bluuebunny/crossref_metadata_2025_split huggingface dataset:
CTNI-18. DESIGNING AND DELIVERING A RANDOMISED CONTROLLED TRIAL OF MEDICINAL CANNABINOIDS IN RECURRENT GLIOBLASTOMA - THE ARISTOCRAT TRIAL
Authors: Short Susan , Savage Joshua , Mant Rhys , Patel Amit , Buckle Peter , Meade Sarah , Boele Florien , Banks Emma , Brazil Lucy , Collinson Fiona , Billingham Lucinda 
Published: November 2023

Abstract

BACKGROUND
ARISTOCRAT is a randomised, double-blind, placebo-controlled phase II trial of temozolomide chemotherapy, with or without cannabinoids (Nabixomols) in patients with MGMT-methylated recurrent GBM and has recently opened to recruitment across the UK.

METHODS
A multi-disciplinary team of co-applicants and trial management group (TMG) members was assembled comprising clinicians, statisticians, trialists, Patient & Public Involvement (PPI), pharmacists and quality of life (QoL) researchers to design a pragmatic phase II randomised study. The protocol randomises on a 2:1 ratio between Nabiximols or matched placebo alongside standard dose temozolomide in patients at first recurrence of IDH wild-type GBM. Patients titrate to an individualised dose based on tolerance to a maximum of 12 oro-mucosal sprays per day. The primary outcome measure is overall survival time with key secondary outcomes including survival at 6, 12 and 24 months, progression-free survival time, health-related QoL and adverse events. Intermediate assessment of feasibility to confirm safety, compliance and achievability of recruitment will be undertaken after 40 patients are randomised. PPI input has been critical in ensuring sensitive and appropriate patient & public messaging and in developing patient information videos.

RESULTS
ARISTOCRAT was rapidly funded via a novel crowdfunding campaign organised by The Brain Tumour Charity during the COVID-19 pandemic. The trial office has since responded to &gt;150 patient enquiries, demonstrating the high level of patient and public enthusiasm for this trial. Coverage in the press also shows a more broad level of interest in the use of cannabis-derived medicines. The study opened to recruitment on 03-Feb-2023 and the first patient was recruited on 08-Mar-2023. The study aims to recruit a total of 234 patients over an 18 month period.

CONCLUSION
ARISTOCRAT will provide robust clinical data on the role of cannabinoids in improving overall survival and the impact on QoL for patients with recurrent GBM.
CTNI-23. SINGLE CELL TRANSCRIPTOMICS, PHARMACOKINETICS, AND PHARMACODYNAMICS OF COMBINED CDK4/6 AND MTOR INHIBITION IN A PHASE 0 TRIAL OF RECURRENT HIGH-GRADE GLIOMA
Authors: Johnson Kevin , Tien An-Chi , Jiang Jun , McNamara James , Chang Yu-Wei , Montgomery Chelsea , DeSantis Anita , Elena Leonel , Fujita Yoko , Kim Seongho , Tovmasyan Artak , Li Jing , Mehta Shwetal , Verhaak Roel , Sanai Nader 
Published: November 2023

