bluuebunny/crossref_metadata_2025_split huggingface dataset:
RADT-34. RE-IRRADIATION REGIMENS FOR RECURRENT GLIOMA: SURVIVAL AND TOXICITY
Authors: de Jong Anouk , Cialdella Fia , van der Boog Arthur , Post Cathalijne , Dankbaar Jan-Willem , Hendrikse Jeroen , Kleynen Karin , Philippens Marielle , Smid Ernst , de Vos Filip , Robe Pierre , David Szabolcs , Snijders Tom , Verhoeff Joost 
Published: November 2024

Abstract
Re-irradiation is a common treatment option for recurrent high-grade glioma (HGG), though the optimal dose-fractionation regimen remains unclear. This report presents single-center data from an ongoing multicenter, retrospective study in the Netherlands. We included adult HGG patients treated with re-irradiation. Dose-fractionation regimens were categorized in 3 groups: conventionally fractionated radiotherapy (CFRT, &lt;3Gy/fraction), hypofractionated radiotherapy (HFRT, 3-5 Gy/fraction) and stereotactic radiotherapy (SRT, ≥5Gy/fraction). We compared baseline characteristics, overall survival, and toxicity including incidence of radionecrosis between groups to identify the optimal dose-fractionation regimen. Of 112 patients, 33 underwent CFRT, 60 HFRT and 19 SRT. 21 patients had a good prognostic Niyazi score, 70 intermediate and 6 poor, with more poor scores in the SRT group. SRT patients had smaller median GTVs compared to HFRT and CFRT (1.9, 20.5, 32.8 respectively, p=0.003). Radiation groups also differed in primary histology (less grade 4 in CFRT, p=0.009), but not in age and KPS. Overall survival (OS) was worse for HFRT (median OS 9 months (95%-CI 6.5-11.5)) compared to CFRT (12 months (8.9-15.2, p=0.039)) and SRT (12 months (9.2-14.8, p = 0.012)), but did not differ between CFRT and SRT (p=0.437). In Cox regression, Karnofsky performance score &lt;80 (hazard ratio (HR): 1.874, p=0.006) and large GTV (HR: 1.011, p=0.003) were independently associated with poor survival, while the fractionation schedule was not. Multivariable logistic regression on toxicity analysis indicated an increased risk of radionecrosis in the CFRT and HFRT groups compared to the SRT group (OR 5.861, p=0.011), even after adjusting for GTV and age. In conclusion, re-irradiation schemes in HGG are univariably, but not independently, associated with overall survival; this relationship seems to be confounded by differences in GTV and possibly by KPS. Radionecrosis was more common in HFRT and CFRT than in SRT. Extension and/or validation of findings will be performed in a multicenter cohort.
CTIM-30. NT-I7, A LONG-ACTING INTERLEUKIN-7, PROMOTES ACTIVATION, CYTOTOXIC FUNCTION, AND SELECTIVE CLONOTYPE EXPANSION OF CD8+ T CELLS IN PATIENTS WITH HIGH GRADE GLIOMAS
Authors: Barozinsky Kaiden , Foltz Jennifer A , Butt Omar H , Zhou Alice Y , Singhal Kartik , Griffith Obi , Griffith Malachi , Etter Kelsey , Grote Cierra , Luo Jingqin , Nehring Leslie , Katumba Ruth , Ferrando-Martinez Sara , Stermer Kristina , Lee Byung Ha , Johanns Tanner , Huang Jiayi , DiPersio John , Chheda Milan , Fehniger Todd , Campian Jian L 
Published: November 2024

