Clinical Trials Group Research Articles

HIV-Specific Patient-Reported Outcome Measures: A Systematic Review of Psychometric Properties.

The management of people living with HIV/AIDS (PLWHA) is multidimensional and complex. Using patient-reported outcome measures (PROMs) has been increasingly recognized to be the key factor for providing patient-centered healthcare to meet the lifelong needs of PLWHA from diagnosis to death. However, there is currently no consensus on a PROM recommended for healthcare providers and researchers to assess health outcomes in PLWHA. The purpose of this systematic review was to summarize and categorize the available validated HIV-specific PROMs in adult PLWHA and to assess these PROMs using the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) methodology. This systematic review followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Literature search of three recommended databases (PubMed, Embase, and PsychINFO) was conducted on January 15, 2021. Studies were included if they assessed any psychometric property of HIV-specific PROMs in adult PLWHA and met the eligibility criteria. The PROMs were assessed for nine psychometric properties, evaluated in each included study following the COSMIN methodology by assessing the following: (1) the methodological quality assessed using the COSMIN risk of bias checklist, (2) overall rating of results, (3) level of evidence assessed using the modified Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach, and (4) level of recommendation. A total of 88 PROMs classified into eight categories, assessing the psychometric properties of PROMs for adult PLWHA, were identified in 152 studies including 79213 PLWHA. The psychometric properties of the majority of the included PROMs were rated with insufficient evidence. The PROMs that received Class A recommendation were the Poz Quality of Life, HIV Symptom Index or Symptoms Distress Module of the ACTG, and the People Living with HIV Resilience Scale. In addition, because of lack of evidence, recommendations regarding use could not be made for most of the remaining assessed PROMs (received class B recommendation). This systematic review recommends three PROMs to assess health outcomes in adult PLWHA. However, all these PROMs have some shortcomings. In addition, most of the included PROMs do not have sufficient evidence for assessing their psychometric properties, and require a more comprehensive validation of the psychometric properties in the future to provide more scientific evidence. Thus our findings may provide a reference to the selection of high-quality HIV-specific PROMs by healthcare providers and researchers for clinical practice and research.

Sex and racial disparities in catheter ablation.

Sex and racial disparities in the presentation, diagnosis, and management of cardiac arrhythmias are recognized. Sex-specific differences in electrophysiological parameters are well known and are predominantly related to differences in ion channel expression and the influence of sex hormones. However, the relationship between hormonal or racial influence and arrhythmia mechanisms, presentation, and management needs to be better defined. Women and racial and ethnic groups are less likely to undergo catheter ablation procedures for treatment of cardiac arrhythmias. Underrepresentation of women and racial/ethnic groups in clinical trials has resulted in significant knowledge gaps. Whether sex and racial disparities in arrhythmia management reflect barriers in access to care, physician bias, patient values, and preferences or other factors requires further study.

Strategies for diverse participant recruitment to a preclinical Alzheimer’s Disease prevention trial: The AHEAD study

AbstractBackgroundImproving the demographic diversity of clinical trial participants, including preclinical Alzheimer’s disease (AD) trial participants, is a scientific, social, and ethical imperative.MethodThe AHEAD Study is an ongoing preclinical AD trial evaluating the efficacy of lecanemab (BAN2401) in biological and cognitive disease progression in cognitively unimpaired biomarker eligible individuals ages 55‐80. The study has an overall goal of at least 15% randomizations from underrepresented populations. The AHEAD Recruitment and Retention Workgroup designed a comprehensive and collaborative recruitment plan tailored to increase diverse participation.ResultRecruitment strategies spanned central infrastructure and national initiatives, existing trial ready cohorts, enhanced site engagement, community outreach, and whenever possible, implementation of evidence‐based tactics. Central infrastructure includes a national call center, a study website with capacity for prescreening and site referral, including priority flags for underrepresented groups at the pre‐screener level; establishment of a website dedicated to Spanish speakers; and implementation of blood‐based screening across all sites and targeted communities. Site engagement approaches include disbursement of specialized funding to support local recruitment efforts tailored to diverse populations and the development of partnerships with community organizations or across sites within a region. Outreach activities, at the national, regional, and local level, include earned media and social media campaigns and award‐winning plays and videos surrounding themes of participation of diverse groups in clinical trials. Throughout, additional funding opportunities enable testing of innovative approaches and novel partnerships for recruitment of underrepresented groups at individual sites. Evaluation and additional support of these initiatives will be based on number of underrepresented participants pre‐screened, screened, and randomized in the study.ConclusionFocused, multipronged approaches and sustainable partnerships with demographically diverse communities are required to promote the participation of underrepresented groups into preclinical AD trials like AHEAD. Our initiatives demonstrate the commitment to increase recruitment of underrepresented groups by supporting successful efforts centrally, at the site‐level and the participant level using a combination of traditional and modern recruitment approaches.

