bluuebunny/crossref_metadata_2025_split huggingface dataset:
DEI-03. COMPASSIONATE USE OF NOVEL AND TARGETED THERAPIES IN RELAPSED AND PROGRESSIVE MALIGNAT PEDIATRIC BRAIN TUMORS: EXPERIENCE OF A SINGLE INSTITUTION
Authors: Solano-Páez Palma , Moreno-Madueño Gloria , Quiroga-Cantero Eduardo , Rivero -Garvia Mónica , Alvarez-Vayo Concepción 
Published: June 2024

Abstract

BACKGROUND
Off-label use of targeted therapy in pediatric Neuro Oncology is often offered to patients in the absence of available Clinical Trials specifically designed to this population. We present here six pediatric patients diagnosed with a malignant brain tumor who received compassionate treatment with targeted/novel therapy, alone or in combination, at disease progression or relapse, in a palliative setting.

METHODS
Retrospective chart review of patients diagnosed with a malignant brain tumor harboring a targeted molecular alteration, who received compassionate prescription of novel therapies not approved for the specific indication, and that were no eligible for a clinical trial. Patient demographics, dose of treatment delivered, tolerance, adverse effects, length of treatment, reason to discontinue the drug and survival rates were analyzed.

RESULTS
Four girls and two boys were identified; Median age at initiation of off-label drug: 4 years (3-17). Tumor type and targeted therapy delivered: DIPG H3 mutant (2), Diffuse Midline Glioma H3 and FGFR mutant (1), SHH-Medulloblastoma (1), ATRT (1), Diffusse Glioma EGFR and MET mutant (1). Off label drugs prescribed were ONC201, Erdafinitib, Sonidegib, Tazemetostat, and combination of crizotinib and erlotinib, respectively. Adverse events were mainly grade 1 and 2, however, 2/6 patients required hospital admission to manage adverse effects related to the experimental drug. One patient discontinued the drug due to side effects. All patients died of disease progression at a median of six months.

CONCLUSIONS
The anecdotical use of compassionate use of experimental drugs do not allow to gather clinical experience or to demonstrate a clinical benefit or impact in survival. Although the tolerance was generally good, the potential side effects caused by off-label drugs in a palliative population deserves a thorough individual assessment for its indication. Urgent need of targeted and novel therapies is warranted for pediatric children with malignant brain tumors.
DEI-06. IMPROVING ACCESS TO POST-MORTEM BRAIN TUMOR TISSUE DONATION BEYOND THE INPATIENT HOSPITAL SETTING
Authors: Lyons Nicole , Nazarian Javad , Eze Augustine , Nourmohammadi Niku , Koptyra Mateusz , Resnick Adam , Minturn Jane , Frenkel Beth , Reingruber Sonora , Wanders Angela , Bornhorst Miriam , Williams Melissa , Monje-Deisseroth Michelle , Hysinger Jared , Liljensten Ann-Helen , Souweidane Mark , Greenfield Jeffrey , Campbell Cindy , Padilla Christopher , Smith Amy , Peck Sydney , Vitanza Nick , Leary Sarah , Stevens Jeff 
Published: June 2024

