Phase II study of NGR-hTNF, a selective vascular targeting agent, in patients with metastatic colorectal cancer after failure of standard therapy
Introduction
Tumour necrosis factor (TNF) was originally identified for its ability to induce powerful antivascular effects, mainly mediated by apoptosis of tumour endothelial cells, even though this cytokine binds unselectively to tumour vasculature.1 Disappointingly, the systemic administration of recombinant human TNF was associated with severe toxicity and the maximum tolerated dose (MTD) resulted 10-fold lower than the estimated effective dose.2, 3, 4, 5, 6, 7, 8 To mitigate this toxicity, the isolated limb perfusion was employed to deliver loco-regionally high doses of TNF combined with chemotherapy, with elevated response rates reported in melanoma and sarcoma patients.9, 10, 11, 12
In order to selectively target TNF to tumour vasculature, NGR-hTNF was prepared by exploiting a ligand-directed approach, with recombinant human TNF fused with the tumour-homing peptide Asp-Gly-Arg (NGR). This peptide is able to specifically bind an aminopeptidase N/CD13 isoform overexpressed by endothelial cells of tumour vessels and its specific binding to the tumour neovasculature has been proven in several tumour types.13, 14, 15, 16 Recently, a CD13-null mice model confirmed that aminopeptidase N activity is crucial for the pathological development of newly formed blood vessels from pre-existing blood vessels.17
NGR-TNF induced antitumour activity at least 10-fold stronger than TNF in murine models and, interestingly, displayed antitumour effects even when delivered at very low doses in the nanogram range (0.005 μg/kg),13, 18 equivalent in humans to a dose of 0.2 μg/m2, which was the selected starting dose of phase I trial.
The early-stage clinical development of NGR-hTNF was based on two dose-defining studies. A phase I study evaluating a wide-ranging dose interval from 0.2 to 60 μg/m2 established the MTD of NGR-hTNF as 45 μg/m2 once every 3 weeks.19 In an additional trial aiming to further explore the low-dose range, 0.8 μg/m2 every 3 weeks was selected as the optimal biological dose based on a combination of dynamic imaging changes, soluble TNF receptor kinetics, tolerability and preliminary activity.20 In the latter study the antivascular effect of NGR-hTNF was confirmed by using dynamic contrast-enhanced magnetic resonance imaging. Interestingly, the decrease in tumour vascularity significantly correlated with radiologically assessed disease stabilisation, and a CRC patient previously refractory to three prior regimens experienced an 18-month PFS and then successfully underwent radical metastasectomy of a 30-cm large abdominal mass.20 Considering the apparent similar activity and good tolerability, the low dose was chosen to be explored in phase II studies.
Despite the recent advances in the treatment of metastatic CRC, which include irinotecan- or oxaliplatin-based front-line regimens and increasing use of targeted agents, most patients develop resistance to these therapies.
Recently, two monoclonal antibodies targeting the epidermal growth factor receptor (EGFR) have shown in two large phase III trials to be more effective than supportive care alone in unselected chemorefractory CRC patients.21, 22 However, the benefits of these antibodies were almost entirely limited to patients whose tumours lacked KRAS mutation.23 Moreover, chemorefractory metastatic CRC is a highly aggressive disease, as revealed by median survivals of 4–6 months reported in patients randomly assigned to receive supportive care only in the two aforementioned phase III trials.21, 22 Therefore, new treatment options are needed to continue the significant progress that has been made in this decade.
Here, we report a phase II study evaluating the activity and safety of NGR-hTNF given as single agent at 0.8 μg/m2 in patients with metastatic CRC resistant or refractory to standard therapies, including biological agents.
Section snippets
Eligibility criteria
Eligible patients had histologically proven CRC and received prior treatment with irinotecan, oxaliplatin and fluoropyrimidine, given in any combination or sequence in the adjuvant or advanced disease settings. Patients could also have received treatment with biological agents. Evidence of resistance to prior treatment was required at the study entry and was defined by radiologically documented progressive disease. Other inclusion criteria were the following: an age of 18 years or older; an
Patients
Globally, 33 patients were enrolled. Patient demographics, baseline characteristics and prior treatments are listed in Table 1. All patients had radiologically documented PD at study entry and had received prior therapy with irinotecan, oxaliplatin and fluoropyrimidine. Twenty-two patients (66.7%) were also pretreated with at least one targeted agent, including cetuximab (n = 18), bevacizumab (n = 3), gefitinib (n = 1), while 11 (33.3%) had been pretreated with chemotherapy only. At baseline,
Discussion
The patient population enrolled in the current multicentre study had been heavily pretreated with a median of three prior chemotherapy lines. Additionally, the majority of patients had previously received also a targeted agent and half of patients presented at baseline three or more CTCs, which is an independent predictor of poor prognosis in metastatic CRC patients, regardless of therapy line.24
NGR-hTNF given as single agent at low dose was extremely well tolerated showing an easily manageable
Conflict of interest statement
None declared.
Acknowledgement
This trial was sponsored by MolMed, Milan, Italy.
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These authors contributed equally.