Abstract | PURPOSE: This phase I trial investigating the vascular targeting agent NGR-hTNF aimed to determine the (a) dose-limiting toxicities, (b) maximum tolerated dose (MTD), (c) pharmacokinetics and pharmacodynamics, (d) vascular response by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and (e) preliminary clinical activity in solid tumors. EXPERIMENTAL DESIGN:
NGR-hTNF was administered once every 3 weeks by a 20- to 60-minute i.v. infusion to cohorts of three to six patients with solid tumors in escalating doses. Pharmacokinetic and pharmacodynamic analyses in blood were done during the first four cycles. DCE-MRI was done in cycle 1 at baseline and 2 hours after the start of the infusion. RESULTS: Sixty-nine patients received a total of 201 cycles of NGR-hTNF (0.2-60 microg/m(2)). Rigors and fever were the most frequently observed toxicities. Four dose-limiting toxicities were observed (at doses of 1.3, 8.1, and 60 microg/m(2)), of which three were infusion related. The MTD was 45 microg/m(2). The mean apparent terminal half-life ranged from 0.963 to 2.08 hours. DCE-MRI results of tumors showed a vascular response to NGR-hTNF. No objective responses were observed, but 27 patients showed stable disease with a median duration of 12 weeks. CONCLUSIONS:
NGR-hTNF was well tolerated. The MTD was 45 microg/m(2) administered in 1 hour once every 3 weeks. DCE-MRI results showed the antivascular effect of NGR-hTNF. These findings call for further research for defining the optimal biological dose and clinical activity of NGR-hTNF as a single agent or in combination with cytotoxic drugs.
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Authors | Hanneke W M van Laarhoven, Walter Fiedler, Ingrid M E Desar, Jack J A van Asten, Sandrine Marréaud, Denis Lacombe, Anne-Sophie Govaerts, Jan Bogaerts, Peter Lasch, Johanna N H Timmer-Bonte, Antonio Lambiase, Claudio Bordignon, Cornelis J A Punt, Arend Heerschap, Carla M L van Herpen |
Journal | Clinical cancer research : an official journal of the American Association for Cancer Research
(Clin Cancer Res)
Vol. 16
Issue 4
Pg. 1315-23
(Feb 15 2010)
ISSN: 1557-3265 [Electronic] United States |
PMID | 20145168
(Publication Type: Clinical Trial, Phase I, Journal Article)
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Chemical References |
- Antineoplastic Agents
- Recombinant Fusion Proteins
- Tumor Necrosis Factor-alpha
- tumor necrosis factor-alpha, CNGRC fusion protein, human
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Topics |
- Adult
- Aged
- Antineoplastic Agents
(adverse effects, pharmacokinetics, therapeutic use)
- Capillary Permeability
(drug effects)
- Drug Administration Schedule
- Female
- Humans
- Magnetic Resonance Imaging
- Male
- Maximum Tolerated Dose
- Middle Aged
- Neoplasms
(drug therapy)
- Recombinant Fusion Proteins
(adverse effects, pharmacokinetics, therapeutic use)
- Tumor Necrosis Factor-alpha
(adverse effects, pharmacokinetics, therapeutic use)
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