Abstract
Between May 2021 and December 2023, approximately 33% of patients were being treated inpatient at the time of consent for post-mortem tissue donation through Gift From A Child. In the past, a major obstacle preventing families from donating post-mortem tissue was the inability to leave the hospital. Care teams and patient families are often concerned that in order to donate, the patient would have to pass away at the hospital. This creates a situation where the desire to donate comes at the cost of patient care and comfort. Through GFAC, children can pass at home, hospital, or hospice and still donate tissue successfully. The ability to donate post-mortem tissue is independent of patient location, ensuring that the focus of the family and care team remains on the child’s care rather than donation logistics. Additionally, patients can successfully donate tissue independent of status at the time of inquiry (declining, stable, urgent). The ability to quickly access a resource at a low burden to the family has been crucial in allowing tissue donation to happen. This also improves patient equity by eliminating access to hospital resources as a reason for a patient family to be required to live near a hospital. This is oftentimes a tremendous financial difficulty for patient families. Through establishing standard operating procedures and appointing tissue navigators, GFAC has streamlined what was previously an extremely complicated process mired in logistical obstacles. Patient families now have access to an efficient process for tissue donation. Previously, families would need to navigate complicated logistics unsupported, now they (or someone on their behalf) only need to contact GFAC or a Research Center of Excellence via phone or email and consent for donation. This ensures that post-mortem tissue can be donated easily, efficiently, and from wherever the patient family chooses.
TRLS-02. SAFETY AND EFFICACY OF BRAF INHIBITOR PLIXORAFENIB (FORE8394; PLX8394) IN CHILDREN AND ADULTS WITH RECURRENT, BRAF-ALTERED PRIMARY CENTRAL NERVOUS SYSTEM TUMORS (PCNST)
Authors: de la Fuente Macarena , Butowski Nicholas A , Taylor Jennie , Yaeger Rona , Tsai Frank Y-C , Janku Filip , Allen Carl E , Ammakkanavar Natraj , Michelson Glenn , Jiang Ping , Samara Emil , Paz Michael , Tussay-Lindenberg Alexia , Wang Kongming , Shepherd Stacie P , Kline Irina , Sherman Eric , Rodon Jordi 
Published: June 2024

Abstract

BACKGROUND
Plixorafenib is a selective, potent BRAFi that inhibits V600 and non-V600 alterations by disrupting BRAF monomers/dimers. Plixorafenib evades paradoxical MAPK pathway activation, eliminating the need for MEKi combination, and is potentially less prone to toxicities and resistance typical of approved BRAFis.

METHODS
Phase 1/2a study (NCT02428712) in children (n=5, aged 4-17 years) and adults (n=108) with BRAF-altered solid tumors assessing safety, PK, and efficacy of oral plixorafenib 900-3600mg/day ± cobicistat (PK enhancer).

RESULTS
Five children, 3 LGG (1 V600E, 1 fusion, 1 amplification), 1 neuroblastoma (G469A) and 1 ND-LCH (V600E), 4-8 prior therapies, received plixorafenib 300-1200 mg/day without cobicistat. Four received BSA-adjusted dosing, which delivered lower exposures than RP2D. All had SD, with duration 66.9+ months for ND-LCH. The fifth (neuroblastoma, 1200 mg/day) had PD. No DLTs, dose reductions, or LFT elevations. One had possibly related Grade 3 headache. Of 9 evaluable MAPKi-naïve adults with V600E PCNST, 4/5 with HGG and 2/4 with LGG/GNT responded; ORR 67% (95% CI: 29.9-92.5), mDOR 13.9 months. Responses in patients with only non-enhancing lesions and/or pilocytic astrocytoma indicate clinically relevant CNS penetration. Responses occurred across V600 solid tumors, ORR 42% (10/24); 1-year PFS 54.4%, 2-year PFS 48.4% in the MAPKi-naïve (non-CRC) subgroup. Of 14 evaluable adults with fusions, 2 responses (melanoma: CR, DOR 62.6+ months; PTC: PR, DOR 4.0+ months), 8 SD (5 with PCNST), 5 PD (3/5 with co-occurring driver mutations). Safety, efficacy, and PK in adults and children and insight into factors affecting plixorafenib exposure (not age or weight dependent) determined the optimal RP2D of plixorafenib as 900 mg QD with cobicistat for ages ≥10 years.

CONCLUSIONS
Plixorafenib had low rates of symptomatic TEAEs with a manageable safety profile, and high ORR in MAPKi-naïve BRAFV600 PCNST. A phase 2 study in children and adults is ongoing (NCT05503797).
TRLS-04. EARLY INSIGHTS FROM PNOC027: PERSONALIZED TREATMENT APPROACHES BASED ON REAL-TIME DRUG SCREENING AND GENOMIC TESTING IN PEDIATRIC AND ADOLESCENT PATIENTS WITH RECURRENT MEDULLOBLASTOMA
Authors: Shatara Margaret , Paul Megan R , Long-Boyle Janel R , Meyer Ashley , Raber Shannon , Yeh-Nayre Lanipua , Jalkanen Aimee , Kilburn Lindsay B , Packer Roger J , Elster Jennifer D , Reddy Alyssa T , Koschmann Carl , Kraya Adam , Resnick Adam C , Prados Michael , Kline Cassie , Mueller Sabine , Wechsler-Reya Robert J , Rubin Joshua B 
Published: June 2024