Catheter ablation of symptomatic atrial fibrillation: Sex, ethnicity, and socioeconomic disparities.

Catheter ablation for treatment of atrial fibrillation (AF), AF ablation, is more effective than antiarrhythmic drugs in reducing AF burden, reducing symptoms and increasing health-related quality of life. Although females more often experience AF-related symptoms, and have more severe symptoms, have lower quality of life, and experience more serious adverse effects of antiarrhythmic drugs than males, they are less likely to undergo AF ablation. Potential explanations for the disparity include older age at diagnosis, longer AF duration, a greater number of comorbidities, more extensive atrial fibrosis, and presumed lower success rate and more complications after AF ablation in women. Studies have failed to show sex-related differences in AF recurrence or serious complications following AF ablation but show more nuisance bleeds in women. Ethnic minorities, such as African Americans and Latin Americans, and individuals of low socioeconomic status are also less likely to undergo AF ablation, possibly associated with greater numbers of comorbidities, lack of patient advocacy, healthcare costs, and inadequate insurance coverage. Inclusion of marginalized patient groups in clinical trials of AF treatment and a personalized, patient-centered approach may expand equality in utilization of AF ablation.

Essential medicines for childhood cancer in Europe: a pan-European, systematic analysis by SIOPE.

Shortages and unequal access to anticancer medicines for children and adolescents are a reality in Europe. The aim of the European Society for Paediatric Oncology (SIOPE) Essential Anticancer Medicines Project was to provide a list of anticancer medicines that are considered essential in the treatment of paediatric cancers to help ensure their continuous access to all children and adolescents with cancer across Europe. This pan-European project, done between Jan 20, 2020, and Feb 18, 2022, was designed to be a systematic collection and review of treatment protocols and strategies that are used to treat childhood cancer in Europe. We formed 16 working groups on the basis of paediatric cancer types, and which were based on the existing SIOPE Clinical Trial Groups. Workings groups consisted of representatives from the SIOPE Clinical Trial Groups, Young SIOPE members, and senior paediatric oncology experts. Each group collected existing treatment protocols that are used to treat the respective cancer types in Europe. Medicines from the standard group of each protocol were extracted. For medicines not on the WHO Essential Medicines List for children (EMLc) 2017, working groups did a literature search to determine whether the medicines should be defined as essential, promising, or neither essential nor promising. Each group provided an individual summary, and all medicines that were considered essential by at least one group were combined in a joint list. The working groups identified 73 treatment protocols used in Europe and defined 66 medicines as essential. For several newer medicines, such as kinase inhibitors or tisagenlecleucel, the supporting evidence was insufficient to consider them essential, so these medicines were defined as promising. 25 medicines were considered promising by at least one working group. 22 (33%) of the 66 essential and none of the promising medicines were included in the WHO EMLc 2017. The WHO EMLc 2021 included two new medicines (everolimus and vinorelbine) following applications we made as a result of this project. Medicines that were defined as essential within this project should be available for the treatment of childhood and adolescent cancer continuously and across Europe. This list can be used to support and guide stakeholders and policy makers in negotiations on a national and European level regarding shortages, accessibility, and affordability of these medicines. None.

The Leipzig Health Atlas-An Open Platform to Present, Archive, and Share Biomedical Data, Analyses, and Models Online.

Clinical trials, epidemiological studies, clinical registries, and other prospective research projects, together with patient care services, are main sources of data in the medical research domain. They serve often as a basis for secondary research in evidence-based medicine, prediction models for disease, and its progression. This data are often neither sufficiently described nor accessible. Related models are often not accessible as a functional program tool for interested users from the health care and biomedical domains. The interdisciplinary project Leipzig Health Atlas (LHA) was developed to close this gap. LHA is an online platform that serves as a sustainable archive providing medical data, metadata, models, and novel phenotypes from clinical trials, epidemiological studies, and other medical research projects. Data, models, and phenotypes are described by semantically rich metadata. The platform prefers to share data and models presented in original publications but is also open for nonpublished data. LHA provides and associates unique permanent identifiers for each dataset and model. Hence, the platform can be used to share prepared, quality-assured datasets and models while they are referenced in publications. All managed data, models, and phenotypes in LHA follow the FAIR principles, with public availability or restricted access for specific user groups. The LHA platform is in productive mode (https://www.health-atlas.de/). It is already used by a variety of clinical trial and research groups and is becoming increasingly popular also in the biomedical community. LHA is an integral part of the forthcoming initiative building a national research data infrastructure for health in Germany.

