Phase I Pharmacokinetic and Pharmacodynamic Study of Recombinant Human Endostatin in Patients With Advanced Solid Tumors

Thomas, James P.; Arzoomanian, Rhoda Z.; Alberti, Dona; Marnocha, Rebecca; Lee, Fred; Friedl, Andreas; Tutsch, Kendra D.; Dresen, Amy; Geiger, Peter; Pluda, James M.; Fogler, William E.; Schiller, Joan H.; Wilding, George

doi:10.1200/jco.2003.12.120

Cited by 217 publications

(133 citation statements)

References 43 publications

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“…Such antibodies have been described in a clinical trial of recombinant human endostatin in which they were not associated with changes in endostatin pharmacokinetic (Thomas et al, 2003). However, the goal of this phase I clinical trial was not to assess clinical efficacy, and no response was observed.…”

Section: Discussionmentioning

confidence: 99%

Autoantibodies to endostatin in patients with breast cancer: correlation to endostatin levels and clinical outcome

et al. 2006

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Circulating autoantibodies to self-antigens overexpressed by cancer cells are common in cancer patients. As specific proteins are expressed during neoangiogenesis, a similar phenomenon might occur with particular antigens of tumour vessels. Collagen XVIII, from which endostatin is cleaved, is highly expressed in the perivascular basement membrane of tumour-associated blood vessels and autoantibodies to endostatin have been reported in cancer patients. The present study analyses the incidence of naturally occurring autoantibodies to endostatin in the sera of breast cancer patients and their relation to endostatin serum levels and patient clinical outcome. Serum samples from 36 patients with localised breast cancer and 59 patients with a fully documented history of metastatic breast cancer were used. The immunoreactivity of serum samples was tested against purified recombinant human endostatin and endostatin levels were determined by immunoassay. We could detect anti-endostatin antibodies in the sera of 66% of the patients with localised disease and 42% of the patients with metastatic disease (P ¼ 0.03). There was no correlation between the presence of antibodies to endostatin and circulating levels of endostatin. The detection of autoantibodies to endostatin was associated with better prognosis in metastatic breast cancer patients (median survival time: 20 vs 8 months, P ¼ 0.03), as was the presence of low levels of serum endostatin (median survival time: 20 vs 9 months, P ¼ 0.007). These results show that a natural immune reaction against endostatin can occur in breast cancer patients. This could have important therapeutic implications with regard to endostatin therapy and raises the question of a possible role of this humoral reaction against endostatin in the neoplastic process.

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Section: Discussionmentioning

confidence: 99%

Autoantibodies to endostatin in patients with breast cancer: correlation to endostatin levels and clinical outcome

et al. 2006

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“…All three phase I studies utilised radiological and biopsy-based indicators of tumour angiogenesis to assess BED. Thomas et al (2003) failed to demonstrate any significant changes by in vivo imaging with dynamic CT (marker of microvessel density), dynamic MRI (marker of tumour blood flow) or [ 18 F]FDG PET (measure of tumour glucose metabolism). No changes in microvessel density, endothelial cell apoptosis, proliferation or vessel maturity were seen in paired pre-and 8-week post-treatment tumour biopsies from patients in this study although only eight sample pairs were available for analysis.…”

Section: Clinical Studiesmentioning

confidence: 95%

“…Although pharmacokinetic data were linear and analysis of serumisolated endostatin in one phase I study (Thomas et al, 2003) did not demonstrate extensive proteolytic degradation, small shifts in mass spectrometry profiles were noted that could be consistent with limited terminal proteolytic cleavage. Of note, no in vitro activity could be demonstrated for re-isolated endostatin in any of the three studies.…”

Section: Immunogenicity Intravascular Proteolysis and A Potential Plmentioning

confidence: 97%

“…While most antiangiogenic ECM fragments have yet to enter clinical development, three phase I trials have been published using recombinant human endostatin in a total of 61 patients with advanced metastatic cancer (including 11 melanoma, 10 sarcoma, nine colorectal, nine lung, seven breast, four renal) (Eder et al, 2002;Herbst et al, 2002a;Thomas et al, 2003). These studies administered daily endostatin doses of 15 -600 mg m À2 day À1 by short intravenous infusion.…”