Abstract

BACKGROUND
PNOC027, a clinical trial conducted by the Pediatric Neuro-Oncology Consortium (PNOC), explores a precision medicine strategy with up to four FDA-approved agents integrating real-time drug screening with whole exome DNA and RNA sequencing to guide personalized treatment approaches for children and young adults with relapsed medulloblastoma.

METHODS
Freshly isolated tumor cells from patients undergo high-throughput drug screening, evaluating responses to 232 clinically available compounds over 72 hours. In vitro drug responses are integrated with tumor genomic and transcriptomic data to predict drug combinations for each patient. Drugs are prioritized based on blood-brain barrier permeability, patient age, prior treatments, and other co-morbidities. Correlative studies include the collection of blood to assess circulating tumor DNA (ctDNA) before surgery and during treatment. Health-related quality of life (HRQOL) assessments will also be collected during therapy.

RESULTS
To date, nine patients have been enrolled. Eight of these have successfully completed real time drug screening with a median turnaround of 7 days from sample receipt. One patient was excluded due to ineligible (non-medulloblastoma) pathology after enrollment. Seven of these had whole exome sequencing, and six had RNA sequencing. Tumor board recommendations were rendered within 21 business days from the date of surgery. Among the diverse drug classes evaluated, histone deacetylase (HDAC) inhibitors, proteasome inhibitors, anthracyclines, DNA crosslinkers, and kinase inhibitors showed the most robust in vitro responses. Six patients received the recommended regimens, experiencing tolerable (grade 1/2) toxicities. Two patients succumbed to disease prior to therapy initiation, three exhibited disease progression while on therapy, and three remain on therapy.

CONCLUSION
PNOC027 demonstrates preliminary feasibility of real-time drug screening combined with DNA/RNA sequencing to inform targeted therapy selection in clinically relevant timeframes and with potential for disease response.
TRLS-05. A PILOT STUDY TO ASSESS THE SAFETY, FEASIBILITY, AND PRELIMINARY EFFICACY OF A NEOEPITOPE-BASED PERSONALIZED DNA VACCINE APPROACH IN PEDIATRIC PATIENTS WITH RECURRENT BRAIN TUMORS
Authors: Shatara Margaret , Rocco Abbey , Beck Mary , McHugh Michele , Lampe Ashley , Meyer Ashley , Ogle Andrea , Brossier Nicole M , Cluster Andrew , Rubin Joshua B , Abdelbaki Mohamed S 
Published: June 2024

Abstract

BACKGROUND
Pediatric brain tumors present a heterogeneous group of neoplasms with limited treatment options, especially at relapse. Hence, innovative therapeutic strategies are imperative. Immunotherapy, specifically immunogenomics, utilizing personalized vaccines based on tumor-specific neoantigens, has emerged as a promising option in other tumors. However, the feasibility of this approach in pediatric brain tumors remain largely unexplored.

METHODS
This single institution feasibility study focuses on sequencing analyses of pediatric brain tumors to identify mutant tumor-specific antigens. The study employs tumor/normal exome sequencing and cDNA-capture sequencing to identify and confirm mutant antigens, respectively. An epitope prediction algorithm prioritizes these antigens with subsequent confirmation of binding to HLA class I molecules. The neoantigen DNA vaccine strategy, utilizing a polyepitope DNA vaccine, is designed to target up to 20 prioritized antigens. The TDS-IM v2.0 device facilitates the administration of the vaccine. The primary objective of the study is to determine the feasibility of adjuvant personalized neoantigen DNA vaccine administration in patients with recurrent or refractory pediatric brain tumors.

