Optimal safety profile and anticancer activity of NGRhTNF coupled with doxorubicin (NGR003 modified phase I combo trial)

Abstract

14056 Background: NGRhTNF is a vascular targeting agent (VTA) exploiting a tumour homing peptide (CNGRCG) selectively binding angiogenic vessels in solid tumors, where NGRhTNF specific binding relies on dynamic interactions with TNF-receptors and aminopeptidase N (CD13). NGRhTNF combines activity on tumour vascular permeability and direct anticancer activity. At low dose, NGRhTNF increases tumour vascular permeability. Consistently, mouse preclinical data indicate significant synergy between low dose NGRhTNF and cytotoxic agents. Thus, we tested NGRhTNF in combination with doxorubicin. Methods: 4 doses of NGRhTNF (0.2, 0.4, 0.8 and 1.6 μg/m2) in combination with doxorubicin (75 mg/m2) have been administered every 3 weeks in 15 patients.Main end- points included safety, anticancer activity and pharmacokinetic. Measurement of circulating tumour (CTC) and endothelial cells, sTNF receptors, along with plasma chemokine profile are being performed. Results: All patients were enrolled (5F/10M). Toxicity was limited to constitutional symptoms, most frequently chills. After a median follow-up of 12 weeks (range 3–28), 5 episodes of chills (1 grade I and 4 grade II) were reported in 4/15 patients.One episode of grade I hypertension was reported. Of note, the toxicity profile commonly-associated to doxorubicin has not been exacerbated. Stabilization of disease occurred in 10/15 patients lasting 13 weeks (range 6–28 with 5 patients still ongoing at December 2006). In addition, partial response was achieved in 2 patients, lasting 23 and 14 (still ongoing) weeks, respectively. It is worth noting that anticancer activity was observed in 12/15 patients of whom 9 had previously received anthracycline-containing regimens and 5 were anthracycline-resistant suggesting a role of NGRhTNF in inducing tumour sensitivity to doxorubicin. Finally, changes in CTC levels over time consistently matched the clinical outcome. Conclusions: Coupling NGRhTNF with doxorubicin induced anticancer activity along with an optimal safety profile in pretreated patients providing support for the phase II combination studies addressing diseases suitable for anthracycline treatment such as sarcoma and ovarian cancer, and planned to start in early 2007. No significant financial relationships to disclose.