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Tom Mikkelsen - One of the best experts on this subject based on the ideXlab platform.

  • a phase i study of cediranib in combination with Cilengitide in patients with recurrent glioblastoma
    Neuro-oncology, 2015
    Co-Authors: Elizabeth R Gerstner, Tom Mikkelsen, Patrick Y Wen, Michael A Levine, Jeffrey J Olson, Thomas Kaley, Dan G Duda, Burt Nabors, Manmeet Ahluwalia, Rakesh K Jain
    Abstract:

    Background Despite being a highly vascularized tumor, glioblastoma response to anti-vascular endothelial growth factor (VEGF) therapy is transient, possibly because of tumor co-option of preexisting blood vessels and infiltration into surrounding brain. Integrins, which are upregulated after VEGF inhibition, may play a critical role in this resistance mechanism. We designed a study of cediranib, a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor, combined with Cilengitide, an integrin inhibitor. Methods This phase I study was conducted through the Adult Brain Tumor Consortium in patients with recurrent glioblastoma. Once the maximum tolerated dose was determined, 40 patients enrolled in a dose expansion cohort with 20 being exposed to anti-VEGF therapy and 20 being naive. The primary endpoint was safety. Secondary endpoints included overall survival, proportion of participants alive and progression free at 6 months, radiographic response, and exploratory analyses of physiological imaging and blood biomarkers. Results Forty-five patients enrolled, and no dose toxicities were observed at a dose of cediranib 30 mg daily and Cilengitide 2000 mg twice weekly. Complete response was seen in 2 participants, partial response in 2, stable disease in 13, and progression in 21; 7 participants were not evaluable. Median overall survival was 6.5 months, median progression-free survival was 1.9 months, and progression-free survival at 6 months was 4.4%. Plasma-soluble VEGFR2 decreased with treatment and placental growth factor, carbonic anhydrase IX, and SDF1α, and cerebral blood flow increased. Conclusions The combination of cediranib with Cilengitide was well tolerated and associated with changes in pharmacodynamic blood and imaging biomarkers. However, the survival and response rates do not warrant further development of this combination.

  • 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
    Neuro-oncology, 2015
    Co-Authors: Burt L Nabors, Tom Mikkelsen, Danica Grujicic, Karen Fink, Rafal Tarnawski, Dohyun Nam, Maria Mazurkiewicz, Michael Salacz, Lynn S Ashby, Vittorina Zagonel
    Abstract:

    Results. Median overall survival was 16.3 months in the standard Cilengitide arm (hazard ratio [HR], 0.686; 95% CI: 0.484, 0.972; P ¼ .032) and 14.5 months in the intensive Cilengitide arm (HR, 0.858; 95% CI: 0.612, 1.204; P ¼ .3771) versus 13.4 months in the control arm. Median progression-free survival assessed per independent review committee was 5.6 months (HR, 0.822; 95% CI: 0.595, 1.134) and 5.9 months (HR, 0.794; 95% CI: 0.575, 1.096) in the standard and intensive Cilengitide arms, respectively, versus 4.1 months in the control arm. Cilengitide was well tolerated.

  • Cilengitide induced temporal variations in transvascular transfer parameters of tumor vasculature in a rat glioma model identifying potential mri biomarkers of acute effects
    PLOS ONE, 2013
    Co-Authors: Tavarekere N Nagaraja, Tom Mikkelsen, Stephen L Brown, Madhava P Aryal, Hassan Bagherebadian, James Yang, Swayamprava Panda, Kelly A Keenan
    Abstract:

