Phase Ib study of NGR-hTNF, a selective vascular targeting agent, administered at low doses in combination with doxorubicin to patients with advanced solid tumours.

Abstract

BACKGROUND:

Asparagine-glycine-arginine-human tumour necrosis factor (NGR-hTNF) is a vascular targeting agent exploiting a tumour-homing peptide (NGR) that selectively binds to aminopeptidase N/CD13, overexpressed on tumour blood vessels. Significant preclinical synergy was shown between low doses of NGR-TNF and doxorubicin.

METHODS:

The primary aim of this phase I trial was to verify the safety of low-dose NGR-hTNF combined with doxorubicin in treating refractory/resistant solid tumours. Secondary objectives included pharmacokinetics (PKs), pharmacodynamics, and clinical activity. In all 15 patients received NGR-hTNF (0.2-0.4-0.8-1.6 microg m(-2)) and doxorubicin (60-75 mg m(-2)), both given intravenously every 3 weeks.

RESULTS:

No dose-limiting toxicity occurred and the combination was well tolerated. Around two cases of neutropenic fevers, lasting 2 days, and two cases of cardiac ejection-fraction drops, one asymptomatic and the other symptomatic, were registered. Only 11% of the adverse events were related to NGR-hTNF and were short-lasting and mild-to-moderate in severity. There was no apparent PK interaction and the shedding of soluble TNF-receptors did not increase to 0.8 microg m(-2). One partial response (7%), at dose level 0.8 microg m(-2), and 10 stable diseases (66%), lasting for a median duration of 5.6 months, were observed.

CONCLUSIONS:

NGR-hTNF plus doxorubicin was administered safely and showed promising activity in patients pre-treated with anthracyclines. The dose level of 0.8 microg m(-2) NGR-hTNF plus doxorubicin 75 mg m(-2) was selected for phase II development.

• Authors: V Gregorc, A Santoro, E Bennicelli, C J A Punt, G Citterio, J N H Timmer-Bonte, F Caligaris Cappio, A Lambiase, C Bordignon, C M L van Herpen
• Journal: British journal of cancer (Br J Cancer) Vol. 101 Issue 2 Pg. 219-24 (Jul 21 2009) ISSN: 1532-1827 [Electronic] England
• PMID: 19568235 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study)

Chemical References

• Recombinant Fusion Proteins
• Tumor Necrosis Factor-alpha
• tumor necrosis factor-alpha, CNGRC fusion protein, human
• Doxorubicin

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, adverse effects, pharmacokinetics)
• Dose-Response Relationship, Drug
• Doxorubicin (administration & dosage, adverse effects, pharmacokinetics)
• Female
• Humans
• Male
• Middle Aged
• Neoplasms (drug therapy, metabolism)
• Recombinant Fusion Proteins (administration & dosage, adverse effects, pharmacokinetics)
• Tumor Necrosis Factor-alpha (administration & dosage, adverse effects, pharmacokinetics)