Clinical Trial Design Research Articles

Framework for the Pathology Workup of Metastatic Castration-Resistant Prostate Cancer Biopsies.

Lineage plasticity and histologic transformation from prostate adenocarcinoma to neuroendocrine prostate cancer (NEPC) occurs in up to 15-20% of patients with castration-resistant prostate cancer (CRPC) as mechanism of treatment resistance and is associated with aggressive disease and poor prognosis. NEPC tumors typically display small cell carcinoma morphology with loss of androgen receptor (AR) expression and gain of neuroendocrine (NE) lineage markers. However, there is a spectrum of phenotypes that are observed during the lineage plasticity process, and the clinical significance of mixed histologies or those that co-express AR and NE markers or lack all markers is not well defined. Translational research studies investigating NEPC have used variable definitions making clinical trial design challenging. Here we discuss the diagnostic workup of metastatic biopsies to help guide the reproducible classification of phenotypic CRPC subtypes. We recommend classifying CRPC tumors based on histomorphology (adenocarcinoma, small cell carcinoma, poorly differentiated carcinoma, other morphologic variant, or mixed morphology) and immunohistochemical markers with a priority for AR, NKX3.1, INSM1, synaptophysin and cell proliferation based on Ki-67 positivity, with additional markers to be considered based on the clinical context. Ultimately, a unified workup of metastatic CRPC biopsies can improve clinical trial design and eventually practice.

The Application of Terlipressin in the Management of Ascites in Liver Cirrhosis: Current Status and Prospects

Ascites due to liver cirrhosis is a common complication in patients with liver disease, severely affecting their prognosis and quality of life. Traditional treatment methods have significant limitations in managing ascites, highlighting the need for new therapeutic approaches. As an antidiuretic drug, terlipressin has shown good efficacy and potential in treating ascites. This review covers terlipressin’s application in managing ascites caused by liver cirrhosis, covering the mechanism of action, usage strategies, clinical effects, and potential side effects. Clinical trial results are discussed to provide a glimpse into the efficacy and safety of terlipressin in managing ascites and its side effects. Additionally, we provide detailed discussions on medication precautions and management strategies for adverse reactions in high-risk patients. Finally, this review outlines future research directions, such as new clinical trial designs, comparisons of terlipressin with other novel drugs, and the exploration of individualized treatment models. These efforts aim to provide references for clinical practice and promote further development in this field.

The Win Ratio Approach in Bayesian Monitoring for Two-Arm Phase II Clinical Trial Designs With Multiple Time-To-Event Endpoints.

To assess the preliminary therapeutic impact of a novel treatment, futility monitoring is commonly employed in Phase II clinical trials to facilitate informed decisions regarding the early termination of trials. Given the rapid evolution in cancer treatment development, particularly with new agents like immunotherapeutic agents, the focus has often shifted from objective response to time-to-event endpoints. In trials involving multiple time-to-event endpoints, existing monitoring designs typically select one as the primary endpoint or employ a composite endpoint as the time to the first occurrence of any event. However, relying on a single efficacy endpoint may not adequately evaluate an experimental treatment. Additionally, the time-to-first-event endpoint treats all events equally, ignoring their differences in clinical priorities. To tackle these issues, we propose a Bayesian futility monitoring design for a two-arm randomized Phase II trial, which incorporates the win ratio approach to account for the clinical priority of multiple time-to-event endpoints. A joint lognormal distribution was assumed to model the time-to-event variables for the estimation. We conducted simulation studies to assess the operating characteristics of the proposed monitoring design and compared them to those of conventional methods. The proposed design allows for early termination for futility if the endpoint with higher clinical priority (e.g., death) deteriorates in the treatment arm, compared to the time-to-first-event approach. Meanwhile, it prevents an aggressive early termination if the endpoint with lower clinical priority (e.g., cancer recurrence) shows deterioration in the treatment arm, offering a more tailored approach to decision-making in clinical trials with multiple time-to-event endpoints.

High-Fidelity Clinical Simulation to Improve a Pediatric Clinical Trial Design: Lessons Learned and Conceptualization of the Return on Investment (ROI) and Return on Engagement (ROE) Analysis.