    Increased efficacy of radiotherapy (RT) 4-8 h after Cilengitide treatment has been reported. We hypothesized that the effects of Cilengitide on tumor transvascular transfer parameters might underlie, and thus predict, this potentiation. Athymic rats with orthotopic U251 glioma were studied at ~21 days after implantation using dynamic contrast-enhanced (DCE)-MRI. Vascular parameters, viz: plasma volume fraction (vp), forward volume transfer constant (Ktrans) and interstitial volume fraction (ve) of a contrast agent, were determined in tumor vasculature once before, and again in cohorts 2, 4, 8, 12 and 24 h after Cilengitide administration (4 mg/kg; N = 31; 6-7 per cohort). Perfusion-fixed brain sections were stained for von Willebrand factor to visualize vascular segments. A comparison of pre- and post-treatment parameters showed that the differences between MR indices before and after Cilengitide treatment pivoted around the 8 h time point, with 2 and 4 h groups showing increases, 12 and 24 h groups showing decreases, and values at the 8 h time point close to the baseline. The vascular parameter differences between group of 2 and 4 h and group of 12 and 24 h were significant for Ktrans (p = 0.0001 and ve (p = 0,0271). Vascular staining showed little variation with time after Cilengitide. The vascular normalization occurring 8 h after Cilengitide treatment coincided with similar previous reports of increased treatment efficacy when RT followed Cilengitide by 8 h. Pharmacological normalization of vasculature has the potential to increase sensitivity to RT. Evaluating acute temporal responses of tumor vasculature to putative anti-angiogenic drugs may help in optimizing their combination with other treatment modalities.

  • a phase i study of cediranib in combination with Cilengitide in patients with recurrent glioblastoma
    Journal of Clinical Oncology, 2013
    Co-Authors: Elizabeth R Gerstner, Tom Mikkelsen, Louis B Nabors, Patrick Y Wen, Tracy T Batchelor, Michael A Levine, Jeffrey J Olson, Thomas Kaley, Stuart A Grossman
    Abstract:

    2054 Background: Despite high vascularity, duration of response of glioblastoma (GBM) to anti-angiogenic therapy is short. One proposed mechanism of resistance is via co-option of native brain blood vessels and tumor infiltration into normal appearing brain. We designed a Phase I study of cediranib, a VEGFR tyrosine kinase inhibitor, in combination with Cilengitide, an integrin inhibitor, to block this infiltrative relapse. Methods: A phase I study was conducted through the Adult Brain Tumor Consortium in patients with recurrent GBM. Once the MTD was determined, 40 patients enrolled in a dose expansion cohort. Standard eligibility criteria were included and all patients needed to have at least 1 cm of residual disease to assess tumor response. In the dose expansion cohort, 20 patients had received prior anti-VEGF therapy and 20 had never received anti-VEGF therapy. The primary endpoint was the safety of cediranib with Cilengitide. Secondary endpoints were overall survival, the proportion of patients alive...

  • Cilengitide induces autophagy mediated cell death in glioma cells
    Neuro-oncology, 2011
    Co-Authors: Stephanie L Lomonaco, Tom Mikkelsen, Susan Finniss, Cunli Xiang, Hae Kyung Lee, Wei Jiang, Nancy Lemke, Sandra A Rempel, Chaya Brodie
    Abstract:

    We studied the effect of the integrin inhibitor Cilengitide in glioma cells. Cilengitide induced cell detachment and decreased cell viability, and induction of autophagy followed by cell apoptosis. In addition, Cilengitide decreased the cell renewal of glioma stem-like cells (GSCs). Inhibition of autophagy decreased the cytotoxic effect of Cilengitide. Pretreatment of glioma cells and GSCs with Cilengitide prior to γ-irradiation resulted in a larger increase in autophagy and a more significant decrease in cell survival. We found that Cilengitide induced autophagy collectively in glioma cells, xenografts, and GSCs, which contributed to its cytotoxic effects and sensitized these cells to γ-radiation.

David A. Reardon - One of the best experts on this subject based on the ideXlab platform.

