Phase I/II trial of cilengitide with cetuximab, cisplatin and 5-fluorouracil in recurrent and/or metastatic squamous cell cancer of the head and neck: findings of the phase I part

Abstract

Background:Novel therapies are needed to improve the poor prognosis of patients with recurrent and/or metastatic squamous cell cancer of the head and neck (SCCHN).Methods:ADVANTAGE is a phase I/II, multicentre study evaluating the integrin inhibitor cilengitide combined with cetuximab and platinum-based chemotherapy in patients with recurrent and/or metastatic SCCHN. The phase I part tested cilengitide (500, 1000 and 2000 mg) twice weekly with standard doses of cetuximab, cisplatin and 5-fluorouracil.Results:Ten patients (9 male, 1 female; median 56 years old) were included in the phase I part. No dose-limiting toxicities (DLTs: grade 3/4 toxicities in the first 3 weeks as defined per protocol) or deaths occurred. The most common adverse events (AEs) were constipation, rash, nausea, anorexia and fatigue. Cilengitide-related grade 3/4 AEs, all of which occurred after the DLT observation period, were anaemia, angioedema, asthenia, mucosal inflammation, nausea and vomiting (one event per category). Best overall tumour response was partial response (PR) for 4 out of 10 patients and stable disease (SD) for 6 out of 10 patients across all cohorts. Disease control rate (complete response, PR and SD) was 100%.Conclusion:Cilengitide combined with cetuximab and platinum-based chemotherapy was well tolerated. No DLTs or unexpected AEs were observed. Cilengitide 2000 mg was considered safe and was selected for the subsequent randomised phase II part assessing progression-free survival.

Focal adhesion complex proteins in epidermis and squamous cell carcinoma

“…112 Treatment of patients with squamous cell carcinomas of the head and neck with cilengitide resulted in partial response or stable disease for all patients tested, and randomized phase II clinical trials are currently in progress. 113 More recently, it was shown that low concentrations of this inhibitor actually stimulate tumor growth by promoting VEGFR-2 trafficking to the endothelial cell surface. 114 It is therefore possible that dose of the drug is highly important in tumor response, which could account for some of the variability seen thus far.…”

The physiology of cardiovascular disease and innovative liposomal platforms for therapy

“…Examples of targeting biomarkers include α V β 3 and α V β 5 integrins, overexpressed on tumor microcapillary endothelial cells. 61 The arginine-glycine-aspartic acid (RGD) tripeptide binds to α V β 3 and α V β 5 integrins, providing a ligand frequently used to target nanoparticles to the tumor. 61 In cardiovascular disease, each stage of the disease presents novel biomarkers and tissue architecture that can be exploited for targeting, akin to cancer.…”

“…61 The arginine-glycine-aspartic acid (RGD) tripeptide binds to α V β 3 and α V β 5 integrins, providing a ligand frequently used to target nanoparticles to the tumor. 61 In cardiovascular disease, each stage of the disease presents novel biomarkers and tissue architecture that can be exploited for targeting, akin to cancer. As an example, myocardial infarction causes blood vessels in the left ventricle to become leaky, potentially favoring nanoparticle penetration into the tissue.…”

Cardiac Protection with Targeted Drug Delivery to Ischemic-Reperfused Myocardium

“…The peptides can bind to target molecule with very high specificity and affinity. For instance, cyclic peptide cilengitide, an integrintargeting RGD peptide, is currently being tested in the phase I/II clinical trial for therapy of recurrent and/or metastatic squamous cell cancer of the head and neck (Vermorken et al, 2011).…”