Background. Despite recent advances in the biology of IDH-wildtype glioblastoma, it remains a devastating disease with median survival of less than 2 years. However, the molecular underpinnings of the heterogeneous response to the current standard-of-care treatment regimen consisting of maximal safe resection, adjuvant radiation, and chemotherapy with temozolomide remain unknown. Methods. Comprehensive histopathologic, genomic, and epigenomic evaluation of paired initial and recurrent glioblastoma specimens from 106 patients was performed to investigate the molecular evolution and cellular phenotypes underlying differential treatment responses. Results. While TERT promoter mutation and CDKN2A homozygous deletion were early events during gliomagenesis shared by initial and recurrent tumors, most other recurrent genetic alterations (eg, EGFR, PTEN, and NF1) were commonly private to initial or recurrent tumors indicating acquisition later during clonal evolution. Furthermore, glioblastomas exhibited heterogeneous epigenomic evolution with subsets becoming more globally hypermethylated, hypomethylated, or remaining stable. Glioblastoma that underwent sarcomatous transformation had shorter interval to recurrence and were significantly enriched in NF1, TP53, and RB1 alterations and the mesenchymal epigenetic class. Patients who developed somatic hypermutation following temozolomide treatment had significantly longer interval to disease recurrence and prolonged overall survival, and increased methylation at 4 specific CpG sites in the promoter region of MGMT was significantly associated with this development of hypermutation. Finally, an epigenomic evolution signature incorporating change in DNA methylation levels across 347 critical CpG sites was developed that significantly correlated with clinical outcomes. Conclusions. Glioblastoma undergoes heterogeneous genetic, epigenetic, and cellular evolution that underlies prognostically different treatment responses.

The glioblastoma tumor immune microenvironment (TIME) is an immunosuppressive barrier to therapy that encumbers glioblastoma responses to immune checkpoint inhibition (ICI). Immunosuppressive cytokines, pro-tumor myeloid cells, and exhausted T-cells are hallmarks of the glioblastoma TIME. Here we integrate spatial and single-cell analyses of patient-matched human glioblastoma samples before and after ICI with genetic, immunologic, single-cell, and pharmacologic studies in preclinical models to reveal that interleukin-6 (IL-6) inhibition reprograms the glioblastoma TIME to sensitize mouse glioblastoma to ICI and radiotherapy. Rare human glioblastoma patients who achieve clinical responses to ICI have lower pre-treatment IL-6 levels compared to glioblastomas who do not respond to ICI. Immune stimulatory gene therapy suppresses IL-6 tumor levels in preclinical murine models of glioblastoma. Furthermore, survival was longer in Il-6 knockout mice with orthotopic SB28 glioblastoma relative to wild-type mice. IL-6 blockade with a neutralizing antibody transiently sensitizes mouse glioblastoma to anti-PD-1 by increasing MHCII+ monocytes, CD103+ migratory dendritic cells (DCs), CD11b+ conventional DCs, and effector CD8+ T cells, and decreasing immunosuppressive Tregs. To translate these findings to a combination treatment strategy for recurrent glioblastoma patients, we show that IL-6 blockade plus ICI durably sensitizes mouse glioblastoma to high-dose radiotherapy.

BACKGROUND:Primary malignant brain tumors (PBT) impose substantial burdens on patients and caregivers. Caregivers are essential in the delivery of outpatient care for patients with PBT but experience high levels of fatigue, distress, and health decline. Although exercise is known to improve outcomes in cancer patients, interventions tailored specifically to the PBT patient-caregiver dyad remain limited. Dyadic intervention, as well as exercise oncology, are emerging areas of active research in neuro-oncology. This scoping review incorporates both principles to evaluate the existing literature on exercise interventions on primary brain tumor patient-caregiver dyads. METHODS:We conducted a comprehensive search of MEDLINE (PubMed), Embase, CINAHL (EBSCO), Rehabilitation & Sports Medicine (EBSCO), and Cochrane Central (Ovid) in December 2025 for studies involving exercise interventions that included adult PBT patients and caregivers. RESULTS:Of the 1126 records screened, eight studies were included: four yoga-based interventions (three feasibility trials and one ongoing multicenter RCT), one pilot ski-based intervention, and three aerobic and resistance training-based interventions (two qualitative and one ongoing trial). The interventions were safe and feasible, with high adherence and retention. The preliminary reported benefits included improvements in fatigue, sleep, quality of life, and caregiver distress for the dyads. Videoconference delivery was effective, particularly during the COVID-19 pandemic. The eight included studies comprised 5-67 dyads, with four being single-arm feasibility studies. CONCLUSIONS:Current literature on dyadic exercise intervention in neuro-oncology consists primarily of small-scale feasibility and pilot studies. Initial findings have demonstrated that such interventions are safe. However, preliminary efficacy remains limited due to the risk of bias and lack of statistical power. Larger randomized clinical trials with objective endpoints are needed to define efficacy and guide evidence-based protocols.

Abstract Background: Developing safe and effective CAR-T therapy for glioblastoma (GBM) has been hindered by antigen heterogeneity, on-target off-tumor toxicity, and CAR-T cell exhaustion. We have developed a novel synthetic Notch (synNotch) receptor-based “prime-and-kill” dual antigen recognition T cell circuit. EGFRvIII, which is expressed by a subset of GBM cells, primes the T-cells to express a CAR that recognizes IL-13Rα2 and EphA2, which are broadly expressed in GBM, thereby eradicating GBM cells expressing either EphA2 or IL-13Rα2 (E-SYNC T-cells). We developed a Phase I clinical trial to evaluate the safety of intravenously infused E-SYNC T-cells. Methods: The study has 2 sequential patient cohorts. Cohort 1 is a 2-level dose-escalation cohort, targeting newly diagnosed patients with EGFRvIII-mutant, MGMT-unmethylated GBM. The E-SYNC cells are manufactured by ex vivo transduction of autologous T-cells with a lentiviral E-SYNC vector, and then intravenously infused after lymphodepleting chemotherapy. Cohort 2 will be a tissue analysis cohort. At the time of recurrence, participants will receive an infusion of E-SYNC T-cells at the maximum tolerated/recommended dose from Cohort 1 prior to a planned clinical surgical resection. The primary objective is safety; secondary objectives are feasibility and (for Cohort 2 only) to determine the priming status of E-SYNC T-cells in the GBM tissues and peripheral blood. We are currently enrolling patients in cohort 1. Results: Autologous E-SYNC cells have been successfully manufactured for 9 patients. To date, we have treated six patients at dose level 1 (DL1: 5x107 CAR+ cells) and two patients at dose level 2 (DL2: 1.5x108CAR+ cells), with no serious adverse events or dose-limiting toxicities. Two of six patients at DL1 remain progression-free for 20 months and 15 months since the initial resection. Digital PCR-based evaluation of the peripheral blood demonstrated the post-infusion persistence of E-SYNC T-cells for at least 40 weeks. Serum analyses show post-infusion increases in CCL2, CCL5, CXCL9, and CCL22. In two patients who recurred within two months following the infusion, the recurrent tumor tissues showed the loss of EGFRvIII, despite the infiltration of E-SYNC cells. Conclusions: We have safely treated eight patients with EGFRvIII+ GBM with autologous E-SYNC cells, with no significant toxicity thus far. Considering the poor prognosis of MGMT-unmethylated GBM patients, the progression-free survival in two patients is promising. To overcome the loss of EGFRvIII as the priming signal, we are also developing a second-generation synNotch-CAR study using Brevican, a brain-specific extracellular matrix protein, to induce the CAR expression (Simic, Watchmaker et al., Science, 386, 2024). Citation Format: Payal B. Watchmaker, Jennifer L. Clarke, Ricardo Almeida, Akane Yamamichi, Abigail Hansen, Harika T. Gopi, Karishma Kumar-Wessel, Megna Reddy, David Y. Oh, Jacob S. Young, Nicholas Butowski, Nancy A. Oberheim Bush, Jennie W. Taylor, John de Groot, Joanna Phillips, Annette M. Molinaro, Brain R. Shy, Wendell Lim, Hideho Okada. First-in-human trial of E-SYNC T-cells, an autologous anti-EGFRvIII SynNotch receptor-induced anti-EphA2/IL13Ra2 CAR T-cells, in adult patients with EGFRvIII+ glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT042.

Cognitive impairment is common in primary brain tumors (PBT), with evidence for cognitive rehabilitation (CR), although with few studies of self-sustaining clinical programs. We conducted a retrospective analysis of a CR program to understand treatment engagement and goal attainment by cognitive and clinical characteristics in those referred with subjective complaints. We retrospectively reviewed records of adults with stable PBT and cognitive complaints referred to neuropsychological evaluation and +/- CR with cognitive and emotional assessments completed upon referral. Impairment type was defined as: absolute ≥ -1.5 SD on ≥ 2 tests, or relative ≥ -1.5 from premorbid intellect on ≥ 2 tests. SMART (Specific, Measurable, Achievable, Relevant, Time-bound) goal (partial or full) attainment was tracked with CR engagement defined as completing ≥ 2 sessions. Chi-square was used to evaluate associations with a two-sided <0.05 p-value threshold. We identified 177 patients with PBT referred between May 2018 to May 2022. The mean age was 50 (SD=13.5); 76% had ≥16 years of education; median time since diagnosis was 35.2 months (IQR=85.4); 14% glioblastoma; 56% IDH-mutant; 34% grade 2; 74% prior radiotherapy; and 62% not working. Among those referred, 21% demonstrated relative and 73% absolute impairment (73% with impaired processing speed, 71% executive functioning, and 63% verbal learning). Of those referred and recommended, 124 (87%) engaged in CR (median 8 visits, IQR=9); 57% fully and 25% partially met their goals. CR engagement and goal achievement were not significantly associated with cognitive and emotional findings upon referral or other clinical factors (all p≥0.05). We confirm that subjective complaints in PBT often have objective impairments and underscore the value of premorbid estimates, especially in highly educated patients. Our data demonstrates high rates of CR engagement when offered. Additional study is warranted to understand treatment response, durability, and the mechanism of action.

Background:Cognitive impairments are common in lower-grade gliomas (grades 1-3), but treatment options are limited. Tele-cognitive rehabilitation offers a potential solution. We conducted an interim pilot study to assess the feasibility, satisfaction, and early efficacy of tele-cognitive rehabilitation. Methods:We enrolled adults with stable LrGG (≥6 months posttreatment) who had subjective and objective cognitive impairments (>1 SD below-average in ≥2 domains). Participants received 3 months of individual Goal Management Training (GMT), app-based ReMind, or texting. Cognition and patient-reported outcomes were assessed at baseline (T1), postintervention (T2), and 9 months postbaseline (T3). We assessed enrollment, adherence, and satisfaction. Adherence was defined as ≥80% of participants completing ≥80% of the protocol; satisfaction as ≥6/7 for GMT and texting, and ≥4/5 for ReMind on a self-report Likert question. We used ANOVA, reliable change indices, and qualitative analytics. Results:Thirty-nine participants were eligible and 33 prospectively enrolled for the study; an 85% enrollment (17-GMT, 8-ReMind, 8-texting; 46.8 median age, 64.8 months from diagnosis, 55% had astrocytoma, and 76% had prior radiotherapy). Eighty-two percent of GMT (adequate), 100% of texting (adequate), and for ReMind 33% of retraining and 50% of compensation (inadequate) completed ≥80% of the protocol. GMT (mean: 6.75/7) and ReMind (mean: 4.5/5) satisfaction were adequate, and texting (mean: 4.5/7) was inadequate. Working memory improved from T1-to-T2 (P = .02, η² = 0.32) in 26% of the GMT group. Conclusions:GMT demonstrates adequate feasibility, satisfaction, and may yield improvements in working memory, while texting and ReMind had challenges in acceptability or feasibility. Individual (tele) GMT warrants further investigation in LrGG.

Cognitive impairments are common in patients with lower-grade gliomas (LrGG, grades 1-3), yet evidence-based interventions are limited. Tele-health cognitive rehabilitation offers a potential solution. We conducted a pilot study investigating the adherence, satisfaction, and preliminary efficacy of tele-cognitive rehabilitation in adults with LrGG. Eligible participants were adults with stable LrGG (≥ 6 months post-treatment) reporting subjective and objective cognitive impairments (>1 SD below average in ≥2 domains). Patients received three months of individual cognitive rehabilitation Goal Management Training (GMT) via telehealth which is a behavioral treatment designed to address cognitive impairments. Cognitive assessments and patient-reported outcomes (PROs) were collected at baseline (T1), post-intervention (T2), and 9 months post-baseline (T3). Adequate adherence required ≥80% of participants completing ≥80% of sessions. Adequate satisfaction was defined as a score ≥6/7 on a post-T2 survey. Preliminary efficacy was assessed using repeated measures t-tests, effect sizes, and reliable change indices (RCI) for within-group changes (T1-T2, T1-T3). Thirty-two patients (median age 48 years; median 61 months post-diagnosis; 46% astrocytoma and 46% oligodendroglioma; 82% IDH mutant; 39% grade 2 and 61% grade 3; 64% prior radiotherapy) were prospectively enrolled between May 2019 and September 2023. GMT adherence was high at 88%. Significant improvements were observed in the WAIS-IV Working Memory Index from T1 (mean z=-0.12, SD 1.13) to T2 (mean z=0.06, SD 1.09; p=0.03, eta²=0.18), with 25% demonstrating reliable improvement. PROs also improved: Fatigue Symptom Inventory Interference Index decreased significantly from T1 (mean=3.37, SD 2.48) to T3 (mean=2.55, SD 2.42; p=0.04, eta²=0.18). Clinically evident fatigue (FSI >3) decreased from 50% at T1 to 25% at T3. The Brief Symptom Inventory (BSI)-Somatic subscale improved significantly both from T1 (mean=0.06, SD 0.84) to T2 (mean=-0.38, SD 0.60; p=0.001, eta²=0.33) and T1-T3 (mean=-0.34, SD 0.76; p=0.01, eta²=0.28). Overall satisfaction with GMT was excellent (mean=6.87/7, SD 0.35). Tele-cognitive rehabilitation using individual GMT is feasible for adults with stable LrGG, demonstrating good adherence and high patient satisfaction. Preliminary results show promising improvements in working memory, fatigue interference, and somatic distress, with some effects sustained 6 months post-intervention. Further research is warranted to confirm efficacy and explore mechanisms of action.

PURPOSE STELLAR (ClinicalTrials.gov identifier: NCT02796261 ) was a phase III, randomized, open-label trial of eflornithine + lomustine versus lomustine monotherapy in patients with recurrent grade 3 astrocytoma. METHODS At trial initiation, eligibility criteria included: age ≥18 years, anaplastic astrocytoma (2016 WHO CNS Tumor classification [WHO CNS4]), first recurrence ≥6 months after radiation and temozolomide (TMZ), Karnofsky performance status ≥70, and no imaging findings consistent with grade 4 glioblastoma. Random assignment (1:1) was stratified by isocitrate dehydrogenase ( IDH ) mutation, age, resection extent, and geography. Patients received eflornithine (2.8 g/m 2 orally, every 8 hours [2 weeks on, 1 week off]) + lomustine (90 mg/m 2 orally, once every 6 weeks), or lomustine monotherapy (110 mg/m 2 once every 6 weeks). The primary end point was overall survival (OS). RESULTS Among 343 patients randomly assigned across 74 sites in eight countries, there was no difference in survival between eflornithine + lomustine and lomustine monotherapy (median OS 23.4 v 20.3 months, hazard ratio [HR], 0.94). Following changes in classification and grading in the 2021 WHO CNS5, a subset analysis of patients with IDH- mutant, grade 3 astrocytoma (n = 196), defined in 2024, before unblinding, showed clinically meaningful improvements in median OS with eflornithine + lomustine versus lomustine monotherapy (34.9 v 23.5 months, HR, 0.64) and median progression-free survival (PFS, 15.8 v 7.2 months, HR, 0.57). No differences were observed among patients with CNS grade 4 disease. Grade ≥3 treatment-emergent adverse events of relevance were related to reversible myelosuppression (eflornithine + lomustine 42% v lomustine monotherapy 29% of patients) and hearing impairment (24% v 0%). No new safety signals were identified. CONCLUSION Clinically meaningful improvements were observed; eflornithine + lomustine doubled PFS and improved OS in patients with recurrent IDH -mutant, grade 3 astrocytoma, but not grade 4 tumors, after prior radiotherapy and TMZ, consistent with its cytostatic mechanism of action.