Abstract
Adult High-grade gliomas (HGGs) often exhibit deregulation of RB-CDK4/6 and mTOR signaling pathways. This study investigated tumor single cell transcriptomics, pharmacokinetics, and pharmacodynamics immediately following combined CDK4/6 (ribociclib) and mTOR (everolimus) inhibition in recurrent HGG. 24 patients with recurrent gliomas harboring RB+, CDKN2A/B deletion or CDK4/6 amplification, and PTEN loss or PIK3CA mutations were enrolled in a phase 0 trial. Patients received ribociclib treatment for 5 days before surgery, including six who received ribociclib (400mg QD) plus everolimus (2.5mg QD), and six dose-escalation cohorts (n = 3 each) reaching ribociclib 600mg QD plus everolimus 70mg QW. No dose-limiting toxicities were observed. Validated LC-MS/MS methods determined total and unbound drug concentrations. Preoperative MRI revealed a marked decrease in gadolinium-enhancement in all patients. In gadolinium-nonenhancing tumor regions, the median unbound concentration of ribociclib was 561 nM, while no unbound everolimus concentrations were detected. Ribociclib’s pharmacodynamic effects in surgical specimens were compared with matched archival tissue using IHC. Across IDH-wild-type tumors, there was significant decrease in MIB1 levels between the matched archival and surgical specimens (p &lt; 0.05) suggesting drug-associated cell cycle inhibition. Single nuclei RNAseq (snRNA) analyses were performed on 17 IDH-wild-type recurrent samples treated with ribociclib plus everolimus and 29 IDH-wild-type recurrences treated with standard therapies. Cellular state analysis based on snRNAseq data demonstrated a decreased neural progenitor-like (NPC-like) malignant cell state compared with standard therapies (p &lt; 0.01), indicating inhibition of the CDK4-driven neural progenitor-like cell state. This observation was validated using snRNA and patient-derived glioma cell lines exposed to ribociclib, showing a consistent decrease in NPC-like proportions and cycling cells (p &lt; 0.05). This study highlights the value of integrating pharmacokinetics/pharmacodynamics and snRNA data to assess treatment effects in phase 0 surgical tissues. These findings support further development of ribociclib, but not everolimus, for the treatment of glioma patients.
CTNI-24. CLINICAL ACTIVITY AND SAFETY OF THE RAF INHIBITOR TOVORAFENIB IN PATIENTS WITH OPTIC PATHWAY GLIOMAS IN THE REGISTRATIONAL PEDIATRIC LOW-GRADE GLIOMA ARM OF THE PHASE 2 FIREFLY-1 (PNOC026) STUDY
Authors: Nysom Karsten , Kilburn Lindsay , Leary Sarah , Landi Daniel , de Vos-Kerkhof E , Perreault Sébastien , Witt Olaf , Ziegler David , Driever Pablo Hernáiz , Franson Andrea , Baxter Patricia , Whipple Nicholas S , Kline Cassie , Segal Devorah , Jabado Nada , Bailey Simon , McCowage Geoffrey , Hansford Jordan , Khuong-Quang Dong-Anh , Gottardo Nicholas , Hassall Timothy , Han Jung Woo , Oren Michal Yalon , Chi Susan , Lee Vai , McLeod Lisa , Qiu Jiaheng , Walter Ashley , Manley Peter , Hargrave Darren 
Published: November 2023

Abstract

BACKGROUND
Optic pathway gliomas (OPG) are low-grade gliomas (LGG) comprising 3-5% of pediatric brain tumors. Morbidity may include visual loss (acuity and visual fields), hypothalamic/pituitary dysfunction, and/or impaired motor function. Genomic alterations of MAPK/BRAF are frequent oncogenic drivers in pediatric LGG. Activity of tovorafenib, an investigational, oral, selective, CNS-penetrant, type II RAF inhibitor in OPGs was analyzed.

METHODS
FIREFLY-1 (NCT04775485) is a phase 2 study evaluating tovorafenib (420 mg/m2 weekly) in patients 6 months–25 years with BRAF-altered recurrent/progressive LGG or solid tumors. Independently assessed overall response rate (ORR), as defined by RANO-HGG and RANO-LGG criteria, are primary and exploratory endpoints.

RESULTS
Of the 77 patients enrolled in arm 1 (measurable disease per RANO-HGG), 42 (55%) had tumors located in the optic pathway. Median age at enrollment was 8 years (range: 2–16); 37 (88%) harbored a BRAF fusion and 5 (12%) a BRAF V600E mutation. The median prior lines of systemic therapy was 3 (range: 1–9), with 69% having received prior MAPK inhibitors. Of the 39 evaluable patients (RANO-HGG), the ORR was 59% (1 CR, 22 PRs) with a median time to response (TTR) of 2.8 months; 14 (36%) had stable disease (SD). Per RANO-LGG (n = 42), the ORR was 43% (5 PRs; 13 MRs) with a median TTR of 4.1 months; 20 (48%) had SD. Visual acuity remained stable in 79% (23) of patients (Cycle 9, n = 29 assessed). The most common treatment-related adverse events (TRAEs) of any grade in this subgroup were hair color changes (81%), increased creatine phosphokinase (55%), anemia (48%), maculopapular rash (45%), and fatigue (41%). Dose modifications occurred in 14 (33%) and discontinuations in 3 (7%) patients due to TRAEs.

