Stupp, Roger and Hegi, Monika E. and Gorlia, Thierry and Erridge, Sara C. and Perry, James and Hong, Yong-Kil and Aldape, Kenneth D. and Lhermitte, Benoit and Pietsch, Torsten and Grujicic, Danica and Steinbach, Joachim Peter and Wick, Wolfgang and Tarnawski, Rafal and Nam, Do-Hyun and Hau, Peter and Weyerbrock, Astrid and Taphoorn, Martin J. B. and Shen, Chiung-Chyi and Rao, Nalini and Thurzo, Laszlo and Herrlinger, Ulrich and Gupta, Tejpal and Kortmann, Rolf-Dieter and Adamska, Krystyna and McBain, Catherine and Brandes, Alba A. and Tonn, Joerg Christian and Schnell, Oliver and Wiegel, Thomas and Kim, Chae-Yong and Nabors, Louis Burt and Reardon, David A. and van den Bent, Martin J. and Hicking, Christine and Markivskyy, Andriy and Picard, Martin and Weller, Michael (2014) Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071-22072 study): a multicentre, randomised, open-label, phase 3 trial. LANCET ONCOLOGY, 15 (10). pp. 1100-1108. ISSN 1470-2045, 1474-5488
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Background Cilengitide is a selective alpha v beta 3 and alpha v beta 5 integrin inhibitor. Data from phase 2 trials suggest that it has antitumour activity as a single agent in recurrent glioblastoma and in combination with standard temozolomide chemoradiotherapy in newly diagnosed glioblastoma (particularly in tumours with methylated MGMT promoter). We aimed to assess cilengitide combined with temozolomide chemoradiotherapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter. Methods In this multicentre, open-label, phase 3 study, we investigated the efficacy of cilengitide in patients from 146 study sites in 25 countries. Eligible patients (newly diagnosed, histologically proven supratentorial glioblastoma, methylated MGMT promoter, and age >= 18 years) were stratified for prognostic Radiation Therapy Oncology Group recursive partitioning analysis class and geographic region and centrally randomised in a 1:1 ratio with interactive voice response system to receive temozolomide chemoradiotherapy with cilengitide 2000 mg intravenously twice weekly (cilengitide group) or temozolomide chemoradiotherapy alone (control group). Patients and investigators were unmasked to treatment allocation. Maintenance temozolomide was given for up to six cycles, and cilengitide was given for up to 18 months or until disease progression or unacceptable toxic effects. The primary endpoint was overall survival. We analysed survival outcomes by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00689221. Findings Overall, 3471 patients were screened. Of these patients, 3060 had tumour MGMT status tested; 926 patients had a methylated MGMT promoter, and 545 were randomly assigned to the cilengitide (n=272) or control groups (n=273) between Oct 31, 2008, and May 12, 2011. Median overall survival was 26.3 months (95% CI 23.8-28.8) in the cilengitide group and 26.3 months (23.9-34.7) in the control group (hazard ratio 1.02, 95% CI 0.81-1.29, p=0 86). None of the predefined clinical subgroups showed a benefit from cilengitide. We noted no overall additional toxic effects with cilengitide treatment. The most commonly reported adverse events of grade 3 or worse in the safety population were lymphopenia (31 [12%] in the cilengitide group vs 26 [10%] in the control group), thrombocytopenia (28 [11%] vs 46 [18%]), neutropenia (19 [7%] vs 24 [9%]), leucopenia (18 [7%] vs 20 [8%]), and convulsion (14 [5%] vs 15 [6%]). Interpretation The addition of cilengitide to temozolomide chemoradiotherapy did not improve outcomes; cilengitide will not be further developed as an anticancer drug. Nevertheless, integrins remain a potential treatment target for glioblastoma.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | MALIGNANT GLIOMA; INTEGRIN ALPHA(V)BETA(3); RECURRENT GLIOBLASTOMA; CLINICAL-TRIAL; UNITED-STATES; TEMOZOLOMIDE; RADIOTHERAPY; EXPRESSION; BRAIN; BEVACIZUMAB; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Neurologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 28 Aug 2019 10:09 |
| Last Modified: | 28 Aug 2019 10:09 |
| URI: | https://pred.uni-regensburg.de/id/eprint/9669 |
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