Clinical trials entail complex processes that are more challenging when they are addressed to pediatric patients and include a decentralized design. High-realistic simulation allows for the testing and refining of procedures, organizational systems, and interactions between professionals and patients/families, narrowing the gap between work-as-imagined and work-as-done. The aim of this research was to analyze the impact of simulation in three key moments of a clinical trial: the baseline visit, home administration of the investigational drug by parents, and the drawing and processing of pharmacokinetics samples by a home nurse. Multidisciplinary meetings were held between the team of Barcelona Children's Hospital and the sponsor to define the simulation objectives. Three simulation scenarios were executed in 2 days. Subsequently, a post-process analysis was performed, including the assessment of the patient/family experience. In the baseline visit scenario, minimum duration was calculated, and main aspects related to task dynamics, materials, and training were identified. In the drug administration scenario, the family was able to carry out the infusion within the time established in the protocol, but with some difficulties. In the home nursing scenario, some recommendations for improving safety and patient experience were suggested. High-realistic clinical simulation can contribute to anticipate risks, refine the design of activities, and to identify specific needs prior to the protocol finalization, a timepoint in the process when modifications can still be made that constitutes a significant return on investment and return on the engagement, in the experience of the patients that will participate in the study. NCT04644575.

Behavioral risk assessment of work-related musculoskeletal disorders among workers of petrochemical industries: protocol of a mixed method study

BackgroundMusculoskeletal disorders (MSDs) are one of the most common occupational diseases and the main cause of disability worldwide. Work-related musculoskeletal disorders (WMSDs) are one of the common health risks and the most important cause of absenteeism due to disability in various industries, including the petrochemical industry, in developed and developing countries. These disorders have important social economic, and significant financial consequences due to direct and hidden costs. Health behaviors play a role in both creating and preventing musculoskeletal disorders in employees. Therefore, by identifying the influencing factors on these behaviors, it is possible to strengthen and improve the preventive behaviors of musculoskeletal disorders through educational intervention programs. This study aims to assess the behavioral risk of work-related musculoskeletal disorders, and design and implement an educational intervention to teach effective behaviors in the prevention of musculoskeletal disorders in petrochemical industry workers.MethodsThis study is a mixed-method study implemented in four stages involving the qualitative study, the design and evaluation of an instrument, the design of an experimental randomized clinical trial, and the psychometric evaluation of the instrument and the evaluation of the program. The research community consists of employees working in the petrochemical industry. The volume of samples in the qualitative study with the purposeful sampling method, in the instrument design stage based on the available sampling method, and also in the experimental study, the samples are employees suffering from work-related musculoskeletal disorders, who were selected based on a simple random method from among the employees of the petrochemical industry. Then they will be divided into intervention and control groups. The instruments of this research include a demographic questionnaire, a researcher-made questionnaire for measuring behavior, and two auxiliary instruments including the visual analog scale (VAS) and the Quebec Disability Scale. Evaluation is done in 4 stages: pre-test, immediately, 3, and 6 months after the intervention of both groups. The obtained data will be analyzed using SPSS software.DiscussionMusculoskeletal disorders related (WMSDs) to work can harm employees’ health in various industries, including the petrochemical industry. This study attempts to evaluate the behavioral risk of work-related musculoskeletal disorders among petrochemical industry workers and design and implement an appropriate educational intervention program.Trial registrationIranian Registry of Clinical Trial (IRCT20240321061346N1). Registered on 2024–04-10.Ethics Status: Ethics code: IR.MODARES.REC.1402.251.

Clinical study design strategies to mitigate confounding effects of time-dependent clearance on dose optimization of therapeutic antibodies.

Time-dependent pharmacokinetics (TDPK) is a frequent confounding factor that misleads exposure-response (ER) analysis of therapeutic antibodies, where a decline in clearance results in increased drug exposure over time in patients who respond to therapy, causing a false-positive ER finding. The object of our simulation study was to explore the influence of clinical trial designs on the frequency of false-positive ER findings. Two previously published population PK models representative of slow- (pembrolizumab) and fast-onset (rituximab) TDPK were used to simulate virtual patient cohorts with time-dependent clearance and the frequency of false-positive ER findings. The impact of varying the number of dose groups, dose range, and sample size was evaluated over time. Study designs with a single tested dose level showed a high probability of showing a false-positive ER finding. When TDPK has a slow onset, use of exposure measures from early timepoints in ER analysis significantly reduces the risk of a false-positive, while with fast onset it did not. Randomization of patients to two dose levels greatly reduced the risk, with a threefold or greater dose range offering the greatest benefit. The likelihood of false-positive increases with a larger sample size, where greater care should be taken to identify confounding factors. Clinical trial simulation supports that appropriate clinical study design and analysis with adequate dose exploration can reduce but cannot entirely eliminate the risk of misleading ER findings.

