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Title: Is NGR-TNF Effective in Patients with Refractory Solid Tumours? Presented at AACR-NCI-EORTC

"Is NGR-TNF Effective in Patients with Refractory Solid Tumours? Presented at AACR-NCI-EORTC"

By Crina Frincu-Mallos, PhD SAN FRANCISCO, CA -- November 6, 2007 -- NGR-TNF, a vascular targeting agent, binds specifically to receptors expressed by tumour vessels, but not by normal vessels. The drug is expected to combine activity on tumour vasculature permeability with an anti-tumour effect, according to research reported here at the 2007 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics. An update of this study presented earlier this year at the annual meeting of the American Society of Clinical Oncology (ASCO) was given by Carla M. Van Herpen, MD, PhD, Department of Medical Oncology, UMC Nijmegen, the Netherlands, on behalf of the EORTC New Drug Development Group, a team of researchers from the Netherlands, Germany, Belgium, and Italy. To date in this phase 1 trial, 70 patients with refractory solid tumours, male to female ratio 46:24, median age 60 years (range, 34 to 79 years) have been enrolled. The most common tumour types were head and neck cancer, melanoma, lung cancer, and gastrointestinal cancer. The investigational agent was given intravenously once every 3 weeks, by 20 minute infusion up to dose level 5, when the infusion time was extended to 1 hour. The study design used a 0.2 mcg/m[² starting dose. Dose escalation was performed by doubling the precedent dose, until the occurrence of a grade 2 adverse event (AE).

To date, 59 patients underwent 171 cycles with NGR-TNF with 58% receiving 2 cycles of treatment.

In order to investigate NGR-TNF toxicities at different dose levels, the patients went through 3 phases, an accelerated phase, a pre-DLT phase, and a DLT phase.

Initially, in case of a dose-limiting toxicity (DLT), the next dose level was chosen applying the continual reassessment method (CRM).

However, starting at 1.95 mcg/m²dose level, the CRM model was replaced by amendment with a "Scheme 3+3", due to the occurrence of multiple DLTs.

In addition to the one DLT reported at ASCO (a grade 3 bronchospasm observed in one patient) this update presents three more DLTs.

At 8.1 mcg/m²dose level, one patient experienced a grade 3 abdominal pain and hypotension DLT. Two DLTs occurred at dose level 60 mcg/m²-- a grade 3 dyspnoea and fever and a grade 3 hypoxia and fever plus a grade 2 rapid shift hypotension-hypertension.

Due to the several DLTs, Dr. Van Herpen and colleagues decided to re-open dose level 16 and evaluate the toxicity of the investigational agent in nine patients.

The investigators report that no DLTs were observed in patients evaluated at 45 mcg/m² NGR-TNF dose level and hence, this is the recommended phase 2 dose.

Dr. Van Herpen and colleagues added that no grade 3 or 4 haematological toxicities were observed in the 59 evaluable patients on trial. Most of the drug-related AEs experienced by patients were mild-to-moderate, and consisted mostly in fever and rigors/chills.

However, only eight patients remain on trial at the time of the presentation, the rest having to discontinue the use of the investigational agent due to disease progression, said Dr. Van Herpen and colleagues.

The investigators were also interested in collecting and analyzing pharmacodynamic data, using delayed contrast-enhancement (DCE) MRI at baseline and 2-hours after the first infusion. At the tested doses, say Dr. van Herpen and colleagues, NGR-TNF was shown to increase vascular permeability up to 1.3 mcg/m²dose level, since both K_trans and K_ep increased with drug infusion. No significant changes in the K_trans and K_ep were by DCE-MRI seen in normal tissue, commented the investigators.

This on-going study is supported by MolMed, Milan, Italy.

[Presentation title: A biological and pharmacologic phase I study of NGR-TNF, a novel vascular targeting agent, in patients with refractory solid tumors (EORTC Protocol 16041). Abstract B78]

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