Background and Aims

Recurrent medulloblastoma and ependymoma are universally lethal, with no approved targeted therapies and few candidates presently under clinical evaluation. Nearly all recurrent medulloblastomas and posterior fossa group A (PFA) ependymomas are located adjacent to and bathed by the CSF, presenting an opportunity for locoregional therapy, bypassing the blood–brain barrier (B-BB). With targeted therapies slow to emerge, we hypothesized we may circumvent the lack of targetable SNVs in these low mutational burden cancers, as well as interpatient and intrapatient heterogeneity, whilst bypassing the B-BB, through the identification of epitopes consistently present across medulloblastoma and ependymoma subgroups (primary, metastatic and recurrent tumour compartments) and administration of CAR T-cells targeting those epitopes directly through the CSF.

Methods

Using next generation sequencing data, DNA and tissue microarrays we identified three cell-surface targets, EPHA2, HER2 and IL13Rα2, across medulloblastoma and ependymoma tumour compartments but not expressed in the normal developing brain. We validated intraventricular versus intravenous delivery of these CAR T-cells as monovalent CARs versus a single trivalent (EPHA2-HER2-IL13Rα2) CAR in T-cell activity trials, dose-response trials and pre-clinical trials.

Results

We show that Intraventricular delivery is an effective treatment for primary, metastatic and recurrent group 3 medulloblastoma and PFA ependymoma in numerous mouse models. One mechanism of failure to CAR T-cell therapy is antigenic escape secondary to epigenetic silencing of the gene targeted by CAR T-cells, therefore we demonstrate that administration of EPHA2 and trivalent CAR T-cells into the CSF, in combination with the hypomethylating agent azacytidine, is a highly effective therapy for multiple metastatic mouse models of group 3 medulloblastoma and PFA ependymoma, respectively, providing a rationale for clinical trials of these approaches in humans.

Conclusions

Locoregional CSF delivery ensures the direct and complete delivery of EPHA2 or trivalent CAR T-cells in combination with azacytidine as an effective therapeutic modality for group 3 medulloblastoma and PFA ependymoma primary, metastases and recurrences, respectively.

Background and Aims

Ependymomas represent the third cause of pediatric brain tumors.
Despite initial treatment including maximal surgery followed by local radiotherapy, half of the patients experience recurrence whose management is not standardized.
Our study aimed at retrospectively evaluate the treatment of recurrence.

Methods

The PEPPI database gathers data of children and adolescents treated for a newly diagnosed grade 2 and 3 ependymoma between 2000 and 2013, in the reference centers of SFCE.
We assessed overall survival (OS) and progression free survival (PFS) after a first relapse taking into account the treatments received.
Landmark analyses were performed at 6 months after relapse to take into account the heterogeneity of the duration of each therapeutic sequences before reirradiation.

Results

Among 202 patients included, 101 patients relapsed and were analysed, 72 had a local recurrence and 26 a distant recurrence.
Median time between the initial surgery and first relapse was 21 months.

Median follow-up was 105 months for the whole base.
Median age at relapse was 7 years.
Seventy nine patients received surgery, 53 patients received reirradiation (preceded by surgery in 92.5% of cases) and 22 patients received chemotherapy.
Fifteen (29.4%) reirradiated patients and eleven (23.4%) non-reirradited patients had metastatic first relapse.
The reirradiation techniques were respectively hypofractionated stereotaxic irradiation for 27 patients (57.4%), normofractioned irradiation for 13 patients (27.7%) and craniospinal irradiation for 7 patients (14.9%).
The median OS were respectively 74.7 with reirradiation and 31.2 months without reirradiation, HR 0.65 [0.36;1.16], p = 0.142 . The median PFS were respectively 16.5 and 15 months, HR 0.83 [0.49;1.41].
In multivariable analyse, complete surgery is statistically significantly associated with an improvement in overall survival (p = 0.042).

Conclusions

In the PEPPI study, complete surgery for recurrent ependymoma was associated with a better OS, and patients that received reirradiation presented a better OS than patients treated without reirradiation.

Background and Aims

Oncogenic driver alterations in FGFR are present in a subset of pediatric gliomas. Debio1347 is an orally available, highly selective FGFR 1-3 inhibitor that had a favorable safety profile and encouraging preliminary clinical activity in an adult phase 1 study.

Methods

Five children with progressive/refractory CNS tumors harboring an FGFR gene alteration following prior chemotherapy were treated with Debio1347 at Memorial Sloan Kettering Cancer Center on single patient use protocols. Patients were treated using the 20 mg tablet formulation at the adult recommended phase 2 dose (80 mg/1.73 m2 * BSA once daily). Toxicities were graded using CTCAEv5.0 and imaging response assessments were performed every 8-12 weeks.