Abstract
Lymphopenia following chemoradiation for high grade gliomas (HGG) is common and is associated with decreased survival. NT-I7 (efineptakin alfa) is a long-acting analog of the lymphocyte pro-survival cytokine, interleukin-7. Our Phase I dose-escalation study of 19 patients with HGG demonstrated early elevations in CD4+ and CD8+ T cells in the first 4 weeks after administration of NT-I7. In this study, we explored the diversity and potential functionality of the NT-I7-expanded T cell population. A subset of 4 subjects with glioblastoma multiforme (GBM) treated at 720 µg/kg of NT-I7 during adjuvant temozolomide in our study (NCT03687957) underwent Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq) of peripheral blood. CITE-seq with TCR clonotype sequencing (10x Genomics 5’) permitted simultaneous tracking of the T cell phenotype at the protein level, individual T cell clones, and gene expression dynamics between 4 timepoints: pre-treatment, and post-treatment weeks 1, 2, and 13. Here, we report the results of differential expression analyses between timepoints and patient-specific differences in T cell clonotype expansions. Both CD4+ and CD8+ T cells in our study patients had increased expression of T cell activation markers LTB, CISH, and CD74. CD8+ T cell subsets demonstrated additional elevations in genes important in cytotoxic function (granzymes (GZMA, GZMB) and perforin (PRF1)), MHC Class II expression (HLA-DRA, HLA-DRB1), and AP-1 transcription factor subunits (JUND, JUN, JUNB, FOS, FOSB). After excluding known viral antigen clonotypes, 2 of 4 patients demonstrated TCR clonotype expansion. Notably, nearly all the expanded TCR clonotypes were found within CD8+ T cells, but not CD4+ T cells. NT-I7 promotes activation, cytotoxic function, and selective clonotype expansion of CD8+ T cells in patients with HGG. This, combined with its role in increased CD4+ T cell counts, suggests NT-I7 may be a powerful tool to restore immune function after treatment-associated lymphopenia in HGG.
CTNI-09. TYPE II RAF INHIBITOR TOVORAFENIB IN RELAPSED/REFRACTORY (R/R) PEDIATRIC LOW-GRADE GLIOMA (PLGG): RESULTS FROM PATIENTS ON A DRUG HOLIDAY (DH) IN THE PHASE 2 FIREFLY-1 TRIAL
Authors: Perreault Sébastien , Khuong-Quang Dong-Anh , Kilburn Lindsay B , Landi Daniel B , Leary Sarah E S , Bailey Simon , Larouche Valérie , Nysom Karsten , Driever Pablo Hernáiz , Baxter Patricia A , Witt Olaf , Oren Michal Yalon , Abdelbaki Mohamed S , Kline Cassie , Whipple Nicholas S , Ziegler David S , van der Lugt Jasper , Hassall Timothy E , Gerber Nicolas U , Segal Devorah , Hansford Jordan R , McCowage Geoffrey , Kang Hyoung Jin , Han Jung Woo , Hargrave Darren , Franson Andrea T , Toledano Helen , Jabado Nada , Gottardo Nicholas G , Chi Susan N , Oren Liat , Tan Enrica E K , Mueller Sabine , Hoke Molly E , Kim Yeonhee , Walter Ashley , Da Costa Daniel , Manley Peter , Waanders Angela J 
Published: November 2024

Abstract

BACKGROUND
Tovorafenib, a selective, CNS-penetrant, type II RAF inhibitor, received US FDA accelerated approval for r/r BRAF-altered pLGG. Results from the ongoing FIREFLY-1 (NCT04775485) phase 2 study (Kilburn LK, et al. Nat Med. 2023) in this population showed clinically meaningful tumor responses and a manageable safety profile.

METHODS
Patients in FIREFLY-1 treated for ≥26 cycles (~24 months) who entered a DH period were routinely assessed every 3 cycles; once-weekly tovorafenib 420 mg/m2 (not to exceed 600 mg) could be restarted if there was radiographic and/or clinical evidence of new disease progression.

RESULTS
As of the April 19, 2024 data cutoff, 26 patients (BRAF fusion: 22; BRAF V600E mutation: 4) (33.8%) of 77 patients in arm 1 (pLGG registrational) had completed 2 years of treatment and started a DH. No patients on a DH withdrew. Twenty-four patients (92.3%) remain on a DH, of which 22 were evaluable for response (duration range: 0.6-10.9 months); duration of response off-treatment ranged from 0.0-8.5 months. (Ranges exclude 2 non-evaluable patients treated beyond radiographic progression who remained on treatment in first 26 cycles due to ongoing clinical benefit; both remain on DH without clinical progression.) Two patients had tumor progression while on a DH and restarted treatment; 1 patient with a BRAF V600E mutation progressed (≥25% in tumor size) after 1 month (rebound growth per O’Hare P., et al. Neuro-Oncol. 2024: ≥25% increase [per RANO-LGG] w/in 6 months of stopping treatment) and has been on retreatment for 4 months; 1 patient with a BRAF fusion progressed after 9 months and has been on retreatment for 3 months. Treatment-related adverse events of any grade experienced by patients on retreatment were alopecia and rash (1 each). Independent radiographic analysis for response during retreatment is ongoing.

