Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Neurological Surgery, Weill Medical College of Cornell University, New York, USA; Department of Pediatrics, Weill Medical College of Cornell University, New York, USA.
Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Pediatrics, Weill Medical College of Cornell University, New York, USA.
Lancet Oncol. 2018 Aug;19(8):1040-1050. doi: 10.1016/S1470-2045(18)30322-X. Epub 2018 Jun 18.
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.
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 [I]-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.
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 cm, with a mean Vd/Vi ratio of 3·4 (SD 1·2). The mean lesion absorbed dose was 0·39 Gy/MBq I (SD 0·20). Systemic exposure was negligible, with an average lesion-to-whole body ratio of radiation absorbed dose higher than 1200.
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 [I]-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.
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.
弥漫性内在脑桥神经胶质瘤是儿童中枢神经系统肿瘤中最致命的肿瘤之一，中位总生存期不到 12 个月。 对流增强递送被提议作为一种将治疗剂直接递送到脑干的有效方法，同时最大限度地减少全身暴露和相关的毒性作用。 我们进行这项研究是为了评估在弥漫性内在脑桥神经胶质瘤儿童中使用针对神经胶质瘤相关 B7-H3 抗原的放射性免疫疗法药物进行对流增强递送的安全性。
我们在纪念斯隆-凯特琳癌症中心（美国纽约州纽约市）进行了一项 1 期、单臂、单中心、剂量递增研究。 合格的患者年龄在 3-21 岁之间，由多学科儿科神经肿瘤学小组一致诊断为弥漫性内在脑桥神经胶质瘤； 在研究入组时，兰斯基（年龄<16 岁）或卡诺夫斯基（年龄≥16 岁）表现评分为至少 50； 最小体重为 8 公斤； 并在入组前至少 4 周但不超过 14 周完成了外部束放射治疗（54.0-59.4 Gy，每 1.8 Gy 分 30-33 次）。 根据标准的 3+3 规则计划了七个剂量递增队列：患者分别接受 9.25、18.5、27.75、37、92.5、120.25 或 148 MBq 的单次输注，浓度约为 37 MBq/mL 通过对流增强递送放射性标记的抗体 [I]-8H9。 主要终点是确定最大耐受剂量。 主要终点的分析在方案人群中进行（接受全计划剂量治疗的患者），所有接受任何剂量研究治疗的患者均包括在安全性分析中。 这项研究在 ClinicalTrials.gov 上注册，编号为 NCT01502917，正在进行扩展队列。
从 2012 年 4 月 5 日至 2016 年 10 月 8 日，共有 28 名儿童入组并接受了试验治疗，其中 25 名可评估主要终点。 由于未观察到剂量限制性毒性，因此未达到最大耐受剂量。 1 名（4%）患者出现与治疗相关的短暂 3 级偏瘫，1 名（4%）患者出现 3 级皮肤感染。 未发生与治疗相关的 4 级不良事件或死亡。 估计分布容积（Vd）与输注体积（Vi）呈线性相关，范围为 1.5 至 20.1 cm，平均 Vd/Vi 比为 3.4（SD 1.2）。 平均病变吸收剂量为 0.39 Gy/MBq I（SD 0.20）。 全身暴露可忽略不计，病变与全身的吸收剂量比值平均高于 1200。
在先前接受过放射治疗的弥漫性内在脑桥神经胶质瘤儿童的脑桥中进行对流增强递送似乎是一种合理且安全的治疗策略。 放射性标记抗体 [I]-8H9 的 PET 基于剂量验证了使用对流增强在脑内递送来实现高病变内给药而全身暴露可忽略不计的原理。 这种治疗策略需要进一步开发，以用于弥漫性内在脑桥神经胶质瘤儿童。
美国国立卫生研究院、达纳基金会、现在就开始治愈、为孩子治愈癌症、莱拉·努苏里基金会、饼干为孩子治愈癌症、克里斯蒂安·里维拉基金会、为治愈而战、科尔基金会、梅里尔和查尔斯·威特默慈善基金会、星期二与米奇慈善基金会和纪念斯隆凯特琳癌症中心。
