Trial Design Research Articles

A Model‐Based Trial Design With a Randomization Scheme Considering Pharmacokinetics Exposure for Dose Optimization in Oncology

ABSTRACTThe primary purpose of an oncology dose‐finding trial for novel anticancer agents has been shifting from determining the maximum tolerated dose to identifying an optimal dose (OD) that is tolerable and therapeutically beneficial for subjects in subsequent clinical trials. In 2022, the FDA Oncology Center of Excellence initiated Project Optimus to reform the paradigm of dose optimization and dose selection in oncology drug development and issued a draft guidance. The guidance suggests that dose‐finding trials include randomized dose–response cohorts of multiple doses and incorporate information on pharmacokinetics (PK) in addition to safety and efficacy data to select the OD. Furthermore, PK information could be a quick alternative to efficacy data to predict the minimum efficacious dose and decide the dose assignment. This article proposes a model‐based trial design for dose optimization with a randomization scheme based on PK outcomes in oncology. A simulation study shows that the proposed design has advantages compared to the other designs in the percentage of correct OD selection and the average number of patients assigned to OD in various realistic settings.

Abstract C016: Age dictates immune response within the tumor microenvironment of triple negative breast cancer

Abstract Age is the biggest risk factor for developing most forms of cancer. In breast cancer, over 50% of patients are over 60 years old; however, less than 25% of patients enrolled in clinical trials are in this age bracket. Furthermore, most mouse modeling is performed in young mice, meaning that from preclinical through clinical stages patients ages are not accurately reflected in trials designs. Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer with no targeted therapies, so many treatment strategies utilize chemotherapy in combination with immunotherapy – which relies on a functional immune response. It is well known that immune function declines as we age, and thus therapeutic responses may differ with age. It is yet unclear how the tumor immune microenvironment changes with age, and how this may impact therapeutic response. Here, we utilize a mouse model which mimics hallmarks of human immune aging to understand how age impacts TNBC immune responses to dictate disease progression and therapeutic response. Immunologically young (8 weeks old) and aged (∼12 months old) FVB mice were orthotopically injected with syngeneic Met1 TNBC cells. Once tumors became palpable, mice were treated with paclitaxel chemotherapy or vehicle control and/or anti-PDL1 immunotherapy to mimic first-line therapeutic strategies. Tumors grew significantly faster in young control mice compared to aged, but young mice had a more robust response to therapy. Notable, only young mice had a significant benefit of combo therapy over monotherapy alone. Despite aged mice having more circulating CD8+ and CD4+ T cells, tumors in aged mice had significantly more infiltration of CD8+ cytotoxic T cells and FOXP3+ inhibitory T-regulatory cells compared to young control mice, yet only tumors in young mice exhibited an increase in T cell infiltration with therapy. Additionally, the ratio of CD8+ T cells and FOXP3+ Tregs was unchanged with age or treatment. Depletion of either CD8+ or CD4+ T cells led to a complete loss of age-associated differences in tumor growth. RNA sequencing analysis suggests that infiltrating T cells in aged mice may be exhausted due to a chronic interferon (IFN) phenotype, indicated by enrichment of IFN-alpha, IFN-gamma, and IL2 pathways, as well as increased expression of immune exhaustion markers PD1, CTLA4, TIM3 and LAG3. Neutralization of IFN-gamma blocks therapeutic response to anti-PDL1 in young mice but has no impact on aged mice. Analysis of published single cell RNAseq data indicated the same IFN response pathways enriched with age in human TNBC. These results demonstrate that the aging tumor immune microenvironment significantly impacts tumor progression and therapeutic response and suggest that targeting IFN signaling may lead to improved therapeutic responses. Together these findings establish a significant impact of immune aging on TNBC disease progression and response to therapy, highlighting the importance of developing age- stratified treatment strategies to improve responses in patients of all ages. Citation Format: Milos Spasic, Adrienne Parsons, Abigail Recko, Elizabeth Mittendorf, Peter van Galen, Sandra McAllister. Age dictates immune response within the tumor microenvironment of triple negative breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C016.

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

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.

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.

A study within a trial (SWAT) of clinical trial feasibility and barriers to recruitment in the United Kingdom - the CapaCiTY programme experience.

