Neuro-oncology Clinical Trials Research Articles

Mapping Progress: An analysis of trends in reporting race and ethnicity data in neuro-oncology clinical trials

Mapping Progress: An analysis of trends in reporting race and ethnicity data in neuro-oncology clinical trials

FLAIR MRI sequence synthesis using squeeze attention generative model for reliable brain tumor segmentation

Manual segmentation of brain tumors using structural magnetic resonance imaging (MRI) is an arduous and time-consuming task. Therefore, automatic and robust segmentation will considerably influence neuro-oncological clinical trials by reducing excessive manual annotation time. Herein, we propose a deep learning model that automatically segments brain tumors even in cases of missing MRI sequences, which are common in practical clinical settings. To address this issue, we enhance a generative adversarial network (GAN) by incorporating a squeeze-and-excitation (SE) attention module into its generator and a PatchGAN into its discriminator. The SE module recalibrates channel responses by explicitly modeling interdependencies, enabling the network to focus on critical regions such as tumor areas. Our proposed generative model is optimized using a combination of adversarial, structural similarity, and mean absolute error losses to synthesize missing MRI sequences more effectively. This enhancement allows our model to synthesize the missing MRI sequence (fluid attenuated inversion recovery [FLAIR]) by leveraging information from other available sequences (T1-weighted, T2-weighted, or contrast-enhanced T1-weighted [T1ce]). For the segmentation task, we employ an optimized nnU-Net model, which is trained using existing sequences and evaluated using both available and synthesized sequences (including missing ones), mimicking real-world scenarios where often only limited MRI sequences are available or usable. Our findings reveal a notable enhancement in brain tumor segmentation, as indicated by a significant increase in overall the Dice similarity coefficient (DSC) from 0.688% (when FLAIR is missing) to 0.873% (when using synthesized FLAIR derived from T2). This improvement brings the segmentation performance closer to what was achieved when real FLAIR was available, where the DSC reaches 0.901%. Moreover, our synthesizing model was also tested on two additional datasets: the BraTS 2020 validation set and BraTS Africa 2023 training set, which produces results comparable to those of BraTS 2021, thereby proving its robustness and generalizability. In addition, the resulting tumor segmentations are subsequently employed to assess the response to treatment in cases where all sequences were available and when synthesis was employed, according to response assessment in neuro-oncology criteria.

1239 Trends in Geospatial Availability of Neuro-oncology Clinical Trials in the United States Over Two Decades

INTRODUCTION: Advances in brain tumors treatments rely on successful neuro-oncology (NO) clinical trials. To date, data on NO trials completion in the US is scarce. Understanding these factors could help improve access to and the design of future clinical trials. METHODS: NO clinical trials registered in the US were analyzed (2000-2019). Univariate and multivariate analysis were used to compare success rates among trials. Geospatial analysis was performed to determine the trial density and failure rates across different states. Trial density was estimated by the number of trials/state population. RESULTS: A total of 2,610 neuro-oncology clinical trials were registered in the US during the study period, of which 1,257 met a primary endpoint – completion or trial failure. North Dakota had the highest trial density (6.03 trials/100,000 residents), followed by South Dakota (5.83) and several Northeastern states (3.90-5.60). The change in trial failure rates did not correlate with trial density by state (p = 0.777). The states with the greatest increase in trial failure rates were Nevada (23.1%), West Virginia, Alaska, and Idaho (all three at 20.0%). Florida showed a trend towards a statistically significant increase in failure rates to 10.9% (p = 0.09). CONCLUSIONS: The results of this study highlight the variations in success rates and geographic distribution of neuro-oncology clinical trials in the United States. Factors beyond trial density may be critical to trial success. The significant geographic variations in trial density and failure rates across states emphasize the need for targeted efforts to improve access participation to trials in certain regions. Further studies aimed at identifying the factors contributing to the increase in trial failure rates are needed to develop strategies to improve trial enrollment.

The AANS/CNS Section on Tumors: a summary of 40 years of advocacy to advance the care of patients with brain and spine tumors.

