Clinical trial NCT00878111: Study of NGR-hTNF Administered at High Doses in Patient With Advanced or Metastatic Solid Tumour
Official title: NGR013: Phase I and Pharmacodynamic Study of NGR-hTNF Administered at High Doses in Patients With Advanced or Metastatic Solid Tumour
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Solid Tumors
Keywords: NGR-hTNF
Solid tumours
High doses
Lead sponsor: AGC Biologics S.p.A.
Sponsor class: INDUSTRY
First posted: 2009-04-08
Enrollment: 48
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Optimal Biologic Dose (OBD)
timeFrame: Before treatment, every 3-6 weeks and at the end of treatment
Secondary outcomes:
measure: Pharmacokinetic
timeFrame: Several time points after 1st, 2nd and 3rd administration
measure: Preliminary antitumor activity
timeFrame: Every 6 weeks
Other outcomes:
Locations:
city: Rozzano
country: Italy
facility: Istituto Clinico Humanitas
state: Milan
Study officials:
affiliation: AGC Biologics S.p.A.
name: Antonio Lambiase, MD
role: STUDY_DIRECTOR
References: