Convection-enhanced delivery for diffuse intrinsic pontine glioma: a single-centre, dose-escalation, phase 1 trial

Abstract

Background: Diffuse intrinsic pontine glioma is one of the deadliest central nervous system tumours of childhood, with a median overall survival of less than 12 months. Convection-enhanced delivery has been proposed as a means to efficiently deliver therapeutic agents directly into the brainstem while minimising systemic exposure and associated toxic effects. We did this study to evaluate the safety of convection-enhanced delivery of a radioimmunotherapy agent targeting the glioma-associated B7-H3 antigen in children with diffuse intrinsic pontine glioma.

Methods: We did a phase 1, single-arm, single-centre, dose-escalation study at the Memorial Sloan Kettering Cancer Center (New York, NY, USA). Eligible patients were aged 3-21 years and had diffuse intrinsic pontine glioma as diagnosed by consensus of a multidisciplinary paediatric neuro-oncology team; a Lansky (patients <16 years of age) or Karnofsky (patients ≥16 years) performance score of at least 50 at study entry; a minimum weight of 8 kg; and had completed external beam radiation therapy (54·0-59·4 Gy at 1·8 Gy per fraction over 30-33 fractions) at least 4 weeks but no more than 14 weeks before enrolment. Seven dose-escalation cohorts were planned based on standard 3 + 3 rules: patients received a single infusion of 9·25, 18·5, 27·75, 37, 92·5, 120·25, or 148 MBq, respectively, at a concentration of about 37 MBq/mL by convection-enhanced delivery of the radiolabelled antibody [124I]-8H9. The primary endpoint was identification of the maximum tolerated dose. The analysis of the primary endpoint was done in the per-protocol population (patients who received the full planned dose of treatment), and all patients who received any dose of study treatment were included in the safety analysis. This study is registered with ClinicalTrials.gov, number NCT01502917, and is ongoing with an expanded cohort.

Findings: From April 5, 2012, to Oct 8, 2016, 28 children were enrolled and treated in the trial, of whom 25 were evaluable for the primary endpoint. The maximum tolerated dose was not reached as no dose-limiting toxicities were observed. One (4%) of 28 patients had treatment-related transient grade 3 hemiparesis and one (4%) had grade 3 skin infection. No treatment-related grade 4 adverse events or deaths occurred. Estimated volumes of distribution (Vd) were linearly dependent on volumes of infusion (Vi) and ranged from 1·5 to 20·1 cm3, with a mean Vd/Vi ratio of 3·4 (SD 1·2). The mean lesion absorbed dose was 0·39 Gy/MBq 124I (SD 0·20). Systemic exposure was negligible, with an average lesion-to-whole body ratio of radiation absorbed dose higher than 1200.

Interpretation: Convection-enhanced delivery in the brainstem of children with diffuse intrinsic pontine glioma who have previously received radiation therapy seems to be a rational and safe therapeutic strategy. PET-based dosimetry of the radiolabelled antibody [124I]-8H9 validated the principle of using convection-enhanced delivery in the brain to achieve high intra-lesional dosing with negligible systemic exposure. This therapeutic strategy warrants further development for children with diffuse intrinsic pontine glioma.

Funding: National Institutes of Health, The Dana Foundation, The Cure Starts Now, Solving Kids' Cancer, The Lyla Nsouli Foundation, Cookies for Kids' Cancer, The Cristian Rivera Foundation, Battle for a Cure, Cole Foundation, Meryl & Charles Witmer Charitable Foundation, Tuesdays with Mitch Charitable Foundation, and Memorial Sloan Kettering Cancer Center.

Copyright © 2018 Elsevier Ltd. All rights reserved.

Figures

Figure 1:. Trial profile

Figure 2:. Relationships between distribution volume and infusion volume

(A) Relationship between Vd and Vi based on total infusion volumes for 17 patients with distribution data. Each data point represents one patient. Distribution volumes were determined from the first set of T2-weighted images acquired at infusion completion. (B) Vd/Vi ratio by dose level. No patients in dose level 1 and only one patient in dose level 2 were scanned for Vd determination. The boxplot is in Tukey convention (ie, maximum whiskers being 1.5 × IQR). Vd=volume distribution. Vi=infusion volume.

Figure 3:. Delivery of [124I]-8H9 to the lesion on PET scans

(A-E) Whole-body scans from a representative patient showing high concentrations of 124I in the brainstem. (A) 2 h after the completion of infusion, delivered activity was seen in the brainstem. (B) 48 h after completion of infusion. Predominant retention was shown in the brainstem infusion site, with a very small amount of activity in the blood pool and liver; excreted activity was seen in the urinary bladder. (C) 4 days after completion of infusion. Activity was still mainly notable in the brainstem, whereas activity in the bladder decreased compared with the 48-h scan; focal uptake in left upper quadrant of the abdomen represents free iodide in stomach. (D) 6 days after completion of infusion. Activity in the brainstem persisted while activity in the remainder of the body, including the bladder, decreased. (E) 8 days after completion of infusion. Activity in the rest of the body was low, whereas activity in the brainstem was still prominently visible. (F-I) Brain PET fused images from a representative patient on cohort 7 (148 MBq, 4000 μL) showing the delivery and retention of [124|]-8H9. The upper sections are axial fused PET/MR images and the lower sections are sagittal fused PET/MR images. Fusion of the PET image onto the Tl-weighted FLAIR images was achieved by co-registering MR images with CT images using bone markers in Hermes Hybrid Viewer 2.6G. The sagittal MR images were reconstructed from axial images. Images are from (F) 2 h, (G) 28 h, (H) 4 days, and (I) 8 days after infusion. (J) Radiation absorbed dose per MBq activity in the lesion and in the whole body. The boxplot is in Tukey convention (ie, maximum whiskers being 1.5× IQR). MR=magnetic resonance. FLAIR=fluid-attenuated inversion recovery.

Figure 4:. Overall survival

(A) Kaplan-Meier curve for the 25 evaluable patients and (B) by dose cohort. The pale lines in A show 95% CI for overall survival probability at each timepoint.