The AANS/CNS Section on Tumors was founded 40 years ago in 1984 to assist in the education of neurosurgeons interested in neuro-oncology, and serves as a resource for other national organizations regarding the clinical treatment of nervous system tumors. The Section on Tumors was the first national physicians' professional organization dedicated to the study and treatment of patients with brain and spine tumors. Over the past 40 years, the Section on Tumors has built solid foundations, including establishing the tumor section satellite meetings, founding the Journal of Neuro-Oncology (the first medical journal dedicated to brain and spine surgical oncology), advancing surgical neuro-oncology education and research, promoting neurosurgical involvement in neuro-oncology clinical trials, and advocating for patients with brain and spine tumors. This review provides a synopsis of the Section on Tumors' history, its challenges, and its opportunities, drawing on the section's archives and input from the 17 section chairs who led it during its first 40 years.

Adult neuro-oncology trials in the United States over 5 decades: Analysis of trials completion rate to guide the path forward.

Clinical trials are important to close the gap between therapeutic unmet needs and scientific advances in neuro-oncology. This study analyzes the landscape of neuro-oncology trials to identify completion rates and guide strategies for the path forward. US-registered adult neuro-oncology clinical trials were extracted from www.clinicaltrials.gov (1966-2019), including funding source, trial type, scope, phase, and subjects' demographics. Completed trials defined as those that had completed participants' examinations or intervention administration for the purpose of the final collection of data for the primary outcome were dichotomized against those that failed to reach completion. Univariate and multivariate analyses were used to detect differences across factors comparing the last 2 decades (2000-2009, 2010-2019). Our search yielded 4522 trials, of which 1257 are eligible for this study. In 25 US states, neuro-oncology trial availability is <0.85/100,000 population. Comparing the past 2 decades, trial completion rate decreased from 88% to 64% (P < .001) and National Institutes of Health funding decreased from 47% to 24% (P < .001). Inclusion of subjects >65-year-old and women increased, while inclusion of Hispanic subjects decreased (P < .001). The top 2 reasons for lack of completion included accrual and operational difficulties. A larger proportion of women, non-Hispanic subjects, and older adults were enrolled in completed trials than in those that failed completion. Our study is the first report on the neuro-oncology clinical trial landscape in the United States and supports the development of strategies to further improve access to these trials. Additionally, attention is needed to identify and modify other factors contributing to lack of completion.

Defining interventions and metrics to improve diversity in CNS clinical trial participation: A SNO and RANO effort.

Despite major strides in cancer research and therapy, these advances have not been equitable across race and ethnicity. Historically marginalized groups (HMG) are more likely to have inadequate preventive screening, increased delays in diagnosis, and poor representation in clinical trials. Notably, Black, Hispanic, and Indigenous people represent 30% of the population but only 9% of oncology clinical trial participants. As a result, HMGs lack equitable access to novel therapies, contradicting the principle of distributive justice, as enshrined in the Belmont report, which demands the equitable selection of subjects in research involving human subjects. The lack of clinical trial diversity also leads to low generalizability and potentially harmful medical practices. Specifically, patients with brain cancer face unique barriers to clinical trial enrollment and completion due to disease-specific neurologic and treatment-induced conditions. Collectively, the intersection of these disease-specific conditions with social determinants of health fosters a lack of diversity in clinical trials. To ameliorate this disparity in neuro-oncology clinical trial participation, we present interventions focused on improving engagement of HMGs. Proposals range from inclusive trial design, decreasing barriers to care, expanding trial eligibility, access to tumor profiling for personalized medical trials, setting reasonable metrics and goals for accrual, working with patient community stakeholders, diversifying the neuro-oncology workforce, and development of tools to overcome biases with options to incentivize equity. The diversification of participation amongst neuro-oncology clinical trials is imperative. Equitable access and inclusion of HMG patients with brain tumors will not only enhance research discoveries but will also improve patient care.