RESULTS
We anticipate the identification of actionable neoantigens in pediatric brain tumors to support the potential efficacy of personalized DNA vaccines. The proposed sequencing strategies, epitope prediction algorithm, and in vitrobinding studies aim to establish a comprehensive methodology for neoantigen identification and prioritization. During the meeting, we will present the study background, rationale, detailed methodology, and design to inform the brain tumor community of this study.

CONCLUSION
This feasibility study is poised to provide essential insights into the development of personalized neoantigen DNA vaccines for recurrent or refractory pediatric brain tumors and aims to demonstrate safety, feasibility, and potential efficacy in targeting mutant tumor-specific antigens. The findings from this study will lay the groundwork for future clinical trials, evaluating the impact of personalized immunotherapy on progression-free and overall survival rates in this challenging patient population.
TRLS-06. PHASE 1 STUDY OF THE CD40 AGONISTIC MONOCLONAL ANTIBODY APX005M (SOTIGALIMAB) IN PEDIATRIC, ADOLESCENT, AND YOUNG ADULT PATIENTS WITH RECURRENT OR PROGRESSIVE CNS TUMORS AND NEWLY DIAGNOSED BRAIN STEM GLIOMA: A PEDIATRIC BRAIN TUMOR CONSORTIUM STUDY (PBTC-051; NCT03389802)
Authors: Lindsay Holly B , Billups Catherine , Baxter Patricia , Hwang Eugene , Lenzen Alicia , MacDonald Tobey , Pollack Ian F , Robison Nathan , Vinitsky Anna , Poussaint Tina Young , Onar-Thomas Arzu , Fangusaro Jason , Dunkel Ira J 
Published: June 2024

Abstract

BACKGROUND
CD40 is a co-stimulatory receptor present on antigen-presenting cells. CD40 agonists are hypothesized to reverse cancer-induced immune suppression and induce tumor cell killing. The PBTC completed a first-in-pediatrics phase 1 study (PBTC-051) of the CD40 agonistic monoclonal antibody APX005M (sotigalimab).

METHODS
Patients 1-21.99 years old with recurrent/progressive/refractory malignant non-brainstem central nervous system (CNS) tumors were eligible for stratum 1, and those with post-radiation pre-progression diffuse intrinsic pontine glioma (DIPG) for stratum 2. Patients received APX005M (sotigalimab) via IV on day 1 of each 21 day cycle. A 3 + 3 statistical design was used for dose escalation through 3 planned dose levels (DL). Patients could receive APX005M (sotigalimab) for 36 cycles or until disease progression, unacceptable toxicity, or death.

RESULTS
31 eligible patients enrolled (20 on stratum 1, 11 on stratum 2) between 2018-2023; 29 were evaluable for dose finding. The most common diagnosis in stratum 1 was ependymoma (35%). DL3 (0.6 mg/kg) was the recommended phase 2 dose (RP2D) for stratum 1 and DL2 (0.3 mg/kg) for stratum 2. Five patients had dose limiting toxicities—two stratum 1 patients at DL3 and three stratum 2 patients at DL3. The most common grade 3+ adverse events at least possibly attributable to APX005M (sotigalimab) were lymphopenia, neutropenia, leukopenia, and increased ALT. Median number of cycles was 2 (1-36) for stratum 1 and 3 (1-19) for stratum 2. No patients had an objective response to APX005M. 6 month progression-free survival (PFS) for stratum 2 patients (calculated from start of treatment) was 30.7±12.8%; median PFS was 3.7 months.

CONCLUSIONS
APX005M was well-tolerated in pediatric patients with both recurrent/refractory/progressive CNS tumors and post-radiation pre-progression DIPG. A RP2D was established for both populations. Future studies of this agent in pediatric neuro-oncology patients should prioritize combination therapy.
TRLS-08. ROVER: A PHASE 1/2 TRIAL IN PROGRESS OF AVAPRITINIB IN PEDIATRIC PATIENTS WITH SOLID TUMORS DEPENDENT ON KIT OR PDGFRA SIGNALING
Authors: Abbou Samuel , Koschmann Carl , Kramm Christof M , Hoffman Lindsey M , Plant-Fox Ashley S , Abdelbaki Mohamed S , Bui Ashley , Casanova Michela , van Tilburg Cornelis M , Khuong-Quang Dong-Anh , Chi Susan N , Shi Hongliang , Bidollari Ilda , Hong Janet , Swamy Preethi , Roche Maria , Morgenstern Daniel A 
Published: June 2024