Section: Clinical Studiesmentioning

confidence: 99%

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The clinical potential of antiangiogenic fragments of extracellular matrix proteins

Clamp

Jayson

2005

Br J Cancer

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Neovasculature development is a crucial step in the natural history of a cancer. While much emphasis has been placed on proangiogenic growth factors such as VEGF, it is clear that endogenous angiogenesis inhibitors also have critical roles in the regulation of this process. Recent research has identified several cryptic fragments of extracellular matrix/vascular basement membrane proteins that have potent antiangiogenic properties in vivo. It has become apparent that many of these fragments signal via interactions with endothelial integrins, although multiple downstream effector pathways have been implicated and endostatin, the first non-collagenous domain of collagen XVIII, influences an intricate signalling network. The activity of these molecules in animal models suggests that they may have significant clinical activity; however, results of phase I/II trials with endostatin were disappointing. Many possible reasons can be found for the failure of these studies. Weaknesses in trial design, endostatin administration regimen and patient selection are identifiable, and importantly the lack of a clearly defined antiangiogenic mechanism for endostatin hindered assessment of biologically effective dose. Additionally, in vivo immunological and proteolytic function-neutralising mechanisms may have negated endostatin's actions. Lessons learned from these studies will aid the future clinical development of other antiangiogenic extracellular matrix protein fragments.

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“…Use of endostatin in clinical trials in cancer therapy has been hampered by difficulties in protein production in large quantities, loss of biologic activity during long-term storage, and cumbersome daily administration requirements. Three phase I clinical trials and a recently reported phase II clinical trial of endostatin in patients with advanced neuroendocrine tumours have not demonstrated anti-tumour activity (Eder et al, 2002;Herbst et al, 2002;Thomas et al, 2003;Kulke et al, 2006). In the phase II study, steady-state trough levels were below the target therapeutic range.…”

mentioning

confidence: 97%

Systemic inhibition of tumour angiogenesis by endothelial cell-based gene therapy

et al. 2007

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Angiogenesis and post-natal vasculogenesis are two processes involved in the formation of new vessels, and both are essential for tumour growth and metastases. We isolated endothelial cells from human blood mononuclear cells by selective culture. These blood outgrowth cells expressed endothelial cell markers and responded correctly to functional assays. To evaluate the potential of blood outgrowth endothelial cells (BOECs) to construct functional vessels in vivo, NOD-SCID mice were implanted with Lewis lung carcinoma cells subcutaneously (s.c.). Blood outgrowth endothelial cells were then injected through the tail vein. Initial distribution of these cells occurred throughout the lung, liver, spleen, and tumour vessels, but they were only found in the spleen, liver, and tumour tissue 48 h after injection. By day 24, they were mainly found in the tumour vasculature. Tumour vessel counts were also increased in mice receiving BOEC injections as compared to saline injections. We engineered BOECs to deliver an angiogenic inhibitor directly to tumour endothelium by transducing them with the gene for human endostatin. These cells maintained an endothelial phenotype and decreased tumour vascularisation and tumour volume in mice. We conclude that BOECs have the potential for tumour-specific delivery of cancer gene therapy.

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Phase I Pharmacokinetic and Pharmacodynamic Study of Recombinant Human Endostatin in Patients With Advanced Solid Tumors

Abstract: Endostatin given daily as a 1-hour intravenous infusion was well tolerated without dose-limiting toxicity at doses up to 300 mg/m2.

Cited by 217 publications

References 43 publications

Autoantibodies to endostatin in patients with breast cancer: correlation to endostatin levels and clinical outcome

Autoantibodies to endostatin in patients with breast cancer: correlation to endostatin levels and clinical outcome

The clinical potential of antiangiogenic fragments of extracellular matrix proteins

Systemic inhibition of tumour angiogenesis by endothelial cell-based gene therapy

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