QLTI-12. ADULT NEURO-ONCOLOGY TRIAL LANDSCAPE IN THE UNITED STATES OVER FIVE DECADES

Abstract PURPOSE The unmet therapeutic needs in neuro-oncology remain significant due to the biological and clinical challenges. Clinical trials are important to close the gap between therapeutic unmet needs and scientific advances. This study aims at analyzing the landscape of neuro-oncology trials to identify completion and failures and guide strategies for the path forward. METHODS US-registered adult neuro-oncology clinical trials were extracted from www.clinicaltrials.gov (1966-2019) to include funding source, trial type, scope, phase, and subjects’ demographics. Trial failures comprised “terminated,” “withdrawn,” and/or “suspended” trials. Univariate and multivariate analysis were used to detect differences across factors and over time. RESULTS Our search yielded 4522 trials, 1257 eligible for this study. In 25 US States, neuro-oncology trials availability is &amp;lt; 0.85/100,000 population. Over time, completed trials have decreased with a significant increased percentage of trial failures from 22% to 36% (p &amp;lt; 0.001). Overtime, NIH funding decreased from 47% to 24% (p &amp;lt; 0.001). Inclusion of subjects ≥ 65-year-old and women increased in the last decade (p &amp;lt; 0.001) while inclusion of Hispanic subjects has decreased (p &amp;lt; 0.001). The top two reasons for failure included accrual and operational difficulties. Industry-funded trials had a trend toward higher failure rate than NIH-funded. A larger proportion of women (p &amp;lt; 0.001), non-Hispanic subjects (p = 0.001), and older adult (p &amp;lt; 0.001) patients were enrolled in completed trials than in failed trials. CONCLUSION Our study is the first report on the neuro-oncology clinical trial landscape in the US over time. The data support the concept that strategies to further the availability of clinical neuro-oncology trials within the US are necessary. As these are developed, attention is needed to identifying and modifying factors contributing to clinical trial failures.

Assessing neuro-oncology clinical trial impact and value: Testing a novel multi-criteria decision analysis app

BackgroundMany clinical trials are conducted globally, creating challenges in deciding which trial outcomes deserve a clinician’s focus and where to direct limited resources. Determining the ‘value’ of a clinical trial relative to others could be useful in this context. The aim of this study was to test a novel web-based application using multi-criteria decision analysis (MCDA) to rank clinical trial value. MethodsThe MCDA tool combines seven metrics: unmet need; target population size; access; outcomes; cost; academic impact and use of results. Clinical trials were ranked according to their calculated ‘value’ – meaning the importance or worth of a trial. We determined face validity of the app using a set of ten published Phase 3 neuro-oncology clinical trials. A survey of neuro-oncology clinicians asked them to rank the same ten clinical trials, and to rank the seven metrics in terms of importance. ResultsThe two highest app-ranked trials were in concordance with that of the survey respondents, and consistent with the two studies that have had the most impact on routine clinical practice in neuro-oncology. Of the seven metrics, surveyed clinicians considered patient outcomes and unmet need to be the most important when determining clinical trial value. ConclusionsThe metrics app was able to rank and produce a numerical ‘value’ for existing phase 3 neuro-oncology clinical trials. In the future, a related app to prospectively rank future trials at the startup stage could be developed to help centers determine which should be prioritized to be conducted at their site.

Current drug development and trial designs in neuro-oncology: report from the first American Society of Clinical Oncology and Society for Neuro-Oncology Clinical Trials Conference.

Successful drug development for people with cancers of the CNS has been challenging. There are multiple barriers to successful drug development including biological factors, rarity of the disease, and ineffective use of clinical trials. Based upon a series of presentations at the First Central Nervous System Clinical Trials Conference hosted by the American Society of Clinical Oncology and the Society for Neuro-Oncology, we provide an overview on drug development and novel trial designs in neuro-oncology. This Review discusses the challenges of therapeutic development in neuro-oncology and proposes strategies to improve the drug discovery process by enriching the pipeline of promising therapies, optimising trial design, incorporating biomarkers, using external data, and maximising efficacy and reproducibility of clinical trials.

Assessing the reporting quality of adult neuro-oncology protocols, abstracts, and trials: Adherence to the SPIRIT and CONSORT statements.