CONCLUSIONS
Tovorafenib demonstrated antitumor activity in recurrent/progressive BRAF-altered OPG and was generally well tolerated. Visual acuity remained stable for the majority with OPGs.
CTNI-25. A PHASE 0/1B STUDY OF AZD1390 PLUS RADIOTHERAPY IN RECURRENT GLIOBLASTOMA PATIENTS
Authors: Sanai Nader , Desai Siddhi , Margaryan Tigran , LoCascio Costanza , Elliott Mackenna , Molloy Jennifer , Harmon Jocelyn , Hong Amy , Melendez Ernesto Luna , Wanebo John , Braun Kelly , Kennedy William , Garcia Michael , Yoo Wonsuk , Tovmasyan Artak , Tien An-Chi , Mehta Shwetal 
Published: November 2023

Abstract

BACKGROUND
ATM inhibition has been hypothesized to potentiate the effects of radiation by preventing acute phase DNA damage repair, and a Phase 1 trial of this combination in patients with GBM is ongoing (NCT03423628). To test this hypothesis, this phase 0/1b study aimed to evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of AZD1390, an ATM inhibitor with BBB penetration, in combination with ex vivo radiation in patients with GBM (NCT05182905).

METHODS
Recurrent GBM patients received 3 days of AZD1390 prior to planned resection at 2-4, 4-6 or 23-25 hours following the final dose. Tumor tissue, cerebrospinal fluid (CSF), and plasma were collected. Total and unbound drug concentrations were measured using validated LC-MS/MS methods. A PK ‘trigger’ determined eligibility for the therapeutic expansion phase. ATM inhibition was assessed via ex vivo radiation and quantification of pRAD50 levels compared to non-radiated control. Patients exceeding the PK threshold were eligible for an expansion phase of study drug plus radiotherapy followed by maintenance regimen.

RESULTS
In 17 patients treated to date, AZD1390 was consistently measured in the Gd-non-enhancing tumor region. All patients (n = 17) exceeded the PK threshold to qualify for the expansion phase of the study. With 5Gy ex-vivo radiation of surgical specimen, pRAD50 expression was significantly suppressed in AZD1390 treated patients compared to untreated controls (geomean 1.8% vs 29.1%, average 94% reduction, p &lt; 0.01). Median 6-month progression-free survival has not been reached at a median clinical follow-up of 4.3 months.

CONCLUSION
AZD1390 is well-tolerated in recurrent GBM patients, achieving pharmacologically relevant concentrations in non-enhancing tumor tissue, and substantially suppressing induction of pRAD50 levels ex vivo post-radiation. This is the first pharmacodynamic evidence that AZD1390 may be a potent radio-potentiator in patients with GBM.
CTNI-34. ZOTIRACICLIB (TG02) FOR NEWLY DIAGNOSED GLIOBLASTOMA IN THE ELDERLY OR FOR RECURRENT GLIOBLASTOMA: FINAL RESULTS OF THE EORTC 1608 STEAM TRIAL
Authors: Rhun Emilie Le , Gorlia Thierry , Felsberg Jörg , Furtner Julia , Jongen Joost , Maurage Claude-Alain , Ducray Francois , Roth Patrick , Hau Peter , Chinot Olivier , Preusser Matthias , Cartalat Stephanie , van den Bent Martin , Collienne Maike , Reifenberger Guido , Weller Michael 
Published: November 2023

Abstract

BACKGROUND
Zotiraciclib (TG02) is an oral multi-cyclin dependent kinase (CDK) inhibitor that is supposed to suppress tumor growth via CDK-9-dependent depletion of survival proteins such as c-MYC and MCL-1 which are frequently overexpressed in glioblastoma.

METHODS
EORTC 1608 (NCT03224104) (STEAM) had a three parallel group (A,B,C) phase Ib, open-label, non-randomized, multicenter design. Groups A and B explored the maximum tolerated dose (MTD) of TG02 in elderly patients with IDH1R132H-non-mutant newly diagnosed glioblastoma or anaplastic astrocytoma, in combination with hypofractionated radiotherapy alone (group A) or temozolomide alone (group B), based on O6-methylguanine DNA methyltransferase promoter methylation status determined centrally. Group C explored single agent activity of TG02 in IDH1R132H-non-mutant glioblastoma or anaplastic astrocytoma at first relapse after temozolomide chemoradiotherapy with a primary endpoint of progression-free survival at 6 months. Secondary objectives included efficacy, quality of life, and safety. Expression of CDK-9, c-MYC and MCL-1 was determined by immunohistochemistry.