International recommendations for plasma Epstein-Barr virus DNA measurement in nasopharyngeal carcinoma in resource-constrained settings: lessons from the COVID-19 pandemic.

The effects of the COVID-19 pandemic continue to constrain health-care staff and resources worldwide, despite the availability of effective vaccines. Aerosol-generating procedures such as endoscopy, a common investigation tool for nasopharyngeal carcinoma, are recognised as a likely cause of SARS-CoV-2 spread in hospitals. Plasma Epstein-Barr virus (EBV) DNA is considered the most accurate biomarker for the routine management of nasopharyngeal carcinoma. A consensus statement on whether plasma EBV DNA can minimise the need for or replace aerosol-generating procedures, imaging methods, and face-to-face consultations in managing nasopharyngeal carcinoma is urgently needed amid the current pandemic and potentially for future highly contagious airborne diseases or natural disasters. We completed a modified Delphi consensus process of three rounds with 33 international experts in otorhinolaryngology or head and neck surgery, radiation oncology, medical oncology, and clinical oncology with vast experience in managing nasopharyngeal carcinoma, representing 51 international professional societies and national clinical trial groups. These consensus recommendations aim to enhance consistency in clinical practice, reduce ambiguity in delivering care, and offer advice for clinicians worldwide who work in endemic and non-endemic regions of nasopharyngeal carcinoma, in the context of COVID-19 and other airborne pandemics, and in future unexpected settings of severe resource constraints and insufficiency of personal protective equipment.

A nonparametric simultaneous confidence band for biomarker effect on the restricted mean survival time.

Study of prognostic and predictive biomarkers plays an important role in the design and analysis of clinical trials. The Cox proportional hazards model is often used to study the biomarker main effect and the treatment-biomarker interaction effect for survival data. The estimated effects can be biased if the proportional hazards assumption is violated. The restricted mean survival time is becoming popular in clinical studies for having a clear intuitive interpretation. In this article, we first propose nonparametric methods to make statistical inference for the one-sample problem of the biomarker effect on the restricted mean survival time; we then extend the methods to the two-sample problem for studying the difference in the biomarker effects between treatment groups in clinical trials. For a given biomarker, the restricted mean survival time is estimated by kernel smoothing methods with the inverse probability of censoring weights. We prove the consistency for the estimates and develop simultaneous confidence bands for the biomarker effects on the restricted mean survival time. The simultaneous confidence bands are evaluated in extensive simulation studies and are found to have good finite sample performance. We then apply the proposed methods to a breast cancer study conducted by the Breast International Group (BIG) to illustrate how the Ki67 biomarker, a protein marker of cell proliferation, affects the survival time of patients, compared between the treatment groups.

Comparative sensitivity of automated (Abbott M2000) and manual plasma HIV-1 RNA PCR assays for the detection of persistent viremia after long-term antiretroviral therapy

BackgroundThe ability of automated, FDA-cleared plasma HIV-1 RNA assays to detect low-level viremia, compared to manual, highly sensitive research-only methods, is not well-defined. We therefore tested paired plasma samples from people with HIV-1 (PWH) on long-term antiretroviral therapy (ART) with both the Abbott M2000 RealTime HIV-1 Viral Load assay (Abbott) and a quantitative reverse transcriptase (RT)-initiated PCR assay that has a reported 95% detection limit of 1 HIV-1 RNA copy/ml (single copy assay, SCA). MethodsPlasma samples from 309 participants in the AIDS Clinical Trials Group study A5321 were tested by both Abbott and SCA. Participants were mostly men (82%). All were on stable ART for a median of 7 years with HIV-1 RNA <40 copies/mL by Abbott. Pooled plasma from each donor was divided and tested. Abbott results were reported as target detected <40 copies/mL but not quantifiable (target detected <40) or target not detected (TND), and SCA results were classified as HIV-1 RNA detected or not detected. ResultsBy Abbott, 17% (51/309) of sample results were target detected <40, whereas 83% (258/309) were TND. Of the samples that were target detected <40 by Abbott, 73% (37/51) had HIV-1 RNA detected by SCA. By contrast, 43% of samples that were TND by Abbott (110/258) had HIV-1 RNA detected by SCA (p < 0.001). ConclusionPlasma samples from PWH with HIV-1 RNA detected but <40 copies/ml by the automated Abbott M2000 assay are likely (73% of 51 samples) to have HIV-1 RNA detected by an optimized manual assay with single copy sensitivity. An Abbott HIV-1 RNA result of target not detected did not exclude low-level viremia: 43% of 258 samples had HIV-1 RNA detected by the single copy assay. These findings indicate that the Abbott M2000 assay cannot exclude the persistence of viremia on ART and thus may have less utility, compared to a manual single copy assay, for assessing the impact of experimental interventions designed to eliminate low-level viremia as a step towards achieving ART-free HIV-1 remission.