Comprehensive and transparent reporting of clinical trial activity is important. The Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 and Consolidated Standards of Reporting Trials (CONSORT) 2010 statements define the items to be reported in clinical trial protocols and randomized controlled trials, respectively. The aim of this methodological review was to assess the reporting quality of adult neuro-oncology trial protocols and trial result articles. Adult primary and secondary brain tumor phase 3 trial protocols and result articles published after the introduction of the SPIRIT 2013 statement, were identified through searches of 4 electronic bibliographic databases. Following extraction of baseline demographic data, the reporting quality of independently included trial protocols and result articles was assessed against the SPIRIT and CONSORT statements respectively. The CONSORT-A checklist, an extension of the CONSORT 2010 statement, was used to specifically assess the abstract accompanying the trial results article. Percentage adherence (standard deviation [SD]) was calculated for each article. Seven trial protocols, and 36 trial result articles were included. Mean adherence of trial protocols to the SPIRIT statement was 79.4% (SD: 0.11). Mean adherence of trial abstracts to CONSORT-A was 75.3% (SD: 0.12) and trial result articles to CONSORT was 74.5% (SD: 0.10). The reporting quality of adult neuro-oncology trial protocols and trial result articles requires improvement to ensure comprehensive and transparent communication of planned neuro-oncology clinical trials and results within the literature. Raising awareness by clinical triallists and implementing mandatory evidence of proof of adherence by journals should improve reporting quality.

Accessible Data Collections for Improved Decision Making in Neuro-Oncology Clinical Trials.

Drug development can be associated with slow timelines, particularly for rare or difficult-to-treat solid tumors such as glioblastoma. The use of external data in the design and analysis of trials has attracted significant interest because it has the potential to improve the efficiency and precision of drug development. A recurring challenge in the use of external data for clinical trials, however, is the difficulty in accessing high-quality patient-level data. Academic research groups generally do not have access to suitable datasets to effectively leverage external data for planning and analyses of new clinical trials. Given the need for resources to enable investigators to benefit from existing data assets, we have developed the Glioblastoma External (GBM-X) Data Platform which will allow investigators in neuro-oncology to leverage our data collection and obtain analyses. GBM-X strives to provide an uncomplicated process to use external data, contextualize single-arm trials, and improve inference on treatment effects early in drug development. The platform is designed to welcome interested collaborators and integrate new data into the platform, with the expectation that the data collection can continue to grow and remain updated. With such features, GBM-X is designed to help to accelerate evaluation of therapies, to grow with collaborations, and to serve as a model to improve drug discovery for rare and difficult-to-treat tumors in oncology.

A critical analysis of neuro-oncology clinical trials.

Limitations in trial design, accrual, and data reporting impact efficient and reliable drug evaluation in cancer clinical trials. These concerns have been recognized in neuro-oncology but have not been comprehensively evaluated. We conducted a semi-automated survey of adult interventional neuro-oncology trials, examining design, interventions, outcomes, and data availability trends. Trials were selected programmatically from ClinicalTrials.gov using primary malignant central nervous system tumor classification terms. Regression analyses assessed design and accrual trends; effect size analysis utilized survival rates among trials investigating survival. Of 3038 reviewed trials, most trials reporting relevant information were nonblinded (92%), single group (65%), nonrandomized (51%), and studied glioblastomas (47%) or other gliomas. Basic design elements were reported by most trials, with reporting increasing over time (OR = 1.24, P < .00001). Trials assessing survival outcomes were estimated to assume large effect sizes of interventions when powering their designs. Forty-two percent of trials were completed; of these, 38% failed to meet their enrollment target, with worse accrual over time (R = -0.94, P < .00001) and for US versus non-US based trials (OR = 0.5, P < .00001). Twenty-eight percent of completed trials reported partial results, with greater reporting for US (34.6%) versus non-US based trials (9.3%, P < .00001). Efficacy signals were detected by 15%-23% of completed trials reporting survival outcomes. Low randomization rates, underutilization of controls, and overestimation of effect size, particularly pronounced in early-phase trials, impede generalizability of results. Suboptimal designs may be driven by accrual challenges, underscoring the need for cooperative efforts and novel designs. The limited results reporting highlights the need to incentivize data reporting and harmonization.

Evolution and implementation of radiographic response criteria in neuro-oncology.

Radiographic response assessment in neuro-oncology is critical in clinical practice and trials. Conventional criteria, such as the MacDonald and response assessment in neuro-oncology (RANO) criteria, rely on bidimensional (2D) measurements of a single tumor cross-section. Although RANO criteria are established for response assessment in clinical trials, there is a critical need to address the complexity of brain tumor treatment response with multiple new approaches being proposed. These include volumetric analysis of tumor compartments, structured MRI reporting systems like the Brain Tumor Reporting and Data System, and standardized approaches to advanced imaging techniques to distinguish tumor response from treatment effects. In this review, we discuss the strengths and limitations of different neuro-oncology response criteria and summarize current research findings on the role of novel response methods in neuro-oncology clinical trials and practice.

