study of ngr-htnf administered at high doses in patient with advanced or metastatic solid tumour

Conditions: Solid Tumors

Summary: the main objective of the trial is to document the safety and antivascular effect of escalating doses of ngr-htnf, from 60 mcg/sqm to 325 mcg/sqm, in patients affected by advanced or metastatic solid tumors not amenable of standard therapies. safety will be established by clinical and laboratory assessment according to nci-ctcae criteria (version 4.02).

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.

Eligibility criteria:
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.

Keywords: ngr-htnf solid tumours high doses