Solid Tumors
Conditions
Keywords
NGR-hTNF, Solid tumours, High doses
Brief 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).
Detailed description
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.
Interventions
DRUGNGR-hTNF
First cohort: iv q3W 60 mcg/sqm over 120 min\* Second cohort: iv q3W 80 mcg/sqm over 120 min\* Third cohort: iv q3W 100 mcg/sqm over 120 min\* Fourth cohort: iv q3W 125 mcg/sqm over 120 min\* Fifth cohort: iv q3W 150 mcg/sqm over 120 min\* Sixth cohort: iv q3W 175 mcg/sqm over 120 min\* Seventh cohort: iv q3W 200 mcg/sqm over 120 min\* Eighth cohort: iv q3W 225 mcg/sqm over 120 min\* Ninth cohort: iv q3w 250 mcg/sqm over 120 min\* Tenth cohort: iv q3w 275 mcg/sqm over 120 min\* Eleventh cohort: iv q3w 300 mcg/sqm over 120 min\* Twelfth cohort: iv q3w 325 mcg/sqm over 120 min\* \* If the first infusion is well-tolerated, the second infusion may be delivered over 90 minutes. If the 90-minute infusion is well tolerated, all subsequent infusions may be delivered over a 60-minute period.
Sponsors
AGC Biologics S.p.A.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Optimal Biologic Dose (OBD) | Before treatment, every 3-6 weeks and at the end of treatment | Evaluating both the safety in terms of maximum tolerated dose (MTD) and the antivascular effect in terms of changes documented with dynamic imaging (DCE-MRI) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetic | Several time points after 1st, 2nd and 3rd administration | Evaluation of plasma levels of sTNF-RI and sTNF-RII and anti-NGR-hTNF antibodies |
| Preliminary antitumor activity | Every 6 weeks | In terms of objective response rate according to RECIST criteria, progression-free and overall survival. |
Countries
Italy
Outcome results
None listed