Cilengitide in patients with recurrent glioblastoma: the results of NABTC 03-02, a phase II trial with measures of treatment delivery
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Cilengitide is a cyclic pentapeptide that is a specific inhibitor of the αvβ3 and αvβ5 integrins. Preclinical studies demonstrate antiangiogenic activity and anti-invasive activity in a number of glioma models. This study was designed to evaluate the efficacy and tumor delivery of cilengitide in patients with recurrent glioblastoma. Patients with recurrent glioblastoma who require a surgical resection for optimal clinical care received 3 intravenous doses of cilengitide at either 500 or 2000 mg (day -8, -4, -1) prior to undergoing tumor resection with corresponding blood samples for plasma to tumor comparisons. After recovery from surgery, patients were treated with cilengitide (2000 mg i.v. twice weekly, maximum of 2 years of treatment). The study accrued 30 patients with recurrent glioblastoma, 26 were evaluable for efficacy. The 6-month progression free survival rate was 12%. Cilengitide was detected in all tumor specimens with higher levels in the group receiving 2000 mg dosing while corresponding plasma concentrations were low, often below the lower limit of detection. These results confirm drug delivery and possibly retention in tumor. This study provides evidence that with established dosing, cilengitide is adequately delivered to the tumor, although as a single agent, efficacy in recurrent glioblastoma is modest. However, these results demonstrating drug delivery to tumor do support continued investigation of this agent as preliminary results from recent studies combining cilengitide with cytotoxic therapies are promising.
KeywordsGlioblastoma Pharmacokinetics Tumor pharmacokinetics Integrins
The Cilengitide was generously provided by Merck KgaA and the National Cancer Institute, NIH. This study was sponsored by NIH Grant U01 CA-062412.
Conflict of interest
Mark R. Gilbert, MD: Research support from Genentech, Advisory Affiliations with Merck, Genentech.
John Kuhn, Pharm D., Kathleen R. Lamborn, PhD, Patrick Y. Wen, MD, Timothy Cloughesy, MD, Lisa M. DeAngelis, MD, Susan Chang, MD, and Michael Prados, MD: None.
Frank Lieberman, MD: Advisory affiliations with Roche/Genentech. Paid consulting with Roche/Genentech and EMD Merck.
Minesh Mehta, MD: Consultant to Adnexus, Bayer, Genenteh, Merck, Schering Plough, YM BioSciences and Tomotherapy; on the Board of Directors of Pharmacyclics, an advisor to Colby and Stemina, and is on the DSMB for Apogenix. He holds stock options in Pharmacyclics and Tomotherapy.
Andrew B. Lassman, MD: Research support from Schering Plough, Sigma Tau, Genentech, Keryx, Astra Zeneca, Exelixis. Advisory affiliations with Bristol-Myers Squibb, Campus Bio, Cephalon, Eisai, Enzon, Genentech, Imclone, Schering-Plough, Merck. Paid consulting with Schering Plough, Merck.
- 1.Lamborn KR, Yung WK, Chang SM, Wen PY, Cloughesy TF, DeAngelis LM, Robins HI, Lieberman FS, Fine HA, Fink KL, Junck L, Abrey L, Gilbert MR, Mehta M, Kuhn JG, Aldape KD, Hibberts J, Peterson PM, Prados MD (2008) Progression-free survival: an important end point in evaluating therapy for recurrent high-grade gliomas. Neuro-oncology 10(2):162–170PubMedCrossRefGoogle Scholar
- 4.Senger DR, Ledbetter SR, Claffey KP, Papadopoulos-Sergiou A, Peruzzi CA, Detmar M (1996) Stimulation of endothelial cell migration by vascular permeability factor/vascular endothelial growth factor through cooperative mechanisms involving the alphavbeta3 integrin, osteopontin, and thrombin. Am J Pathol 149(1):293–305PubMedGoogle Scholar
- 13.Nabors L, Rosenfeld S, Mikkelsen T et al (2004) NABTT 9911: a phase I trial of EMD 121974 for treatment of patients with recurrent malignant gliomas. Neuro-oncology 6(4):379Google Scholar
- 14.Reardon D, Fink K, Nabors B, Cloughesy T, Plotkin S, Schiff D, Raizer J, Krueger S, Picard M, Mikkelsen T (2007) Phase IIa trial of cilengitide (EMD121974) single-agent therapy in patients (pts) with recurrent glioblastoma (GBM): EMD 121974-009. J Clin Oncol 25(Suppl. 18):2002Google Scholar
- 17.Nabors LB, Mikkelsen T, Rosenfeld SS, Hochberg F, Akella NS, Fisher JD, Cloud GA, Zhang Y, Carson K, Wittemer SM, Colevas AD, Grossman SA (2007) Phase I and correlative biology study of cilengitide in patients with recurrent malignant glioma. J Clin Oncol 25(13):1651–1657PubMedCrossRefGoogle Scholar
- 18.Stupp R, Goldbrunner B, Neyns B, Schlegel U, Clement P, Grabenbauer G, Hegi ME, Nippgen M, Picard M, Weller M (2007) 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). J Clin Oncol 25(Suppl. 18):2000Google Scholar
- 19.Eskens FA, Dumez H, Hoekstra R, Perschl A, Brindley C, Bottcher S, Wynendaele W, Drevs J, Verweij J, van Oosterom AT (2003) Phase I and pharmacokinetic study of continuous twice weekly intravenous administration of Cilengitide (EMD 121974), a novel inhibitor of the integrins alphavbeta3 and alphavbeta5 in patients with advanced solid tumours. Eur J Cancer 39(7):917–926PubMedCrossRefGoogle Scholar
- 20.Reardon DA, Fink KL, Mikkelsen T, Cloughesy TF, O’Neill A, Plotkin S, Glantz M, Ravin P, Raizer JJ, Rich KM, Schiff D, Shapiro WR, Burdette-Radoux S, Dropcho EJ, Wittemer SM, Nippgen J, Picard M, Nabors LB (2008) Randomized phase II study of cilengitide, an integrin-targeting arginine-glycine-aspartic acid peptide, in recurrent glioblastoma multiforme. J Clin Oncol 26(34):5610–5617PubMedCrossRefGoogle Scholar
- 21.MacDonald TJ, Stewart CF, Kocak M, Goldman S, Ellenbogen RG, Phillips P, Lafond D, Poussaint TY, Kieran MW, Boyett JM, Kun LE (2008) Phase I clinical trial of cilengitide in children with refractory brain tumors: Pediatric Brain Tumor Consortium Study PBTC-012. J Clin Oncol 26(6):919–924PubMedCrossRefGoogle Scholar
- 23.Nabors LB, Mikkelsen T, Batchelor TT, Lesser G, Rosenfeld M, Ye X, Piantadosi S, Olson J, Brem S, Grossman SA (2009) NABTT 0306: a randomized phase II trial of EMD 121974 in conjunction with concomitant and adjuvant temozolomide with radiation therapy in patients with newly diagnosed glioblastoma multiforme (GBM). J Clin Oncol 27(15s):abstr. 2001Google Scholar