  • Cilengitide a prototypic integrin inhibitor for the treatment of glioblastoma and other malignancies
    Genes & Cancer, 2011
    Co-Authors: David A. Reardon, David A Cheresh
    Abstract:

    Integrins are critical intermediaries in a wide spectrum of cancer cell activities and thus represent a highly attractive target in oncology therapy. Nonetheless, successful exploitation of anti-integrin therapeutics has proven challenging to date for cancer patients. In this review, we will focus on Cilengitide, an RGD pentapeptide inhibitor of α V integrins. Although several integrin inhibitors are under clinical evaluation, Cilengitide is the most clinically advanced and is emerging as a prototype for this class of anticancer therapy. A foundation of encouraging preclinical studies led to a well-designed clinical development plan that culminated in a pivotal phase III study of Cilengitide in combination with radiation therapy and temozolomide chemotherapy for newly diagnosed glioblastoma patients. Accrual to this study recently completed, while phase II studies of Cilengitide are ongoing for head and neck cancer as well as lung cancer. Important future considerations for Cilengitide and other integrin-targeting agents will likely include the identification of optimal combinatorial regimens and the delineation of biomarkers associated with efficacy.

  • Cilengitide an rgd pentapeptide ανβ3 and ανβ5 integrin inhibitor in development for glioblastoma and other malignancies
    Future Oncology, 2011
    Co-Authors: David A. Reardon, Bart Neyns, Michael Weller, Joerg C Tonn, Louis B Nabors, Roger Stupp
    Abstract:

    Cilengitide, a cyclicized arginine-glycine-aspartic acid-containing pentapeptide, potently blocks ανβ3 and ανβ5 integrin activation. Integrins are upregulated in many malignancies and mediate a wide variety of tumor-stroma interactions. Cilengitide and other integrin-targeting therapeutics have preclinical activity against many cancer subtypes including glioblastoma (GBM), the most common and deadliest CNS tumor. Cilengitide is active against orthotopic GBM xenografts and can augment radiotherapy and chemotherapy in these models. In Phase I and II GBM trials, Cilengitide and the combination of Cilengitide with standard temozolomide and radiation demonstrate consistent antitumor activity and a favorable safety profile. Cilengitide is currently under evaluation in a pivotal, randomized Phase III study (Cilengitide in Combination With Temozolomide and Radiotherapy in Newly Diagnosed Glioblastoma Phase III Randomized Clinical Trial [CENTRIC]) for newly diagnosed GBM. In addition, randomized controlled Phase II studies with Cilengitide are ongoing for non-small-cell lung cancer and squamous cell carcinoma of the head and neck. Cilengitide is the first integrin inhibitor in clinical Phase III development for oncology.

  • Cilengitide an rgd pentapeptide ανβ3 and ανβ5 integrin inhibitor in development for glioblastoma and other malignancies
    Future Oncology, 2011
    Co-Authors: David A. Reardon, Bart Neyns, Michael Weller, Joerg C Tonn, Louis B Nabors, Roger Stupp
    Abstract:

    Cilengitide, a cyclicized arginine–glycine–aspartic acid-containing pentapeptide, potently blocks ανβ3 and ανβ5 integrin activation. Integrins are upregulated in many malignancies and mediate a wide variety of tumor–stroma interactions. Cilengitide and other integrin-targeting therapeutics have preclinical activity against many cancer subtypes including glioblastoma (GBM), the most common and deadliest CNS tumor. Cilengitide is active against orthotopic GBM xenografts and can augment radiotherapy and chemotherapy in these models. In Phase I and II GBM trials, Cilengitide and the combination of Cilengitide with standard temozolomide and radiation demonstrate consistent antitumor activity and a favorable safety profile. Cilengitide is currently under evaluation in a pivotal, randomized Phase III study (Cilengitide in Combination With Temozolomide and Radiotherapy in Newly Diagnosed Glioblastoma Phase III Randomized Clinical Trial [CENTRIC]) for newly diagnosed GBM. In addition, randomized controlled Phase I...

