Clinical Trial Setting Research Articles

Genomic therapy matching in rare and refractory cancers: Updated results from a retrospective cohort study in the Molecular Screening and Therapeutic (MoST) program.

1540 Background: Biomarker actionability and therapy matching are two central concepts in precision oncology. However, the best strategy to align therapy with genomic alterations remains unclear. Here we report the updated results from a cohort study conducted in an Australian precision oncology program (MoST, ACTRN12616000908437), examining a therapy matching strategy based on comprehensive genomic profiling (CGP) results. Methods: All patients (pts) with rare or advanced solid tumours undergoing CGP from 2016 to 2021 after exhausting standard treatments were included. The primary outcome was overall survival (OS) from the date of CGP result, estimated using the Kaplan-Meier method. Pts were grouped according to tiers of actionability determined by matching against the TOPOGRAPH knowledge base ( https://topograph.info ) and stratified into clinically active (Tier 1-3, therapies with evidence from prospective trials), investigational (Tier 3B and 4, therapies with evidence from another cancer type, preclinical, or retrospective studies), or unmatched tier groups. To assess between-group differences in OS, hazard ratios (HR) were estimated in a time-varying Cox regression model adjusting for time to initiation of subsequent therapy. Results: This updated analysis included 3,383 pts (79% rare and less common). The median follow-up was 22.6 months (mo). For 2,065 pts who did not receive treatment after CGP, the median OS (mOS) was 8.2 mo (95% CI 7.4 to 9.0). For 1,318 pts who received ≥1 line of therapy after CGP, the mOS was 14.1 mo (13.4 to 15.2). 1,270 pts (38%) carried a genomic alteration linked to clinically active therapies (Tier 1-3). Of these, 116 (3.4%) received matched treatment after CGP, experiencing longer survival compared with 410 (32.2%) that received only unmatched therapy (mOS 21.2 v 12.8 mo, HR 0.58, 0.45 to 0.76, P<0.001). Whilst receiving a matched therapy in the investigational tier group (n=133, T3B/4) did not show significant differences in outcomes (mOS 14.5 v unmatched 12.8 mo, n=536, HR 0.88, 0.72 to 1.08, p=0.24), exploratory analyses identified differences in survival for a subset of 41 pts with Switch/Sucrose Non-Fermentable complex mutations receiving matched Tier 4 therapies (mOS 30.1 v 9.6 mo, HR 0.29, 0.17 to 0.51, P<0.0001). Pts receiving repurposed drugs that matched solely on biomarkers in non-cognate cancer types (Tier 3B) showed no survival difference over unmatched therapy (n=35 v 469, mOS 13.6 v 12.5 mo, HR 0.96, 0.65 to 1.41, p=0.83). Conclusions: This study provides insight into how biomarker-linked therapies can be rationally prioritised in rare and advanced cancer populations. Addressing the barriers of access to Tier 1-3 therapies may broaden the utility of genomic biomarker testing. Off-label drug repurposing without direct supporting evidence should only be undertaken in a clinical trial setting.

Real world outcomes of patients treated with first line chemo-immunotherapy (IO) for small cell lung cancer (SCLC): Impact of brain metastases and patterns of subsequent therapy.