RESULTS
The MTD was 150 mg twice weekly in combination with radiotherapy alone (group A) or temozolomide alone (group B) in elderly patients. Two dose-limiting toxicities were observed at 150 mg, one in group A (grade 3 seizure) and one in group B (multiple grade 1 events). Main toxicities included neutropenia, gastrointestinal disorders, and hepatotoxicity. Progression-free survival at 6 months in group C was 6.7%. CDK9 and its indirect targets, c-MYC and MCL-1, were confirmed to be expressed and their expression was correlated, supporting a regulatory role for CDK-9. The protein levels of CDK-9 and MCL-1 correlated with overall survival.

CONCLUSION
TG02 exhibits overlapping toxicity with alkylating agents and low clinical activity as a single agent. Larger randomized trials are required to explore activity in combination with RT or TMZ. The role of CDK-9 and its down-stream effectors as prognostic factors and therapeutic targets in glioblastoma warrants further study.
CTNI-37. CLINICAL ACTIVITY OF RAF INHIBITOR TOVORAFENIB ACCORDING TO PRIOR MAPK INHIBITOR TREATMENT IN THE REGISTRATIONAL PEDIATRIC LOW-GRADE GLIOMA ARM OF THE PHASE 2 FIREFLY-1 (PNOC026) STUDY
Authors: Khuong-Quang Dong-Anh , Nysom Karsten , Landi Daniel , Ziegler David , Driever Pablo Hernáiz , Leary Sarah , Bailey Simon , van der Lugt Jasper , Perreault Sébastien , Waanders Angela , Baxter Patricia , Witt Olaf , Hargrave Darren , McCowage Geoffrey , Hansford Jordan , Toledano Helen , Oren Liat , Tan Enrica E K , Gerber Nicolas , Kang Hyoung Jin , Larouche Valérie , Abdelbaki Mohamed S , Cornelio Izzy , Kim Yeonhee , Walter Ashley , Manley Peter , Kilburn Lindsay 
Published: November 2023

Abstract

BACKGROUND
Pediatric low-grade glioma (pLGG) is the most common childhood brain tumor. Genomic alterations of RAF are common oncogenic drivers in pLGG. Tovorafenib is an investigational, selective, CNS-penetrant, type II RAF inhibitor.

METHODS
FIREFLY-1 (NCT04775485) is a phase 2 study evaluating tovorafenib monotherapy. Registrational arm 1 enrolled patients aged 6 months–25 years of age with recurrent or progressive LGG harboring an activating BRAF alteration. Tovorafenib 420 mg/m2 (600 mg max) was administered weekly (tablet or liquid suspension). Independently assessed overall response rate (ORR), as defined by RANO-HGG and RANO-LGG criteria, are primary and exploratory endpoints.

RESULTS
As of December 22 2022, 69 (RANO-HGG) and 76 (RANO-LGG) of 77 patients in arm 1 were evaluable at baseline and had ≥9 months of follow-up. Median age at enrollment was 8 years (range 2–21), and 60% (n = 46) patients had received prior MAPK inhibitor (MAPKi) therapy. Among the evaluable patients, the ORR was 62% (RANO-HGG, n = 69) and 45% (RANO-LGG, n = 76), respectively. The ORR in patients previously treated with MAPKis (n = 41 [RANO-HGG]; n = 45 [RANO-LGG]) was 68% (4 CRs; 24 PRs) (RANO-HGG) and 44% (5 PRs; 15 MRs) (RANO-LGG). In MAPKi-naïve patients (28 [RANO-HGG]; 31 [RANO-LGG]), the ORR was 54% (15 PRs) (RANO-HGG) and 45% (7 PRs; 7 MRs) (RANO-LGG). Among 136 patients in arms 1 and 2 of FIREFLY-1, the most common treatment-related adverse events (TRAEs) of any grade were hair color changes (71%), fatigue (40%) and maculopapular rash (38%). Tovorafenib dose modifications occurred in 39 (29%) and discontinuations in 4 (3%) patients due to TRAEs.