Irinotecan demonstrates anti-tumor efficacy in preclinical glioma models but clinical results are modest due to drug delivery limitations. Convection enhanced delivery (CED) improves drug delivery by increasing intratumoral drug concentration. Real-time magnetic resonance imaging of infusate delivery during CED may optimize tumor coverage. This phase 1 trial examines the safety and tolerability of liposomal irinotecan and gadolinium delivered via CED using real-time MRI guidance in recurrent high-grade glioma patients. Initially, a 3 + 3 dose-escalating, single dose trial was planned with 4 cohorts based on a fixed drug dose and volume. After 9 patients, a protocol amendment allowed for variable volume and dose of the study agent based on tumor size. The amended design specified ‘personalized’ drug volume but fixed concentration of 20 mg/mL of liposomal irinotecan in the first cohort escalating to 40 mg/mL in the second cohort. Eighteen patients with recurrent WHO grade 3 or 4 gliomas (diameter 1–4 cm) were treated. Based on the tumor volume, the total dose of liposomal irinotecan was 20–680 mg in a total volume of 2–17 ml. Technical challenges were overcome by real-time MRI guidance and protocol amendment. The only dose-limiting toxicity (DLT) was a grade 3 stroke. Safety and survival information is presented. CED of liposomal irinotecan using real-time MRI in patients with recurrent high-grade glioma is feasible. Image-guidance allowed for improved placement of CED cannulas and optimal tumor coverage. Our results warrant further study with repeat CED dosing.

Glioblastoma (GBM) is the most common primary malignant brain tumor, with a poor prognosis due to resistance to radiation therapy (RT) and temozolomide (TMZ). Galectin-3 (Gal-3), a carbohydrate-binding protein, is implicated in GBM progression, treatment resistance, immune evasion, and poor survival. TB006, a humanized monoclonal antibody targeting Gal-3, has shown potential to enhance TMZ efficacy and reverse therapy-induced Gal-3 upregulation in preclinical models. Preliminary data demonstrate that Gal-3 is upregulated in GBM cells and orthotopic models following TMZ treatment, while TB006 reduces Gal-3 expression, suppresses tumor growth, and improves survival. Additional studies show TB006 inhibits GBM cell migration and invasion. Despite a favorable safety profile in Phase Ia and Phase Ib/IIa Alzheimer’s trial, optimal dosing and utility of TB006 in GBM remain unexplored. We propose three aims: (1) investigate PK/PD simulations of TB006 to support a proposed starting clinical dose; (2) evaluate TB006’s antitumor efficacy in combination with RT and TMZ using patient-derived xenograft models; and (3) conduct a Phase 1 window-of-opportunity trial in recurrent GBM patients undergoing reoperation to evaluate tumor concentration of TB006, Gal-3 modulation, and to assess safety, tolerability, PK/PD, and early efficacy. This translational study aims to test the hypothesis that TB006, by targeting Gal-3, will improve glioblastoma sensitivity to standard of care RT and TMZ, resulting in enhanced treatment efficacy and survival. Successful completion will inform dosing strategies, support development of a Phase 2 trial, and lay the groundwork for precision medicine approaches targeting galectin-driven mechanisms in GBM.