Results

All adverse events were grade 1-2. Most common treatment-related adverse events were ALT increased, hypoalbuminemia and hyperphosphatemia (4 patients). Two patients met criteria for partial response and two patients had stable disease. A 13 month-old patient with a spinal cord high-grade glioma harboring two FGFR1 mutations (V592M, K687) had tumor reduction of 91.7% maintained for 12 months. A 26-month-old patient with a pilomyxoid astrocytoma harboring an FGFR1-TACC1 fusion had a tumor reduction of 74.5% maintained for 9 months. Prolonged disease stabilization was noted in an eight year-old patient with metastatic suprasellar pilomyxoid astrocytoma harboring an FGFR1 mutation (9 months) and in a 14 year-old patient with posterior fossa glioneuronal tumor harboring an FGFR3-TACC3 fusion (18 months and ongoing).

Conclusions

Debio1347 demonstrated tolerable toxicity and promising anti-tumor efficacy in pediatric patients with refractory FGFR altered gliomas. Further studies in this population are warranted.

Background and Aims

Neuroblastoma metastasis to the central nervous system (CNS) or leptomeninges (LM) carries a dismal prognosis. In a phase 1/2 trial conducted at MSKCC, intraventricular compartmental radioimmunotherapy (cRIT) with ¹³¹I-Omburtamab targeting B7-H3 was safe and improved survival.¹ We report interim results of safety, dosimetry, pharmacokinetics and efficacy of cRIT with ¹³¹I-Omburtamab on the first multi-center, international trial for patients with CNS neuroblastoma.

Methods

Eligible patients had CNS neuroblastoma with stable systemic disease, adequate cerebrospinal fluid flow and adequate major organ function. A treatment cycle consisted of a 2mCi dosimetry dose and a 50mCi treatment dose, with adjustments for patients under three years or one year of age. Dosimetry, pharmacokinetics by CSF and blood sampling and safety were investigated during a 5-week period. Response and survival were noted by the clinical status and magnetic resonance imaging at 5 and 26 weeks with long term follow-up for overall survival up to 3 years.

Results

The interim analysis includes 17 patients (10 at MSKCC; 7 at other sites) who received at least one cycle of ¹³¹I-omburtamab before 30-Jun-2019 and have been followed for at least six months. 8 patients received 1 cycle; 9 patients received two cycles. The median follow-up time for these patients is 179 days. 15 patients remain alive at the cut-off date. The OLINDA mean absorbed doses were 3.46 mSv/MBq in the brain and 5.97 mSv/MBq in the liver. Dosimetry level estimates in the cerebrospinal fluid at 0.56 Gray/mCi were orders of magnitude higher than those in the blood at 0.008 Gray/mCi. The most common SAEs were related to myelosuppression. Overall, the administration of ¹³¹I-Omburtamab was well tolerated.

Conclusions

Administration of cRIT with ¹³¹I-Omburtamab is feasible and safe in a multi-center setting. ¹³¹I-Omburtamab shows favorable dosimetry.

¹Kramer et al. International Society of Paediatric Oncology 2019 Congress

Background and Aims

The survival rate after posterior fossa tumors (PTF) reaches 90 percent. High toxicity and very long treatment lead to a decrease in cognitive and motor functions. Cognitive and motor functions are important for everyday life, they have a connection with academic achievements and quality of life. We hypothesized that the group randomized to an active executive functions training program would demonstrate significantly increased scores on a primary outcome measure of executive functions compared to the group that didn`t receive the training.

Methods

The 63 children between the ages of 6 and 17 years (M =11.6, SD=3.4, 56% male) took part in the study. Inclusion criteria were: survivor of posterior fossa tumor/healthy control, staying in Clinical Rehabilitation Research Center for 32 days, written informed consent from the participant or his legal guardian/representative. The training program consisted of training in neurotracker for 10 minutes, training in fitlight for 10 minutes and training in dynavision for 10 minutes. The training was conducted for 14 days, at least 6 and no more than 8 classes for each child. The control group did not receive training interventions. The change in cognitive functions was controlled using CANTAB, the change in motor skills was monitored using the VMI (fine motor skills), BOT-2 (gross motor skills) and eye tracking (eye movements).

Results

As a result, it was found that even 6 lessons of 30 minutes are enough to get highly improved fine motor skills (P=0.006), working memory(P=0.0005), attention (P=0.005), and hand-eye coordination (P=0.006). No significant differences in cognitive and motor functions in the control group were found.

Conclusions

Thus, the training program aimed to train executive functions could be effectively applied in the rehabilitation of such patients.