Abstract

BACKGROUND
Advanced pediatric solid tumors, including central nervous system (CNS) tumors with PDGFRA and/or KIT mutations/amplifications are aggressive diseases with limited treatment options. KIT alterations occur in germ cell tumors and high-grade glioma (HGG); platelet-derived growth factor receptor alpha (PDGFRA) alterations are common in sarcoma and HGG. No KIT-/PDGFRA-targeted therapies are currently approved for pediatric patients. The selective KIT and PDGFRA inhibitor avapritinib has demonstrated potent activity against KIT activation-loop (exon 17) and juxtamembrane (exon 11) mutants (IC50&lt;2 nM), and PDGFRA activation-loop (D842V) mutants (half-maximal inhibitory concentration [IC50]=0.24 nM). Cellular IC50 of wild-type PDGFRA was 95 nM. CNS penetration in preclinical models (steady-state brain-to-plasma ratios, 0.74–1.00) indicates potential for CNS antitumor activity. Avapritinib is approved in the USA and Europe to treat adults with indolent systemic mastocytosis, in the USA for adults with advanced systemic mastocytosis (AdvSM), and in Europe for adults with AdvSM after ≥1 prior systemic therapy. Avapritinib is also approved to treat adults with unresectable/metastatic gastrointestinal stromal tumors harboring PDGFRA exon 18 mutations (including D842V) in the USA and PDGFRA D842V mutations in Europe.

METHODS
ROVER, a 2-part phase 1/2, multicenter, open-label study (NCT04773782), is investigating avapritinib (once daily, administered in continuous 28-day cycles) in pediatric patients aged 2 to &lt;18 years with relapsed/refractory solid tumors that harbor PDGFRA and/or KIT mutations/amplifications or patients with diffuse midline glioma H3K27-altered (DMG-H3K27a). Objectives include safety, efficacy, and pharmacokinetics. Part 1 will enroll ≥12 patients; primary endpoint is to determine the recommended Part 2 dose (RP2D). Part 2 will enroll ≥25 patients at the RP2D; primary endpoint is objective response rate per RECIST v1.1 for solid tumors and Response Assessment in Neuro-Oncology for CNS tumors. Study enrollment is planned at 26 sites in 9 countries, including North America, Europe, and Asia/Pacific.
ETMR-12. INFANTILE CENTRAL NERVOUS SYSTEM JUVENILE XANTHOGRANULOMA WITH SOMATICCSF1R MUTATION - RESPONSIVE TO IMATINIB MONOTHERAPY
Authors: Martinez-Torres Valerie , Etienne Kayla , Di Long , Rosenberg Andrew , Gultekin Sakir , Dhir Aditi , McCrea Heather J , Gampel Bradley 
Published: June 2024

Abstract

BACKGROUND
Juvenile xanthogranuloma (JXG) of the central nervous system(CNS) is a rare non-Langerhans cell histiocytosis typically affecting children and young adults. CSF1R mutations have been reported for peripheral JXG but have not previously been reported in CNS JXG. Treatment of CNS JXG relies on maximal safe surgical resection followed by cytotoxic chemotherapy, radiotherapy and/or molecular targeted therapy involving MAPK signaling pathway. Imatinib has been effective in treating tenosynovial giant cell tumor with CSF1R mutations.

