Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma and methylated O⁶-methylguanine-DNA methyltransferase (MGMT) gene promoter: Key results of the multicenter, randomized, open-label, controlled, phase III CENTRIC study.

Abstract

LBA2009 Background: Cilengitide (CIL) is a selective αvβ3 and αvβ5 integrin inhibitor. In a phase II study in patients with newly diagnosed glioblastoma, CIL added to standard temozolomide (TMZ) and radiotherapy (RT) was well tolerated and appeared to confer improved survival in patients with glioblastoma and methylated MGMT gene promoter (Stupp et al. J Clin Oncol. 2010;28:2712-8). Methods: This multicenter, randomized, controlled, open-label, phase III study randomized (1:1) patients (≥ 18 years) with newly diagnosed, histologically proven supratentorial glioblastoma (WHO Grade IV) and centrally determined MGMT gene promoter methylation. Treatment consisted of CIL 2000 mg twice weekly i.v. plus standard TMZ/RT→TMZ (concomitant and adjuvant temozolomide and radiotherapy; Stupp et al. N Engl J Med. 2005;352:987-96) or standard TMZ/RT→TMZ alone. CIL was to be administered for ≥ 18 months, or until disease progression or unacceptable toxicity. Primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS) per investigator read and safety. Results: 272 patients received CIL plus TMZ/RT→TMZ, and 273 were treated with TMZ/RT→TMZ alone (intention-to-treat population). 54% and 52% of patients were male, and 42% and 44% had ECOG-PS ≥ 1, respectively. 75% of patients of both arms were ≥ 50 years old. Overall, baseline characteristics were well balanced across treatment arms. Median OS was 26.3 months in both arms (Hazard Ratio [HR] = 1.02 [95%CI: 0.81-1.29], p = 0.86). Median PFS per investigator read was 13.5 months in the CIL arm and 10.7 months in the control arm (HR = 0.93 [95%CI: 0.76-1.14], p = 0.48). Treatment was generally well tolerated and the known safety profile of CIL was confirmed. Conclusions: CIL failed to prolong PFS or OS in patients with newly diagnosed glioblastoma and methylated MGMT gene promoter. The previously reported safety profile of CIL in addition to standard therapy was confirmed. Clinical trial information: NCT00689221.

Bevacizumab plus Radiotherapy–Temozolomide for Newly Diagnosed Glioblastoma

“…Sim ilarly, a difference of 2.8 months between in vestigator and independent-review assessments was observed in the CENTRIC trial (Cilengitide in Combination with Temozolomide and Radiotherapy in Newly Diagnosed Glioblastoma Phase III Randomized Clinical Trial; ClinicalTrials.gov number, NCT00689221) of cilengitide plus radiotherapy-temozolomide for newly diagnosed glioblastoma. 33 The adapted Macdonald Response Criteria, which were used to assess progression, anticipated some of the key features of the Response Assessment in Neuro-Oncology (RANO) Working Group criteria, which were not available at the time of the initiation of our study. 25,26 The adapted Macdonald Response Criteria addressed the observed limitations of imaging assessment by including qualitative evaluation of both noncontrast-enhancing components (by means of T 2 -weighted imaging or fluid-attenuated inversion recovery [FLAIR]) and small contrastenhancing lesions (at least one diameter <10 mm).…”

MGMT testing—the challenges for biomarker-based glioma treatment

“…From the academic and caregivers perspective, however, it will be difficult to European randomized controlled phase II study, which completed accrual in 2012, will become available in 2014 [16]. The CORE study is a formal companion to the CENTRIC trial, in which the integrin inhibitor cilengitide was added to (not replacing) radiochemotherapy with TMZ in MGMT-unmethylated glioblastoma patients [14]. In this study, radiochemotherapy with TMZ was compared with radiochemotherapy with TMZ plus cilengitide at two different dosing schedules in a randomized phase II three-arm design.…”

“…Due to its high prognostic and predictive relevance, assessment of the MGMT status has become state-of-the-art in current and planned clinical trials in glioma as a prognosticator and to stratify patients [9] or even patient selection into trials accordingly [14][15][16][17]. In addition, it is nowadays frequently requested in routine diagnostics as a prognostic tool.…”

“…In addition, the challenge for these trials also extends to the definition of the scientifically sound comparator (standard therapy) arm. Results from studies exploring safety and efficacy of vascular endothelial growth factor (VEGF) inhibitors, [10][11][12][13], the integrin inhibitor cilengitide [14,15], the protein kinase C (PKC) inhibitor enzastaurin [16], the inhibitor of the mammalian target of rapamycin, temsirolimus [17] have been eagerly awaited, and will be discussed.…”

Cilengitide treatment of newly diagnosed glioblastoma patients does not alter patterns of progression

“…The observation that no change in the patterns of progression in a cohort of cilengitide-treated patients compared to a cohort of patients from the experimental arm of the EORTC 26981/22981 NCIC CE.3 was observed is reassuring. The major limitation of the present study is the small sample size and the uncertainty of its relevance in the future: preliminary results from the subsequently performed phase 3 trial, CENTRIC, indicate that the primary endpoint of prolonging overall survival was not reached [13]. Yet, our analysis serves as a baseline and reference for the future study of the role of modulation of integrins in the treatment of newly diagnosed glioblastoma.…”