Clinical trials evaluating desensitising agents. Some design and analysis issues.

IntroductionThe purpose of this short communication is to draw attention to an efficient design for trials to evaluate desensitising agents, and an appropriate statistical analysis. MethodsTwo recent sensitivity trials conducted by the Bristol Dental School Clinical Trials Group are reviewed. ResultsThe methodology used was effective to establish efficacy of the products evaluated. ConclusionsThis methodology is recommended for wider use. Clinical SignificanceEffective clinical trial methodology enables establishment of efficacy of desensitising products leading to patient benefit.

Device-based neuromodulation for cardiovascular diseases and patient' s age.

The autonomic nervous system plays an important role in the pathogenesis of cardiovascular diseases. With aging, autonomic activity changes, and this impacts the physiological reactions to internal and external signals. Both sympathetic and parasympathetic responses seem to decline, reflecting functional and structural changes in nervous regulation. Although some investigators suggested that both the sympathetic and parasympathetic activities were suppressed, others found that only the parasympathetic activity was suppressed while the sympathetic activity increased. In addition, cardiac innervation progressively diminishes with aging. Therefore, one may suggest that neuromodulation interventions may have different effects, and older age groups can express an attenuated response. This article aims to discuss the effect of device-based neuromodulation in different cardiovascular diseases, depending on the patient's age. Thus, we cover renal denervation, pulmonary artery denervation, baroreceptor activation therapy, vagus nerve stimulation, spinal cord stimulation, ganglionated plexi ablation for the management of arterial and pulmonary hypertension, heart failure, angina and arrhythmias. The results of many clinical studies appeared to be unconvincing. In view of the low rate of positive findings in clinical studies incorporating neuromodulation approaches, we suggest the underestimation of advanced age as a potential contributing factor to poorer response. Analysis of outcomes between different age groups in clinical trials may shed more light on the true effects of neuromodulation when neutral/ambiguous results are obtained.

Highly robust causal semiparametric U-statistic with applications in biomedical studies.

With our increased ability to capture large data, causal inference has received renewed attention and is playing an ever-important role in biomedicine and economics. However, one major methodological hurdle is that existing methods rely on many unverifiable model assumptions. Thus robust modeling is a critically important approach complementary to sensitivity analysis, where it compares results under various model assumptions. The more robust a method is with respect to model assumptions, the more worthy it is. The doubly robust estimator (DRE) is a significant advance in this direction. However, in practice, many outcome measures are functionals of multiple distributions, and so are the associated estimands, which can only be estimated via U-statistics. Thus most existing DREs do not apply. This article proposes a broad class of highly robust U-statistic estimators (HREs), which use semiparametric specifications for both the propensity score and outcome models in constructing the U-statistic. Thus, the HRE is more robust than the existing DREs. We derive comprehensive asymptotic properties of the proposed estimators and perform extensive simulation studies to evaluate their finite sample performance and compare them with the corresponding parametric U-statistics and the naive estimators, which show significant advantages. Then we apply the method to analyze a clinical trial from the AIDS Clinical Trials Group.

Characterising diflunisal as a transthyretin kinetic stabilizer at relevant concentrations in human plasma using subunit exchange

Transthyretin (TTR) dissociation is the rate limiting step for both aggregation and subunit exchange. Kinetic stabilisers, small molecules that bind to the native tetrameric structure of TTR, slow TTR dissociation and inhibit aggregation. One such stabiliser is the non-steroidal anti-inflammatory drug (NSAID), diflunisal, which has been repurposed to treat TTR polyneuropathy. Previously, we compared the efficacy of diflunisal, tafamidis, tolcapone, and AG10 as kinetic stabilisers for transthyretin. However, we could not meaningfully compare diflunisal because we were unsure of its plasma concentration after long-term oral dosing. Herein, we report the diflunisal plasma concentrations measured by extraction, reversed phase HPLC separation, and fluorescence detection after long-term 250 mg BID oral dosing in two groups: a placebo-controlled diflunisal clinical trial group and an open-label Japanese polyneuropathy treatment cohort. The measured mean diflunisal plasma concentration from both groups was 282.2 M 143.7 M (mean standard deviation). Thus, quantification of TTR kinetic stabilisation using subunit exchange was carried out at 100, 200, 300, and 400 concentrations, all observed in patients after 250 mg BID oral dosing. A 250 M diflunisal plasma concentration reduced the wild-type TTR dissociation rate in plasma by 95%, which is sufficient to stop transthyretin aggregation, consistent with the clinical efficacy of diflunisal for ameliorating transthyretin polyneuropathy.

