Phase 1 and expanded imaging study of tozuleristide in patients with pediatric primary central nervous system tumors.

Objective: Fluorescence-guided surgery has been shown to increase the extent of resection in adult high-grade glioma. The peptide-dye conjugate tozuleristide is a fluorescence-guided surgical agent under development to aid in visualization of tumor tissue during CNS tumor resection. The goals of this study were to assess safety, pharmacokinetics, and the fluorescent signal of tozuleristide in primary CNS tumors in pediatric patients with CNS cancers and to determine a recommended dose for phase 2 studies.

Childhood Cancer Data Initiative: Expanded access to tumor molecular profiling for children, adolescents, and young adults.

The Molecular Characterization Initiative (MCI), a key effort of the NCI's Childhood Cancer Data Initiative (CCDI), was launched in 2022 in collaboration with the Children's Oncology Group (COG) to bring comprehensive genomic and molecular profiling to children, adolescents and young adults diagnosed with cancer. The MCI provides paired tumor and germline molecular testing, with results returned to clinicians to inform care. De-identified data are made available to the research community through the CCDI Data Ecosystem to facilitate the discovery of new treatment strategies.

Phase 1 study of ABI-009 (nab-rapamycin) for surgically refractory epilepsy (RaSuRE).

Objective: Seizures that are refractory to medical and surgical therapy increase the risk of morbidity and mortality in children with epilepsy. Novel therapeutic trials for this population remain sparse and suboptimal. This Phase 1 study evaluates the (1) safety, tolerability, and (2) preliminary efficacy of ABI-009 (nab-rapamycin) in children with medically and surgically refractory epilepsy.

Measles Oncolytic Virus as an Immunotherapy for Recurrent/Refractory Pediatric Medulloblastoma and Atypical Teratoid/Rhabdoid Tumor: Results from PNOC005.

Purpose: Pediatric recurrent medulloblastoma and atypical teratoid/rhabdoid tumor (ATRT) are largely incurable and warrant novel therapies. PNOC005 is a phase I clinical trial investigating the safety and tolerability of intratumoral or intrathecal administration of oncolytic measles virus (MV-NIS) in children and young adults with recurrent medulloblastoma or ATRT.

Patients And Methods: We investigated (i) the safety of a measles virus variant, MV-NIS, in a pediatric phase I study and (ii) the mechanisms of MV-NIS and the potential benefit of combination with immune checkpoint inhibition (ICI).

Children with medulloblastoma treated with modified ACNS0821 temozolomide, irinotecan, and bevacizumab: The Seattle Children's Hospital experience.

Background: Effective therapy for medulloblastoma at the time of relapse is limited. The objective of this study is to review outcomes from the Seattle Children's Hospital (SCH) institutional standard therapy for relapsed medulloblastoma, modified from the published ACNS0821 regimen.

Methods: Retrospective review of patients treated for relapsed medulloblastoma from 2012-2024 treated with modified ACNS0821 therapy, including combination bevacizumab, irinotecan, and temozolomide, referred to as ".

Phase 3 randomized trial of high-dose methotrexate for young children with high-risk embryonal brain tumors: A report from the Children's Oncology Group.

Background: Embryonal brain tumors are the leading cause of cancer death in young children.

Methods: ACNS0334 was a phase 3 randomized study evaluating high-dose methotrexate in young children < 36 months old with newly diagnosed high-risk embryonal brain tumors. Treatment included three cycles of induction chemotherapy with or without methotrexate followed by three cycles of high-dose consolidation chemotherapy with hematopoietic stem cell infusion.

Isotretinoin has no effect on event-free survival across high-risk medulloblastoma molecular groups when added to maintenance: A secondary analysis of the Children's Oncology Group ACNS0332 data.

Background: The Children's Oncology Group (COG) study ACNS0332 examined the effect of adding carboplatin and isotretinoin to high-risk medulloblastoma therapy. Isotretinoin arms were closed early due to futility, but the effect of carboplatin was shown to vary by individual medulloblastoma subgroups. Because isotretinoin arms were closed before subgroup classification was available, a differential effect of isotretinoin among various subgroups was not examined.

Locoregional Infusion of EGFR806-CAR T Cells for Recurrent or Refractory Pediatric CNS Tumors: Results of the Completed BrainChild02 Phase 1 Clinical Trial.

Background: Relapsed/refractory pediatric CNS tumors have a poor prognosis. EGFR is commonly overexpressed, but EGFRvIII mutations are uncommon. To target these tumors, we used chimeric antigen receptor (CAR) T cells with a binder based on mAb806 which recognizes ectopically expressed wild-type EGFR and EGFRvIII.

Targeted detection of sequence variants in cell-free DNA from cerebrospinal fluid in pediatric central nervous system tumors.