  • Cilengitide in patients with newly diagnosed glioblastoma multiforme and unmethylated mgmt gene promoter protocol of a multicenter randomized open label controlled phase ii study
    Journal of Clinical Oncology, 2010
    Co-Authors: Louis B Nabors, David A. Reardon, Karen Fink, G J Lesser, J Trusheim, S N Raval, Christine Hicking, Martin Picard, Tom Mikkelsen
    Abstract:

    TPS151 Background: Expected median survival is poor for patients with glioblastoma multiforme (GBM). Cilengitide, an investigational selective αvβ3/5 integrin inhibitor, has demonstrated antitumor activity against GBM in previous phase II studies. CORE (Cilengitide in combination with temozolomide [TMZ] and radiotherapy [RTX]) will assess the efficacy and safety of 2 regimens of Cilengitide in GBM patients with an unmethylated MGMT promoter. The study is a companion trial to CENTRIC, which includes patients with newly diagnosed GBM with methylated MGMT promoter. Methods: CORE is a phase II, randomized, multicenter, open-label, controlled, trial investigating 2 regimens of i.v. Cilengitide in combination with standard therapy [RTX/TMZ then TMZ; Stupp et al NEJM 2005] vs standard therapy alone (2:2:1 ratio). The 2 Cilengitide regimens compare 2,000 mg twice weekly vs. 2,000 mg 5 times weekly on each day of RTX during 6 weeks of RTX/TMZ, followed by Cilengitide 2,000 mg twice-weekly combined with TMZ, follow...

  • Cilengitide in newly diagnosed glioblastoma with mgmt promoter methylation protocol of a multicenter randomized open label controlled phase iii trial centric
    Journal of Clinical Oncology, 2010
    Co-Authors: Roger Stupp, David A. Reardon, Monika E Hegi, Sara Erridge, Yongkil Hong, Martin Picard, M J Van Den Bent, Helen Wheeler, James R Perry, Michael Weller
    Abstract:

    TPS152 Background: Infiltration and migration is characteristic of glioblastoma. Cilengitide, a novel selective αvβ3/5 integrin inhibitor, interferes with tumor cell attachment, tumor-stroma crosstalk and angiogenesis. Activity appears most pronounced when Cilengitide is combined with an active cytotoxic agent or radiotherapy (RT), and particular sensitivity to temozolomide (TMZ) has been shown in tumors with a methylated MGMT promoter. Methods: CENTRIC is an international, randomized, controlled phase III study of Cilengitide 2000 mg twice weekly i.v. in addition to standard TMZ/RT→MZ compared to standard TMZ/RT→TMZ (Stupp et al. NEJM 2005). For nonprogressive patients, maintenance Cilengitide is continued for up to 18 months. This trial is organized in a collaborative effort by Merck KGaA (Germany), the European Organization for Research and Treatment (EORTC) and the Canadian Brain Tumor Consortium (CBTC). Overall survival time is the primary endpoint. Secondary objectives include progression-free survi...

Roger Stupp - One of the best experts on this subject based on the ideXlab platform.

  • 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, 2014
    Co-Authors: Roger Stupp, Monika E Hegi, Thierry Gorlia, Sara Erridge, James C Perry, Yongkil Hong, Kenneth D Aldape, Benoit Lhermitte, Torsten Pietsch, Danica Grujicic
    Abstract:

    Summary 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.

  • Cilengitide an rgd pentapeptide ανβ3 and ανβ5 integrin inhibitor in development for glioblastoma and other malignancies
    Future Oncology, 2011
    Co-Authors: David A. Reardon, Bart Neyns, Michael Weller, Joerg C Tonn, Louis B Nabors, Roger Stupp
    Abstract:

    Cilengitide, a cyclicized arginine-glycine-aspartic acid-containing pentapeptide, potently blocks ανβ3 and ανβ5 integrin activation. Integrins are upregulated in many malignancies and mediate a wide variety of tumor-stroma interactions. Cilengitide and other integrin-targeting therapeutics have preclinical activity against many cancer subtypes including glioblastoma (GBM), the most common and deadliest CNS tumor. Cilengitide is active against orthotopic GBM xenografts and can augment radiotherapy and chemotherapy in these models. In Phase I and II GBM trials, Cilengitide and the combination of Cilengitide with standard temozolomide and radiation demonstrate consistent antitumor activity and a favorable safety profile. Cilengitide is currently under evaluation in a pivotal, randomized Phase III study (Cilengitide in Combination With Temozolomide and Radiotherapy in Newly Diagnosed Glioblastoma Phase III Randomized Clinical Trial [CENTRIC]) for newly diagnosed GBM. In addition, randomized controlled Phase II studies with Cilengitide are ongoing for non-small-cell lung cancer and squamous cell carcinoma of the head and neck. Cilengitide is the first integrin inhibitor in clinical Phase III development for oncology.