CONCLUSIONS
Tovorafenib provided durable tumor responses off-treatment in patients with r/r pLGG on a DH in FIREFLY-1.
CTNI-15. A PERIOPERATIVE STUDY OF SAFUSIDENIB IN PATIENTS WITH IDH1 MUTATED GLIOMA
Authors: Whittle James , Rosenthal Mark , Spiteri Montana , Tobler Robert , Topp Monique , Cain Sarah , Jones Jordan , Shaya Sammy , Valkovic Adam , Fatunla Oluwaseun , Dimou James , Roberts-Thomson Samuel , McArdle David , Lui Elaine , Nijagal Brunda , Mitchell Camilla , Grimmond Sean , Best Sarah , Freytag Saskia , Drummond Kate 
Published: November 2024

Abstract

BACKGROUND
IDH mutations cause aberrant accumulation of (R)-2-hydroxyglutarate (2-HG), an oncometabolite that promotes tumorigenesis through abnormal hypermethylation of histones and DNA as well as suppression of normal cellular differentiation. IDH inhibition significantly improves progression free survival in patients with IDH mutant WHO grade 2 glioma, however most patients progress, and there is a lack of understanding on mechanistic reasons for failure.

METHODS
We tested Safusidenib, an oral, blood brain barrier penetrant IDH1 R132X enzyme inhibitor in a single arm, open label perioperative study. Patients with IDH1 mutated glioma, treatment naïve to radiation or chemotherapy, received Safusidenib (250 mg BID) for four weeks following surgical biopsy and prior to definitive resection (Part A). After resection patients continued Safusidenib until toxicity or progression (Part B). Translational endpoints include paired whole genome transcriptome sequencing (WGTS), single nuclei RNA sequencing (snRNAseq), spatial transcriptomics and spatial metabolomics as well as longitudinal sampling of blood and CSF for circulating tumour DNA (ctDNA). Here we are reporting Part A of the study.

RESULTS
As of May/27/2024 10 patients (mean age 37, 40% female) have been enrolled: seven with astrocytoma, three with oligodendroglioma; six had prior surgical resection. Pharmacokinetic sampling showed a mean tumor concentration 2457 ng/mL (range 957.0 – 4810) with tumor:plasma ratio 0.33. Consistent with mechanism, tumor 2-HG reduced 86% from biopsy (mean 75.0μM, range 7.8-203) to surgery (10.3μM, range 2.3 – 30.8), as well as identification of novel biomarkers of response. Paired tumour snRNAseq reveals transcriptional shift with changing cell-to-cell communication, and increased immune infiltration post-treatment, validated by spatial transcriptomics. Additionally, we find reduced heterogeneity consistent with a more differentiated tumour state. Treatment was well tolerated with ongoing follow-up.

CONCLUSIONS
This innovative trial facilitates intra-patient comparisons and confirmation of the on-target effects of Safusidenib, enhancing understanding of the mechanisms of response and resistance. The approach serves as a proof of concept for advancing drug development in glioma through perioperative trials.
CTNI-20. ADDRESSING SKIN ADVERSE EVENTS (AES) DURING MIRDAMETINIB TREATMENT IN PATIENTS WITH NEUROFIBROMATOSIS TYPE 1-ASSOCIATED PLEXIFORM NEUROFIBROMAS (NF1-PN): GUIDANCE FROM A MULTIDISCIPLINARY GROUP OF EXPERTS ON THE MANAGEMENT OF MEK INHIBITOR-ASSOCIATED SKIN AES
Authors: Hirbe Angela , Anadkat Milan , Boull Christina , Moertel Christopher , Nickerson Molly , Weber Michael , Babovic-Vuksanovic Dusica , Gershon Timothy 
Published: November 2024

