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Lancet Oncol. 2014 Sep;15(10):1100-8. doi: 10.1016/S1470-2045(14)70379-1. Epub 2014 Aug 19.

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.

Author information

1
UniversitätsSpital Zürich, Zurich, Switzerland; Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland. Electronic address: roger.stupp@usz.ch.
2
Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.
3
EORTC Headquarters, Brussels, Belgium.
4
Edinburgh Cancer Centre, University of Edinburgh, Edinburgh, UK.
5
Sunnybrook Health Sciences Centre, Toronto, ON, Canada.
6
The Catholic University of Korea, Seoul St Mary's Hospital, Seoul, South Korea.
7
The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
8
Department of Neuropathology, Universität Bonn, Bonn, Germany.
9
Clinic for Neurosurgery, Clinical Center Serbia and Medical Faculty University of Belgrade, Belgrade, Serbia.
10
Klinikum der J W Goethe Universität Frankfurt, Frankfurt, Germany.
11
Heidelberg University Medical Center & German Cancer Research Center, Heidelberg, Germany.
12
Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology Gliwice Branch, Gliwice, Poland.
13
Samsung Medical Center, Sungkyunkwan Univ School of Medicine, Seoul, South Korea.
14
Universitätsklinikum Regensburg, Regensburg, Germany.
15
Universitätsklinikum Freiburg, Freiburg, Germany.
16
Medical Center Haaglanden, The Hague, Netherlands.
17
Taichung Veterans General Hospital, Taichung, Taiwan.
18
Bangalore Institute of Oncology, Bangalore, India.
19
Szegedi Tudományegyetem, Szeged, Hungary.
20
Tata Memorial Centre, Navi Mumbai, India.
21
Universitätsklinikum Leipzig, Leipzig, Germany.
22
Greater Poland Cancer Centre, Poznań, Poland.
23
The Christie NHS FT, Manchester, UK.
24
Bellaria-Maggiore Hospital, AUSL-IRCCS Institute of Neurological Sciences-Bologna, Italy.
25
Klinikum der Universität München, München, Germany.
26
University Hospital Ulm, Ulm, Germany.
27
Seoul National University Bundang Hospital, SNU College of Medicine, Seoul, South Korea.
28
University of Alabama at Birmingham, Birmingham, AL, USA.
29
Dana-Farber Cancer Institute, Boston, MA, USA.
30
Erasmus MC-Cancer Institute, Rotterdam, Netherlands.
31
Merck KGaA, Darmstadt, Germany.
32
UniversitätsSpital Zürich, Zurich, Switzerland.

Abstract

BACKGROUND:

Cilengitide is a selective αvβ3 and αvβ5 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.

FUNDING:

Merck KGaA, Darmstadt, Germany.

PMID:
25163906
DOI:
10.1016/S1470-2045(14)70379-1
[Indexed for MEDLINE]
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