DISP-14. DEFINING INTERVENTIONS AND METRICS TO IMPROVE DIVERSITY IN CNS CLINICAL TRIAL PARTICIPATION: A SNO AND RANO EFFORT

Abstract Despite major strides in cancer research, care, and therapy, these advances have not been equitable across race and ethnicity. Groups underrepresented in medicine (URM) are more likely to have inadequate preventive screening, increased delays in diagnosis, and poor representation in clinical trials. Notably, Black and Latino Americans represent 29% of the population but only reflect 8% of oncology clinical trial participants. Recent studies have shown that this disparity is also present in neuro-oncology as women, Black, and Latino Americans remain under-accrued in clinical trials. Brain tumor patients already face unique barriers to clinical trial enrollment and completion due to disease-specific conditions–such as impaired motor function, cognition, language deficits, and caregiver dependency–which pose additional difficulties in clinical trial consent, enrollment, and adherence. As part of this collaborative initiative, we evaluated the impact of how a lack of diversity in cancer research is detrimental to scientific discovery and propose interventions focused on improving URM engagement with clinical research. Recommendations include the creation of inclusive trial design at the onset, decreasing barriers to care, expanding trial eligibility, and equitable access to tumor profiling for personalized medical trials. Additionally, setting reasonable metrics and goals for accrual and engagement with patient and community stakeholders will ultimately help to diversify trial participants. Lastly, diversification and inclusion practices within the neuro-oncology workforce, including all personnel involved in clinical research, will help to minimize bias, promote concordant care, and assist with developing sustainable solutions. The diversification of participation in neuro-oncology clinical trials is imperative. The lack of diversity in clinical trials can contribute to improper generalizability of treatment efficacy, resulting in potentially harmful practices. Equitable access and inclusion of URM brain tumor patients will not only enhance research discoveries but will also result in improved patient care for all cancer patients.

EPCT-06. Phase I study of ribociclib and everolimus post-radiotherapy in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG) and high-grade glioma (HGG): Updated report from the COllaborative Network for NEuro-Oncology Clinical Trials (CONNECT)

BACKGROUND: Dual inhibition of CDK4/6 and mTOR in DIPG and pediatric HGG has strong biologic rationale, given prevalent genetic alterations resulting in upregulated cell cycle and PI3K/mTOR pathways in these diseases, as well as non-overlapping agent toxicities. This study sought to evaluate safety/tolerability and determine the recommended phase 2 dose (RP2D) of ribociclib and everolimus among children with newly diagnosed DIPG and HGG post-radiotherapy. METHODS: Patients were enrolled according to a Rolling-6 design and received oral ribociclib and everolimus once daily for 21 and 28 days, respectively, starting 2-4 weeks post-completion of radiotherapy. All HGG and biopsied DIPG patients were screened for RB protein presence by immunohistochemistry. Pharmacokinetics and survival data were analyzed. RESULTS: Nineteen patients enrolled (median age: 8 years [range: 2-18]). Three patients enrolled at each of dose levels 1 and 2 without dose-limiting toxicities (DLTs). Thirteen patients enrolled at dose level 3, with one patient experiencing a DLT (grade 3 infection). One patient came off therapy prior to cycle 9 due to cardiac toxicity. The most common grade 3/4 toxicities were neutropenia (33%), leucopenia (17%), and lymphopenia (11%). Steady-state everolimus exposures in combination were 1.9±0.9-fold higher than single-agent administration. Median overall survival (OS) for 15 patients with DIPG was 13.9 months, with 12-, 24-, and 36-month OS of 53.3%, 38.9%, and 38.9%. Median event-free survival for four patients with HGG was 10.5 months. Among patients with tumor molecular profiling, two longer survivors (OS: 20, >37 months) had evidence of cell cycle upregulation with CDKN2A/B deletion and CDK4 overexpression identified. CONCLUSIONS: The combination of ribociclib and everolimus was well-tolerated post-radiotherapy in children with newly diagnosed DIPG and HGG, with a RP2D of ribociclib 170 mg/m2 days 1-21 and everolimus 1.5 mg/m2 days 1-28. Results will inform a molecularly-guided phase II study currently underway to evaluate efficacy.

