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
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.
- SourceAvailable from: Paolo Frumento
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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 "
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. "
ABSTRACT: Our findings that PlGF is a cancer target and anti-PlGF is useful for anticancer treatment have been challenged by Bais et al. Here we take advantage of carcinogen-induced and transgenic tumor models as well as ocular neovascularization to report further evidence in support of our original findings of PlGF as a promising target for anticancer therapies. We present evidence for the efficacy of additional anti-PlGF antibodies and their ability to phenocopy genetic deficiency or silencing of PlGF in cancer and ocular disease but also show that not all anti-PlGF antibodies are effective. We also provide additional evidence for the specificity of our anti-PlGF antibody and experiments to suggest that anti-PlGF treatment will not be effective for all tumors and why. Further, we show that PlGF blockage inhibits vessel abnormalization rather than density in certain tumors while enhancing VEGF-targeted inhibition in ocular disease. Our findings warrant further testing of anti-PlGF therapies.Cell 04/2010; 141(1):178-90. DOI:10.1016/j.cell.2010.02.039 · 33.12 Impact Factor
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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). "
ABSTRACT: Identification of molecular alterations in key proteins involved in breast cancer cell proliferation and survival resulted in the development of a new treatment strategy with target-based agents. The anti-ErbB-2 monoclonal antibody (mAb) trastuzumab and the dual epidermal growth factor receptor/ErbB-2 tyrosine kinase inhibitor lapatinib are effective in patients with breast cancer that overexpresses ErbB-2. The anti-vascular endothelial growth factor-A mAb bevacizumab is approved in combination with taxanes for treatment of unselected patients with metastatic breast cancer. In addition, preclinical data suggest that signaling inhibitors can prevent or overcome resistance to endocrine therapy in estrogen receptor positive (ER+) breast cancer. However, the majority of signaling inhibitors explored in breast cancer patients has shown little activity, at least when used as monotherapy; and the results of clinical trials in ER+ breast cancer of combinations of signaling inhibitors and endocrine therapies are rather disappointing. Negative findings are likely due to mechanisms of intrinsic or acquired resistance to target-based agents. Breast carcinoma is a complex and heterogeneous disease and several different molecular alterations are involved in its pathogenesis and progression. The redundancy of oncogenic pathways activated in cancer cells, the heterogeneity of the mechanisms of resistance, and the plasticity of tumor cells that are capable to adapt to different growth conditions, significantly hamper the efficacy of each signaling inhibitor in breast cancer. Therefore, a comprehensive approach that takes into account the complexity of the disease is definitely required to improve the efficacy of target-based therapy in breast cancer.Endocrine Related Cancer 07/2009; 16(3):675-702. DOI:10.1677/ERC-08-0208 · 4.91 Impact Factor