State of the art and perspectives of gene therapy in heart failure. A scientific statement of the Heart Failure Association of the ESC, the ESC Council on Cardiovascular Genomics and the ESC Working Group on Myocardial & Pericardial Diseases.

Gene therapy has recently become a reality in the treatment of cardiovascular diseases. Strategies to modulate gene expression using antisense oligonucleotides or small interfering RNA are proving to be safe and effective in the clinic. Adeno-associated viral vector-based gene delivery and CRISPR-Cas9-based genome editing have emerged as efficient strategies for gene delivery and repair in humans. Overall, gene therapy holds the promise not only of expanding current treatment options, but also of intervening in previously untackled causal disease mechanisms with little side effects. This scientific statement provides a comprehensive overview of the various modalities of gene therapy used to treat heart failure and some of its risk factors, and their application in the clinical setting. It discusses specifically the possibilities of gene therapy for hereditary heart diseases and (non)-genetic heart failure. Furthermore, it addresses safety and clinical trial design issues and challenges for future regulatory strategies.

Delta-like ligand 3 (DLL3) landscape in pulmonary and extra-pulmonary neuroendocrine neoplasms.

Delta-like Ligand 3 (DLL3) targeting therapies are promising in small cell lung cancer (SCLC) treatment. However, DLL3 expression in SCLC and other neuroendocrine neoplasms (NEN) is heterogeneous and not well characterized. We describe the landscape of DLL3 at the mRNA and protein levels across SCLC, large cell neuroendocrine carcinoma (LCNEC), and non-small cell lung cancer. Additionally, we explore its expression in extra-pulmonary NEN (EP-NEN) using a standardized DLL3 IHC assay. DLL3 expression is enriched in SCLC, LCNEC along with combined histology lung cancers. Moreover, we find a wide range of DLL3 expression in high-grade EP-NEN. We describe heterogenous DLL3 expression not only in SCLC but also in different NEN types. This comprehensive characterization of DLL3 can help guide future clinical trial design targeting DLL3 in NEN including LCNEC and EP-NEN that are lacking standard of care treatment options.

A Partially Randomized Patient Preference, Sequential, Multiple‐Assignment, Randomized Trial Design Analyzed via Weighted and Replicated Frequentist and Bayesian Methods

ABSTRACTResults from randomized control trials (RCTs) may not be representative when individuals refuse to be randomized or are excluded for having a preference for which treatment they receive. If trial designs do not allow for participant treatment preferences, trials can suffer in accrual, adherence, retention, and external validity of results. Thus, there is interest surrounding clinical trial designs that incorporate participant treatment preferences. We propose a Partially Randomized, Patient Preference, Sequential, Multiple Assignment, Randomized Trial (PRPP‐SMART) which combines a Partially Randomized, Patient Preference (PRPP) design with a Sequential, Multiple Assignment, Randomized Trial (SMART) design. This novel PRPP‐SMART design is a multi‐stage clinical trial design where, at each stage, participants either receive their preferred treatment, or if they do not have a preferred treatment, they are randomized. This paper focuses on the clinical trial design for PRPP‐SMARTs and the development of Bayesian and frequentist weighted and replicated regression models (WRRMs) to analyze data from such trials. We propose a two‐stage PRPP‐SMART with binary end of stage outcomes and estimate the embedded dynamic treatment regimes (DTRs). Our WRRMs use data from both randomized and non‐randomized participants for efficient estimation of the DTR effects. We compare our method to a more traditional PRPP analysis which only considers participants randomized to treatment. Our Bayesian and frequentist methods produce more efficient DTR estimates with negligible bias despite the inclusion of non‐randomized participants in the analysis. The proposed PRPP‐SMART design and analytic method is a promising approach to incorporate participant treatment preferences into clinical trial design.

