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Merck KGaA, MDxHealth Explore Personalized Rx Strategy for Glioblastoma Patients with Methylated MGMT

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Merck KGaA and MDxHealth have extended an existing personalized medicine research collaboration so that the drug firm will fund the development, regulatory activities, and commercial launch of a companion diagnostic being advanced by MDxHealth for an investigational glioblastoma drug in Merck's pipeline.

If approved by the regulatory authorities, MDxHealth's PredictMDx for Glioblastoma will be launched as a companion test alongside a new drug regimen comprising Merck's integrin inhibitor cilengitide plus temozolomide and radiotherapy. Integrins are receptors that play a critical role in the growth and repair of blood vessels.

MDxHealth's diagnostic will help discern which glioblastoma patients have the methylated MGMT gene and therefore should receive Merck's treatment. "As part of the expanded collaboration, Merck has agreed to support MDxHealth's development and regulatory activities for the MGMT test and, after regulatory approval, the coordinated launch together with cilengitide in glioblastoma," the partners announced in a statement. The companies did not disclose the financial details of their agreement.

Merck is investigating the safety and efficacy of the cilengitide plus temozolomid-based radiochemotherapy regimen in the CENTRIC (Cilengitide in Combination with Temozolomide and Radiotherapy in Newly Diagnosed Glioblastoma Phase III Randomized Clinical) trial, a randomized, open-label Phase III study that the drug developer is conducting in collaboration with the European Organization for Research and Treatment of Cancer. Patients enrolled in the trial will be randomized to either receive the cilengitide-containing regimen or just temozolomide with radiotherapy. Those receiving the cilengitide regimen will receive follow-on treatment with cilengitide monotherapy until their disease progresses.

More than 500 newly diagnosed glioblastoma patients, who have methylated MGMT gene promoter status as established by MDxHealth's companion test, have been enrolled in the trial. The MGMT gene promoter controls expression of the MGMT gene, which is involved in cellular DNA repair.

In past studies, researchers have found that cancer patients whose tumors harbor the methylated form of the MGMT gene promoter have abnormal gene expression that makes them more likely to respond to certain chemotherapy regimens, such as temozolomide.

A Phase I/IIa study conducted by researchers from Merck and other institutions received early signs that glioblastoma patients with methylated MGMT genes were deriving greater benefit from the addition of cilengitide to standard chemotherapy than those without this molecular marker. In the study, reported in the Journal of Clinical Oncology in 2010 and led by Roger Stupp of Switzerland's Centre Hospitalier Universitaire Vaudois, investigators enrolled 52 newly diagnosed glioblastoma patients and treated them with cilengitide in addition to standard radiotherapy with concomitant and adjuvant temozolomide until their disease progressed or for up to 35 weeks in order to track whether the regimen impacted their progression-free survival at six months.

In this study, 69 percent and 33 percent of patients experienced progression-free survival for six and 12 months, respectively. Median progression-free survival for study participants was eight months. Moreover, 68 percent of patients in the trial stayed alive for a year, while 35 percent stayed alive for two years.

"Progression-free survival and overall survival were longer in patients with tumors with MGMT promoter methylation (13.4 and 23.2 months) versus those without MGMT promoter methylation (3.4 and 13.1 months)," Stupp et al. reported, adding that the combination of cilengitide with temozolomide and radiotherapy was well tolerated by study participants.

One year before the publication of this data, researchers from London's Breakthrough Breast Cancer Research Centre and elsewhere reported in Nature Medicine data from an in vivo study in which they found that low concentrations of integrin inhibitors, such as cilengitide, actually promoted tumor growth by driving angiogenesis. However, by targeting the cilengitide/temozolomide-based radiochemotherapy regimen to a genomically targeted subpopulation of glioblastoma patients, Merck may be able to work around the biological mechanisms that appeared to be driving cancers with integrin inhibition in the Nature Medicine study.

In response to this finding, researchers involved in the CENTRIC trial wrote to Nature Medicine pointing out that the in vivo analysis by Reynolds et al. didn't consider glioma models, wasn't studied in combination with radiochemotherapy, and used a treatment schedule for cilengitide that is not used in humans.

"In fact, a paradoxical proangiogenic effect of cilengitide may be operative in certain settings and contribute to an antitumor effect of cilengitide in combination with radiotherapy or chemotherapy," Michael Weller of University Hospital Zurich, Stupp and colleagues further wrote in the editorial. "This consideration relates to the vascular normalization effect of antiangiogenic agents, which we have proposed to underlie the preferential clinical benefit apparently seen in glioblastoma patients with MGMT promoter methylation."

In the Phase III CENTRIC trial, researchers will assess whether cilengitide significantly improves glioblastoma patients' overall survival compared to standard treatment as the primary endpoint. Other endpoints in the trial included progression-free survival, safety, tolerability, population pharmacokinetics, and quality of life. CENTRIC is being conducted at a number of study sites located in Europe, North America, Latin America, and in the Asia Pacific region. Study investigators expect to release the final data from the CENTRIC trial in the first half of 2013.

"The Phase III trial CENTRIC is an event-driven study; thus results are expected when the required number of events (deaths) is reached," a spokesperson for Merck told PGx Reporter. "After review of the complete dataset, we will determine our further strategy, including the strategy with regulatory authorities."

Merck received orphan drug status for cilengitide in Europe in 2004 as a glioma treatment and the same status from US health regulators in 2005 for malignant glioma.

According to MDxHealth, PredictMDx for Glioblastoma is the company's most advanced product. "The patented epigenetic gene test PredictMDx is attractive for brain cancer drug developers since this could provide an opportunity to better target their new drugs in the interest of the patient," the company said in a statement.

Merck is also developing cilengitide as a treatment for NSCLC patients and conducting a Phase I/II trial in this indication. Although MGMT gene methylation status of patients is a predictive marker specific for glioblastoma patients, Merck is also exploring pharmacogenomic strategies for cilengitide in NSCLC.

"At Merck Serono, we have embraced the principle of the personalized approach to cancer care, which centers on biomarker-guided drug development," the company spokesperson said. "All currently ongoing clinical trials of cilengitide include a biomarker program with the aim of identifying reliable biomarkers. Any identified reliable biomarker will be implemented, as adequate. Therefore we included also in this study a biomarker program."

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