The CapaCiTY programme includes three, multi-centre, randomised controlled trials aiming to develop an evidence based adult chronic constipation treatment pathway. The trials were conducted in the United Kingdom, National Health Service, aiming to recruit 808 participants from 26 March 2015 to 31 January 2019. Sites were selected based on their responses to site feasibility questionnaires (2014-2015), a common tool employed by sponsors to assess a site's recruitment potential and ability to undertake the trial protocol. Failure to recruit the planned sample jeopardises reliability of results and wastes significant time and resources. The purpose of this study was to investigate barriers to recruitment in 2017. We conducted site feasibility assessments with thirty-nine sites prior to trial commencement. Twenty-seven were selected to participate in the CapaCiTY programme, twelve were deemed unsuitable. We compared site contracted recruitment rates with actual recruitment rates and conducted a telephone survey and analysis from 5 July to 7 December 2017 (n = 24) to understand barriers to recruitment. Three sites declined to participate in the survey. At the time of survey, 15% of sites in the CapaCiTY programme were meeting recruitment targets, 85% were recruiting half or less of their target. Of these, 28% recruited no participants. The main barriers to recruitment were lack of resources, high workloads, lack of suitable participants and study design not being compatible with routine care. Despite multiple strategies employed to overcome these barriers, the trials were eventually stopped due to futility, recruiting only 34% of the programme sample size. Improving the reliability of site feasibility assessments could potentially save a substantial amount in failed research investments and speed up the time to delivery of new treatments. We recommend 1) investment in training researchers in conducting and completing site feasibility; 2) funders to require pilot and feasibility data in grant applications, with an emphasis on patient and public involvement in trial design; 3) conducting site feasibility assessment at the pre-award stage; 4) development of a national database of sites' previous trial recruitment performance; 5) data-driven site level assessment of recruitment potential. ISRCTN11791740; 16/07/2015, ISRCTN11093872; 11/11/2015, ISRCTN11747152; 30/09/2015.

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.

Multi-objective optimization in EDM of functionally graded Fe-Al using grey relational analysis

Abstract Functionally Graded Materials (FGMs) are multipurpose materials with a specific goal of managing changes in structural, thermal, or functional qualities. They feature a spatial variation in microstructure and/or composition. The current work prepared three layers of sample with different chemical compositions of Fe-Al FGM (50 Al-50 Fe, 45 Al-55 Fe, and 40 Al-60 Fe) at. % produced by powder metallurgy, then studied the machining behavior of these samples. The literature on the machining behavior of FGM was reviewed, and the influence of electrical discharge machine (EDM) process parameters such as voltage (V), current (I), pulse-on time, and pulse-off time on performance characteristics (material removal rate (MRR), tool wear rate (TWR), and surface roughness (Ra)) was investigated. The optimal machining settings for Fe-Al FGM samples will be ascertained by use of Grey Relational Analysis (GRA), which is based on the Taguchi approach, after an experimental investigation of the L18 orthogonal array design of trials. The GRA findings verify that V 140 volts, Ip10 A, Ton 100 μs, and Toff 75 μs is the optimal combination of process parameters. It has been found that the voltage is more significantly affected than the rest of the input parameters to obtain greater material removal rate (MRR) and lower tool wear rate (EWR) and surface roughness (Ra) through the response table. According to the study, choosing the right process parameters can improve the multi-performance feature.

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.

Meta-Analysis: Evaluating Placebo Rates Across Outcomes in Eosinophilic Oesophagitis Randomised Controlled Trials.