METHODS
Case Report

RESULTS
A 3 month old male presented with fever, lymphadenopathy, and macrocephaly (45.5cm, 99.97%) with bulging fontanelles. Head ultrasound revealed dilated ventricles and brain MRI demonstrated multiple dural-based masses, the largest measuring 6.6 x 5.3 x 5.7 cm was located along the right tentorium and caused obstructive hydrocephalus. Patient underwent right frontal endoscopic third ventriculostomy and choroid plexus cauterization to treat hydrocephalus and right parietal craniotomy to resect the superficial dural-based mass for tissue diagnosis. Pathology was most consistent with a JXG that harbored a somatic CSF1R (NM_001288705.3) mutation. DNA Methylation profiling was unmatched. PET scan was negative for non-CNS lesions. Due to the multiple masses on presentation, the surgical risks of resection of the largest lesion, as well as having a targetable mutation, we opted for medical therapy. As Pexidartinib, a selective CSF1R inhibitor, was not available for infants, patient was started on liquid imatinib 340 mg/m2/day monotherapy. Three months after initiation of imatinib, the smaller parietal lesions resolved and after six months, the largest mass continued to shrink (6.3 x 2.9 x 2.9 cm). Treatment has been well tolerated without adverse events or drug interruptions.

CONCLUSION
This is the first report of CNS JXG with a CSF1R mutation. Importantly, it demonstrates that imatinib is a potentially safe and effective form of monotherapy for this rare disease.
ETMR-14. THE SINGLE-CELL LANDSCAPE OF PINEOBLASTOMA IDENTIFIES AN ONCOGENIC PHOTORECEPTOR PROGRAM AS A TUMORIGENIC VULNERABILITY UNIFYING DISTINCT EMBRYONAL CNS TUMOR ENTITIES
Authors: Gudenas Brian , Englinger Bernhard , Liu Anthony P Y , Ahmad Sheikh Tanveer , Zhao Miao , Meredith David , Pfaff Elke , Paul Leena , Hadley Jennifer , Batts Melissa , Klimo Jr. Paul , Boop Frederick A , Gajjar Amar , Robinson Giles W , Orr Brent A , Lin Hong , Alexandrescu Sanda , Jones David T W , Swartling Fredrik , Filbin Mariella G , Northcott Paul A 
Published: June 2024

Abstract

BACKGROUND
Pineoblastoma (PB) is a rare and aggressive childhood brain tumor with highly variable outcomes. PB is diagnostically characterized by expression of the photoreceptor identity transcription factor CRX, while tumors can be further classified into molecular subgroups (PB-miRNA1, PB-miRNA2, PB-MYC/FOXR2, and PB-RB1), each marked by unique clinico-molecular features. However, developmental origins of PB subgroup heterogeneity and mechanisms governing malignancy remain unknown.

METHODS
We assembled a single-nucleus RNA-sequencing cohort (n=25) of primary PB tumors, including cases from all subgroups. A single-cell transcriptional atlas of the mouse pineal gland, covering 11 developmental stages (E11-P21), was created as a reference to map PB subgroup origins. Developmental trajectory analysis in the pineal gland showed a progression from pinealocyte progenitors to an early-, mid- and mature stage of pinealocyte differentiation.

RESULTS
Cross-species bioinformatics identified significant associations between PB subgroups and pinealocyte progenitors, mitotic cells expressing Crx, Otx2 and Neurod1. Single-nuclei gene regulatory networks in PB tumors identified CRX, OTX2, and NEUROD1 as master regulators of an oncogenic photoreceptor program conserved across PB subgroups. Surprisingly, this photoreceptor program was also highly expressed in retinoblastoma (RETB) and Group3 medulloblastoma (G3-MB). The molecular association between PB, RETB and G3-MB was further supported by DNA methylation and bulk RNA-seq, suggesting up-regulation of the oncogenic photoreceptor program is a unifying molecular connection of distinct CNS tumor entities. Querying this photoreceptor program across the developing pineal gland, retina, and cerebellum, identified conserved yet transient expression within each developmental lineage, suggesting the photoreceptor program may be a developmental vulnerability. In-vivo dependency assays for Otx2 and Neurod1 performed in a novel genetically engineered mouse model of the PB-RB subgroup confirmed their selective essentiality in photoreceptor-positive tumors.

CONCLUSIONS
Collectively, these findings uncover the photoreceptor program as a shared oncogenic dependency underlying anatomically distinct embryonal CNS tumors and provide a path towards rational clinical translation.