Co-Occurrence of High-Risk Lesions Is a Consistent Predictor of Ultra-High Risk Multiple Myeloma in Newly Diagnosed and Relapsed/Refractory Patients - Meta-Analysis of 5,808 Trial Patients

Background: Myeloma patient outcomes remain heterogeneous, despite improving treatment options for newly diagnosed (NDMM) and relapsed/refractory (RRMM) disease. Improved individual risk prediction is highly desirable to support physicians and patients in increasingly complex joint decision-making processes. There is a specific need for readily accessible and easy to implement risk prediction tools that allow application in clinical trials and standard care. We previously reported on the utility of extended genetic profiling for refined outcome prediction in NDMM, including gain(1q), t(4;14) and del(17p) as a minimum set, to enable calling co-occurrence of two or more risk lesions, also termed double hit. To investigate its utility for prognostication in a wider context, we performed a meta-analysis of randomized clinical trials including in total 11150 patients with extended molecular profiling data for 5808 NDMM and RRMM patients. Methods: This collaboration of the EMN, UNITO, HOVON, UK-MRA and GMMG academic study groups, to which industry contributed results following request, identified in total 14 prospective randomized interventional trials with availability of extended genetic profiles, i.e. complete information on risk markers gain(1q), t(4;14), del(17p) as minimum requirement, which were included in the analysis: nine trials for NDMM (four including transplant eligible (TE), three transplant ineligible (TNE), two both) and five trials for RRMM. Outcome analysis in relation to presence of no (no hit), one (single hit) or two or more (double hit) risk markers was performed for each trial individually using Cox proportional hazards models. Summary level meta-analysis was performed using the generic inverse-variance method in a random-effects model to synthesize hazard ratios (HR) for progression-free survival (PFS) and overall survival (OS). Heterogeneity was assessed using the I2 statistic and Cochran's Q test. Results: In total 5808 trial patients were included in the analysis, 4807 NDMM patients (3296 transplant-eligible (TE), 1511 transplant-ineligible (TNE)), as well as 1001 patients with RRMM. Frequencies for presence of single (median: 38%; range 32%-48%) or double hit (14%; 9%-22%) were comparable between trials. OS was shortest for patients with double hit disease; meta-analysis summary HR for OS were 2.97 (95% CI: 2.37-3.71; P<0.0001) for double hit and 1.87 (95% CI: 1.60-2.19; P<0.0001) for single hit by meta-analysis (Figure 1). Summary HRs for PFS by meta-analysis were 2.18 (95% CI: 1.92-2.47; P<0.0001) for double hit and 1.63 (1.43-1.86; P<0.0001) for single hit. Estimated between-study heterogeneity was moderate (I2: 25%-59%). Results were consistent between NDMM and RRMM trials, and between trials with proteasome inhibitor (e.g. GMMG-HD4/HOVON-65; MUKFive) and immunomodulatory drug (IMiD) based regimens (e.g. GMMG-MM5; MUKSeven)(Figure 1). The association of double hit with shortened OS was most pronounced for trials with modern, intensive PI/IMiD induction/ASCT/maintenance treatments concepts, including FORTE (OS HR: 8.22; 95% CI: 4.06-16.65), GMMG-HD6 (OS HR 4.21; 2.20-8.08) and NCRI Myeloma XI (TE; OS HR: 3.65; 2.75-4.83). Hazard ratios were lower in trials for older, transplant-ineligible patients, but outcome was still consistently poorest for those patients with double hit MM. Conclusions: This large meta-analysis demonstrates consistent risk-discrimination by extended genetic profiling in NDMM and, for the first time, RRMM. Our results strongly support assessment of and reporting on single hit/high risk and double hit/ultra-high risk patient groups in clinical trials, including trials for RRMM. These data also highlight the importance of access to extended genetic profiling in routine patient care, with the minimum requirement of obtaining a complete set of results for gain(1q), t(4;14) and del(17p) for all patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Understanding the Patient Experience of Those Who Have Undergone or Considered CAR T-Cell Therapy in the United States: CAR T-Cell Therapy Patient Engagement Project (CPEP)