CONCLUSIONS
Tovorafenib provided clinically meaningful tumor responses, including those with a best response reported of SD or PD using another MAPKi, in patients with BRAF-altered pLGG regardless of prior MAPKi therapy, and has a manageable safety profile.
CTNI-39. REGOMA-OS: A LARGE ITALIAN MULTICENTER, PROSPECTIVE, OBSERVATIONAL STUDY ANALYZING REGORAFENIB EFFICACY AND SAFETY IN RECURRENT GLIOBLASTOMA PATIENTS
Authors: Caccese Mario , Desideri Isacco , Villani Veronica , Simonelli Matteo , Buglione Michela , Chiesa Silvia , Franceschi Enrico , Gaviani Paola , Stasi Irene , Caserta Claudia , Brugnara Sonia , Lolli Ivan , Bennicelli Elisa , Bini Paola , Cuccu Angelo Salvatore , Scoccianti Silvia , Magni Giovanna , De Salvo Gian Luca , Zagonel Vittorina , Lombardi Giuseppe 
Published: November 2023

Abstract

BACKGROUND
in the randomized phase 2 REGOMA trial, regorafenib (REG) showed promising activity in recurrent glioblastoma (GBM) patients (PTS); subsequently, in Italy the National Health System has permitted the reimbursement of the REG as second-line therapy. We performed a large multicenter, prospective and observational study to confirm REGOMA data in a real-world setting. Materials and

METHODS
major inclusion criteria were: histologically confirmed diagnosis of GBM according to WHO 2016 and relapse after Stupp treatment, good performance status (ECOG PS 0-1), good liver function. REG was administered at standard dose of 160mg/die for 3 weeks on/1 week off. Brain MRI was performed within 14 days before starting REG and every 8-12 weeks, subsequently. Primary endpoint was overall survival. RANO criteria were used for response evaluation, CTACAE v. 5 for adverse events.

RESULTS
from Sept 2020 to Oct 2022, 192 recurrent GBM PTS were enrolled from 29 Cancer Centres in Italy: median age was 58ys (IQR 52.8-67.0), 68% male, ECOG PS was 0 in 85 (44%), 115 PTS (60%) undertook steroids at baseline. MGMT was methylated in 43%, IDHwt in 92%. Median follow-up was 16.6 months (IQR 12.6-19.6). Median OS was 8.2ms (95% CI 6.5-9.6), 12ms-OS 34.7% (95%CI 27.2-42.4); median PFS was 2.6ms (95%CI 2.3-2.9), 6ms-PFS 14.3%. Radiological response was PR and SD in 12 (8%) and 25 (16%) PTS. 77 (44%) PTS received third-line therapy. The median of REG cycles per patient was 3 (IQR 2.0-4.0). Grade 3-4 adverse events (AE) were reported in 53 (28%) PTS; reduction/delay and permanent discontinuation due to AE in 36% and 8% of PTS. No death was considered as treatment-related AE.

CONCLUSIONS
compared to the REGOMA trial, this large Italian multicenter, prospective and observational trial confirmed the results in terms of overall survival with a good toxicity profile of REG in recurrent GBM PTS.
CTNI-44. NEOADJUVANT TREATMENT WITH ST101, C/EBPΒ ANTAGONIST, TRIGGERS NECROSIS AS A PATHOLOGICAL RESPONSE IN NEWLY DIAGNOSED GBM PATIENTS. TISSUE-BASED ANALYSIS FROM A SURGICAL WINDOW OF OPPORTUNITY TRIAL
Authors: Iwamoto Fabio , Vainstein-Haras Abi , Rotolo Jim , Levrero Clara , Michel Robert , Kostelecky Nicolas , Papaioannou Anastasia , Buerki Robin 
Published: November 2023

Abstract

BACKGROUND
CCAAT/enhancer-binding protein β (C/EBPβ) is a master regulator of mesenchymal transformation in GBM (Carro, 2010) and is required for maintenance of immunosuppressive tumor-associated macrophage (TAM) populations. ST101 is a first-in-class C/EBPβ antagonist, that promotes selective tumor cell death without impacting normal cell viability (Darvishi, 2022). In an ongoing phase 1/2 clinical study in rGBM (NCT04478279), ST101 administration resulted in 1 durable PR and 5 SD (range 18 to 53+ weeks). We designed a window of opportunity study to assess the effect of ST101 on clinical outcomes and pharmacodynamic biomarkers in the neoadjuvant setting in newly diagnosed GBM (ndGBM).

