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

Abstract

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%]

Differential gene expression profiling of matched primary renal cell carcinoma and metastases reveals upregulation of extracellular matrix genes

“…However, other ECM components (e.g. integrins, heparanases, and matrix metalloproteinases) have inhibitors that are currently under study in phase I/II/III clinical trials [27][28][29][30][31][32][33]. Kinase genes have also recently been reported to be upregulated in metastatic tumors relative to primary ccRCC tumors [34].…”

“Combo” nanomedicine: Co-delivery of multi-modal therapeutics for efficient, targeted, and safe cancer therapy

“…Combination therapies using two or more therapeutic agents targeting specific pathways can synergistically eradicate cancer and halt tumor growth, however certain combinations may be more detrimental or quality of life may decrease despite an increase in survival time [65,66]. There are currently hundreds of combination therapies undergoing clinical evaluation, and Table 1 lists several examples of recently completed Phase III clinical trials [67][68][69][70][71][72][73][74][75][76][77]. Targeting multiple constituents within a single pathway may allow for a maximum inhibition of that particular signaling network, possibly even a complete shutdown [78,79].…”

Identification of an Endogenously Generated Cryptic Collagen Epitope (XL313) That May Selectively Regulate Angiogenesis by an Integrin Yes-associated Protein (YAP) Mechano-transduction Pathway

“…These novel findings are surprising given the wealth of experimental data indicating the high concentration of RGD peptides inhibit rather than induce angiogenesis (11,28,29). A growing body of evidence now suggests that low concentrations of certain RGD peptides may actually enhance angiogenesis and tumor growth (30), which may explain at least in part the minimal impact of cyclic RGD peptide antagonists of ␣v␤3 and ␣v␤5 in human clinical trials (31). Our current studies provide new evidence suggesting that in addition to variations in concentrations that may alter the biological response of certain RGD peptides, the specific composition of the amino acids C-terminal to the RGD motif within naturally occurring epitopes may confer unique pro-angiogenic and inflammatory activity.…”