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Merck at ASCO 2007: Encouraging Results in Progression-Free,Survival in Patients With Aggressive Brain Tumors (glioblastoma),Using Cilengitide in Phase I/IIa Study

Phase III trial planned
Abstracts: 2000, 2002

CHICAGO/DARMSTADT, Germany, June 4, 2007 – Results of a Phase I/IIa study presented today at the American Society of Clinical Oncology (ASCO) annual meeting in Chicago demonstrate the clinical activity of cilengitide in patients with newly diagnosed glioblastoma – a particularly aggressive form of brain tumor. Cilengitide is a highly selective integrin inhibitor targeting the tumor and its vasculature.

Fifty-two patients with newly diagnosed glioblastoma were treated with cilengitide, combined with a standard regimen of radiotherapy and temozolomide following tumor resection or biopsy. The study reached the predefined primary endpoint with 69% of patients being alive and progression free at six months, and showed a median progression free survival (PFS) of 8.1 months. In a defined patient subgroup with the methylated MGMT gene promoter in the tumor tissue, 91% of patients had six months PFS and the median has not yet been reached. These results are encouraging when compared to the historical control of the EORTC-NCIC phase III trial [overall population: 54% 6 months PFS, median PFS of 6.9 months;(1) methylated MGMT gene promoter subgroup: 69% PFS and 10.3 months median PFS].(2)

Lead investigator Dr. Roger Stupp of the University of Lausanne Hospital in Switzerland, commented: “We are excited by these findings. They demonstrate the potential of cilengitide to make a real difference to the outcome of patients with this aggressive type of brain cancer, where currently available treatment options are limited and prognosis is poor. We look forward to learning more about the benefits of this promising agent in larger patient populations.”

Also presented at ASCO was a Phase IIa randomized multicenter trial, examining two dosing levels of cilengitide monotherapy (500mg and 2000mg) in 81 patients with recurrent gliobl astoma. Following surgery or biopsy, more than 98% of these patients had previously been treated with radiotherapy and temozolomide and had relapsed on these treatments. The PFS rate was 16% and 10% at six and 12 months, respectively. While the target of 25% of patients being progression free at six months was not met, there was a subset of patients with very clear and prolonged clinical response, which indicated biological activity. Durable significant responses have been observed with stabilization so far for up to two years. The observed median overall survival was 6.5 months with the low dose and 9.9 months with the high dose of cilengitide. These results are encouraging considering the limited treatment options for recurrent glioblastoma patients.

“These results of cilengitide in glioblastoma – a very difficult to treat tumor – are important. New highly active, well-tolerated targeted therapies inducing significant responses are strongly needed. Based on these results, we are planning a Phase III trial to investigate the benefits of cilengitide in glioblastoma in a larger confirmatory trial,” said Dr. Wolfgang Wein, Senior Executive Vice President, Oncology, Merck Serono – a division of Merck KGaA, Darmstadt, Germany.

“Cilengitide is part of the Merck Serono Oncology portfolio – led by the epidermal growth factor receptor-targeting monoclonal antibody Erbitux® – and the clinical programs for these investigational products demonstrate Merck Serono’s commitment to developing new treatment options for patients with cancer,” Dr. Wein stated.

There are 189,000 new cases of cancers of the brain and nervous system globally each year, and 142,000 deaths. This accounts for 1.7% of new cancers and 2.1% of cancer deaths.(3) Brain tumors account for as many as 90% of all primary central nervous system tumors.(4) The commonest type of primary brain tumor is glioma, accounting for 80% of all malignant brain tumors. Of these, 50% are glioblastomas, the most aggressive type of brain tumor.

Average survival time for newly diagnosed glioblastoma patients receiving the current best available treatment is only 12-15 months.(1) Glioblastomas currently have a near 80% mortality rate within two years, irrespective of the treatment. It is therefore essential that novel treatment options and in particular, targeted therapies such as cilengitide, are investigated.

About the studies
Study 1 (newly diagnosed glioblastoma) is a multicenter, open-label, uncontrolled Phase I/IIa study investigating cilengitide and temozolomide with concomitant radiotherapy, followed by temozolomide and cilengitide maintenance therapy in patients with newly diagnosed glioblastoma. After tumor resection or biopsy, patients were treated with standard temozolomide and radiotherapy. In addition, cilengitide (500mg, iv, twice per week) was started one week before temozolomide and radiotherapy and given throughout for the duration of chemotherapy or until disease progression. The primary endpoint was progression-free survival at six months. The study was conducted at 16 centers in Germany, Switzerland and Belgium.

Study 2 (recurrent glioblastoma) is a multicenter, open-label, randomized, uncontrolled Phase IIa study investigating cilengitide as a single agent in patients with recurrent glioblastoma. Patients were randomized to receive either 500mg or 2000mg of iv cilengitide twice per week until disease progression. The primary endpoint was progression-free survival at six months. The secondary endpoints included response rate, survival, time to disease progression, safety, tolerability and pharmacokinetics. The study was carried out at 15 centers in the US.

About cilengitide
Cilengitide was developed by Merck. It is the first in a new class of targeted anti-cancer therapies in glioblastoma – known as integrin inhibitors – that are thought t o work by targeting the tumor and its vasculature.

Integrins are cell surface receptors that are improperly regulated in many cancer types which 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 KGaA-initiated studies, the U.S. 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. An initial Phase I/II study in adult high-grade glioma (including glioblastoma) patients showed encouraging results.(5) Seven NCI-sponsored studies with cilengitide monotherapy in various tumor types, including newly diagnosed glioblastoma, recurrent glioblastoma in adults and recurrent brain tumors in children are currently ongoing. An additional NCI sponsored Phase II trial combining cilengitide with radiotherapy and temozolomide in patients newly diagnosed with glioblastoma is also ongoing.

Merck KGaA 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 KGaA, Darmstadt, Germany, licensed the right to market Erbitux outside the US and Canada from ImClone Systems Incorporated of New York in 1998. In Japan, Merck KGaA has co-exclusive marketing rights with ImClone Systems. Merck KGaA 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 KGaA is also investigating among other cancer treatments the use of Stimuvax® (formerly referred to as BLP25 Li posome 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 Biomira Inc. of Edmonton, Alberta, Canada, with the exception of Canada where the companies share rights.

1. Stupp et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005; 352:987-996.
2. Hegi et al., MGMT gene silencing and benefit from temozolomide in glioblastoma. NEJM 2005; 352(10):997-1003.
3. Max Parkin et al. Global Cancer Statistics, 2002. CA Cancer J Clin 2005; 55:74-108.
4. Levin et al. Neoplasms of the central nervous system. In DeVita VT Jr, Hellman S, Rosenberg SA, eds: Cancer: Principles and Practice of Oncology. 6th ed. Philadelphia, Pa: Lipponcott Williams & Wilkens 2001; 2100-2160.
5. Nabors et al. Phase I and Correlative Biology Study of Cilengitide in Patients with Recurrent Malignant Glioma. J Clin Oncol 2007; 25: 1651-1657.

Merck is a global pharmaceutical and chemical company with sales of EUR 6.3 billion in 2006, a history that began in 1668, and a future shaped by 35,091 employees in 62 countries. Its success is characterized by innovations from entrepreneurial employees. Merck's operating activities come under the umbrella of Merck KGaA, in which the Merck family holds an approximately 70% interest and free shareholders own the remaining approximately 30%. In 1917 the U.S. subsidiary Merck & Co. was expropriated and has been an independent company ever since.


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