Glioblastoma (GBM) is highly aggressive with poor prognosis, especially in recurrent cases where treatments are limited. Intra-arterial (IA) Yttrium-90 (Y90) microsphere therapy, FDA-approved for hepatocellular carcinoma, offers the potential for targeted radiotherapy in recurrent GBM (rGBM). The FRONTIER trial evaluated the safety and feasibility of IA Y90-glass microsphere treatment for rGBM under an FDA Investigational Device Exemption. Materials and This prospective, single-arm, multi-center study included patients with rGBM in non-dominant, non-eloquent regions. The primary endpoint was 30-day incidence of treatment-related limiting toxicities (primarily ≥grade 3 non-hematologic, with exclusions). Secondary endpoints included adverse event (AE) rate, neurological changes, technical success (PET absorbed dose within ±20% of target), and efficacy. Treatment regions, defined via cerebral angiography-MRI fusion to cover the recurrent lesion, were targeted with 40±4Gy. Post-treatment evaluations included MRI, Y90-PET, and neurological assessments. The procedure was well-tolerated by all twelve subjects and discharge occurred the following day with no decline in neurologic status. No limiting toxicities or device-related AEs were reported. Five patients experienced 8 procedure-related AEs (6 Grade 1, 2 Grade 3). Technical success was 100%, with post-treatment Y90-PET derived median absorbed dose of 41.5 Gy to the treatment region (median volume 80.3 cc). The median tumor absorbed dose was considerably higher at 124.2 Gy (median tumor volume 5.8 cc), indicating preferential tumor perfusion. At 2 months, 67% had stable disease, and 33% showed reduced T1-contrast enhancing volume within the treated area. Median progression-free survival was 3.1 (95% CI 0.92-NE) and overall survival (OS) was 9.3 months (95% CI 5.0-NE) from Y90 treatment. Exploratory analysis revealed a significant OS benefit for patients receiving a tumor absorbed dose above the median (11.9 vs 5.7 months, p=0.0073). Results from this initial cohort suggest IA Y90-microsphere therapy is technically feasible and well-tolerated in rGBM. Further investigation is warranted.

The current standard-of-care (SOC) practice for defining the clinical target volume (CTV) for radiation therapy (RT) in patients with glioblastoma still employs an isotropic 1–2 cm expansion of the T2-hyperintensity lesion, without considering the heterogeneous infiltrative nature of these tumors. This study aims to improve RT CTV definition in patients with glioblastoma by incorporating biologically relevant metabolic and physiologic imaging acquired before RT along with a deep learning model that can predict regions of subsequent tumor progression by either the presence of contrast-enhancement or T2-hyperintensity. The results were compared against two standard CTV definitions. Our multi-parametric deep learning model significantly outperformed the uniform 2 cm expansion of the T2-lesion CTV in terms of specificity (0.89 ± 0.05 vs 0.79 ± 0.11; p = 0.004), while also achieving comparable sensitivity (0.92 ± 0.11 vs 0.95 ± 0.08; p = 0.10), sparing more normal brain. Model performance was significantly enhanced by incorporating lesion size-weighted loss functions during training and including metabolic images as inputs.