Abstract
ReNeu (NCT03962543) is a trial of the investigational, oral, selective MEK1/2 inhibitor (MEKi) mirdametinib in adults (≥18 years) and children (2-17 years) with NF1-PN. Skin adverse events (AEs) were common in ReNeu, and some discontinuations were noted with low-grade AEs. A multidisciplinary team retrospectively reviewed skincare practices at one high-enrolling site (n=12) with no discontinuations due to skin AEs; these were incorporated into ReNeu trial recommendations and recently updated. The purpose was to prevent/manage skin AEs and maintain protocol treatment adherence. MEKi skin AEs vary by pubertal status, therefore recommendations also vary by pubertal status. All patients were counseled to adopt hygienic skincare practices, including bathing daily, and using mild cleansers and hypoallergenic skin moisturizers (cream or ointment-based emollient; minimum BID) to prevent dry skin. Prepubescent patients were advised to incorporate diluted bleach baths (3-4 times/week) when initiating mirdametinib or after rash development. Treatments recommended for mild-to-severe dermatitis were hydrocortisone cream (2.5% BID) on face/skinfold areas and triamcinolone ointment (0.1% BID) on trunk/extremities. Treatments for mild acneiform eruptions included topical clindamycin lotion (1.0% BID) until resolution, with optional hydrocortisone cream (2.5% BID). For moderate-to-severe acneiform eruptions, cephalexin (20 mg/kg/day divided BID, max 500 mg, ≤6 weeks), amoxicillin (25 mg/kg/day divided BID, max 875 mg, ≤6 weeks), or oral fluconazole (20 mg/kg/day, max 100 mg, 5 days then once weekly for 3 months) were suggested. Postpubescent patients were advised to initiate topical 1.0% clindamycin lotion and oral doxycycline or minocycline (50-mg daily, 3 months) with mirdametinib initiation. Patients with subsequent mild-to-severe acneiform eruptions were advised to apply hydrocortisone cream (2.5% BID) or triamcinolone ointment (0.1% BID). Referral to a dermatologist was suggested for all patients with uncontrolled dermatitis, worsening acneiform eruptions, or infection. Proactive skincare practices appeared effective at this site, but prospective validation is necessary before making clinical recommendations.
CTNI-30. A PHASE 2 DOUBLE-BLIND, RANDOMIZED, PROSPECTIVE, PLACEBO CONTROLLED STUDY OF NANO₂TM COMBINED WITH RADIATION AND TEMOZOLOMIDE IN PATIENTS WITH NEWLY-DIAGNOSED GLIOBLASTOMA: RESTORE
Authors: Badruddoja Michael A , Placencia Crystal , Unger Evan , Gellert Scott , Stea Baldassarre , Peters Katherine B , Kong Xiao-Tang , Aiken Robert , Goldin Caroline , Mahadevan Daruka , Goldlust Samuel A 
Published: November 2024

Abstract

INTRODUCTION
Glioblastoma (GBM) commonly has extensive hypoxic regions, possibly due to thrombosis from tumor-produced pro-coagulant factors. Radiation-induced cell death relies on oxygen free radicals and oxygen fixation of DNA-strand breaks. In the absence of oxygen tumor cells can repair the DNA strand breaks leading to treatment resistance. Hypoxic cells also exhibit chemoresistance due to decreased drug efficacy, limited drug diffusion, and poor delivery to distant cells. This study hypothesizes that increasing oxygen delivery to hypoxic GBM tissue using NanO₂ (2% w/v dodecafluoropentane emulsion) infusion will enhance the effectiveness of radiation therapy (RT) and chemotherapy (CT).

METHODS
Patients diagnosed with GBM per CNS5-WHO criteria receive standard chemoradiation: 30 fractions of focal RT with 60 Gy, delivered as 2 Gy fractions five days per week for six weeks with concurrent oral TMZ at 75 mg/m²/day for six weeks. Patients are randomized in a 1:2 ratio to receive either a placebo (0.9% Sodium Chloride) or NanO₂ infusion administered immediately prior to each RT dose. Patients continuously breathe oxygen during infusion and RT. Following six weeks of RT with temozolomide, patients have a four-week break before starting adjuvant temozolomide.

RESULTS
Ten patients have been enrolled in the RESTORE trial. Seven continue to be followed through maintenance treatment and long term follow up. There have been 23 non-hematologic adverse events described as CTCAE severity grade 3 and above. Grade 4, hematologic toxicity occurred in two patients, with one patient experiencing prolonged pancytopenia necessitating hematologic support and discontinuation of temozolomide. Two patients discontinued therapy due to early tumor progression.