Introduction Chimeric antigen receptor T-cell therapy (CAR T) represents a revolution in cancer therapeutics for patients with relapsed, refractory, or recurrent malignancies; however, there is still a lack of longitudinal data on real-world patient experiences, particularly regarding education, treatment expectations, patient burden, and preferred patient reported outcomes (PROs) assessing quality of life (QoL). This non-interventional study aims to identify treatment priorities, values, goals, educational needs, and care experiences of individuals considering and participating in CAR T clinical trials, with the goal to generate knowledge to help optimize future clinical trial operations, communications, and QoL assessments. Methods Individuals with hematologic or solid malignancies were recruited through the Gryt Health Cancer Community and social media to enroll in this IRB-approved, mixed-methods study. Participants were recruited into two groups: individuals considering and eligible for a CAR T clinical trial (Group 1), and individuals who participated in a CAR T clinical trial (Group 2). This initial analysis includes: a 1:1 semi-structured interview obtaining individual perceptions of/experiences with CAR T; 1 of 2 patient advisory boards (PABs) utilizing both quantitative questions and qualitative discussion to garner patient insight on CAR T; and 3 of 4 surveys exploring key domains of QoL through assessment of relevance of an existing patient reported outcome measure (PROM) in comparison to a proposed CAR T-specific PROM. Results Twenty-two participants were enrolled. All participants completed at least the initial 1:1 interview. Both groups perceived freedom from standard/maintenance therapies and current level of pain as an expected/experienced benefit of CAR T. Group 1's initial impressions of CAR T were generally positive, while many in Group 2 reported initial hesitation due to perceived similarity to other treatment. Both groups noted their experiences and/or perceptions of stem cell transplant (SCT) influenced their thoughts on CAR T. Group 2 participants noted that CAR T was far less difficult than SCT, despite their initial fears of the therapies' similarities. Group 1 participants were optimistic about avoiding toxicities associated with SCT by pursuing CAR T instead. In Survey 1, participants completed the PROMIS-29 v2.0 to measure the perceived relevance of the instrument. Comparison of reflection responses showed that Group 2 participants found the questions less relevant than those in Group 1. Overall, participants indicated that the current PROMIS-29 v2.0, while somewhat relevant, has gaps to be addressed, including assessment of potential long-term side effects and their impact on QoL at each phase of CAR T (pre-infusion, acute post infusion period, and long-term follow-up). In Survey 2, both groups identified the following QoL aspects to be addressed by a CAR T-specific PROM: exercise, ability to carry out daily responsibilities, memory, and sleep. In Survey 3, both groups reviewed a proposed CAR T-specific PROM and felt it would be useful assessing their treatment concerns and QoL. Most participants indicated the PROM would be a useful tool for communication with their care team, and access to results over time would be useful for reflection and may impact willingness to complete the PROM. PAB questions highlighted aspects of CAR T education in need of improvement. For both groups, CAR T education most commonly began with the patient's care team, with some solely relying on their doctors' suggestions and others conducting their own additional research. When asked about preferable CAR T educational formats, both groups most often answered a 1:1 discussion with a member of their care team. Noted second most often was the ability to speak with patients who had received CAR T already. Both groups had varying understanding of the science, the mechanism of action, and the manufacturing of CAR T. Conclusion This study reflects on the heterogeneity of experiences of those who are considering or have undergone CAR T-cell therapy, providing meaningful information regarding the educational needs and lived experiences throughout the CAR T treatment experience. Ongoing analysis will continue to identify perceived burdens of CAR T and trial participation, assess lived experiences, and assess the proposed CAR T-specific PROM to be tested in future studies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Genome-Wide Association Study Identifies Variants Associated with Clinical Outcomes in Pediatric Patients with Newly Diagnosed Acute Myeloid Leukemia