Statistical operating characteristics of current early phase dose finding designs with toxicity and efficacy in oncology

ABSTRACT Traditional phase I dose finding cancer clinical trial designs aim to determine the maximum tolerated dose (MTD) of the investigational cytotoxic agent based on a single toxicity outcome, assuming a monotone dose-response relationship. However, this assumption might not always hold for newly emerging therapies such as immuno-oncology therapies and molecularly targeted therapies, making conventional dose finding trial designs based on toxicity no longer appropriate. To tackle this issue, numerous early-phase dose finding clinical trial designs have been developed to identify the optimal biological dose (OBD), which takes both toxicity and efficacy outcomes into account. In this article, we review the current model-assisted dose finding designs, BOIN-ET, BOIN12, UBI, TEPI-2, PRINTE, STEIN, and uTPI to identify the OBD and compare their operating characteristics. Extensive simulation studies and a case study using a CAR T-cell therapy phase I trial have been conducted to compare the performance of the aforementioned designs under different possible dose-response relationship scenarios. The simulation results demonstrate that the performance of different designs varies depending on the particular dose-response relationship and the specific metric considered. Based on our simulation results and practical considerations, STEIN, PRINTE, and BOIN12 outperform the other designs from different perspectives.

Sample size calculations based on day-to-day variability of stress biomarkers in persons with dementia and their family caregivers

Introduction: Accurate estimates of intra-individual variability are necessary for proper design of clinical trials and epidemiological studies where the stress biomarkers cortisol and dehydroepiandrosterone sulfate (DHEA-S) are measured for dyads of persons with dementia (PWDs) and their family caregivers (FCGs). The aim is to determine the number of consecutive sampling days required to detect effect differences in clinical trials, and to accurately estimate regression coefficients in epidemiological studies where stress biomarkers are exposure variables in regression models with future disease as outcome. Methods: Clinical trial data from dyads of PWDs and their FCGs were used. Salivary cortisol and DHEA-S samples were collected five days a week, for eight consecutive weeks. From this data, we created formulas and graphical tools for the number of required sampling days needed to detect effect differences, and we calculated number of days needed for regression coefficients to be estimated with<10% bias. Results: A total of 5791 salivary samples from 34 dyads were used. For morning cortisol, five consecutive sampling days at baseline and an equal number of days at study termination is sufficient to detect a treatment difference>5% of baseline level with>20 dyads per group. When stress biomarkers are used in epidemiological studies at least six consecutive sampling days are required. Conclusion: Based on a large number of consecutive measurements of stress biomarkers we calculated the sufficient numbers of sampling days for clinical trials and for epidemiological studies to produce credible results. Our findings will aid researchers in the study design phase.

Key challenges in developing a gene therapy for Usher syndrome: machine-assisted scoping review.

Despite compelling empirical evidence demonstrating its efficacy, gene therapies for usher syndrome (USH) are not yet available for the patient's usage. This scoping review assessed the current scenario and analysed the challenges in implementing gene therapies for USH. A literature search was conducted using PubMed and Google Scholar through an artificial intelligence (AI) tool, MaiA, focusing on relevant publications from the last 10 years. We followed the methodological guidance of the Joanna Briggs Institute (JBI) and adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Scoping Reviews (PRISMA-ScR) checklist. Of 517 records, 51 reports were considered for final analysis. It identified and categorized challenges across four key areas: preclinical, clinical, economic, and regulatory. Of all, many reports (30) highlighted the preclinical challenges where the USH gene development process encountered roadblocks. Specifically, preclinical challenges included the lack of suitable in-vivo models and effective delivery methods. Clinical challenges focused on establishing clear endpoints and long-term safety and efficacy. Economic challenges addressed diagnostic issues and manufacturing hurdles, while regulatory challenges focused on expedited evaluation processes and guidance for clinical development. Our analysis uncovered key barriers to clinical translation of USH gene therapy and strategies to address them. Researchers are employing innovative approaches, including novel delivery methods such as minigenes and nanoparticles, inventive clinical trial designs, cohesive regulatory frameworks, strategic market assessments, and collaborative research initiatives. These efforts hold promise for impactful disease-cure and modifying interventions ultimately enhancing the quality of life for USH patients.

Integrating parent voices into research at the extremes of prematurity: what are we doing and where should we go?

When a baby is born premature, a landscape of potential problems replaces an imagined future. Outcomes become the measures of success. Researchers are recognizing that we need the direct input of parents to select meaningful outcomes. In this article, we describe how researchers and clinicians in neonatology have historically defined outcomes and the limitations of these methods. We chart the integration of stakeholders-patients and parents-into outcomes selection. 'Parent-important outcomes' are those deemed most important by parents, as the voices of their children. We outline a path toward determining parent-important outcomes in neonatology through mixed methods research. We conclude by suggesting how parent-important outcomes can be integrated into neonatal follow up research and clinical trial design. Ultimately, all researchers of prematurity aim in some way to improve outcomes that parents and patients care about. We hope this article will remind us of this beacon.