  • Cilengitide an rgd pentapeptide ανβ3 and ανβ5 integrin inhibitor in development for glioblastoma and other malignancies
    Future Oncology, 2011
    Co-Authors: David A. Reardon, Bart Neyns, Michael Weller, Joerg C Tonn, Louis B Nabors, Roger Stupp
    Abstract:

    Cilengitide, a cyclicized arginine–glycine–aspartic acid-containing pentapeptide, potently blocks ανβ3 and ανβ5 integrin activation. Integrins are upregulated in many malignancies and mediate a wide variety of tumor–stroma interactions. Cilengitide and other integrin-targeting therapeutics have preclinical activity against many cancer subtypes including glioblastoma (GBM), the most common and deadliest CNS tumor. Cilengitide is active against orthotopic GBM xenografts and can augment radiotherapy and chemotherapy in these models. In Phase I and II GBM trials, Cilengitide and the combination of Cilengitide with standard temozolomide and radiation demonstrate consistent antitumor activity and a favorable safety profile. Cilengitide is currently under evaluation in a pivotal, randomized Phase III study (Cilengitide in Combination With Temozolomide and Radiotherapy in Newly Diagnosed Glioblastoma Phase III Randomized Clinical Trial [CENTRIC]) for newly diagnosed GBM. In addition, randomized controlled Phase I...

  • phase i iia study of Cilengitide and temozolomide with concomitant radiotherapy followed by Cilengitide and temozolomide maintenance therapy in patients with newly diagnosed glioblastoma
    Journal of Clinical Oncology, 2010
    Co-Authors: Roger Stupp, Bart Neyns, Monika E Hegi, Paul Clement, Adrian F Ochsenbein, Uwe Schlegel, Roland Goldbrunner, Gerhard G Grabenbauer, Matthias Simon, Pierreyves Dietrich
    Abstract:

    Purpose 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 and Methods Patients (age 18 to 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. Results 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. Conclusion 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. J Clin Oncol 28:2712-2718. © 2010 by American Society of Clinical Oncology

  • Cilengitide in newly diagnosed glioblastoma with mgmt promoter methylation protocol of a multicenter randomized open label controlled phase iii trial centric
    Journal of Clinical Oncology, 2010
    Co-Authors: Roger Stupp, David A. Reardon, Monika E Hegi, Sara Erridge, Yongkil Hong, Martin Picard, M J Van Den Bent, Helen Wheeler, James R Perry, Michael Weller
    Abstract:

    TPS152 Background: Infiltration and migration is characteristic of glioblastoma. Cilengitide, a novel selective αvβ3/5 integrin inhibitor, interferes with tumor cell attachment, tumor-stroma crosstalk and angiogenesis. Activity appears most pronounced when Cilengitide is combined with an active cytotoxic agent or radiotherapy (RT), and particular sensitivity to temozolomide (TMZ) has been shown in tumors with a methylated MGMT promoter. Methods: CENTRIC is an international, randomized, controlled phase III study of Cilengitide 2000 mg twice weekly i.v. in addition to standard TMZ/RT→MZ compared to standard TMZ/RT→TMZ (Stupp et al. NEJM 2005). For nonprogressive patients, maintenance Cilengitide is continued for up to 18 months. This trial is organized in a collaborative effort by Merck KGaA (Germany), the European Organization for Research and Treatment (EORTC) and the Canadian Brain Tumor Consortium (CBTC). Overall survival time is the primary endpoint. Secondary objectives include progression-free survi...

Michael Weller - One of the best experts on this subject based on the ideXlab platform.

