Two cilengitide regimens in combination with standard treatment for patients with newly diagnosed glioblastoma and unmethylated MGMT gene promoter: results of the open-label, controlled, randomized phase II CORE study

Nabors, L. Burt; Fink, Karen; Mikkelsen, Tom; Grujičić, Danica; Tarnawski, Rafał; Nam, Do Hyun; Mazurkiewicz, Maria; Salacz, Michael; Ashby, Lynn S.; Zagonel, Vittorina; Depenni, Roberta; Perry, James; Hicking, Christine; Picard, Martin; Hegi, Monika E.; Lhermitte, Benoît; Reardon, David A.

doi:10.1093/neuonc/nou356

Cited by 198 publications

(139 citation statements)

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“…The investigation of patients with an unmethylated MGMT promoter in the tumour was subject of an exploratory phase 2 study (CORE) initiated shortly after CENTRIC. 24 7…”

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confidence: 99%

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

Stupp

Hegi

Gorlia

et al. 2014

The Lancet Oncology

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865

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BACKGROUND Cilengitide is a selective v 3 and v 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) •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%]

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“…The investigation of patients with an unmethylated MGMT promoter in the tumour was subject of an exploratory phase 2 study (CORE) initiated shortly after CENTRIC. 24 7…”

mentioning

confidence: 99%

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

Stupp

Hegi

Gorlia

et al. 2014

The Lancet Oncology

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578

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“…However, neither as a single agent nor in combination with CCNU, it was superior to CCNU monotherapy in a phase III trial in recurrent glioblastoma [31]. in this patient population was found either [52].…”

Section: Bevacizumab Alone and Combination Therapymentioning

confidence: 76%

Pharmacotherapies for the treatment of glioblastoma – current evidence and perspectives

Seystahl

Gramatzki

Roth

2016

Expert Opinion on Pharmacotherapy

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INTRODUCTION Glioblastoma, the most common malignant brain tumor, exhibits a poor prognosis with little therapeutic progress in the last decade. Novel treatment strategies beyond the established standard of care with temozolomide-based radiotherapy are urgently needed. AREAS COV-ERED We reviewed the literature on glioblastoma with a focus on phase III trials for pharmacotherapies and/or innovative concepts until December 2015. EXPERT OPINION In the last decade, phase III trials on novel compounds largely failed to introduce efficacious pharmacotherapies beyond temozolomide in glioblastoma. So far, inhibition of angiogenesis by compounds such as bevacizumab, cediranib, enzastaurin or cilengitide as well as alternative dosing schedules of temozolomide did not prolong survival, neither at primary diagnosis nor at recurrent disease. Promising strategies of pharmacotherapy currently under evaluation represent targeting epidermal growth factor receptor (EGFR) with biomarker-stratified patient populations and immunotherapeutic concepts including checkpoint inhibition and vaccination. The clinical role of the medical device delivering 'tumor-treating fields' in newly diagnosed glioblastoma which prolonged overall survival in a phase III study has remained controversial. After failure of several phase III trials with previously promising agents, improvement of concepts and novel compounds are urgently needed to expand the still limited therapeutic options for the treatment of glioblastoma. Areas coveredWe reviewed the literature on glioblastoma with a focus on phase III trials for pharmacotherapies and/or innovative concepts until December 2015. Expert opinionIn the last decade, phase III trials on novel compounds largely failed to introduce efficacious pharmacotherapies beyond temozolomide in glioblastoma. So far, inhibition of angiogenesis by compounds such as bevacizumab, cediranib, enzastaurin or cilengitide as well as alternative dosing schedules of temozolomide did not prolong survival, neither at primary diagnosis nor at recurrent disease.Promising strategies of pharmacotherapy currently under evaluation represent targeting epidermal growth factor receptor (EGFR) with biomarker-stratified patient populations and immunotherapeutic concepts including checkpoint inhibition and vaccination. The clinical role of the medical device delivering "tumor-treating fields" in newly diagnosed glioblastoma which prolonged overall survival in a phase III study has remained controversial. After failure of several phase III trials with previously promising agents, improvement of concepts and novel compounds are urgently needed to expand the still limited therapeutic options for the treatment of glioblastoma. 3 Article highlights• For patients with newly diagnosed glioblastoma, the standard of care remains temozolomide-based radiochemotherapy.• Phase III data on bevacizumab, cilengitide, and alternative dosing schedules for temozolomide did not show a survival benefit in newly diagnosed glioblastoma• For elderly patients ...

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“…Two prospective randomized trials evaluated the role of cilengitide in combination with standard treatment, in patients with a methylated MGMT gene promoter (CENTRIC) and in those with an unmethylated MGMT status (CORE). They both failed in demonstrating an OS gain (47,48). Other agents, namely enzastaurin and temsirolimus, have been studied in phase II trials, without any improvement in OS or PFS (41).…”

Section: Gliadel (Carmustine) Implantable Wafersmentioning

confidence: 99%

Current Standards of Care in Glioblastoma Therapy

et al. 2017

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Glioblastoma (GBM) is the most common primary malignant brain tumor in adults. Regardless of ideal multidisciplinary treatment, including maximal surgical resection, followed by radiotherapy plus concomitant and maintenance temozolomide (TMZ), almost all patients experience tumor progression with nearly universal mortality and a median survival of less than 15 months. The addition of bevacizumab to standard treatment with TMZ revealed no increase in overall survival (OS) but improved progression-free survival (PFS). In newly diagnosed GBM, methylation of the O6-methylguanine-DNA methyltransferase (MGMT) promoter has been shown to predict response to alkylating agents, as well asgnosis. Therefore, MGMT promoter status may have a crucial role in the choice of single modality treatment in fragile elderly population. No standard of care is established in recurrent or progressive GBM. Treatment alternatives may include supportive care, surgery, re-irradiation, systemic therapies, and combined modality therapy. Despite numerous clinical trials, the identification of effective therapies is complex because of the lack of appropriate control arms, selection bias, small sample sizes, and disease heterogeneity. Tumor-treating fields plus TMZ represent a major advance in the field of GBM therapy, and should be Standards of Care in Glioblastoma Therapy 198 considered for patients with newly diagnosed GBM with no contraindications. As a disease with such a poor prognosis, treatment of GBM should go beyond improving survival and aim at preserving and even improving the quality of life of both the patient and the caregiver.

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Two cilengitide regimens in combination with standard treatment for patients with newly diagnosed glioblastoma and unmethylated MGMT gene promoter: results of the open-label, controlled, randomized phase II CORE study

Cited by 198 publications

References 17 publications

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

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

Pharmacotherapies for the treatment of glioblastoma – current evidence and perspectives

Current Standards of Care in Glioblastoma Therapy

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