Utilizing gene expression profiling for the identification of small cell lung cancer subtypes

Abstract. Small cell lung cancer is a highly aggressive form of lung cancer associated with poor prognosis and limited treatment options. Gene expression profiling has emerged as a valuable tool for classifying SCLC into distinct molecular subtypes, each with its own unique therapeutic vulnerabilities and biomarkers. Recent studies have identified four primary subtypes: SCLC-A, SCLC-N, SCLC-P, and SCLC-Y, with additional classification into neuroendocrine (NE) high, NE-low, and non-NE tumors. Advanced understanding of the molecular characteristics of these subtypes presents new opportunities for targeted therapeutic approaches. The paper underscores the potential for a shift toward personalized therapy for SCLC, taking into account the inter- and intratumoral heterogeneity and dynamic subtype interconversion in response to treatment. Incorporating subtype-specific biomarkers in clinical trial designs could lead to the first-ever molecular biomarker-driven approach in the management of SCLC, greatly enhancing treatment effectiveness and patient outcomes.

Two-Stage Recruitment Design to Reduce Magnetic Resonance Imaging Screening Cost for a Theoretical Clinical Trial of White Matter Hyperintensity Progression.

White matter hyperintensities (WMH) and their progression are associated with risk of dementia and stroke, so are an important target for clinical trials. The cost of broad magnetic resonance imaging (MRI) screening to identify eligible individuals, however, limits the feasibility of designing clinical trials targeting WMH. A low-cost retinal or clinical screening measure before MRI could reduce recruitment costs versus an MRI-only screening design in a hypothetical clinical trial. Data from the Atherosclerosis Risk in Communities study with valid retinal and WMH measurements (N=1311) were used. To identify a population at greater likelihood of significant WMH on MRI and thus reduce the number of screening MRIs required, we evaluated 3 theoretical prescreening measures: (1) retinal, (2) clinical, (3) combined clinical-retinal. Given a target sample for clinical trials (N=646), we calculated screening sample sizes based on the proportion within the population having an elevated score for each prescreening measure (separately) multiplied by the proportion of significant WMH among those with that prescreening feature. Recruitment costs were calculated using estimated retinal and MRI cost estimates. Compared with the estimated cost of MRI-only screening (>$4.24 million, requiring MRI on 6526 participants), prescreening for a high clinical score resulted in total cost of $2.47 million, with an initial screening group of 52 778 participants, with MRI in 3801. A high clinical-retinal score cutoff resulted in costs of $2.9 million while requiring 13 572 participants, with 3801 completing MRI. A 2-stage design with low-cost prescreening measures is a promising approach, resulting in reduced theoretical recruitment costs compared with an MRI-only design.

The PERMIT guidelines for designing and implementing all stages of personalised medicine research

Personalised medicine (PM) research programmes represent the modern paradigm of complex cross-disciplinary research, integrating innovative methodologies and technologies. Methodological research is required to ensure that these programmes generate robust and reproducible evidence. The PERMIT project developed methodological recommendations for each stage of the PM research pipeline. A common methodology was applied to develop the recommendations in collaboration with relevant stakeholders. Each stage was addressed by a dedicated working group, specializing in the subject matter. A series of scoping reviews that mapped the methods used in PM research and a gap analysis were followed by working sessions and workshops where field experts analyzed the gaps and developed recommendations. Through collaborative writing and consensus building exercises, the final recommendations were defined. They provide guidance for the design, implementation and evaluation of PM research, from patient and omics data collection and sample size calculation to the selection of the most appropriate stratification approach, including machine learning modeling, the development and application of reliable preclinical models, and the selection and implementation of the most appropriate clinical trial design. The dissemination and implementation of these recommendations by all stakeholders can improve the quality of PM research, enhance the robustness of evidence, and improve patient care.