  • Cilengitide an rgd pentapeptide ανβ3 and ανβ5 integrin inhibitor in development for glioblastoma and other malignancies
    Future Oncology, 2011
    Co-Authors: David A. Reardon, Bart Neyns, Michael Weller, Joerg C Tonn, Louis B Nabors, Roger Stupp
    Abstract:

    Cilengitide, a cyclicized arginine-glycine-aspartic acid-containing pentapeptide, potently blocks ανβ3 and ανβ5 integrin activation. Integrins are upregulated in many malignancies and mediate a wide variety of tumor-stroma interactions. Cilengitide and other integrin-targeting therapeutics have preclinical activity against many cancer subtypes including glioblastoma (GBM), the most common and deadliest CNS tumor. Cilengitide is active against orthotopic GBM xenografts and can augment radiotherapy and chemotherapy in these models. In Phase I and II GBM trials, Cilengitide and the combination of Cilengitide with standard temozolomide and radiation demonstrate consistent antitumor activity and a favorable safety profile. Cilengitide is currently under evaluation in a pivotal, randomized Phase III study (Cilengitide in Combination With Temozolomide and Radiotherapy in Newly Diagnosed Glioblastoma Phase III Randomized Clinical Trial [CENTRIC]) for newly diagnosed GBM. In addition, randomized controlled Phase II studies with Cilengitide are ongoing for non-small-cell lung cancer and squamous cell carcinoma of the head and neck. Cilengitide is the first integrin inhibitor in clinical Phase III development for oncology.

  • Cilengitide an rgd pentapeptide ανβ3 and ανβ5 integrin inhibitor in development for glioblastoma and other malignancies
    Future Oncology, 2011
    Co-Authors: David A. Reardon, Bart Neyns, Michael Weller, Joerg C Tonn, Louis B Nabors, Roger Stupp
    Abstract:

    Cilengitide, a cyclicized arginine–glycine–aspartic acid-containing pentapeptide, potently blocks ανβ3 and ανβ5 integrin activation. Integrins are upregulated in many malignancies and mediate a wide variety of tumor–stroma interactions. Cilengitide and other integrin-targeting therapeutics have preclinical activity against many cancer subtypes including glioblastoma (GBM), the most common and deadliest CNS tumor. Cilengitide is active against orthotopic GBM xenografts and can augment radiotherapy and chemotherapy in these models. In Phase I and II GBM trials, Cilengitide and the combination of Cilengitide with standard temozolomide and radiation demonstrate consistent antitumor activity and a favorable safety profile. Cilengitide is currently under evaluation in a pivotal, randomized Phase III study (Cilengitide in Combination With Temozolomide and Radiotherapy in Newly Diagnosed Glioblastoma Phase III Randomized Clinical Trial [CENTRIC]) for newly diagnosed GBM. In addition, randomized controlled Phase I...

  • Cilengitide in newly diagnosed glioblastoma with mgmt promoter methylation protocol of a multicenter randomized open label controlled phase iii trial centric
    Journal of Clinical Oncology, 2010
    Co-Authors: Roger Stupp, David A. Reardon, Monika E Hegi, Sara Erridge, Yongkil Hong, Martin Picard, M J Van Den Bent, Helen Wheeler, James R Perry, Michael Weller
    Abstract:

    TPS152 Background: Infiltration and migration is characteristic of glioblastoma. Cilengitide, a novel selective αvβ3/5 integrin inhibitor, interferes with tumor cell attachment, tumor-stroma crosstalk and angiogenesis. Activity appears most pronounced when Cilengitide is combined with an active cytotoxic agent or radiotherapy (RT), and particular sensitivity to temozolomide (TMZ) has been shown in tumors with a methylated MGMT promoter. Methods: CENTRIC is an international, randomized, controlled phase III study of Cilengitide 2000 mg twice weekly i.v. in addition to standard TMZ/RT→MZ compared to standard TMZ/RT→TMZ (Stupp et al. NEJM 2005). For nonprogressive patients, maintenance Cilengitide is continued for up to 18 months. This trial is organized in a collaborative effort by Merck KGaA (Germany), the European Organization for Research and Treatment (EORTC) and the Canadian Brain Tumor Consortium (CBTC). Overall survival time is the primary endpoint. Secondary objectives include progression-free survi...

