Souweidane MM, et al. - In children with diffuse intrinsic pontine glioma, researchers determined the safety of convection-enhanced delivery of a radioimmunotherapy agent targeting the glioma-associated B7-H3 antigen. Outcomes suggested convection-enhanced delivery in the brainstem of children who have previously received radiation therapy is a rational and safe therapeutic strategy. The principle of using convection-enhanced delivery in the brain to achieve high intra-lesional dosing with negligible systemic exposure was validated via PET-based dosimetry of the radiolabelled antibody [¹²⁴I]-8H9.

Methods

• At the Memorial Sloan Kettering Cancer Center (New York, NY), a phase 1, single-arm, single-center, dose-escalation study was performed.
• Patients were eligible if 3–21 years of age and had diffuse intrinsic pontine glioma diagnosed by multidisciplinary pediatric neuro-oncology team consensus, 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.
• Based on standard 3 + 3 rules, researchers planned 7 dose-escalation cohorts: 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.
• Identifying the maximum tolerated dose was the primary endpoint for this study.
• They performed analysis of the primary endpoint 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.

Results

• Twenty-eight children were enrolled and treated in the trial from April 5, 2012, to Oct 8, 2016, and of these, 25 could be evaluated for the primary endpoint.
• Researchers did not reach the maximum tolerated dose, as they encountered no dose-limiting toxicities.
• Treatment-related transient grade 3 hemiparesis was observed in one (4%) of 28 patients and grade 3 skin infection was reported in one (4%) patient.
• They noted no treatment-related grade 4 adverse events or deaths.
• Estimated volumes of distribution (Vd) were noted to have linear association with volumes of infusion (Vi), which 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 of 0.39 Gy/MBq ¹²⁴I was observed (SD 0.20).
• In this study, negligible systemic exposure was noted, with an average lesion-to-whole body ratio of radiation absorbed dose higher than 1,200.