EPCT-05. Phase Ib study of unesbulin (PTC596) in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG) and high-grade glioma (HGG): A report from the COllaborative Network for NEuro-Oncology Clinical Trials (CONNECT)

BACKGROUND: The B-cell-specific Moloney murine leukemia virus integration site-1 (BMI-1) protein, implicated in self-renewal and DNA-damage signaling, is highly expressed in DIPG and HGG. Preclinically, BMI-1 modulation by unesbulin (PTC596 [which mediates hyperphosphorylation and subsequent degradation of BMI-1]) leads to DIPG/HGG cell proliferation blockade, mitotic abnormalities, and tumor cell sensitization to radiation-induced DNA damage. METHODS: This phase Ib study sought to determine the maximally tolerated dose/ recommended phase 2 dose (RP2D) of unesbulin administered concurrently with radiotherapy and adjuvantly in children with newly diagnosed DIPG or HGG. Patients were enrolled according to a Rolling-6 design and received oral unesbulin twice weekly during radiotherapy and as maintenance therapy. RESULTS: Twenty-seven patients enrolled (median age: 8.5 years [range: 2-18]), including 18 patients with DIPG and nine patients with HGG. Unesbulin was administered in capsule formulation in the first nine patients, then tablet formulation for subsequent patients. Within the capsule formulation group, three dose-limiting toxicities (DLTs) were observed in two patients on dose level 2 (grade 4 neutropenia). Within the tablet formulation group, four DLTs were experienced by three patients on dose level 2 (grade 3 ALT elevation, grade 3 dehydration/vomiting, grade 3 decreased ejection fraction, grade 4 neutropenia). Dose level 1 was declared the RP2D, and six additional patients enrolled in the expansion cohort at this dose without DLTs. Most common drug-related grade 3/4 toxicities were neutropenia (48%), leucopenia (35%), and elevated ALT (26%). Similar pharmacokinetic profiles were observed for capsule and tablet formulations, consistent with adult data. Survival outcomes and genomics results will be shared at time of presentation. CONCLUSIONS: The RP2D of unesbulin in children newly diagnosed with DIPG or HGG is 200mg/m2 twice weekly, concurrent with and following radiotherapy. The recently opened surgical cohort will assess intratumoral pharmacokinetics and inhibition of tumor BMI-1 signaling, with results forthcoming.

The Impact of COVID-19 on Neuro-Oncology Clinical Trials During Wave 1 and Wave 2 at a Frontline Detroit Healthcare System (P12-9.007)

The Impact of COVID-19 on Neuro-Oncology Clinical Trials During Wave 1 and Wave 2 at a Frontline Detroit Healthcare System (P12-9.007)

Correlation between Response Assessment in Neuro-Oncology (RANO) Criteria and Clinical Outcome in Patients with Brain Tumor

Response assessment in neuro-oncology (RANO) criteria was established to improve the assessment of tumor response and provide guidance on the assessment of response and endpoints in neuro-oncology clinical trials. Neurologic assessment in neuro-oncology (NANO) scale is an instrument used for assessing neurological function objectively and practical in intracranial tumor patients. This study aimed to determine the association between RANO criteria with clinical outcome measured by NANO scale in intracranial tumors patients. There were 36 intracranial tumor patients that were studied in Haji Adam Malik General Hospital Medan. The RANO criteria were obtained by comparing the size of the enhanced lesion using Computed Tomography (CT) scan within an interval of a minimum of four weeks of treatment. NANO scale is a quantifiable evaluation of nine relevant neurologic domains based on examination. The NANO scale included gait, strength, ataxia, sensation, visual fields, facial strength, language, level of consciousness, and behavior as assessed domains from the medical record. We analyzed the correlation between the RANO criteria and NANO scale score using the Spearman correlation test. There were 19 males and 17 females. The mean age was 45.22±9.68 years. There were 20 patients (55.6%) with meningioma, 11 patients (30.6%) with glioma, 3 patients (8.3%) with brain metastase, and 2 patients (5.6%) with craniopharyngioma. The mean NANO scale scores for stable and progressive RANO criteria were 4.29±2.02 and 7.88±2.99, respectively. There was a significant correlation between RANO criteria and NANO scale score in patients with intracranial tumor (r = 0.468; p = 0.004). Patients with stable RANO had lower NANO scale scores indicating better response to treatment and clinical outcome.

