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

This study is ongoing, but not recruiting participants.
Information provided by (Responsible Party):
MolMed S.p.A. Identifier:
First received: April 7, 2009
Last updated: October 8, 2015
Last verified: October 2015

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).

Condition Intervention Phase
Solid Tumors
Drug: NGR-hTNF
Phase 1

Study Type: Interventional
Study Design: 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

Further study details as provided by MolMed S.p.A.:

Primary Outcome Measures:
  • Optimal Biologic Dose (OBD) [ Time Frame: Before treatment, every 3-6 wks and 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 Outcome Measures:
  • Pharmacokinetic [ Time Frame: Several time points after 1^st, 2^nd and 3^rd administration ]
    Evaluation of plasma levels of sTNF-RI and sTNF-RII and anti-NGR-hTNF antibodies

  • Preliminary antitumor activity [ Time Frame: Every 6 wks ]
    In terms of objective response rate according to RECIST criteria, progression-free and overall survival.

Estimated Enrollment: 48
Study Start Date: April 2009
Estimated Study Completion Date: June 2016
Estimated Primary Completion Date: June 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: A: escalating dose levels of NGR-hTNF
NGR-hTNF administered at high doses
Drug: 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.

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.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts 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.
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Please refer to this study by its identifier: NCT00878111

Istituto Clinico Humanitas
Rozzano, Milan, Italy, 20089
Sponsors and Collaborators
MolMed S.p.A.
Study Director: Antonio Lambiase, MD MolMed S.p.A.
  More Information

Responsible Party: MolMed S.p.A. Identifier: NCT00878111     History of Changes
Other Study ID Numbers: NGR013
2008-000816-33 ( EudraCT Number )
Study First Received: April 7, 2009
Last Updated: October 8, 2015

Keywords provided by MolMed S.p.A.:
Solid tumours
High doses processed this record on March 24, 2017