e20639 Background: The addition of IO to chemotherapy for first-line treatment of SCLC has improved median overall survival (OS). No OS difference was observed in patients with brain metastases in the clinical trial setting, however outcomes need to be assessed in the non-clinical trial setting. Methods: This retrospective study included 121 patients with SCLC who received ICI-based therapy between 2016-2022 at the Ohio State University. Medical records were extracted via chart review and data was collected in REDCap. Clinical characteristics were summarized using descriptive statistics and compared between patients with and without brain metastasis using Kruskal-Wallis test (continuous outcomes) and Fisher’s exact test (categorical outcomes). Kaplan-Meier survival analysis were used to assess the survival outcomes. All statistical analysis was done in SAS 9.4. Results: Median age at diagnosis was 64.7 years (IQR: 60.1-69.7). Our cohort included 53.8% males and 46.2% females, majority (89.1%) of patients were white, 7.6% were African Americans. Baseline ECOG status was 0 (11.9 %), 1(50%) and > = 2 (38.1%). 97% were current or former smokers. Most had extensive stage disease (96.6%) at diagnosis. Most common sites of metastasis at diagnosis were liver (46.2%), bone (42.9%), brain (35.3%), lymph nodes (34.7%). All patients received first line chemotherapy with atezolizumab (atezo), 40% received atezo with cycle one of chemotherapy, 47% had atezo added with the second cycle, and 13% had atezo added after cycle 2. Median OS for all patients was 9.5 months (95% CI 8.1, 12.9 months); 81% had disease progression at a median follow up of 8.5 months (95% CI 5.2-16.8). 52% patients received second line therapy, 18% received third line and 12% received fourth line and beyond. Subsequent therapies included chemotherapy (29.8%), immunotherapy (4.1%) and clinical trials (14.1%). CNS progression was seen in 47.9%. Median OS for patients with baseline brain metastasis was not significantly different than patients without,11.8 months (95% CI 8-17.6 months) compared to 8.3 months (95% CI 6.2-12.9 months), p:0.26. For patients without baseline brain metastases, median time to developing brain metastasis from starting chemo-IO was 7.3 months [IQR: 5.3-14.1 months]. There was no significant association between the development of brain metastasis and age, sex, or race. At CNS progression 36.4% received SBRT, 18.2% received WBRT. Conclusions: Median overall survival in this cohort was shorter than what has been reported in the phase 3 trials with first line chemo-IO. OS for patients with brain metastases did not differ significantly than for those without, and there was a higher rate of SRS/SBRT versus WBRT. Just over half of patients received subsequent lines of therapy highlighting the need for continued improvement in treatment options for SCLC.

A dual institution real-world study of avelumab for advanced Merkel cell carcinoma.

e21514 Background: Merkel cell carcinoma (MCC) is a rare, aggressive, cutaneous neoplasm with an increasing incidence rate and poor prognosis. The treatment landscape has changed dramatically over the last half decade, beginning with the 2017 approval of the anti-programmed death-ligand 1 (PD-L1) monoclonal antibody avelumab. Accelerated approval for avelumab was based on data from the JAVELIN Merkel 200 study, which demonstrated an objective response rate (ORR) of 33% in previously treated subjects (≥2L). In the first-line (1L) clinical-trial setting, avelumab was associated with an ORR of 40% and a durable response rate (DRR) of 30%. There are limited data regarding the efficacy of avelumab in the real-world setting. Methods: We performed a Mass General Brigham (MGB) Institutional Review Board-approved retrospective study of patients with advanced MCC. Clinical data regarding the disease course, including diagnosis and treatment, were collected from the Electronic Health Record and stored in a REDCap database. Response category was assigned based on the text of the radiology reports and clinician notes. Analysis was performed in R. Results: 1249 patients with MCC were identified; 260 received systemic therapy; 54 were treated with avelumab (our primary analysis cohort, PAC). Median age of the PAC was 74 years. 80% were male. 83% had an initial ECOG of 0 or 1. 20% were immunosuppressed at the time of MCC diagnosis. The real-world response rate (rwORR) for all patients treated with avelumab was 45.83%. rwORR in the 1L was 53.57% and 35% in the second line and beyond. The median duration of treatment response in the 1L was 518 days and 144 days for ≥2L. Median progression-free survival was 158 days and 95 days, and median overall survival was 553 days and 323 days for 1L and > 2L, respectively. Conclusions: Our study provides important data about the real-world treatment of patients with advanced MCC. The response rate and progression-free survival were consistent with those observed in other real-world studies as well as the clinical trials. While the subjects studied in previously published studies differ from that in MGB cohort, the overall body of literature continues to demonstrate positive outcomes attributable to avelumab monotherapy in both the 1L as well as second-line or beyond and in patients with competent, as well as compromised, immune systems. Limitations of this study include its retrospective nature. Furthermore, given the small sample size, we are limited in making statistical inferences from the current data set and specific results may not be generalizable to all patients with MCC.

Therapy effect on AI-derived thalamic atrophy using clinical routine MRI protocol: A longitudinal, multi-center, propensity-matched multiple sclerosis study.

