Phase I clinical trial of cilengitide in children with refractory brain tumors: Pediatric Brain Tumor Consortium Study PBTC-012.
OBJECTIVE
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.


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/m(2). 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/m(2) 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/m(2), the 6-month cumulative incidence estimate of ITH is 23% (SE = 13%). No ITH was observed at 1,800 mg/m(2). 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.


CONCLUSIONS
The phase II dosage of intravenous cilengitide in children with refractory brain tumors is 1,800 mg/m(2). 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.
MacDonald
Tobey J
TJ
Children's National Medical Center, 111 Michigan Ave, NW, Washington, DC 20010, USA. tmacdona@cnmc.org
Stewart
Clinton F
CF
Kocak
Mehmet
M
Goldman
Stewart
S
Ellenbogen
Richard G
RG
Phillips
Peter
P
Lafond
Deborah
D
Poussaint
Tina Young
TY
Kieran
Mark W
MW
Boyett
James M
JM
Kun
Larry E
LE
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000293:Adolescent; D000328:Adult; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D004334:Drug Administration Schedule; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D007262:Infusions, Intravenous; D008279:Magnetic Resonance Imaging; D008297:Male; D012910:Snake Venoms / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D016896:Treatment Outcome
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D020533:Angiogenesis Inhibitors; D012910:Snake Venoms; C422910:Cilengitide