Genetic aberrations in leukemic blasts are associated with clinical outcomes in patients with AML. However, the role of inherited genetic variants with regards to variation in AML treatment outcome remains obscure. To that end, we conducted a genome wide association study (GWAS) on 400 newly diagnosed pediatric AML patients to identify single nucleotide polymorphism (SNPs) that may be associated with minimal residual disease (MRD1) after induction 1 chemotherapy, event-free survival (EFS) and overall survival (OS). In this study, we utilized whole-genome genotyping with Illumina's Omni2.5Exome-8 BeadChip array to investigate SNPs for association with clinical outcome in 2 pediatric AML cohorts: the multi-site AML02 [NCT00136084, n=167] and AML08 [NCT00703820, n=233] trials. Post GWAS quality control, 1,365,439 unphased SNP genotypes were selected for imputation using TOPMed Imputation Server. Following imputation and additional quality control filtering, 6,741,200 SNPs evaluated for association with clinical outcomes (MRD1, EFS and OS). To improve statistical rigor, two GWAS approaches were utilized: i) A one-stage GWAS with both clinical trial cohorts combined (n=400) and ii) A two-stage GWAS where we utilized a two-step iterative resampling procedure (PMID: 26377241) by splitting the cohort at a 70:30 ratio into discovery and replication cohorts, balanced by clinical trial, treatment arm and initial risk group at diagnosis (100 randomizations performed). For each of the 100 iterations of the two-stage GWAS, we used the discovery cohort to perform a genome-wide analysis, followed by a replication screen. SNPs replicated in at least 20 of 100 rounds of discovery-replication were prioritized. A comparison of the two approaches showed all significant SNPs in the two-stage GWAS were also captured in the one-stage GWAS. For EFS, a Bonferroni-adjusted genome-wide significant association was observed for a SNP in CSMD1 and this SNP was replicated in 83 out of 100 discovery-replication rounds for two-stage GWAS. For CSMD1 SNP, presence of variant A allele has significantly reduced EFS (HR=3.29, 95% CI (2.177-4.975), P=1.61x10-8, Figure 1A). CSMD1 is a membrane-bound complement inhibitor that has been shown to act as a putative tumor suppressor gene in other malignancies (PMIDs:27764775, 35623420). Another significant marker worth mentioning was an intronic SNP in CDKN2B-AS1 that associated with poor outcome [EFS: HR=2.37, 95% CI (1.700-3.317), P=4.40x10-7] and [OS: HR=2.87, 95% CI (1.954-4.225), P=8.06x10-8, Figure 1B]. This marker is in high linkage disequilibrium with 26 other SNPs within the CDKN2B and CDKN2B-AS1 cluster. The product of this gene is an RNA molecule that interacts with polycomb repressive complex-1 (PRC1) and -2 (PRC2) involved in silencing other genes within this cluster through epigenetic mechanisms (PMID: 20716771). CDKN2B-AS1 has been reported to play a role in tumorigenesis and chemoresistance in pediatric T-cell acute lymphoblastic leukemia and with the risk of chronic lymphocytic leukemia (PMIDs: 32976214/23770605). Though limited by numbers, this is one of the largest GWAS conducted in pediatric AML to identify SNPs associated with clinical outcomes. Our top results show that genetic variation in several genes of biological relevance may impact MRD1, EFS and OS. Future studies are aimed at looking at SNP/gene and association with gene expression collected from leukemic cells at time of diagnosis to establish AML-specific eQTLs and functional validation of the most promising candidates. Additionally, future analyses will include other subgroups such as cytogenetic risk group and validation of these findings in larger cohort of patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Clinical Trial Diversity in Oncology: FDA Takes Action with Post-Marketing Requirements or Commitments.

In recent years, there has been a renewed focus on promoting the inclusion of patients from racial and ethnic minority groups in oncology clinical trials. FDA Oncology has long pointed to the underrepresentation of racial minorities in registration trials leading to approval. US FDA's Guidance on diversity discusses how diversity could be handled within clinical trials, giving recommendations on broadening eligibility criteria, inclusive trial practices, and alternative trial designs. While there is no specific guidance from the FDA on cancer clinical trials, the recommendation is to include a representative population applicable to the US population. With the recent renewed focus on diversity in oncology clinical trials, FDA Oncology has recently asked for the completion of a Diversity Plan during drug development and has issued post-marketing commitments and requirements at the time of approval. As FDA has started to issue post-marketing requirements or commitments regarding diversity in 2020, we sought to analyze the post-marketing studies asking for a study of racial and ethnic minorities issued by the FDA's Office of Oncologic Diseases (OOD). The analysis demonstrated the need to increase the enrollment of a diverse patient population in cancer clinical trials.

403P Gender trend over time of principal investigators within large Australian cancer clinical trials groups

Despite increased global effort in promoting gender equity in medicine, progress remains slow, particularly with respect to clinical research and leadership roles. Our study assesses trends in female Principal Investigators (PI) amongst academic Cancer Clinical Trials Groups in Australia.

