; Brostjan et al, 2008), concerning the decrease of biologically active free VEGF levels after the first administration of a BV-containing regimen, as measured by ELISA assay on immunodepleted plasma samples. Moreover, for the first time, our data demonstrated that the triplet plus BV was able to significantly reduce VEGF plasma levels independently from the baseline concentrations, suggesting that the standard dose of BV is able to "
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    ABSTRACT: The identification of molecular and genetic markers to predict or monitor the efficacy of bevacizumab (BV) represents a key issue in the treatment of metastatic colorectal cancer (mCRC). Plasma levels of vascular endothelial growth factor (VEGF), placental growth factor (PlGF), soluble VEGF receptor 2 (sVEGFR-2) and thrombospondin-1 (TSP-1) were assessed by ELISA assay at different time points in a cohort of 25 patients enroled in a phase II trial of GONO-FOLFOXIRI plus BV as first-line treatment of mCRC. VEGF: -2578A/C, -1498C/T, -1154A/G, -634C/G and 936C/T; and VEGFR-2: -604A/G, +1192C/T and +1719A/T, polymorphisms were assessed in a total of 54 patients. Treatment with GONO-FOLFOXIRI plus BV determined a prolonged and significant reduction in plasma free, biologically active VEGF concentration. Interestingly, VEGF concentrations remained lower than at baseline also at the time of PD. Conversely, PlGF levels increased during the treatment if compared with baseline, suggesting a possible role in tumour resistance; moreover, sVEGFR-2 increased at the time of PD, as well as TSP-1. No association of assessed polymorphisms with outcome was found. Our study suggested the possible mechanisms of resistance to combined therapy in those patients with a progressive disease to be tested in ongoing phase III randomised studies.
    British Journal of Cancer 03/2011; 104(8):1262-9. DOI:10.1038/bjc.2011.85 · 4.82 Impact Factor
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    • "Related to Bais' remark that 5D11D4 is in vast excess of its ligand (Bais et al., 2010), it is noteworthy that anti-VEGF also circulates in vast excess over its ligand. Indeed, in cancer patients and mice, comparable plasma levels were reported for VEGF and PlGF (10 to 100 pg/ml) and for anti-VEGF and anti-PlGF mAbs delivered at effective doses (300 to 600 mg/ml), resulting in >10 6 -fold excess of mAb over ligand (Gordon et al., 2001; Lassen et al., 2009; Riisbro et al., 2009). Furthermore, it should be noticed that in the gene transfer experiments, 16D3 blocked CNV, even though its plasma titers were only 10 3 -fold higher than circulating human PlGF levels. "
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    • "Bevacizumab is a humanized mAb that binds VEGF and prevents its interaction with VEGF receptors, thus leading to inhibition of VEGF-induced angiogenesis. Bevacizumab can be administered safely, without dose-limiting toxicities, up to the dose of 10 mg/kg every 2 weeks, and can be combined with chemotherapy without apparent synergistic toxicity (Gordon et al. 2001, Margolin et al. 2001). In pretreated metastatic breast cancer bevacizumab has very limited activity as single agent (Cobleigh et al. 2003) and, when added to capecitabine, produced an increase in response rates that did not translate into improved PFS or overall survival in a randomized phase III trial (Miller et al. 2005a). "
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