Merck Serono announced the launch of its phase II clinical study CERTO, which will investigate the efficacy and safety of the novel combination of the investigational integrin inhibitor, cilengitide, and Erbitux (cetuximab), with cisplatin and either vinorelbine or gemcitabine, as 1st-line treatment for patients with advanced non-small cell lung cancer (NSCLC).

This study is a new addition to Merck Serono's global clinical development programme that is evaluating cilengitide in a number of cancer types with high unmet medical need. The clinical programme has been focusing on CENTRIC so far ? a phase III clinical trial in glioblastoma multiforme (GBM). It now also includes the recently started CORE trial in GBM and ADVANTAGE in squamous cell carcinoma of the head and neck (SCCHN). ADVANTAGE began enrolling patients in October 2008.

"Despite recent advances in NSCLC treatment, it remains a notoriously difficult-to-treat cancer with a poor prognosis," said Professor Johan F. Vansteenkiste from University Hospital Gasthuisberg, Leuven and Chair of the CERTO trial Steering Committee. "The combination of the selective integrin inhibitor cilengitide and the targeted agent Erbitux plus platinum-based chemotherapy, is being studied in NSCLC in the CERTO trial. The results of this trial will hopefully lead the way to even better outcomes for lung cancer patients."

"In previous trials, cilengitide has already shown clinical activity in GBM in combination with chemoradiation and as a single agent, with only rare incidents of grade 3 or 4 related toxicity. Cilengitide is now being tested in combination with Erbitux and standard chemotherapy in NSCLC," said Dr. Frank T. Weber, senior vice president and head of medical science and innovation at Merck Serono. "Combination is key for patients and these trials demonstrate our continued commitment to the development of novel anti-cancer therapies."

Cilengitide, developed in Merck's own laboratories, is the first in a new class of investigational anti-cancer therapies called integrin inhibitors to reach Phase III development. Integrin inhibitors target integrins - specific cell surface receptors that are improperly regulated in many tumor types and involved in cancer growth. Cilengitide is thought to work by targeting tumor cells directly and by preventing the formation of new blood vessels to the tumor, a process known as angiogenesis.1

CERTO is an exploratory phase II, multicenter, open-label, randomized, controlled study investigating two cilengitide regimens in combination with Erbitux and platinum-based chemotherapy (cisplatin/vinorelbine or cisplatin/gemcitabine) compared to Erbitux and platinum-based chemotherapy alone as 1st-line treatment for patients with advanced NSCLC.

CENTRIC is a phase III, multicenter, open-label, controlled study to assess the efficacy and safety of cilengitide in combination with standard chemotherapy (temozolomide, or TMZ) plus radiotherapy versus standard chemotherapy plus radiotherapy alone, in a specific subgroup of newly diagnosed patients with GBM. Patients recruited into the CENTRIC trial will have their tumor tissue screened for methylation of the MGMT (methylguanine-DNA methyltransferase) gene promoter. This gene promoter acts as a controlling element in the expression of MGMT, an enzyme which reduces the efficacy of the chemotherapy. The CENTRIC trial is being conducted in collaboration with the European Organization for Research and Treatment of Cancer (EORTC) and the Canadian Brain Tumour Consortium (CBTC).

CORE is an exploratory companion trial to CENTRIC evaluating cilengitide in GBM patients with unmethylated MGMT status. CORE is a Phase II, multicenter, open-label study investigating two cilengitide regimens in combination with standard treatment (temozolomide with concomitant radiation therapy, followed by temozolomide maintenance therapy).

ADVANTAGE is an exploratory phase II, open-label, randomized, controlled study of cilengitide investigating the combination of different regimens of cilengitide added to cisplatin, 5-FU and Erbitux in patients with recurrent/metastatic SCCHN.

Cilengitide is currently being developed by Merck KGaA. Cilengitide is the first in a new class of investigational anti-cancer therapies called integrin inhibitors to reach phase III of development; it is currently being investigated for the treatment of glioblastoma, SCCHN and NSCLC. Integrin inhibitors are thought to work by targeting the tumor and its vasculature.

Integrins are cell surface receptors that are improperly regulated in many cancer types. This lack of regulation enables them to enhance tumor growth, survival and invasiveness. Integrins are fundamental in the process of angiogenesis (blood vessel growth) - a process that is essential for tumors as it enables them to grow past a finite size.

In addition to the Merck-sponsored studies, the US National Cancer Institute (NCI) is sponsoring a number of clinical trials under a Cooperative Research and Development Agreement (CRADA) with Merck KGaA for the development of cilengitide.

Erbitux is a first-in-class and highly active IgG1 monoclonal antibody targeting the epidermal growth factor receptor (EGFR). As a monoclonal antibody, the mode of action of Erbitux is distinct from standard non-selective chemotherapy treatments in that it specifically targets and binds to the EGFR. This binding inhibits the activation of the receptor and the subsequent signal-transduction pathway, which results in reducing both the invasion of normal tissues by tumour cells and the spread of tumours to new sites. It is also believed to inhibit the ability of tumour cells to repair the damage caused by chemotherapy and radiotherapy and to inhibit the formation of new blood vessels inside tumours, which appears to lead to an overall suppression of tumour growth.

The most commonly reported side effect with Erbitux is an acne-like skin rash that seems to be correlated with a good response to therapy. In approximately 5 per cent of patients, hypersensitivity reactions may occur during treatment with Erbitux; about half of these reactions are severe.

Erbitux has already obtained market authorization in 76 countries. It has been approved for the treatment of colorectal cancer in 75 countries and for the treatment of squamous cell carcinoma of the head and neck (SCCHN) in 71 countries:

Merck licensed the right to market Erbitux outside the US and Canada from ImClone Systems, a wholly-owned subsidiary of Eli Lilly and Company, in 1998. In Japan, ImClone Systems, Bristol-Myers Squibb Company and Merck jointly develop and commercialize Erbitux. Merck has an ongoing commitment to the advancement of oncology treatment and is currently investigating novel therapies in highly targeted areas, such as the use of Erbitux in colorectal cancer, squamous cell carcinoma of the head and neck and non-small cell lung cancer. Merck has also acquired the rights for the cancer treatment UFT (tegafur-uracil) - an oral chemotherapy administered with folinic acid (FA) for the first-line treatment of metastatic colorectal cancer.

Merck is also investigating among other cancer treatments the use of Stimuvax (formerly referred to as BLP25 Liposome Vaccine) in the treatment of non-small cell lung cancer. The vaccine was granted fast-track status in September 2004 by the FDA. Merck obtained the exclusive worldwide licensing rights from Oncothyreon Inc., Bellevue, Washington, USA.