METHODS
The study will enroll 12 ndGBM patients to be treated with 2-4 500 mg ST101 IV QW) before surgical resection. After surgery, patients will continue ST101 QW + standard chemoradiation with temozolomide.

RESULTS
As of June 9th, 2023, 6 patients with ndGBM received 2-3 doses of ST101. MRI performed before and after neoadjuvant ST101 indicated stable disease in all patients. At surgery, however, histopathology of tumor samples showed that 4/6 patients had geographic necrosis, indicative of treatment effect after ST101 monotherapy. Evaluation of immunostaining for ST101 and molecular changes in the post-treatment tissue by bulk and single nucleus RNAseq will be conducted.

CONCLUSIONS
ndGBM treated with neoadjuvant ST101 monotherapy shows extensive treatment effects on the tumors that have never been treated with chemoradiation. Stability of enhancing lesions after ST101 monotherapy may not reflect the extent of treatment effect as revealed by treatment-related necrosis in the resected tissue. Analyses of the pharmacodynamics effects of ST101 on GBM cells and tumor microenvironment will be completed and presented. In addition, this study demonstrates the feasibility of a multi-institutional window of opportunity clinical trial in ndGBM patients, a decisive opportunity for determining the penetration and on-target activity of novel agents in neuro-oncology.
CTNI-52. SURVIVAL OUTCOMES IN RECURRENT GLIOBLASTOMA (RGBM) PATIENTS TREATED WITH A SINGLE INTRA-TUMORAL ADMINISTRATION OF BIZAXOFUSP, AN IL-4R-TARGETING TOXIN, IN A PHASE IIB TRIAL
Authors: Sampson John , Achrol Achal Singh , Aghi Manish , Bankiewicz Krystof , Bexon Martin , Brem Steven , Brenner Andrew , Chowdhary Sajeel , Coello Melissa , Desjardins Annick , Ellingson Benjamin , Floyd John , Han Seunggu , Kesari Santosh , Mardor Yael , Merchant Fahar , Merchant Rosemina , Randazzo Dina , Vogelbaum Michael A , Vrionis Frank , Wembacher-Schroeder Eva , To Minh D , Zabek Miroslaw , Butowski Nicholas 
Published: November 2023

Abstract

BACKGROUND
Bizaxofusp (MDNA55) is an IL4R-targeting toxin in development for recurrent (r)GBM, a universally fatal disease with mOS of 6-9 months. IL-4R is overexpressed in GBM and surrounding tumor microenvironment, with high expression associated with poor clinical outcome. Method: Efficacy and safety were evaluated in a single-arm, open-label, multi-center Ph2 study using convection-enhanced delivery of Bizaxofusp. The primary endpoint of mOS was compared to results from a blinded eligibility-matched external control arm (ECA). OS was defined as time from relapse to death/censor. IL-4R expression was determined by immunohistochemistry of available archival tumor tissues from both arms.

RESULTS
Bizaxofusp showed an acceptable safety profile at doses of up to 240 μg. Forty-four subjects were treated with Bizaxofusp per protocol; 81 ECA subjects met the eligibility criteria of the study. The Bizaxofusp group had a significantly longer mOS (12.85 months compared to 7.7 months for ECA; HR, 0.62; 95% CI, 0.42-0.89). Amongst the unmethylated MGMT and high IL-4R sub-groups, subjects treated with Bizaxofusp had significantly longer mOS when compared to the ECA. Eleven patients (25%) treated with Bizaxofusp survived &gt;24 months; 3 patients were still alive (29.9, 32.8 and 40.1 months) at last follow-up. High IL-4R expression was associated with improved survival (mOS, 15.8 versus 9.8 months; HR, 0.7; 95% CI, 0.39-1.46) at all doses. However at high doses (180 μg) subjects with low IL-4R expression had significantly longer survival versus low dose Bizaxofusp (mOS, 15.4 versus 9.1 months; HR, 0.28; 95% CI, 0.09-0.91).

CONCLUSION
In patients with rGBM, a single treatment of Bizaxofusp resulted in significantly improved OS compared to eligibility-matched ECA. High-dose Bizaxofusp was equally effective irrespective of IL4R expression. A Phase 3 registration trial will use a novel hybrid design with a propensity-matched ECA comprising two-thirds of the control arm, setting a new precedent for GBM clinical trials.