Abstract B036: Pathway repression in progression on osimertinib therapy in NSCLC via a comprehensive genomic and epigenomic circulating tumor DNA (ctDNA) assay

Abstract Background: Osimertinib is currently the most common precision therapy for patients with non- small cell lung cancer (NSCLC) with EGFR mutations. While it prolongs progression-free survival, resistance eventually develops in many, leading to disease progression. Somatic NGS has identified resistance mutations in the EGFR pathway and other oncogenes, but these account for only 40-45% of cases, suggesting non-genetic factors, such as epigenetic changes, may be involved. This study investigates the epigenetic landscape at diagnosis and progression on first- line osimertinib, focusing on cases with and without canonical resistance mutations. Methods: We defined two cohorts from GuardantINFORM, a clinico-genomics database, restricting to only patients with a test on the Guardant Infinity platform, a comprehensive blood-based NGS assay, that analyzes DNA sequence variants and performs extensive methylation profiling (∼15Mb) in >20,000 differentially methylated regions (DMRs) assessed for sample-specific methylation patterns. (A) Diagnosis Cohort: Comprised of 34 NSCLC patients with blood samples collected within six days prior to the initiation of first-line osimertinib therapy. (B) Progression Cohort: Comprised of 36 patients who were on first-line osimertinib therapy, with blood samples collected within 60 days of discontinuation. The progression cohort was further stratified based on the presence or absence of known resistance mutations identified through somatic variant analysis by Guardant360. Gene set enrichment analysis was conducted on these methylation profiles using the Reactome database to define pathway-level differences between the cohorts. Results: Pathway enrichment analysis in the diagnosis and progression cohorts found expected biological processes in NSCLC such as extracellular matrix organization, G- protein coupled receptor (GPCR) signaling, and FGFR pathways. Additionally, the progression cohort lacking canonical resistance mutations (n=23) exhibited unique enrichment in two specific pathways: Glucose-dependent Insulinotropic Polypeptide and Physiological Factors. These pathways include genes such as GATA4, which has been implicated in the epithelial- mesenchymal transition (EMT)—a process associated with transforming to a small cell phenotype, a known mechanism of resistance to EGFR inhibition, including osimertinib. Conclusion: This study demonstrates the utility of epigenetic profiling via liquid biopsies in uncovering non-genetic mechanisms underlying osimertinib resistance in advanced NSCLC. Identification of unique epigenetic pathways in progressing patients without canonical resistance mutations highlights the potential for discovering novel biomarkers of resistance. Further investigation into these findings may advance our understanding of resistance mechanisms across various cancer therapies, particularly for patients without identified genomic resistance, and inform clinical decision-making and trial design. Citation Format: Aaron Hardin, Leslie Bucheit, Amar Das, Craig Eagel, Helmy Eltoukhy. Pathway repression in progression on osimertinib therapy in NSCLC via a comprehensive genomic and epigenomic circulating tumor DNA (ctDNA) assay [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr B036.

EANM expert opinion: How can lessons from radiobiology be applied to the design of clinical trials? Part I: back to the basics of absorbed dose-response and threshold absorbed doses.

This study by the EANM radiobiology working group aims to analyze the efficacy and toxicity of targeted radionuclide therapy (TRT) using radiopharmaceuticals approved by the EMA and FDA for neuroendocrine tumors and prostate cancer. It seeks to understand the correlation between physical parameters such as absorbed dose and TRT outcomes, alongside other biological factors. We reviewed clinical studies on TRT, focusing on the relationship between physical parameters and treatment outcomes, and applying basic radiobiological principles to radiopharmaceutical therapy to identify key factors affecting therapeutic success. The analysis revealed that mean absorbed dose alone is insufficient to predict treatment response or toxicity. For absorbed doses below a certain threshold, outcomes are unpredictable, while doses above this threshold improve the likelihood of biological responses. However, even at higher absorbed doses, response plateaus indicate the need for additional parameters to explain outcome variability, including heterogeneity in target expression, anatomical disease location, (epi)genetics, DNA repair capacity, and the tumor microenvironment, aspects that will be discussed in Part II of this analysis. Understanding radiobiology is crucial for optimizing TRT. More dosimetric data is needed to refine treatment protocols. While absorbed dose is critical, it alone does not determine TRT outcomes. Future research should integrate biological parameters with physical dosimetry to enhance efficacy and minimize toxicity.