High placebo responses have limited drug development in eosinophilic oesophagitis. The optimal configuration of trial outcomes is uncertain. To inform more efficient future trial designs, to characterise clinical, endoscopic and histologic placebo responses in eosinophilic oesophagitis randomised controlled trials (RCTs). We updated a Cochrane systematic review and meta-analysis, searching multiple databases to January 1, 2024, to identify placebo-controlled RCTs evaluating medical therapies for patients with eosinophilic oesophagitis. The primary outcome was the pooled proportion of study-defined clinical, endoscopic and histologic responders and remitters randomised to placebo, using an intention-to-treat approach and random-effects model. Sources of heterogeneity were explored using meta-regression. We included 25 RCTs. The pooled proportion of clinical response was 41.0% [95% CI: 29.7%-52.8%] with substantial heterogeneity (I2 = 74.9%). On meta-regression, older age and a higher probability of being randomised to placebo reduced the likelihood of clinical response to placebo. The pooled proportion of histologic remission defined as a peak eosinophil count [PEC] ≤ 6 eosinophils per high power field [HPF] or ≤ 1 eosinophil/HPF was 4.3% [95% CI: 2.6%-6.2%] (I2 = 23.6%) and 1.3% [95% CI: 0.5%-2.5%] (I2 = 0%), respectively. The standardised mean difference in the Eosinophilic Oesophagitis Endoscopic Reference Score to placebo was -0.25 [95% CI: -0.41, -0.10]. Over 40% of patients in eosinophilic oesophagitis trials respond clinically to placebo, and this is associated with trial design factors such as randomisation ratio and trial population. Objective endoscopic and histologic measures are associated with very low placebo responses.

A scoping review of nursing interventions for reducing the negative impacts of domestic violence among women.

Incidences of domestic violence against women are increasingly every years. Domestic violence has the negative impacts on physical problems, psychological problems, and can even cause death. Nurses have a role for providing interventions to reduce the impact of domestic violence on women. The purpose of this study is to explore methods of nursing interventions in reducing the traumatic effect of domestic violence among women. This study used a scoping review method. The literature used in this study from CINAHL, PubMed, and Scopus databases. Search articles used the keywords domestic violence, impact, women, and victims. PRISMA Extension for Scoping Reviews are used for selecting articles. The inclusion criteria for the articles in this study were that the sample was female victims of sexual violence, randomized control trial or quasi-experimental research design, and last 10 years for publications period (2013-2022). From three databases, we found 579 articles. After elimination-based inclusion and exclusion criteria, we found 10 articles discussing the effect of nursing interventions in reducing the impact of domestic violence on female victims. Most of the studies from USA and the range of respondents in the articles is 112-1250 respondents. The methods used in providing nursing interventions are classified into three, namely self-management programs, counseling programs, social support programs. The activities carried out in nursing interventions in the form of psychoeducation, relaxation, meditation, and also discussions about solving problems encountered. All articles show that nursing interventions are effective in reducing the impact of domestic violence on women. Nurses have an important role to provide comprehensive nursing care to victims of domestic violence by paying attention to various aspects, namely physical, psychological, and spiritual aspects to improve safety and comfort of patients. This study is the basis for nurses to provide comprehensive nursing care to reduce the impact of domestic violence among women victims of domestic violence.

A potential platform for future vaccine trials identifies high incidence of symptomatic and asymptomatic influenza infection among children aged 6-23 months in South Africa.

Approaches for determining whether influenza vaccination prevents infection, attenuates illness, or both, are important for developing improved vaccines. We estimated influenza infection incidence, and evaluated symptom ascertainment methodologies in children to inform future vaccine trial design. We conducted a prospective cohort study among children aged 6-23 months from May-October 2022. Study nurses collected symptom and temperature data and mid-turbinate nasal swabs twice-weekly irrespective of symptoms; caregivers entered symptom data daily and collected nasal swabs weekly. Samples were tested for influenza using PCR. Of 230 healthy, screened children, 93 were enrolled of whom 87 (94%) completed 6-months follow-up. 95% (4245/4476) of scheduled nurse, 90% (2045/2276) of caregiver swabs, 99% (92/93) of baseline blood collections and 67% (9245/13768) of scheduled symptom diaries were completed. PCR-confirmed influenza incidence was 65% (60/93) for ≥1 infection; 11 (18%) individuals had 2 and 1 (2%) had 3 episodes. Of 73 episodes, 55 (75%) had ≥1 symptom and 37 (51%) had fever (measured and/or reported). Median infection duration was 7 days (interquartile range 4-9). Human RNase P gene was detected in 99% (2032/2045) of caregiver-collected swabs, through which 5 additional episodes were identified. Per episode, caregiver's diaries of reported and measured fever were 19%(25/73,34%) and 11%(15/73,21%) higher than nurse-reported (11/73,15%) and -measured fevers (7/73,10%), respectively. The incidence of influenza infection was high and mainly symptomatic suggesting that this platform could be suitable for future trials of vaccine efficacy and correlates of protection against infection and illness in children.