The emergence of liquid biopsy technologies holds great promise in the cancer setting, including in pediatric central nervous system (CNS) tumors. In contrast to broad lower-depth sequencing, commonly referred to as low pass whole genome sequencing (WGS), targeted platforms with a higher depth of coverage have also been established. Here, we review targeted liquid biopsy techniques with applicability to pediatric CNS tumors.

Intracerebroventricular B7-H3-targeting CAR T cells for diffuse intrinsic pontine glioma: a phase 1 trial.

Diffuse intrinsic pontine glioma (DIPG) is a fatal central nervous system (CNS) tumor that confers a median survival of 11 months. As B7-H3 is expressed on pediatric CNS tumors, we conducted BrainChild-03, a single-center, dose-escalation phase 1 clinical trial of repetitive intracerebroventricular (ICV) dosing of B7-H3-targeting chimeric antigen receptor T cells (B7-H3 CAR T cells) for children with recurrent or refractory CNS tumors and DIPG. Here we report results from Arm C, restricted to patients with DIPG.

ZIC1 is a context-dependent medulloblastoma driver in the rhombic lip.

Transcription factors are frequent cancer driver genes, exhibiting noted specificity based on the precise cell of origin. We demonstrate that ZIC1 exhibits loss-of-function (LOF) somatic events in group 4 (G4) medulloblastoma through recurrent point mutations, subchromosomal deletions and mono-allelic epigenetic repression (60% of G4 medulloblastoma). In contrast, highly similar SHH medulloblastoma exhibits distinct and diametrically opposed gain-of-function mutations and copy number gains (20% of SHH medulloblastoma).

Low-Pass Whole Genome Sequencing of Cell-Free DNA from Cerebrospinal Fluid: A Focus on Pediatric Central Nervous System Tumors.

Background: Cell-free DNA (cfDNA) technology has allowed for cerebrospinal fluid (CSF), a previously underutilized biofluid, to be analyzed in new ways. The interrogation of CSF-derived cfDNA is giving rise to novel molecular insights, particularly in pediatric central nervous system (CNS) tumors, where invasive tumor tissue acquisition may be challenging. Contemporary disease monitoring is currently restricted to radiographic surveillance by magnetic resonance imaging and CSF cytology to directly detect abnormal cells and cell clusters.

Radiographic and visual response to the type II RAF inhibitor tovorafenib in children with relapsed/refractory optic pathway glioma in the FIREFLY-1 trial.

Background: Due to their anatomical locations, optic pathway gliomas (OPGs) can rarely be cured by resection. Given the importance of preserving visual function, we analyzed radiological and visual acuity (VA) outcomes for the type II RAF inhibitor tovorafenib in the OPG subgroup of the phase 2 FIREFLY-1 trial.

Methods: FIREFLY-1 investigated the efficacy (arm 1, n = 77), safety, and tolerability (arms 1/2) of tovorafenib (420 mg/m2 once weekly; 600 mg maximum) in patients with BRAF-altered relapsed/refractory pediatric low-grade glioma (pLGG).

Phase 2 trial of veliparib, local irradiation, and temozolomide in patients with newly diagnosed high-grade glioma: a Children's Oncology Group study.

Background: The outcome for pediatric patients with high-grade glioma (HGG) remains poor. Veliparib, a potent oral poly(adenosine diphosphate-ribose) polymerase (PARP) 1/2 inhibitor, enhances the activity of radiotherapy and DNA-damaging chemotherapy.

Methods: We conducted a single-arm, non-randomized phase 2 clinical trial to determine whether treatment with veliparib and radiotherapy, followed by veliparib and temozolomide, improves progression-free survival in pediatric patients with newly diagnosed HGG without H3 K27M or BRAF mutations, compared to patient-level data from historical cohorts with closely matching clinical and molecular features.

Pediatric Central Nervous System Embryonal Tumors: Presentation, Diagnosis, Therapeutic Strategies, and Survivorship-A Review.

Central nervous system (CNS) embryonal tumors represent a diverse group of neoplasms and have a peak incidence in early childhood. These tumors can be located anywhere within the CNS, and presenting symptoms typically represent tumor location. These tumors display distinctive findings on neuroimaging and are staged using magnetic resonance imaging of the brain and spine as well as evaluation of cerebrospinal fluid.

Locoregional CAR T Cells for the Treatment of CNS Tumors in Children: Investigational Drug Service Pharmacy Activities.

Background: A major obstacle in translating the therapeutic potential of chimeric antigen receptor (CAR) T cells to children with central nervous system (CNS) tumors is the blood-brain barrier. To overcome this limitation, preclinical and clinical studies have supported the use of repeated, locoregional intracranial CAR T-cell delivery. However, there is limited literature available describing the process for the involvement of an investigational drug service (IDS) pharmacy, particularly in the setting of a children's hospital with outpatient dosing for CNS tumors.