Merck KGaA: Study Shows Cilengitide Increased Overall Survival in Patients With Glioblastoma

• Data presented at ASCO support investigation of cilengitide in Phase III study, CENTRIC, for patients with newly diagnosed glioblastoma multiforme

Merck KGaA: Study Shows Cilengitide Increased Overall Survival in Patients With Glioblastoma

Results from an independent Phase II study of patients with newly diagnosed glioblastoma multiforme (GBM) show that cilengitide given in combination with chemoradiotherapy (concomitant and adjuvant temozolomide with radiotherapy) may extend survival.¹ These findings were presented at the annual meeting of the American Society of Clinical Oncology (ASCO) in Orlando.

Demonstrating the commitment of Merck KGaA, Darmstadt, Germany, to personalizing cancer care with innovative, targeted therapies, cilengitide is the first in a new class of investigational anti-cancer therapies called integrin inhibitors having reached Phase III development. These are thought to work by targeting tumor cells and the vascular network required to nourish the tumor and promote cancer cell growth.

The NABTT-0306 study, sponsored by the National Cancer Institute and run by the New Approaches to Brain Tumor Therapy (NABTT) Adult Brain Tumor Consortium, randomized 94 patients with newly diagnosed GBM to two different doses of cilengitide (500 or 2,000 mg) in combination with chemoradiotherapy to estimate overall survival as the primary endpoint. Secondary endpoints included progression-free survival and a safety assessment of this regimen. Prior to the randomized part of the study, a safety run-in phase involving 18 patients was completed as planned at 500, 1,000, and 2,000 mg dose levels.

The primary endpoint results demonstrated a trend towards increased overall survival in the 2,000 mg dose study arm compared to the 500 mg dose cilengitide study arm. Pooling together the results from both treatment arms, patients in this randomized study experienced a median survival time of 18.9 months (95% CI 16.6–21.9), with an overall survival rate at 12-month follow-up of 79.5% (95% CI 71–87).¹ In historical controls in this setting, median survival time and 12-month survival rate with chemoradiotherapy alone have been reported as 14.6 months and 61.1% (95% CI 55–67), respectively.²

“We are encouraged by these results. Glioblastoma is a highly aggressive and challenging cancer type with very poor prognosis and we urgently need to explore new treatment options, such as cilengitide, in Phase III studies to offer real improvements in outcomes,” commented lead study investigator, Professor Burt Nabors, Professor of Neurology at the University of Alabama, Birmingham, USA.

These findings add to existing evidence of cilengitide’s clinical activity and tolerability from previous trials in GBM, both as a single agent and in combination with chemoradiotherapy, with only rare incidents of grade 3 or 4 drug-related toxicity.^3-9 On the basis of these results, cilengitide is being investigated further in the Phase III study, CENTRIC^a and Phase II study, CORE^b .

“We are united with the glioblastoma community in exploring the potential of cilengitide for patients with this devastating disease and, as part of our overall aim of personalizing cancer care for all patients, we remain committed to the ongoing development of cilengitide as a combination therapy in GBM and other cancer types,” said Dr Wolfgang Wein, Executive Vice President, Oncology, Merck KGaA.

Cilengitide development program in GBM

a. 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 assessed 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 Organisation for Research and Treatment of Cancer (EORTC) and the Canadian Brain Tumour Consortium (CBTC).

b. 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 radiotherapy, followed by temozolomide maintenance therapy).

Burden of disease

• Every year, there are 189,000 new cases of cancer of the brain and nervous system globally and 142,000 deaths¹⁰
• GBM is the most aggressive form of primary brain tumor. Despite advances in imaging techniques and currently best available treatments, more than 70% of patients die within 2 years⁷

For more information on these studies log on to www.clinicaltrials.gov .

References

1. Nabors LB, et al. ASCO Congress 2009; Abstract No: 2001. Updated information presented at meeting.

2. Stupp R, et al. N Engl J Med 2005;352:987-96.

3. Stupp R, et al. ASCO Annual Meeting 2007; Abstract No: 2000.

4. Reardon DA, et al. J Clin Oncol 2008;26(34):5610-7.

5. Nabors LB, et al. J Clin Oncol 2007;25(13):1651-7.

6. MacDonald TJ, et al. J Clin Oncol 2008;26(6):919-24.

7. Reardon DA, et al. Expert Opin Investig Drugs 2008;17(8):1225-35.

8. Stupp R, et al. J Clin Oncol 2007;25(13):1637-8.

9. Gilbert M, et al. SNO Annual Meeting 2007; Abstract No: MA-39.

10. Parkin DM, et al. CA Cancer J Clin 2005;55:74-108.

About cilengitide

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 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.

About Merck

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Merck is a global pharmaceutical and chemical company with total revenues of € 7.6 billion in 2008, a history that began in 1668, and a future shaped by 32,700 employees in 60 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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Dr. Raphaela Farrenkopf, +49 6151-72 2274