Effectiveness of a three-component intervention supporting unemployed individuals with mental health issues in their job search and mental health recovery (3for1): study protocol of a non-randomized controlled study.

There is a vicious cycle between unemployment and mental health issues. Unemployed individuals with mental health issues require individualized support at multiple levels in order to promote their mental health, and obtain and retain employment. The 3for1-intervention program aims to provide such support with three components (short-term psychotherapy, job coaching based on the Individual Placement and Support approach, and peer support). This study protocol outlines how the effectiveness of this three-component intervention program in terms of re-employment, mental health, and psychosocial outcomes will be evaluated. The 3for1-intervention program will be evaluated with a non-randomized controlled trial design in a multi-center study. 500 eligible participants aged between 18 and 60 years from six job centers in Southern Germany will be allocated to a control group or an intervention group. Allocation is time-based, with the control group being recruited first, followed by recruitment of the intervention group. The control group will receive treatment as usual, whereas the intervention group will receive treatment as usual as well as access to the three intervention components over a period of 12 months. Assessment will be conducted at baseline (t0), and 12 (t1) and 18 (t3) months later. The primary outcome will be the proportion of participants who are in employment subject to social insurance contributions at t1. Differences between control and intervention group will be tested with logistic regression analysis, controlling for relevant covariates. Analyses of secondary outcomes will relate to group differences regarding re-employment, health and well-being, social integration, help-seeking, and self-stigma at t1 and t2, applying logistic regression analysis or analysis of covariance. Additionally, usage of health services will be measured to evaluate the intervention program's cost effectiveness. The 3for1-intervention aims to improve employability and mental health outcomes of a vulnerable population with high need for assistance. Improvements for this population would benefit the German welfare state as well. This study could provide valuable insights into the feasibility, implementation, and sustainability of this individualized, multi-level support program within German job centers. This trial is registered with the German Clinical Trials Register: DRKS00029002 (registered on 11 May 2022).

Impact of arteriovenous fistula formation on trajectory of kidney function decline: a target trial emulation

Abstract Background Prior nonrandomised studies have suggested nephroprotective effects of arteriovenous fistula (AVF) formation, but these are plausibly susceptible to immortal time and selection biases. Methods We studied patients attending nephrology clinics in the West of Scotland during 2010-2022 with an eGFR ≤15mL/min/1.73m2 and no prior AVF. Using target trial emulation and a sequential trial design, we simulated a hypothetical trial that would randomise patients to either undergo AVF formation immediately or not to undergo AVF formation. The primary outcome was the difference in eGFR slope for the first six months of follow-up, estimated using a mixed-effects model. The secondary outcomes were 5-year absolute risks of dialysis and death, estimated using the Aalen-Johansen and Kaplan-Meier estimators respectively. Results 1,364 unique patients (mean age 51.1, 55.7% male) contributed 3,125 person-trials, with 561 in the AVF and 2,564 in the no AVF group. Mean eGFR was 12.6mL/min/1.73m2 and the median number of eGFR measurements per person-trial was 7 (IQR 4 – 12). Slope of eGFR decline did not differ significantly between the AVF and no AVF groups (between group difference -0.67mL/min/1.73m2/year, 95%CI -1.43, 0.10). The 5-year absolute risk of dialysis was 87% (95%CI 84, 91) in the AVF group and 75% (95%CI 73, 77) in the no AVF group and the 5-year survival probability was 77% (95%CI 70, 83) in the AVF group and 67% (95%CI 64, 69) in the no AVF group. Conclusions In this study of patients with advanced CKD, there was no evidence of a nephroprotective effect of AVF formation.

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.

