Phase I clinical and magnetic resonance imaging study of the vascular agent NGR-hTNF in patients with advanced cancers (European Organization for Research and Treatment of Cancer Study 16041).
OBJECTIVE
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.


METHODS
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.
Department of Medical Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands. h.vanlaarhoven@onco.umcn.nl
Hanneke W M
HW
van Laarhoven
Walter
W
Fiedler
Ingrid M E
IM
Desar
Jack J A
JJ
van Asten
Sandrine
S
Marréaud
Denis
D
Lacombe
Anne-Sophie
AS
Govaerts
Jan
J
Bogaerts
Peter
P
Lasch
Johanna N H
JN
Timmer-Bonte
Antonio
A
Lambiase
Claudio
C
Bordignon
Cornelis J A
CJ
Punt
Arend
A
Heerschap
Carla M L
CM
van Herpen
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002199:Capillary Permeability / Q000187:drug effects*; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D011993:Recombinant Fusion Proteins / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; C464839:tumor necrosis factor-alpha, CNGRC fusion protein, human