Pamiparib, a small-molecule poly (ADP-ribose) polymerase (PARP) 1/2 inhibitor, demonstrates strong PARP-DNA complex trapping, antitumor activity, and blood–brain barrier penetration. This phase Ib/II dose-escalation study (NCT03150862) investigated pamiparib’s tolerability/safety and efficacy when combined with radiotherapy and/or low-dose temozolomide (TMZ) in patients with treatment-naïve (Arms A and B) and recurrent/refractory (Arm C) glioblastoma. The recommended phase II dose for Arm A was pamiparib 60 mg twice daily (BID) for 6 weeks with 6–7 weeks radiotherapy; the recommended dose for Arm C was pamiparib 60 mg BID plus 60 mg TMZ (days 1–7; 28-day cycle). The Arm B escalation cohort completed enrollment; the expansion cohort was not opened. Grade ≥3 treatment-emergent adverse events (TEAEs)/serious TEAEs were observed in 55.0%/36.7% (Arm A), 44.4%/22.2% (Arm B), and 66.0%/38.3% (Arm C) of patients. Disease control and objective response rates were 67.9% and 11.3%, respectively, for treatment-naïve patients in the dose-escalation and -expansion studies, and 40.9% and 13.6%, respectively, for recurrent/refractory patients. Median overall survival for treatment-naïve MGMT unmethylated patients was 12.8 months and 7.3 months for recurrent/refractory MGMT methylated and unmethylated patients. Pamiparib with radiotherapy and/or low-dose TMZ was tolerable for treatment-naïve or recurrent/refractory glioblastoma. Treatment-emergent cytopenia was manageable and reversible with dose reductions/interruptions. Combination regimens demonstrated antitumor activity.

10017 Background: Dordaviprone (ONC201), a first in class imipridone, has demonstrated safety and efficacy in an integrated analysis of patients with recurrent H3 K27M-mutant diffuse midline glioma across clinical studies. Here, we report efficacy and safety findings from two prospectively defined clinical trial arms that evaluated single-agent dordaviprone response in recurrent H3 K27M-mutant glioma. Methods: Phase 2 trialONC013 (Arm B) and Phase 1 trial ONC014 (Arm F) were designed to evaluate the objective response rate (ORR) by RANO-HGG criteria of dordaviprone in adult and pediatric patients, respectively, with recurrent H3 K27M-mutant diffuse glioma. Open label dordaviprone was administered once weekly at 625 mg for adults and at a dose scaled by body weight for pediatrics. Responses were investigator-assessed by RANO criteria. Eligibility required measurable enhancing recurrence by RANO-HGG criteria, radiotherapy completed ≥90 days prior to dordaviprone unless unequivocal progression qualified per RANO, Karnofsky or Lansky performance status >60. DIPG, spinal tumors, leptomeningeal disease, and CSF dissemination were excluded. Results: ONC013 Arm B enrolled 30 patients (median age 32, range, 21-66 years) with the majority having a primary midline non-brainstem tumor (n = 19, 63.3%) and one prior recurrence (n = 22, 73.3%). The ORR was 16.7% (95% CI, 5.6-34.7) with 5 partial responses (PR). The median duration of response (DOR) and time to response (TTR) were 15.1 months (7.5-not reached) and 3.8 months (1.8-4.6), respectively. Three patients experienced a grade ≥3 treatment-related adverse events (TR-AE), none had treatment-related serious AEs (TR-SAEs), and 1 had TR-AE leading to dose reduction (ALT increase). ONC014 Arm F enrolled 11 patients (median age 14, range 11-19 years). Most had a primary midline non-brainstem tumor (n = 7, 63.6%) and 1 prior recurrence (n = 6, 65.6%). Two (18.2%) radiographic responses were reported, 1 response (9.1%) qualified by RANO criteria. One PR occurred with > 95% tumor regression and an 8.5-month DOR (1.9-month TTR). Another patient experienced a > 50% tumor regression (4.3-month TTR) that did not meet RANO PR criteria due to initiation of 2.5 mg dexamethasone post-baseline. 12-month PFS rate was not reached; 12-month OS rate was 27.3% (6.5, 53.9). One patient experienced a grade ≥3 TR-TEAE (9.1%); no TR-SAEs, treatment-related deaths, or TR-AE leading to treatment discontinuation occurred. Conclusions: In prospective clinical trials designed to evaluate ORR, single-agent dordaviprone response and safety in adult and pediatric recurrent H3 K27M-mutant diffuse glioma were similar to previously pooled analyses. Clinical trial information: NCT03295396 and NCT03416530 .