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Phase I Clinical Trial of Cilengitide in Children With Refractory Brain Tumors: Pediatric Brain Tumor Consortium Study PBTC-012

Tobey J. MacDonald, Clinton F. Stewart, Mehmet Kocak, Stewart Goldman, Richard G. Ellenbogen, Peter Phillips, Deborah Lafond, Tina Young Poussaint, Mark W. Kieran, James M. Boyett, Larry E. Kun

From the Children's National Medical Center, Washington, DC; Dana-Farber Cancer Institute; Children's Hospital Boston, Boston, MA; Children's Hospital of Philadelphia, Philadelphia, PA; St Jude Children's Research Hospital; Pediatric Brain Tumor Consortium, Memphis, TN; Children's Hospital and Medical Center, Seattle, WA; and Children's Memorial Hospital, Chicago, IL

Corresponding author: Tobey J. MacDonald, MD, Children's National Medical Center, 111 Michigan Ave, NW, Washington, DC 20010; e-mail: tmacdona{at}cnmc.org

Purpose: A phase I trial of the antiangiogenesis agent cilengitide (EMD 121974), an alpha v beta 3,5 integrin antagonist, was performed to estimate the maximum-tolerated dose (MTD) and describe dose-limiting toxicities (DLTs) and the incidence and severity of other toxicities when administered to children with refractory brain tumors.

Patients and Methods: Thirty-one assessable patients received intravenous cilengitide over 1 hour twice a week for up to 52 weeks at dosages from 120 to 2,400 mg/m². Serial blood and urine samples for clinical pharmacology studies were obtained in a subset of consenting patients.

Results: No DLTs were observed, and thus, the MTD was not estimated. Three of 13 patients at the dosage level of 2,400 mg/m² experienced grade 3 or 4 intratumoral hemorrhage (ITH) possibly related to the study drug; however, two of the ITH events were asymptomatic and, by the current toxicity criteria, would be classified as grade 1. For patients treated at cilengitide 2,400 mg/m², the 6-month cumulative incidence estimate of ITH is 23% (SE = 13%). No ITH was observed at 1,800 mg/m². Three patients completed 1 year of protocol therapy; one patient with glioblastoma multiforme demonstrated complete response, and two patients had stable disease (SD). An additional patient had SD for more than 5 months.

Conclusion: The phase II dosage of intravenous cilengitide in children with refractory brain tumors is 1,800 mg/m². A phase II trial to assess the efficacy of cilengitide therapy for children with refractory brain tumors is being developed by the Children's Oncology Group.

Supported in part by National Institutes of Health Grant No. U01 CA81457 for the Pediatric Brain Tumor Consortium and the American Lebanese Syrian Associated Charities.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.