CONCLUSION
This study is ongoing, assessing the safety and potential efficacy of NanO₂ in improving treatment outcomes for GBM by enhancing oxygen delivery to hypoxic tumor regions.
CTNI-32. A MULTICENTER PHASE 1 TRIAL OF TUCATINIB, TRASTUZUMAB, AND CAPECITABINE WITH STEREOTACTIC RADIOSURGERY IN PATIENTS WITH BRAIN METASTASES FROM HER2 POSITIVE BREAST CANCER (TUTOR)
Authors: Ahluwalia Manmeet , Ozair Ahmad , Bardhan Mainak , Bellur Shreyas , Starosciak Amy , Perche Dilanis , Khosla Atulya , Leon-Ariza Daniel , Rubens Muni , Odia Yazmin , Mehta Minesh , Kotecha Rupesh , McDermott Michael , Sandoval-Leon Ana , Mahtani Reshma , Peereboom David 
Published: November 2024

Abstract

BACKGROUND
Nearly 20-40% of HER2+ breast cancer patients develop brain metastases (BMs), where stereotactic radiosurgery (SRS) is standard-for-care for local control. Tucatinib, an oral HER2-selective TKI, is safe and efficacious in HER2+ breast cancer in combination with capecitabine and trastuzumab. Synergism between these 3 drugs (TCT) and radiation may enhance DNA damage. This phase 1 trial aims to evaluate TCT plus SRS for HER2+ breast cancer BMs (BCBM).

METHODS
TUTOR is a pre-registered (NCT05553522), single-arm, multicenter, ongoing, phase 1 trial that aims to determine the safety and efficacy of TCT+SRS in HER2+ BCBM patients. Patients with age 18-80 years, ECOG score 0-2, normal organ function, and ≤10 newly-diagnosed BMs are being enrolled at six US centers. Any number of prior systemic therapies are allowed, except tucatinib and capecitabine. Key exclusion criteria include leptomeningeal metastases, intra-tumoral or peri-tumoral hemorrhage, and BMs ≤5 mm of optic chiasm/nerve. Primary endpoint is maximum tolerated dose (MTD) of tucatinib, in this 3 + 3 de-escalation study starting at dose level (DL) 300 mg BID. DL-1 is 250 mg BID, and DL-2 is 200 mg BID. Secondary endpoints include efficacy as determined by response rate, intracranial progression-free survival (PFS), extracranial PFS, and overall survival. Neurocognitive outcomes are assessed using Hopkins Verbal Learning, Controlled Oral Word Association, Trail Making, and Grooved Pegboard Tests. Toxicities are assessed using CTCAE v5.0. Quality of life is assessed using Functional Assessment of Cancer Therapy with Brain Tumor module. Patients are administered tucatinib with SRS as per treating radiation oncologist, followed by tucatinib for two weeks, i.e. dose-limiting toxicity (DLT) period, followed by TCT until progression or intolerable toxicity. DLTs are defined by Grade 3 or 4 thrombocytopenia, grade 4 anemia, grade 4 neutropenia lasting &gt;7 days, febrile neutropenia, and any non-hematologic toxicity of grade ≥3 (excluding alopecia). Cohort expansion at MTD to 40 patients is planned. Patient enrollment started in February 2023 and remains ongoing.
CTNI-37. INTERIM SAFETY ANALYSIS OF THE PHASE IB/II RANDOMIZED ANTI-GLUTAMATERGIC DRUG REPURPOSING TRIAL GLUGLIO IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA (NCT05664464)
Authors: Wirsching Hans-Georg , Roth Patrick , Fischer Angela , Hundsberger Thomas , Migliorini Denis , Romagna Lorenz , Läubli Heinz , Seystahl Katharina , Imback Lukas , Hortobagyi Tibor , Held Leonhard , Bink Andrea , Weller Michael 
Published: November 2024

