Study of NGR-hTNF Administered at High Doses in Patient With Advanced or Metastatic Solid Tumour
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).
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||NGR013: Phase I and Pharmacodynamic Study of NGR-hTNF Administered at High Doses in Patients With Advanced or Metastatic Solid Tumour|
- Optimal Biologic Dose (OBD) [ Time Frame: Before treatment, every 3-6 wks and end of treatment ] [ Designated as safety issue: Yes ]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)
- Pharmacokinetic [ Time Frame: Several time points after 1^st, 2^nd and 3^rd administration ] [ Designated as safety issue: Yes ]Evaluation of plasma levels of sTNF-RI and sTNF-RII and anti-NGR-hTNF antibodies
- Preliminary antitumor activity [ Time Frame: Every 6 wks ] [ Designated as safety issue: No ]In terms of objective response rate according to RECIST criteria, progression-free and overall survival.
|Study Start Date:||April 2009|
|Estimated Study Completion Date:||June 2013|
|Estimated Primary Completion Date:||June 2013 (Final data collection date for primary outcome measure)|
|Experimental: A: escalating dose levels of NGR-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.
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.