Study of NGR-hTNF Administered at High Doses in Patient With Advanced or Metastatic Solid Tumour

Pre-clinical studies provide the support that NGR-TNF is endowed with a higher therapeutic index in animal models and studies of the mechanism of action showed that NGR-TNF can induce tumour necrosis when used at relatively high doses.

Recently, a phase I dose-escalation study of NGR-hTNF has explored the dose range between 0.2 and 60 µg/m2, showing DLT at 60 mcg/m2 experienced as transient acute infusion reaction few minutes after the first administration start. Considering the relationship with the infusion of these events, a further dose escalation will be explored in the present phase I study by using both a longer infusion time (i.e., 120 minutes instead of 60 minutes) and a mild premedication.

The first cohort (n=4) of patients will be treated with NGR-hTNF administered at 60 mcg/m2 IV every three weeks, that is a dose level 33% higher than MTD and recommended dose selected in the previous phase I trial (i.e., 45 mcg/m2). If ≤1 of 4 patients experience DLT during the first cycle, following cohorts will be treated with escalating doses (from 80 to 325 mcg/m2) of NGR-hTNF IV every three weeks.

Inclusion criteria

• Patients ≥18 years with selected metastatic solid tumours recognized to be highly vascularised and not amenable to any clinical improvement by current standard treatments

• Colorectal cancer (CRC) patients previously resistant to standard systemic regimens (including biologic agents)
• Gastric cancer (GC) patients treated with no more than two standard systemic regimens for metastatic disease
• Hepatocellular carcinoma (HCC) patients previously resistant to standard systemic regimens
• Pancreatic carcinoma (PC) patients treated with no more than one standard systemic regimen for metastatic disease
• Non small cell lung carcinoma (NSCLC) patients treated with no more than two standard systemic regimens (including biologic agents) for metastatic disease
• Neuroendocrine (NE) tumours refractory to somatostatin analogue treatment
• Other rare tumours including malignant pleural mesothelioma (MPM), soft-tissue sarcoma (STS), and renal cell carcinoma (RCC), resistant/refractory to current standard treatments
• Life expectancy more than 3 months
• ECOG Performance status 0-1
• Adequate baseline bone marrow, hepatic and renal function, defined as follows:

• Neutrophils >1.5 x 10^9/L and platelets > 100 x 10^9/L
• Bilirubin <1.5 x ULN
• AST and/or ALT <2.5 x ULN in absence of liver metastasis
• AST and/or ALT <5 x ULN in presence of liver metastasis
• Serum creatinine <1.5 x ULN
• Creatinine clearance (estimated according to Cockcroft-Gault formula) ≥ 50 ml/min
• Patients may have had prior therapy providing the following conditions are met before treatment start:

• Chemotherapy, radiation therapy, hormonal therapy, or immunotherapy: wash-out period of 28 days
• Surgery: wash-out period of 14 days
• Patients must give written informed consent to participate in the study.

Exclusion criteria

• Concurrent anticancer therapy
• Patients must not receive any other investigational agents while on study
• Patients with myocardial infarction within the last six (6) months, unstable angina, New York Heart Association (NYHA) grade II or greater congestive heart failure, or serious cardiac arrhythmia requiring medication
• Uncontrolled hypertension
• Prolonged QTc interval (congenital or acquired) > 450 ms
• Patient with significant peripheral vascular disease
• History or evidence upon physical examination of CNS disease unless adequately treated (e.g., primary brain tumor, any brain metastasis, seizure not controlled with standard medical therapy), or history of stroke
• Patients with active or uncontrolled systemic disease/infections or with serious illness or medical conditions, which is incompatible with the protocol
• Known hypersensitivity/allergic reaction or contraindications to human albumin preparations or to any of the excipients
• Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol
• Pregnancy or lactation. Patients - both males and females - with reproductive potential (i.e. menopausal for less than 1-year and not surgically sterilized) must practice effective contraceptive measures throughout the study. Women of child-bearing potential must provide a negative pregnancy test (serum or urine) within 14 days prior to registration.