Phase I/IIa Study of Cilengitide and Temozolomide With Concomitant Radiotherapy Followed by Cilengitide and Temozolomide Maintenance Therapy in Patients With Newly Diagnosed Glioblastoma
ABSTRACT Invasion and migration are key processes of glioblastoma and are tightly linked to tumor recurrence. Integrin inhibition using cilengitide has shown synergy with chemotherapy and radiotherapy in vitro and promising activity in recurrent glioblastoma. This multicenter, phase I/IIa study investigated the efficacy and safety of cilengitide in combination with standard chemoradiotherapy in newly diagnosed glioblastoma.
Patients (age > or = 18 to < or = 70 years) were treated with cilengitide (500 mg) administered twice weekly intravenously in addition to standard radiotherapy with concomitant and adjuvant temozolomide. Treatment was continued until disease progression or for up to 35 weeks. The primary end point was progression-free survival (PFS) at 6 months.
Fifty-two patients (median age, 57 years; 62% male) were included. Six- and 12-month PFS rates were 69% (95% CI, 54% to 80%) and 33% (95% CI, 21% to 46%). Median PFS was 8 months (95% CI, 6.0 to 10.7 months). Twelve- and 24-month overall survival (OS) rates were 68% (95% CI, 53% to 79%) and 35% (95% CI, 22% to 48%). Median OS was 16.1 months (95% CI, 13.1 to 23.2 months). PFS and OS were longer in patients with tumors with O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation (13.4 and 23.2 months) versus those without MGMT promoter methylation (3.4 and 13.1 months). The combination of cilengitide with temozolomide and radiotherapy was well tolerated, with no additional toxicity. No pharmacokinetic interactions between temozolomide and cilengitide were identified.
Compared with historical controls, the addition of concomitant and adjuvant cilengitide to standard chemoradiotherapy demonstrated promising activity in patients with glioblastoma with MGMT promoter methylation.
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ABSTRACT: High-grade glioma (HGG) are optimally treated with maximum safe surgery, followed by radiotherapy (RT) and/or systemic chemotherapy (CT). Recently, the treatment of newly diagnosed anaplastic glioma (AG) has changed, particularly in patients with 1p19q codeleted tumors. Results of trials currenlty ongoing are likely to determine the best standard of care for patients with noncodeleted AG tumors. Trials in AG illustrate the importance of molecular characterization, which are germane to both prognosis and treatment. In contrast, efforts to improve the current standard of care of newly diagnosed glioblastoma (GB) with, for example, the addition of bevacizumab (BEV), have been largely disappointing and furthermore molecular characterization has not changed therapy except in elderly patients. Novel approaches, such as vaccine-based immunotherapy, for newly diagnosed GB are currently being pursued in multiple clinical trials. Recurrent disease, an event inevitable in nearly all patients with HGG, continues to be a challenge. Both recurrent GB and AG are managed in similar manner and when feasible re-resection is often suggested notwithstanding limited data to suggest benefit from repeat surgery. Occassional patients may be candidates for re-irradiation but again there is a paucity of data to commend this therapy and only a minority of selected patients are eligible for this approach. Consequently systemic therapy continues to be the most often utilized treatment in recurrent HGG. Choice of therapy, however, varies and revolves around re-challenge with temozolomide (TMZ), use of a nitrosourea (most often lomustine; CCNU) or BEV, the most frequently used angiogenic inhibitor. Nevertheless, no clear standard recommendation regarding the prefered agent or combination of agents is avaliable. Prognosis after progression of a HGG remains poor, with an unmet need to improve therapy.Surgical Neurology International 02/2015; 6(Suppl 1):S9-S44. DOI:10.4103/2152-7806.151331 · 1.18 Impact Factor
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ABSTRACT: Tumour-associated macrophages (TAMs) are enriched in glioblastoma multiformes (GBMs) that contain glioma stem cells (GSCs) at the apex of their cellular hierarchy. The correlation between TAM density and glioma grade suggests a supportive role for TAMs in tumour progression. Here we interrogated the molecular link between GSCs and TAM recruitment in GBMs and demonstrated that GSCs secrete periostin (POSTN) to recruit TAMs. TAM density correlates with POSTN levels in human GBMs. Silencing POSTN in GSCs markedly reduced TAM density, inhibited tumour growth, and increased survival of mice bearing GSC-derived xenografts. We found that TAMs in GBMs are not brain-resident microglia, but mainly monocyte-derived macrophages from peripheral blood. Disrupting POSTN specifically attenuated the tumour-supportive M2 type of TAMs in xenografts. POSTN recruits TAMs through the integrin αvβ3 as blocking this signalling by an RGD peptide inhibited TAM recruitment. Our findings highlight the possibility of improving GBM treatment by targeting POSTN-mediated TAM recruitment.Nature Cell Biology 01/2015; 17(2). DOI:10.1038/ncb3090 · 20.06 Impact Factor
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ABSTRACT: Malignant gliomas are the most common malignant primary brain tumors and one of the most challenging forms of cancers to treat. Despite advances in conventional treatment, the outcome for patients remains almost universally fatal. This poor prognosis is due to therapeutic resistance and tumor recurrence after surgical removal. However, over the past decade, molecular targeted therapy has held the promise of transforming the care of malignant glioma patients. Significant progress in understanding the molecular pathology of gliomagenesis and maintenance of the malignant phenotypes will open opportunities to rationally develop new molecular targeted therapy options. Recently, therapeutic strategies have focused on targeting pro-growth signaling mediated by receptor tyrosine kinase/RAS/phosphatidylinositol 3-kinase pathway, proangiogenic pathways, and several other vital intracellular signaling networks, such as proteasome and histone deacetylase. However, several factors such as cross-talk between the altered pathways, intratumoral molecular heterogeneity, and therapeutic resistance of glioma stem cells (GSCs) have limited the activity of single agents. Efforts are ongoing to study in depth the complex molecular biology of glioma, develop novel regimens targeting GSCs, and identify biomarkers to stratify patients with the individualized molecular targeted therapy. Here, we review the molecular alterations relevant to the pathology of malignant glioma, review current advances in clinical targeted trials, and discuss the challenges, controversies, and future directions of molecular targeted therapy. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.Neoplasia (New York, N.Y.) 03/2015; 114(3). DOI:10.1016/j.neo.2015.02.002 · 5.40 Impact Factor