EXTH-19. AN INTERNATIONAL ACCELERATOR PROGRAMME FOR RESEARCHERS DEVELOPING NOVEL THERAPIES FOR BRAIN TUMOURS

Abstract Developing a comprehensive translational programme for brain tumours involves navigating numerous challenges, including robustness of preclinical studies, safety, clinical trial design, understanding and addressing regulatory requirements, and funding. Recognising the difficulty of this journey, the Brain Tumour Research Novel Therapeutics Accelerator (BTR-NTA) was launched in 2023. The BTR-NTA is an accelerator programme providing independent expert guidance to de-risk drug or device development through systematic evaluation. The international, multidisciplinary BTR-NTA Committee spans expertise across the entire therapeutic development pipeline. Supported by Brain Tumour Research, the BTR-NTA programme is free for academic applicants. Researchers at any stage of therapeutic development may apply to BTR-NTA. Accepted applicants proceed as follows: 1. Applicants outline their current and prospective data and findings. The proposal and all supporting materials are covered under a confidentiality agreement that protects applicants’ intellectual property; 2. Proposals are reviewed by the BTR-NTA Committee; 3. Applicants and BTR-NTA Committee meet in-person to constructively evaluate the work; and 4. Applicants receive a comprehensive report with feedback on strengths, identification of potential risks, and guidance on next steps. The BTR-NTA Committee dedicates time for in-person meetings with each applicant, and extensive time pre- and post-meeting. Since the launch of BTR-NTA in 2023,14 international groups have applied to the programme and seven therapies have been advanced to the in-person review by the BTR-NTA Committee. Of the applicants who provided feedback on the BTR-NTA programme, all intended to adjust or refine their future work based on the Committee’s input and the average rating of the programme’s helpfulness was 9.5 out of 10. The ultimate goal of BTR-NTA is to help researchers with a potential therapy for brain tumours to navigate the development journey and reach the clinic in an efficient way. This programme will support the development of novel therapies to improve outcomes for patients with brain tumours.

BIOM-66. GENOME-WIDE DNA METHYLATION PATTERNS IN PERIPHERAL BLOOD OF PATIENTS WITH GLIOBLASTOMA ENROLLED ON THE PHASE II VERTU TRIAL

Abstract BACKGROUND For patients with glioblastoma, the identification of a non-invasive biomarker for longitudinal molecular profiling could improve risk stratification, clinical trial design, and surveillance. In a secondary analysis of the phase II randomized VERTU trial (ACTRN12615000407594) of adult patients with newly diagnosed MGMT-unmethylated glioblastoma, we assessed the feasibility of characterizing peripheral blood genome-wide DNA methylation patterns. METHODS DNA was extracted from whole blood and serum samples at baseline and end-of-treatment (EOT) from patients enrolled on VERTU, which evaluated the PARP inhibitor veliparib combined with radiotherapy and temozolomide. Infinium FFPE QC qPCR and DNA Restoration Kits were used to restore and concentrate fragmented serum DNA. Genomic DNA was plated, bisulfite converted, and profiled for methylation patterns at >935,000 CpG sites using the Infinium MethylationEPIC microarray V2.0. Quality control, pre-processing, leukocyte deconvolution, and calling of MGMT status were completed in R Studio. RESULTS Peripheral blood methylation data were generated and passed quality control for 104/104 baseline and 24/34 EOT samples available for analysis. The median concentration of genomic DNA at baseline and EOT was 104.50 ng/μl (range:1.97-550) and 0.98 ng/μl (range:0.11-19.8). The deconvoluted median leukocyte proportions differed significantly between baseline and EOT for neutrophils (0.64vs0.90,p<0.01), CD4 memory (0.09vs0.00,p<0.01), CD4 naive (0.03vs0.01,p=0.02), CD8 memory (0.04vs0.00,p<0.01), monocyte (0.07vs0.03,p<0.01), natural killer (0.05vs0.00,p<0.01), and T regulatory (0.000vs0.001,p=0.01) cells. There were no differences in baseline leukocyte proportions between patients with (n=6) and without (n=98) biopsy-proven pseudoprogression. 2/104 samples were determined to be MGMT-methylated based on peripheral blood methylation analysis. Unsupervised hierarchical clustering based on the 1,000 most differentially methylated CpG sites generated two patient clusters (n=64, n=40). CONCLUSIONS To our knowledge, this is the first study to demonstrate the feasibility of analyzing peripheral blood methylation patterns from patients with glioblastoma receiving chemoradiation on a randomized clinical trial. Efforts are underway to correlate these blood methylation patterns with previously published tumor tissue methylation patterns and clinical outcomes.