Validation of the Prognostic Utility of ESTRO/EORTC Oligometastatic Disease Classification: A Secondary Analysis From the Population-Based Phase II SABR-5 Trial

The recently developed European Society for Radiotherapy and Oncology (ESTRO)/European Organization for Research and Treatment of Cancer (EORTC) oligometastatic disease (OMD) classification has not been validated in terms of its prognostic significance. This study stratified patients from the phase II SABR-5 trial based on ESTRO/EORTC criteria and compared progression-free survival (PFS) and overall survival (OS) to determine the prognostic significance of the classification scheme. The SABR-5 trial was a single arm phase II study conducted at the 6 regional cancer centers across British Columbia (BC), Canada, where SABR for oligometastases was only offered on trial. Patients with up to 5 oligometastases (total or not controlled by prior treatment and including induced OMD) underwent SABR to all lesions. Patients were 18 years of age or older, Eastern Cooperative Oncology Group 0 to 2, and life expectancy ≥6 months. PFS and OS were calculated using the Kaplan-Meier method and differences between OMD groups were assessed with log-rank tests. Univariable and multivariable analyses were performed using Cox regression modeling. Between November 2016 and July 2020, 381 patients underwent SABR on trial. Median follow-up was 27 months (interquartile range, 18-36). The most frequent OMD group was de novo OMD (69%), followed by repeat (16%) and induced (13%). OMD groups differed significantly in PFS (P < .001) but not OS (P=.069). The OMD classification was an independent predictor of both PFS (P=.005) and OS (P=.002). Of the 5 classification factors, only chronicity (synchronous, hazard ratio, 0.52; P=.027) and oligoprogression (hazard ratio, 2.05; P=.004) were independently prognostic for OS. In this large prospective cohort, the ESTRO/EORTC classification was an independent predictor of PFS and OS and should be used to identify specific patient groups for clinical trials. In this trial population, the prognostic power is largely attributable to chronicity and oligoprogression. Simplification of the framework may be possible in the future and allow for greater ease of use; however, further data on underrepresented OMD groups and histologies will be required.

Validation of the Prognostic Utility of ESTRO/EORTC Oligometastatic Disease Classification: A Secondary Analysis from the Population-Based Phase II SABR-5 Trial

<h3>Purpose/Objective(s)</h3> The recently developed ESTRO/EORTC oligometastatic disease (OMD) classification has not been validated in terms of its prognostic significance. This study stratified patients from the phase II SABR-5 trial based on ESTRO/EORTC criteria, and compared progression-free survival (PFS) and overall survival (OS) to determine the prognostic significance of the classification scheme. <h3>Materials/Methods</h3> The SABR-5 trial was a single arm phase II study conducted at the 6 regional cancer centers across British Columbia, where SABR for oligometastases was only offered on trial. Patients with up to 5 oligometastases (total or not controlled by prior treatment, and including induced oligometastatic disease) underwent SABR to all lesions. Patients were 18 years of age or older, ECOG 0-2, and life expectancy ≥ 6 months. PFS and OS were calculated using the Kaplan-Meier method and differences between OMD groups were assessed with log-rank tests. Univariable and multivariable analyses were performed using Cox regression modelling. <h3>Results</h3> Between November 2016 and July 2020, 381 patients underwent SABR on trial. Prostate was the most frequent primary tumor histology (32%), followed by colorectal (17%) and breast (11%). Most patients (69%) underwent SABR to one metastasis and 10% received SABR to 3 or more lesions. Median follow-up was 27 months (IQR 18–36). The most frequent OMD group was de-novo oligometastatic disease (69%), followed by repeat (16%) and induced (13%). In total, 62 patients received SABR to oligoprogressive lesions. OMD groups differed significantly in PFS (p<0.001) but not OS (p=0.069). The OMD classification was an independent predictor of both PFS (p=0.005) and OS (p=0.002). Of the five classification factors, only chronicity (synchronous, HR=0.54, p=0.027) and oligoprogression (HR=2.05, p=0.004) were independently prognostic for OS. Classifying OMD states by only these two factors resulted in a 3 groups (synchronous, oligorecurrence/oligopersistence and oligoprogression) with more statistically significant differences in OS and PFS. <h3>Conclusion</h3> In this large prospective cohort, the EORTC/ESTRO classification was an independent predictor of PFS and OS and should be used to identify specific patient groups for clinical trials. In this cohort, the prognostic power is largely attributable to chronicity and oligoprogression. Simplification of the framework may be possible in the future and allow for greater ease-of-use, however, further data on underrepresented histologies and OMD groups will be required.