Phase II study of NGR-hTNF, a novel vascular targeting agent (VTA), administered as single agent at low dose in patients with colorectal cancer refractory to standard regimens

Background: NGR-hTNF is a VTA exploiting a tumor-homing peptide (NGR) that selectively binds to aminopeptidase N/CD13 highly expressed on tumor blood vessels. NGR-hTNF combines activity on tumour vascular permeability and direct anticancer activity. In preclinical models, NGR-hTNF showed antitumor activity at both low and high doses. Methods: Pts with CRC refractory to standard treatments, including biological agents, were enrolled to evaluate a low dose of NGR-hTNF given at 0.8 μg/m2 as 1-hour intravenous infusion every 3 weeks (q3w). This phase II trial had a 2-stage design with 16 and 27 pts to be enrolled in stage 1 and 2, respectively. Progression-free survival (PFS) was the primary end point and reassessment was performed q6w. Results: 32 pts (16 M/16 F; PS 0/1 26/6; median age: 65 years, range 53-79) received 111 cycles (median 2, range 1-10) and 13 pts (41%) were treated with ≥4 doses. The median number of prior regimens was 3 (range: 2-5), with 8 pts (25%) pre-treated with ≥4 lines. In the first stage, one pt (6%) achieved a confirmed partial response lasting 5 months and 9/16 pts (56%) had a stable disease (SD). The median and 3-month PFS were 2.9 months (95% CI 1.93.9) and 47% (95% CI 21-71%), respectively. After completion of the second stage, a total of 4 pts were progression-free at 4.5 months, with one pt still on treatment after 7 months. Neither grade 3-4 treatment-related adverse events nor toxicityrelated death were observed. Main grade 1-2 toxicities per patient were infusionrelated chills (41%) and transient blood pressure increase (9%). The study is currently recruiting patients into a subsequent cohort of 12 patients treated with a weekly schedule of administration. Conclusions: Based on the favourable and manageable toxicity profile and preliminary evidence of activity in heavily pretreated CRC patients, NGR-hTNF will be further developed both as single agent and in combination with standard chemotherapeutics. A large number of preclinical studies have shown that tumor necrosis factor-alpha (TNF-α) has potent antitumor activity. However, its clinical use has been hampered by severe systemic toxicity, with MTD significantly lower than ED in humans1. The antivascular effects of TNF-α provided the rationale for developing a vascular targeting strategy aimed at increasing the local antitumor activity and at enabling systemic administration of therapeutic doses. NGR-hTNF is a novel therapeutic vascular targeting agent (VTA) that has been genetically engineered by coupling the N-terminus of human TNF-α with the C-terminus of the tumor-homing peptide Cys-Asn-Gly-Arg-Cys (NGR) (Figure 1). The cell surface receptor for the NGR-containing peptide is a CD13/aminopeptidase N (APN) isoform selectively expressed by endothelial cells of newly formed human tumor vessels,2-4 including colorectal cancer (Figure 2). Recently, in an APN-null mice model was shown that although aminopeptidase N activity is not essential for embryonic and fetal development including de novo blood vessel formation and normal adult function, it is critical for the pathological development of new blood vessels from existing blood vessels in disease.5 65 (53-79) Median age, years (range) 17 (59) 12 (41) Circulating tumor cells (CTC) 18 years old • Prior treatment with fluoropyrimidine, oxaliplatin and irinotecan based regimens (including combination with biological agents) • Patients with radiological documented progressive disease at study entry • ECOG Performance Status 0-1 • Adequate baseline bone marrow, hepatic and renal function. Normal cardiac function and absence of uncontrolled hypertension • No clinical signs of CNS involvement • Written informed consent to participate in the study