  • Cilengitide modulates attachment and viability of human glioma cells but not sensitivity to irradiation or temozolomide in vitro
    Neuro-oncology, 2009
    Co-Authors: Gabriele Maurer, Roger Stupp, Michael Weller, Isabel Tritschler, Barbara Adams, Ghazaleh Tabatabai, Wolfgang Wick
    Abstract:

    Cilengitide is a cyclic peptide antagonist of integrins alphavbeta3 and alphavbeta5 that is currently being evaluated as a novel therapeutic agent for recurrent and newly diagnosed glioblastoma. Its mode of action is thought to be mainly antiangiogenic but may include direct effects on tumor cells, notably on attachment, migration, invasion, and viability. In this study we found that, at clinically relevant concentrations, Cilengitide (1-100 microM) induces detachment in some but not all glioma cell lines, while the effect on cell viability is modest. Detachment induced by Cilengitide could not be predicted by the level of expression of the Cilengitide target molecules, alphavbeta3 and alphavbeta5, at the cell surface. Glioma cell death induced by Cilengitide was associated with the generation of caspase activity, but caspase activity was not required for cell death since ectopic expression of cytokine response modifier (crm)-A or coexposure to the broad-spectrum caspase inhibitor zVAD-fmk was not protective. Moreover, forced expression of the antiapoptotic protein marker Bcl-X(L) or altering the p53 status did not modulate Cilengitide-induced cell death. No consistent effects of Cilengitide on glioma cell migration or invasiveness were observed in vitro. Preliminary clinical results indicate a preferential benefit from Cilengitide added to temozolomide-based radiochemotherapy in patients with O(6)-methylguanine DNA methyltransferase (MGMT) gene promoter methylation. Accordingly, we also examined whether the MGMT status determines glioma cell responses to Cilengitide alone or in combination with temozolomide. Neither ectopic expression of MGMT in MGMT-negative cells nor silencing the MGMT gene in MGMT-positive cells altered glioma cell responses to Cilengitide alone or to Cilengitide in combination with temozolomide. These data suggest that the beneficial clinical effects derived from Cilengitide in vivo may arise from altered perfusion, which promotes temozolomide delivery to glioma cells.

  • phase i iia trial of Cilengitide emd121974 and temozolomide with concomitant radiotherapy followed by temozolomide and Cilengitide maintenance therapy in patients pts with newly diagnosed glioblastoma gbm
    Journal of Clinical Oncology, 2007
    Co-Authors: Roger Stupp, Bart Neyns, Monika E Hegi, Martin Picard, Paul Clement, Uwe Schlegel, Roland Goldbrunner, Gerhard G Grabenbauer, Johannes Nippgen, Michael Weller
    Abstract:

    2000 Background: To evaluate safety, toxicity, and efficacy of the combination of the cyclic RGD pentapeptide Cilengitide (EMD121974), an inhibitor of integrins avβ3 and avβ5, in addition to standa...

M Hussain - One of the best experts on this subject based on the ideXlab platform.

  • Cilengitide (EMD 121974, NSC 707544) in asymptomatic metastatic castration resistant prostate cancer patients: a randomized phase II trial by the prostate cancer clinical trials consortium
    Investigational New Drugs, 2011
    Co-Authors: Deborah A Bradley, Robert S Dipaola, Mitchell E Gross, Charles J Ryan, Stephanie Daignault, D C Smith, Eric Small, Mark N. Stein, Alice Chen, M Hussain
    Abstract:

    Background Integrins are involved in prostate cancer metastasis by regulating cell adhesion, migration, invasion, motility, angiogenesis and bone metabolism. We evaluated the efficacy of two dose levels of Cilengitide in patients (pts) with castrate resistant prostate cancer (CRPC). Methods Chemotherapy-naïve, asymptomatic metastatic CRPC pts were randomized to Cilengitide 500 mg or 2,000 mg IV twice weekly using parallel 2-stage design. The primary endpoint was rate of objective clinical progression at 6-months. Secondary endpoints included clinical and PSA response rates, safety and effects of Cilengitide treatment on circulating tumor cells (CTCs) and bone remodeling markers. Results Forty-four pts were accrued to first stage (22/arm). Median number of cycles was three in both arms (500 mg arm: 1–8; 2,000 mg arm: 1–15). At 6 months, two pts (9%) on the 500 mg arm and five pts (23%) on the 2,000 mg arm had not progressed. Best objective response was stable disease (SD) in seven pts for 9.9[8.1,20.9] months. There were three grade 3 and no grade 4 toxicities. At 12 weeks, analysis of bone markers did not reveal significant trends. At progression, bone specific alkaline phosphatase and N-telopeptide increased in all pts, less so in pts on the 2,000 mg arm and in pts on both arms who obtained SD at 6 months. CTCs increased over time in both arms. Conclusion Cilengitide was well tolerated with modest clinical effect in favor of the higher dose. The unique trial design including a shift from response rate to objective progression as the endpoint, and not acting on PSA increases was feasible.

  • Cilengitide in asymptomatic metastatic androgen independent prostate cancer aipc patients pts a randomized phase ii trial
    Journal of Clinical Oncology, 2008
    Co-Authors: Deborah A Bradley, Mitchell E Gross, Evan T Keller, Charles J Ryan, Stephanie Daignault, R P Dipaola, D C Smith, Paul Mathew, A P Chen, M Hussain
    Abstract:

    5144 Background: Integrins αvβ3 and αvβ5 are involved in PC metastasis by regulating cell adhesion, migration, invasion, motility and angiogenesis. αvβ3 integrin is important in bone metabolism and may play a role in PC growth in bone. Cilengitide is a selective, competitive inhibitor of αvβ3 and αvβ5 integrins. Methods: Chemo-naive pts with asymptomatic progressive metastatic AIPCa were randomized to Cilengitide 500 mg or 2,000 mg IV 2X/week (wk) in 6-wk cycles using Simon 2-stage optimal design. Disease was assessed q 12 wks. The primary end point was 6 month (m) objective progression rate (PgR) (excluding PSA). Historically a 75% PgR is expected. We hypothesized Cilengitide would lower the 6 m PgR to 55%. > 6 pts/arm with no Pg were needed to move to 2nd stage. Pts with asymptomatic Pg at 1st assessment were permitted to receive 1 more cycle followed by reassessment. Secondary end points include safety, response rate, changes in circulating tumor cells (CTCs) and bone markers. Results: 44 pts were accr...

  • emd121974 nsc 707544 Cilengitide in asymptomatic metastatic androgen independent prostate cancer aipca patients pts a randomized trial by the prostate cancer clinical trials consortium nci 6372
    Journal of Clinical Oncology, 2007
    Co-Authors: Deborah A Bradley, Kathleen A Cooney, Robert S Dipaola, Rodney L Dunn, Mitchell E Gross, Charles J Ryan, D C Smith, Paul Mathew, A D Colevas, M Hussain
    Abstract:

    5137 Background: Integrins avβ3 and avβ5 are essential to PCa metastasis by regulating cell adhesion, migration, invasion and motility. Cilengitide is a potent and selective avβ3 and avβ5 integrin receptor antagonist that in phase I studies has shown clinical activity. Methods: Pts with asymptomatic, metastatic chemo-naive AIPCa with PSA or objective progression, no visceral disease, minimum PSA of 5ng/ml, and adequate organ function were randomized to Cilengitide 500 mg or 2,000 mg IV 2X weekly in 6-week cycles, using modified randomized selection design. Disease status was assessed every 12 weeks. The primary end point is objective progression rate (not including PSA) at 6 months. The Simon 2-stage optimal design is used to accrue 53 pts/arm. After first stage (20 pts/arm), accrual continues if ≥ 6 pts have not progressed. If second stage accrual is initiated, at end of study, the better performing arm will be chosen for further study provided at least 18/53 pts in that arm have not progressed. Secondar...