Abstract IA017: ctDNA based detection of MRD in colon cancer: Towards clinical implementation

Abstract Patient selection for adjuvant treatment remains a challenge with our current clinicopathologic criteria. While adjuvant chemotherapy has been shown to improve relapse risk and survival in stage III colon cancer and perhaps less so in stage II disease, the absolute benefit remains modest, risking the over-treatment of many patients and potential under-treatment of some. Additionally, beyond fluoropyrimidine and oxaliplatin, no new adjuvant therapy has been shown to improve survival over the past 2 decades, especially for MMR proficient tumors. The ability of ctDNA to detect minimal residual disease offers a paradigm shift to the conventional tissue- based risk assessment. Post-op ctDNA detection has been shown to be one of the strongest independent prognostic markers in curatively resected colorectal cancer. Alongside technological advancement, multiple randomized trials are investigating different applications of ctDNA MRD analysis in the clinic, from adjuvant treatment de-escalation in patients with ctDNA-negative result, treatment escalation in ctDNA-positive result to the role of ctDNA as a surveillance tool. Understanding the strengths and limitations of this test will help inform future trial design and optimize clinical implementation. Citation Format: Jeanne Tie. ctDNA based detection of MRD in colon cancer: Towards clinical implementation [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 IA017.

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.

A framework for N-of-1 trials of individualized gene-targeted therapies for genetic diseases.

Individualized genetic therapies-medicines that precisely target a genetic variant that may only be found in a small number of individuals, as few as only one-offer promise for addressing unmet needs in genetic disease, but present unique challenges for trial design. By nature these new individualized medicines require testing in individualized N-of-1 trials. Here, we provide a framework for maintaining scientific rigor in N-of-1 trials. Building upon best practices from traditional clinical trial design, recent guidance from the United States Food and Drug Administration, and our own clinical research experience, we suggest key considerations including comprehensive baseline natural history, selection of appropriate clinical outcome assessments (COAs) individualized to the patient genotype-phenotype for safety and efficacy assessment over time, and specific statistical considerations. Standardization of N-of-1 trial designs in this fashion will maximize efficient learning from this next generation of targeted individualized therapeutics.

Can AI-powered avatars replace human trainers? An empirical test of synthetic humanlike spokesperson applications

Purpose This study aims to investigate the effectiveness of widely adopted but under-studied synthetic humanlike spokespersons (SHS) compared to organic human spokespersons in workplace training videos. The primary aim is to evaluate whether employees will rate training videos more negatively when they perceive their trainer to be synthetic such as those videos made with the AI-powered tools Synthesia or HeyGen. Results suggest that while ratings are more negative when the viewer perceives syntheticness, the change is only mild across most measures deployed here. When measures were calculated by using actual modality and not perceived modality, no significant change in rating was found. This study deployed three measures: actual knowledge transfer, perceived effectiveness and brand impression. It is guided by a convergence of AI Literacy Theory, the Technology Acceptance Model and the Theory of Reasoned Action. Design/methodology/approach Over 250 professionals assessed the effectiveness of training videos in a 2 × 2 trial design. Participants were randomly assigned to view one of four training videos featuring either a synthetic or organic spokesperson for a fictional business. After watching the video, participants answered Likert-scale survey questions and multiple-choice quiz-style questions to provide comparative measurements of actual knowledge transfer effectiveness, perceived effectiveness, brand impression and the effectiveness of the synthetic deception. The study used both ANOVA and multiple regression analyses to control for potential confounding variables and ensure the robustness of the findings. Findings The results indicate no significant differences between SHS and organic human spokespersons in terms of actual effectiveness (quiz scores), perceived effectiveness or brand impression, based on actual modality comparisons. However, when respondents perceived syntheticness, the avatar triggered the negative uncanny valley phenomenon and slightly decreased overall scores in perceived effectiveness and brand impression. Notably, more than half of respondents did not detect that the SHS was synthetic. Demographic variables such as gender, age or household income had no significant impact on the results. Practical implications Organizations can justifiably consider incorporating SHS into their training programs, leveraging these synthetic agents to deliver cost-effective and scalable learning solutions. The findings suggest that SHS can be used effectively for goals such as actual knowledge transfer without compromising training quality, and that other perceptual goals may be within reach as well. This may offer a viable alternative to traditional, organic human spokespersons, opening up new opportunities for enhancing training efficiency and accessibility across various industries. Originality/value Synthetic avatars, as outlined here, are a demonstrably effective new option in the array of available learning technologies. They are being adopted en masse but without significant study of their effectiveness. This research provides foundational quantitative assessments designed to address that gap in the literature and practice. The data presented here is highly valuable for practitioners and scholars interested in cutting-edge learning tools. Given the rapid advancement of technology, this study provides an important benchmark for evaluating future improvements in these tools. Furthermore, it offers actionable recommendations for integrating AI-powered avatars into professional development, enhancing understanding of the roles advanced technologies play in educational and training programs.

