Phase I and pharmacokinetic study of continuous twice weekly intravenous administration of Cilengitide (EMD 121974), a novel inhibitor of the integrins αvβ3 and αvβ5 in patients with advanced solid tumours

Eskens, Ferry A.L.M.; Dumez, Herlinde; Hoekstra, Ronald; Perschl, A; Brindley, C.; Böttcher, Sebastian; Wynendaele, Wim; Drevs, Joachim; Verweij, Jaap; Oosterom, A.T. van

doi:10.1016/s0959-8049(03)00057-1

Cited by 220 publications

(178 citation statements)

References 18 publications

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“…Results from a number of clinical trials reveal consistent pharmacokinetic measures [42,44,[83][84][85].…”

Section: Pharmacokinetics and Metabolismmentioning

confidence: 91%

“…The initial phase I trials of cilengitide prioritized the evaluation of safety and toxicity with secondary pharmacokinetic and correlative endpoints. An initial phase I study enrolled 37 patients with advanced solid tumors [85].…”

Section: Clinical Efficacymentioning

confidence: 99%

“…Phase I studies of cilengitide monotherapy among adult solid tumor and GBM patients did not identify dose dependent or dose-limiting toxicity despite wide dosing ranges of cilengitide tested (up to 2400 mg/m 2 which approximates 4000 mg twice weekly) [42,44,85]. Furthermore, no consistent toxicities have been observed in additional phase II studies [9,43,83,85,101,102]. Among all adverse events reported, regardless of causality, among patients treated with cilengitide, the most common observed nonhematologic toxicities include fatigue, nausea, dyspnea, headache, peripheral edema, diarrhea, constipation and anorexia.…”

Section: Safety and Tolerabilitymentioning

confidence: 99%

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Cilengitide: an RGD pentapeptide ανβ3 and ανβ5 integrin inhibitor in development for glioblastoma and other malignancies

et al. 2011

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Cilengitide, a cyclicized arginine-glycine-aspartic acid-containing pentapeptide, potently blocks 3 and 5 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 cancer subtypes including glioblastoma (GBM), the most common and deadliest central nervous system (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 (TMZ) and radiation demonstrate consistent anti-tumor activity and a favorable safety profile. Cilengitide is currently under evaluation in a pivotal, randomized phase III study (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.

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“…Results from a number of clinical trials reveal consistent pharmacokinetic measures [42,44,[83][84][85].…”

Section: Pharmacokinetics and Metabolismmentioning

confidence: 91%

Section: Clinical Efficacymentioning

confidence: 99%

Section: Safety and Tolerabilitymentioning

confidence: 99%

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Cilengitide: an RGD pentapeptide ανβ3 and ανβ5 integrin inhibitor in development for glioblastoma and other malignancies

et al. 2011

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“…A phase I study exploring a continuous twice weekly i.v. administration schedule showed excellent clinical tolerability with no drug-related side effects following a predefined dose escalation schedule (Eskens et al, 2003). Pharmacokinetic analysis demonstrated that plasma concentrations exceeding those that yielded optimal antiangiogenic activity in preclinical models were reached.…”

Section: Other Inhibitors Of Endothelial Cell Proliferationmentioning

confidence: 95%

Angiogenesis inhibitors in clinical development; where are we now and where are we going?

Eskens

2004

Br J Cancer

174

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Angiogenesis is crucial for tumour growth and the formation of metastases. Various classes of angiogenesis inhibitors that are each able to inhibit one of the various steps of this complex process can be distinguished. Results from clinical studies with these agents are summarised. In general, it has been shown that most angiogenesis inhibitors can be safely administered, but that tumour regressions are rare. Combining angiogenesis inhibitors with cytotoxic chemotherapy can enhance anticancer activity. Recently, some promising data with regard to clinical efficacy have been presented. While performing clinical studies with angiogenesis inhibitors, defining biological activity is crucial, but thus far no validated techniques are available. It is conceivable that in the near future various classes of angiogenesis inhibitors will be combined in an attempt to further improve antiangiogenic and anticancer activity.

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“…One such cyclic RGD peptide is cilengitide (EMD 121974), cyclo-(Arg-GlyAsp-D-Phe-(N-Me)-Val). [17][18][19] Cilengitide disrupts VE-cadherin localization at cell junctions, and increases endothelial monolayer permeability 20 and disrupts angiogenesis in vitro 21 and in vivo. 22 In a tumor-induced CAM assay, it inhibits cell-matrix contact and angiogenesis.…”

mentioning

confidence: 99%

The αVβ3/αVβ5 integrin inhibitor cilengitide augments tumor response to melphalan isolated limb perfusion in a sarcoma model

Hagen

Seynhaeve

Wiel-Ambagtsheer

et al. 2012

Intl Journal of Cancer

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Isolated limb perfusion (ILP) with melphalan and tumor necrosis factor (TNF)-a is used to treat bulky, locally advanced melanoma and sarcoma. However, TNF toxicity suggests a need for better-tolerated drugs. Cilengitide (EMD 121974), a novel cyclic inhibitor of alpha-V integrins, has both anti-angiogenic and direct anti-tumor effects and is a possible alternative to TNF in ILP. In this study, rats bearing a hind limb soft tissue sarcoma underwent ILP using different combinations of melphalan, TNF and cilengitide in the perfusate. Further groups had intra-peritoneal (i.p.) injections of cilengitide or saline 2 hr before and 3 hr after ILP. A 77% response rate (RR) was seen in animals treated i.p. with cilengitide and perfused with melphalan plus cilengitide. The RR was 85% in animals treated i.p. with cilengitide and ILP using melphalan plus both TNF and cilengitide. Both RRs were significantly greater than those seen with melphalan or cilengitide alone. Histopathology showed that high RRs were accompanied by disruption of tumor vascular endothelium and tumor necrosis. Compared with ILP using melphalan alone, the addition of cilengitide resulted in a three to sevenfold increase in melphalan concentration in tumor but not in muscle in the perfused limb. Supportive in vitro studies indicate that cilengitide both inhibits tumor cell attachment and increases endothelial permeability. Since cilengitide has low toxicity, these data suggest the agent is a good alternative to TNF in the ILP setting.Since the continued growth of solid tumors requires angiogenesis, an anti-angiogenic approach to cancer therapy is logical. Since angiogenesis is mediated in part by adhesion receptors of the integrin family, including the alpha-V (aV) integrins, 1,2 there is a strong rationale for assessing the effects of integrin inhibitors in cancer treatment. Cilengitide (EMD

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Phase I and pharmacokinetic study of continuous twice weekly intravenous administration of Cilengitide (EMD 121974), a novel inhibitor of the integrins αvβ3 and αvβ5 in patients with advanced solid tumours

Cited by 220 publications

References 18 publications

Cilengitide: an RGD pentapeptide ανβ3 and ανβ5 integrin inhibitor in development for glioblastoma and other malignancies

Cilengitide: an RGD pentapeptide ανβ3 and ανβ5 integrin inhibitor in development for glioblastoma and other malignancies

Angiogenesis inhibitors in clinical development; where are we now and where are we going?

The αVβ3/αVβ5 integrin inhibitor cilengitide augments tumor response to melphalan isolated limb perfusion in a sarcoma model

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