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.

Figure 1

Incidence of grade 3–4 adverse events by dose levels. For each dose level of asparagine–glycine–arginine–human tumour necrosis factor (NGR-hTNF) and doxorubicin the following number of cycles were administered, respectively: 0.2–60 : 12–12; 0.2–75 : 27–17; 0.4–75 : 13–11; 0.8–75 : 25–12; 1.6–75 : 12–10.

Figure 2

Left ventricular ejection fraction (LVEF) values over time for all patients.

Figure 3

Mean asparagine–glycine–arginine–human tumour necrosis factor (NGR-hTNF) C_max (A) and doxorubicin AUC (B) during the first three cycles by dose level. Mean plasma concentrations of soluble TNF receptors tumour necrosis factor receptor I (TNF-RI) (C) and tumour necrosis factor receptor II (TNF-RII) (D) during the first cycle by dose level. Abbreviations: C_max, maximal plasma concentration; AUC, area under the plasma concentration vs time curve up to the last detectable concentration.

Figure 4

Waterfall diagram showing maximal changes of target lesions by dose levels (A) and progression-free survival (PFS) durations while on the previous regimen and on the current study treatment (B).