Thibang Diphatlha: a sequential multiple assignment randomized trial designed to increase timely adoption of cervical cancer treatment in Botswana.

Delays and missed opportunities for timely treatment contribute significantly to stark inequities in cervical cancer mortality in low- and middle-income countries (LMICs) compared to high-income countries. The vast majority (approximately 90%) of new cases and deaths occur in LMICs, particularly those with high rates of HIV such as Botswana. To date, most of the implementation and cancer control research in Botswana and other LMICs has focused on cancer prevention and screening, with limited focus on cancer treatment. As such, there is a critical need to identify effective strategies to ensure timely care, and to understand contextual factors that shape the response to strategies. Without this fundamental knowledge, cervical cancer will remain a public health crisis in Botswana and other LMICs. To help fill this known gap, this study tests the effectiveness of adaptive strategies on timely treatment adoption using a hybrid (type III) Sequential Multiple Assignment Randomized Trial (SMART) design and evaluate contextual mechanisms contributing to the success or failure of each adaptive strategy. The adaptive strategies are designed to target contextual determinants identified in our prior work, including delayed communication of results to patients, individual and structural barriers to accessing treatment, and suboptimal care coordination between referring and cancer treatment clinics, and are supported by systematic evidence of the effectiveness of nudge strategies in clinical care. The primary implementation outcome is adoption, defined as the initiation of treatment within 90days. Secondary outcomes include fidelity, reach, acceptability, implementation costs, and cancer and HIV-related clinical outcomes. The rationale for the study is that enhancing coordination, communication, and navigation through centralized outreach will both increase timely treatment adoption and be scalable and sustainable after the project is completed. This innovative study seeks to decrease cervical cancer mortality in LMICs by developing and implementing effective and sustainable strategies that can be sustained and adapted to other contexts. Additionally, this study seeks to advance the long-term impact of global implementation science through strong and sustained partnerships in Botswana and other LMICs. ClinicalTrials.govNCT05952141. Registered on July 11, 2023. https://clinicaltrials.gov/study/NCT05952141 PROTOCOL VERSION AND DATE: Version 1 (September 28, 2024).

The Evolving Role of Neoadjuvant Radiation Therapy in Pancreatic Adenocarcinoma

Background/Objectives: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers. Surgical resection is the most reliable chance for cure, but high rates of positive margins and local failure persist. Neoadjuvant therapies (NAT), including chemotherapy and radiation therapy (RT), are being explored to improve surgical outcomes, particularly in borderline resectable (BRPC) and locally advanced pancreatic cancer (LAPC). This review aims to summarize the current landscape and future directions for neoadjuvant RT (NART) in PDAC. Methods: The review includes a detailed analysis of past and ongoing clinical trials investigating various NART approaches in PDAC, with an emphasis on different RT techniques, fractionation schemes, and their integration into multimodal treatment strategies. Results: Early evidence suggests that NART can improve resection margins and local control. However, recent trials, including the Alliance A021501 and LAP-07 trials, have failed to demonstrate significant survival benefits with the addition of RT to NAT. Nevertheless, nuances in trial design and execution continue to keep the question of NART open. Newer approaches, such as stereotactic magnetic resonance-guided adaptive radiation therapy (SMART), show promise in improving local control and survival, but further phase 3 trials are needed. Conclusions: While NART has shown potential in improving local control in PDAC, its impact on overall survival remains unclear. Ongoing trials, particularly those utilizing advanced techniques like SMART, are critical in defining the role of RT in the neoadjuvant setting for PDAC. Collaboration across multidisciplinary teams is essential to optimize treatment strategies and trial outcomes.