Gordon MS, Margolin K, Talpaz M, Sledge Jr GW, Holmgren E, Benjamin R 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
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.
Available from: Douglas A Ross
- "Local delivery of lower doses may still result in a high tissue load that is similar to or greater than that seen with systemic oncological dosing regimens. This is an important consideration because of the known side effect of poor wound healing when using bevacizumab.11,12 "
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ABSTRACT: Hereditary hemorrhagic telangiectasia (HHT) is a disease characterized by mucocutaneous telangiectasias and visceral arteriovenous malformations. The genetic mutations that cause this disease result in elevated levels of vascular endothelial growth factor, which is inhibited by bevacizumab.
Previous studies have shown bevacizumab treatment to be effective in reducing symptoms, but study protocols have all used oncological dosing parameters, which carry several well-described serious side effects. This study investigates whether drastically lower dosages of bevacizumab than normally
used in oncological treatment could control epistaxis in patients with HHT and medically refractory epistaxis. A prospective, open-label, noncomparative study enrolled six patients receiving 0.125-mg/kg infusions of bevacizumab once every 4 weeks for a total of six infusions. Severity of epistaxis
was assessed with the epistaxis severity score, and quality-of-life measures were followed with the 20-item Sino-Nasal Outcome Test and 36-item Short Form surveys. A statistically significant improvement was seen in the control of epistaxis severity and frequency, with minimal negative side
effects and high patient satisfaction. Very low dose bevacizumab treatment is an effective method of controlling medically refractory epistaxis in patients with HHT and additional investigation to optimize dosing guidelines is warranted.
Available from: PubMed Central
- "Our observation that baseline body weight and albumin are significantly associated with bevacizumab clearance in AGC is consistent with previous findings in other solid tumors (14,15). It is well known that clearance of other IgG antibodies is faster in patients with lower serum albumin levels (26). "
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ABSTRACT: Altered pharmacokinetics of antibody drugs has been reported in advanced gastric cancer (AGC). We aim to evaluate bevacizumab pharmacokinetics in AGC from the Phase III trial (AVAGAST), and explore the influence of patient variables. Bevacizumab concentrations (Cp) were measured in plasma samples taken following disease progression from 162 patients (7.5 mg/kg every 3 weeks). Predicted Cp [median and 90% prediction interval] was simulated using the population pharmacokinetic model established for other cancers (PPK model) and compared to observed Cp. Bevacizumab clearance was estimated using NONMEM and compared between subgroups. Patient characteristics of AGC are similar to other cancers except for lower body weight despite higher percentage of males. Eighty-five percent of observed Cp was below the median predicted Cp and 38% below the lower boundary of the 90% prediction interval. Median bevacizumab clearance in AGC was 4.5 versus 3 mL/day/kg in other cancers. Bevacizumab clearance was significantly faster (p < 0.05) in patients without gastrectomy (n = 42) or lower albumin. Clearance appeared to be faster in patients with lower total protein, higher ECOG scores, more metastatic sites, and poorer response. No significant difference in bevacizumab concentrations and clearance was observed between Asian and Non-Asian patients. AGC patients exhibited significantly lower bevacizumab exposure due to an approximate 50% increase in clearance versus other cancers. Bevacizumab is cleared faster in patients without prior gastrectomy. No significant difference in bevacizumab pharmacokinetics was observed between Asian and Non-Asian patients. The underlying mechanism for faster bevacizumab clearance in AGC is unknown and warrants further research.
Electronic supplementary material
The online version of this article (doi:10.1208/s12248-014-9631-6) contains supplementary material, which is available to authorized users.
Available from: Jun Soma
- "Anti-VEGF agents are generally well tolerated, but hypertension and asymptomatic proteinuria are common dose-related adverse effects, frequently occurring together . The incidence of proteinuria ranges from 21%–63% . Although this proteinuria is largely asymptomatic and low-grade, nephrotic-range proteinuria occurs in 1%–2% of bevacizumab-treated patients . "
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ABSTRACT: Bevacizumab, a recombinant humanized monoclonal antibody for vascular endothelial growth factor, has been widely used in various cancers offering substantial clinical benefit. It is reportedly associated with development of high-grade proteinuria and nephrotic syndrome with the histology of thrombotic microangiopathy, but there has been no report describing the development of immunoglobulin A nephropathy in bevacizumab-treated patients.
A 68-year-old man with metastatic rectal cancer was treated with bevacizumab. He presented with hematuria and proteinuria 15 and 17 months, respectively, after bevacizumab initiation. Bevacizumab was stopped at 17 months. Renal biopsy at 19 months revealed immunoglobulin A nephropathy, with numerous paramesangial hemispherical deposits and thrombotic microangiopathy. Electron microscopy showed numerous paramesangial electron-dense deposits of various sizes, and subendothelial injuries. Proteinuria almost completely resolved 8 months after bevacizumab cessation, although hematuria persisted. Follow-up renal biopsy 11 months after bevacizumab cessation showed a marked decrease in mesangial immunoglobulin A deposits and paramesangial electron-dense deposits, which correlated with a gradual decrease in serum immunoglobulin A.
This is the first case report that confirmed histologically the development and resolution of immunoglobulin A nephropathy during and after bevacizumab therapy. This case shows that there may be other mechanisms of glomerular injury by bevacizumab besides glomerular endothelial injury leading to thrombotic microangiopathy.
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