CTNI-20. FEASIBILITY OF SINGLE-PASS STEREOTACTIC NEEDLE BIOPSY IN RECURRENT GLIOBLASTOMA PATIENTS TO SUPPORT CLIA-CERTIFIED TUMOR PHARMACODYNAMICS FOR A PHASE 0/2 CLINICAL TRIAL

Abstract BACKGROUND In neuro-oncology clinical trials, pharmacodynamic (PD) analysis of tumor tissue before and after experimental therapy is challenging. Today, Phase 0 studies in brain tumor patients typically employ archival tissue from a prior resection as the baseline PD comparator. However, the time-interval between tissue acquisitions can be months to years and often includes confounding exposure to other therapies. Here, we demonstrate the feasibility of a pre-treatment, single-pass stereotactic needle biopsy to support CLIA-certified genetic screening and tumor PD analysis in a Phase 0/2 clinical trial. METHODS In support of an ongoing Phase 0/2 ‘trigger’ trial testing CDK4/6 plus ERK1/2 inhibition in recurrent glioblastoma (GBM), a single-pass stereotactic biopsy was completed in select patients prior to enrollment. Each biopsy yields six tissue cores for immunohistochemistry (IHC) and genetic characterization. Using CLIA-certified protocols, genomic DNA (gDNA) was extracted from two cores, followed by library preparation and next-generation sequencing of a customized panel of 37 genes (IvySeq). In the four remaining cores, IHC staining was performed for RB, pRB, pERK, pS6, CDKN2A, MIB-1, ClCas-3 and pH2AX. RESULTS Single-pass stereotactic needle biopsies were collected from five recurrent GBM patients. No intraoperative, perioperative, or radiographic evidence of morbidity was observed. 800-2400ng of gDNA was isolated from each stereotactic biopsy. IvySeq analysis detected CDKN2A deletion, ATRX loss, and mutations in IDH, PTEN and TP53 genes. Based on IHC and genetic analyses of the biopsied samples, three patients were enrolled into the Phase 0/2 clinical trial and baseline value were used for PD analysis. CONCLUSION Single-pass stereotactic needle biopsy is a feasible and safe strategy to collect pre-treatment tissue in support of a Phase 0 clinical trial, enabling CLIA-certified genetic analysis for trial screening and tumor PD analysis.

EPID-24. TRANSCRIPT: A cenTRAl NERVOUS SYSTEM CANCER CLINICAL tRIals PostmorTem

Abstract BACKGROUND Despite the growing number of neuro-oncology clinical trials, there have been limited advances in the treatment of malignant primary central nervous system tumors. We surveyed the landscape of past, ongoing, and planned trials to assess trends in their interventions, outcomes, and design considerations to guide future studies. METHODS Data on interventional trials on ClinicalTrials.gov were accessed programmatically using AACT and R. Neuro-oncology trials were isolated using primary malignant brain tumor classification terms. Instrument names from PROQOLID were used to identify clinical outcome assessment (COA) use. Linear regression was used to assess chronological trends; power analyses utilized CBTRUS survival rates among trials investigating overall survival. RESULTS We identified 3039 interventional brain tumor trials that started between 1966 and 2025. Trials were most frequently phase II (43%), completed (40%), non-blinded (92%), single-group assignment (65%), non-randomized (51%) studies targeting glioblastoma (45%). Planned outcomes were reported by 93% of trials; this included adverse event or toxicity (54%), overall/x-year survival (44%), progression free survival (43%), maximum tolerated dose (16%), and objective response rate (14%). Evaluating the anticipated and actual trial enrollment, we estimate that only 10% and 8% of trial arms, respectively, were sufficiently powered to assess overall survival endpoints. 21% of trials mentioned the use of a COA (first trial initiated in 1992), majority of which were patient-reported outcomes. Among these, 25% and 58% reported COA as a primary or secondary outcome, respectively. The rate of COA use increased linearly over time at 1.1%/year but remained less than 5 trials per year until 2003. Ongoing work is investigating treatment mechanisms of actions and evidence of preclinical efficacy among brain tumor studies. CONCLUSIONS Low randomization rates and underpowered trial design may impede interpretability of efficacy. Increasing trends in COA use suggests cumulative influence of advocacy efforts to holistically evaluate net clinical benefit of interventions.