A randomized multi-center phase II trial of the angiogenesis inhibitor Cilengitide (EMD 121974) and gemcitabine compared with gemcitabine alone in advanced unresectable pancreatic cancer

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: 99%

“…Importantly, cilengitide is not associated with hemorrhages, delayed wound healing or wound dehiscence, or other adverse events when administered peri-operatively to GBM patients undergoing craniotomy [86]. In addition, cilengitide does not appear to exacerbate toxicity associated with chemotherapy or radiotherapy [43,84].…”

Section: Safety and Tolerabilitymentioning

confidence: 99%

Cilengitide: An RGD Pentapeptide ανβ3 and ανβ5 Integrin Inhibitor in Development for Glioblastoma and Other Malignancies

et al. 2011

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“…However, such highly concentrated antibody solutions can demonstrate high viscosities in some cases, 10 which can lead to serious difficulties in their development as drug products suitable for subcutaneous administration 10 because high viscosity may increase the injection time and pain at the site of injection, adversely affecting patient compliance. 12,13 High viscosity of a concentrated antibody solution also poses difficulties during bioprocessing of the drug substance. During downstream ultrafiltration and diafiltration steps, high viscosity of the antibody solution may increase the back pressure of the pump and decrease the transmembrane flux, which may increase the processing time, destabilize the drug substance and increase manufacturing costs.…”

Section: Introductionmentioning

confidence: 99%

Molecular basis of high viscosity in concentrated antibody solutions: Strategies for high concentration drug product development

Tomar

Kumar

Singh

et al. 2016

mAbs

160

145

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Effective translation of breakthrough discoveries into innovative products in the clinic requires proactive mitigation or elimination of several drug development challenges. These challenges can vary depending upon the type of drug molecule. In the case of therapeutic antibody candidates, a commonly encountered challenge is high viscosity of the concentrated antibody solutions. Concentration-dependent viscosity behaviors of mAbs and other biologic entities may depend on pairwise and higher-order intermolecular interactions, non-native aggregation, and concentration-dependent fluctuations of various antibody regions. This article reviews our current understanding of molecular origins of viscosity behaviors of antibody solutions. We discuss general strategies and guidelines to select low viscosity candidates or optimize lead candidates for lower viscosity at early drug discovery stages. Moreover, strategies for formulation optimization and excipient design are also presented for candidates already in advanced product development stages. Potential future directions for research in this field are also explored.

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“…Z kolei terapia PEFG (cisplatyna, epirubicyna, 5-FU, gemcytabina) w porównaniu z gemcytabiną w monoterapii przedłuża czas przeżycia i okres bez progresji, lecz wykazuje więcej działań niepożądanych [56]. Dodanie bewacizumabu do gemcytabiny z erlotinibem było nieskuteczne i kosztowne [57], podobnie jak VEGFR 1, VEGFR 2 i VEGFR 3 [58], a także innych preparatów hamujących angiogenezę [59]. Połączenie gemcytabiny z infliksymabem nie przyniosło dodatkowych korzyści [60].…”

Section: Terapia łąCzona Z Zastosowaniem Gemcytabiny W Zaawansowanym unclassified

Randomized trials in exocrine pancreatic cancer

Andrén‐Sandberg¹,

Hedberg²,

Winter³

et al. 2011

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StreszczenieLeczenie raka trzustki jest poważnym problemem współczes -nej medycyny. Rak ten stanowi ok. 3% nowotworów wykrywanych corocznie na świecie i zajmuje 4. miejsce pod względem śmiertelności wśród nowotworów złośliwych. Agresywny przebieg, późne rozpoznanie oraz oporność na stosowane leczenie powoduje, że 5-letnie przeżycie nie przekracza 5%. Podstawową metodą terapii wczesnych postaci nowotworu jest radykalny zabieg, jednak w chwili rozpoznania u 80-90% chorych proces nowotworowy jest zaawansowany, a guz nieoperacyjny. Jedną z możliwości poprawy wyników leczenia raka trzustki jest stosowanie terapii uzupełniającej. W niniejszym artykule przedstawiono przegląd aktualnych badań z randomizacją dotyczących leczenia adiuwantowego, neoadiuwantowego, monoterapii, terapii skojarzonej oraz leczenia bólu czy roli odżywiania w terapii raka trzustki. AbstractTreatment of pancreatic cancer is a major oncological challenge. Pancreatic cancer remains a highly lethal disease and is the 4 th leading cause of cancer-related deaths in the United States, with a 5-year survival of less than 5%. The poor prognosis of this cancer is due to its propensity for early local invasion and metastasis. Most patients present with advanced disease, precluding curative surgical resection, which remains the only potential curative approach. The adjuvant treatment may improve the prognosis in pancreatic cancer. This article presents a review of randomized clinical trials including adjuvant and neoadjuvant treatment, monotherapy and combination therapy, pain relief and the role of nutrition in pancreatic cancer treatment. WstępLeczenie raka trzustki jest poważnym problemem współczesnej medycyny. Stanowi on ok. 3% nowotworów wykrywanych corocznie na świecie i zajmuje 4. miejsce pod względem śmiertelności wśród nowotworów złośli-wych. Agresywny przebieg, późne rozpoznanie oraz oporność na stosowane leczenie powoduje, że 5-letnie przeżycie nie przekracza 5%, a większość chorych umiera w ciągu 3-6 mies. od rozpoznania. Podstawową metodą terapii wczesnych postaci nowotworu jest radykalny zabieg, jednak w chwili rozpoznania u 80-90% chorych proces nowotworowy jest zaawansowany, a guz nieoperacyjny [1]. Jedną z możliwości poprawy wyników leczenia raka trzustki jest stosowanie terapii uzupełniającej.W niniejszym artykule przedstawiono przegląd aktualnych badań z randomizacją dotyczących leczenia adiuwantowego, neoadiuwantowego, monoterapii, terapii skojarzonej oraz leczenia bólu czy roli odżywiania w terapii raka trzustki.

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A randomized multi-center phase II trial of the angiogenesis inhibitor Cilengitide (EMD 121974) and gemcitabine compared with gemcitabine alone in advanced unresectable pancreatic cancer

Cited by 112 publications

References 27 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

Molecular basis of high viscosity in concentrated antibody solutions: Strategies for high concentration drug product development

Randomized trials in exocrine pancreatic cancer

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