Abstract
The advent of cancer neuroscience has significantly advanced our understanding of brain tumor biology, yet the clinical implications remain largely unexplored. Glutamate, the most abundant excitatory neurotransmitter, presents a potential therapeutic target in brain tumors. Glioblastoma cells synthesize and secrete large amounts of glutamate, driving epilepsy, neuronal death, tumor growth, and invasion. Several brain-penetrating drugs, approved for other conditions, can inhibit glutamate synthesis, secretion, and signaling. These drugs include: (i) gabapentin, an anti-seizure medication that inhibits the glutamate synthesis enzyme branched-chain amino acid transaminase 1; (ii) sulfasalazine, an anti-inflammatory drug that blocks the cystine-glutamate exchanger system Xc, reducing glutamate secretion; and (iii) memantine, a cognitive enhancer that prevents glutamate-driven, calcium-induced neuronal death and tumor cell invasion by blocking N-methyl-D-aspartate type glutamate receptors. The multi-center, open-label, parallel-group, two-arm, 1:1 randomized phase Ib/II trial GLUGLIO is investigating the efficacy of a daily oral anti-glutamatergic triple combination of gabapentin, sulfasalazine, and memantine until tumor progression, in conjunction with standard chemoradiotherapy, compared to chemoradiotherapy alone. The primary endpoint is progression-free survival at 6 months (PFS-6). A sample size of 120 patients was determined to detect an increase in PFS-6 from 50% to 70%, with 80% power, using exploratory hypothesis testing at a one-sided significance level of 10%. Secondary endpoints include overall survival, seizure-free survival, response rate, quality of life for patients and caregivers, symptom burden, cognitive functioning, tumor glutamate levels (measured by magnetic resonance spectroscopy), and the use of anti-convulsants and steroids. Each drug is dosed up to the maximum approved amount. Results from the phase Ib part of the trial, including an interim safety analysis, will be presented at the conference.
CTNI-39. UPDATE ON GBM AGILE: A GLOBAL, PHASE 2/3 ADAPTIVE PLATFORM TRIAL TO EVALUATE MULTIPLE REGIMENS IN NEWLY DIAGNOSED AND RECURRENT GLIOBLASTOMA
Authors: Lassman Andrew , Alexander Brian , Berry Donald , Berry Nicholas , Buxton Meredith , Colman Howard , Gan Hui , de Groot John , de la Fuente Macarena , Drappatz Jan , Ducray Francois , Ellingson Benjamin , Gordon Gary , Hyddmark Emma , Johnson Adam , Khasraw Mustafa , Lee Eudocia , Lim Michael , McGlothlin Anna , Mellinghoff Ingo , Mikkelsen Tom , Nghiemphu Phioanh , Perry James , Powell Ashley , Sulman Erik , Tanner Krik , Untch Sarah , Weller Michael , Wen Patrick , Wick Antje , Yung Alfred , Cloughesy Timothy 
Published: November 2024

Abstract

BACKGROUND
GBM AGILE (Glioblastoma Adaptive, Global, Innovative Learning Environment) is a biomarker based, multi-arm, international, seamless Phase 2/3 platform trial designed to rapidly identify and confirm experimental therapies that improve overall survival for approval along with their associated biomarker signatures. GBM AGILE is a collaboration between academic investigators, patient organizations, and industry to support new drug applications for newly diagnosed (ND) and recurrent glioblastoma.

METHODS
The primary objective of GBM AGILE is to identify therapies that improve the overall survival in patients with ND or recurrent glioblastoma. Bayesian response adaptive randomization is used within subtypes of the disease to assign participants to investigational arms based on their performance. GBM AGILE operates under a Master Protocol allowing multiple drugs to be evaluated simultaneously and over time against a common control. New experimental therapies are added as information about promising new drugs is identified, while therapies are removed as they complete evaluation. Six investigational arms have been included to date. Along with an adaptive trial design, shared control arm and operational processes, GBM AGILE continues to incorporate new design and operational elements. One recent design element added to the Master Protocol for consideration for future arms is an extended evaluation period, of up to 11 months, for arms that reach maximum sample size in Stage 1 (Stage 1: learn most responsive signature) without having reached a decision for futility or graduation. Allowing data to mature and additional events to accumulate may increase the ability of the trial to detect efficacy, and if appropriate, for an arm to graduate to Stage 2 (Stage 2: confirm activity in graduating signature). Using improved and flexible processes, GBM AGILE continues to serve as a global trial that supports the efficient and rapid incorporation and evaluation of new experimental therapies for patients with glioblastoma. NCT number: NCT03970447.