Intraarterial delivery of bevacizumab and cetuximab utilizing blood-brain barrier disruption in children with high-grade glioma and diffuse intrinsic pontine glioma: results of a phase I trial

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  • 1 Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, Florida;
  • | 2 Department of Radiology, NewYork-Presbyterian Hospital—Weill Cornell Medicine, New York, New York;
  • | 3 Department of Neurosurgery, NewYork-Presbyterian Hospital—Weill Cornell Medicine, New York, New York; and
  • | 4 Department of Neurosurgery, Lenox Hill Hospital/Hofstra Northwell School of Medicine, New York, New York
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OBJECTIVE

Delivery of drugs intraarterially to brain tumors has been demonstrated in adults. In this study, the authors initiated a phase I trial of superselective intraarterial cerebral infusion (SIACI) of bevacizumab and cetuximab in pediatric patients with refractory high-grade glioma (diffuse intrinsic pontine glioma [DIPG] and glioblastoma) to determine the safety and efficacy in this population.

METHODS

SIACI was used to deliver mannitol (12.5 ml of 20% mannitol) to disrupt the blood-brain barrier (BBB), followed by bevacizumab (15 mg/kg) and cetuximab (200 mg/m2) to target VEGF and EGFR, respectively. Patients with brainstem tumors had a balloon inflated in the distal basilar artery during mannitol infusion.

RESULTS

Thirteen patients were treated (10 with DIPG and 3 with high-grade glioma). Toxicities included grade I epistaxis (2 patients) and grade I rash (2 patients). There were no dose-limiting toxicities. Of the 10 symptomatic patients, 6 exhibited subjective improvement; 92% showed decreased enhancement on day 1 posttreatment MRI. Of 10 patients who underwent MRI at 1 month, 5 had progressive disease and 5 had stable disease on FLAIR, whereas contrast-enhanced scans demonstrated progressive disease in 4 patients, stable disease in 2, partial response in 2, and complete response in 1. The mean overall survival for the 10 DIPG patients was 519 days (17.3 months), with a mean posttreatment survival of 214.8 days (7.2 months).

CONCLUSIONS

SIACI of bevacizumab and cetuximab was well tolerated in all 13 children. The authors’ results demonstrate safety of this method and warrant further study to determine efficacy. As molecular targets are clarified, novel means of bypassing the BBB, such as intraarterial therapy and convection-enhanced delivery, become more critical.

Clinical trial registration no.: NCT01884740 (clinicaltrials.gov)

ABBREVIATIONS

BBB = blood-brain barrier; BBBD = BBB disruption; CTCAE = Common Toxicity Criteria for Adverse Events; DIPG = diffuse intrinsic pontine glioma; GBM = glioblastoma; HGG = high-grade glioma; ICA = internal carotid artery; SIACI = superselective intraarterial cerebral infusion.

Image from Mavridis et al. (pp 404–415).

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