The effect of disease modifying therapies (DMTs) on brain atrophy in persons with multiple sclerosis (pwMS) is typically investigated in highly standardized clinical trial settings or single-center academic institutions. We aimed at utilizing artificial intelligence (AI)-based volumetric analysis on routine unstandardized T2-FLAIR scans in determining the effect of DMTs on lateral ventricular volume (LVV) and thalamic volume (TV) changes in pwMS. The DeepGRAI (Deep Gray Rating via Artificial Intelligence) registry is a multi-center, longitudinal, observational, real-word study with a convenience sample of 1002 relapsing-remitting (RR) pwMS from 30 United States sites. Brain MRI exams acquired as part of the routine clinical management were collected at baseline and on average at 2.6-years follow-up. The MRI scans were acquired either on 1.5T or 3T scanners with no prior harmonization. TV was determined using the DeepGRAI tool and lateral ventricular volume LVV was measured using NeuroSTREAM software. After propensity matching based on baseline age, disability and time of follow-up, untreated pwRRMS had significantly greater TV change when compared to treated pwRRMS (-1.2% vs. -0.3%, p=0.044). PwRRMS treated with high-efficacy DMTs had significant and two-fold lower% LVV change when compared to pwRRMS treated on moderate-efficacy DMTs (3.5% vs. 7.0%, p=0.001). PwRRMS who stopped DMT during the follow-up had significantly greater annualized% TV change compared to pwRRMS who remained on their DMT (-0.73% vs. -0.14%, p=0.012) and significantly greater annualized% LVV change (3.4% vs. 1.7%, p=0.047). These findings were also observed in a propensity analysis that additionally incorporated matching for scanner model at both baseline and follow-up visits. LVV and TV measured on T2-FLAIR scans can detect treatment-induced short-term neurodegenerative changes measured in a real-word unstandardized, multicenter, clinical routine setting.

Real-world experience of tebentafusp for uveal melanoma via an Australian access program.

e21554 Background: Uveal melanoma (UM) is a rare melanoma subset, with distinct biology, genetics, and limited active therapies. Tebentafusp (tebe) has demonstrated a survival advantage however low response rates and a toxicity profile making real-world administration challenging. Methods: Data was retrospectively collected for patients (pt) enrolled into a tebentafusp access program at two tertiary Australian centres. Data fields included: baseline patient, disease and prior treatment characteristics; and tebe administration, response, toxicity and survival outcomes. Results: From May 2021 to February 2023, 19 pt received tebe for UM: 7 males, average age 61 years (range 39-86). All pt presented with local disease at diagnosis, with time to metastases greater than 12 months (mo) in 15/19. Prior to tebe, all patients had hepatic and 6/19 extra-hepatic metastases (6 bone, 4 lymph node, 2 peritoneal, 2 dermal and/or subcutaneous). Baseline PET scan demonstrated FDG-avid disease in 13/14. Primary disease treatment included enucleation (7/19) and radiotherapy 13/19). For advanced disease, prior systemic therapies included: none (12/19); anti-PD1 (3) or anti-CTLA4 (2) as monotherapy; or in combination (5); and anti-PD1 with anti-LAG3 (2). Prior to tebe baseline LDH was elevated in 10/19 (53%) and average neutrophil to lymphocyte ratio was 9.22 (range 0.9-49.5). The median time receiving tebe was 5.5 mo (range < 1-18). The median progression free survival (PFS) was < 3mo. 5 pt remain on tebe with 2 pt treated with tebe beyond 12 and 18mo duration. Best response obtained by PET or cross-sectional imaging was: a partial response in 4/19, stable/mixed in 4/19, progressive disease in 8/19, and unknown/not evaluable in 3/19. The majority of patients ceased tebe due to disease progression (10), change of therapy (4) or death (2). Only one patient ceased due to toxicity. At last review 14/19 (74%) patients were still alive and 4/19 had received one or more lines of systemic therapy after tebe including immunotherapy (1), targeted therapy (1) and/or clinical trials (4). Common adverse events included: rash (63%), hypotension (47%), pruritis (42%) and pyrexia (32%). Supportive measures were required (e.g. hydration, antihistamines, topical steroids) for 13 patients. Cytokine release syndrome (CRS) was reported in 63% (12/19) with only 3 demonstrating grade 2 severity. CRS management included oral (1) or intravenous steroids (2) and zero patients required additional immunosuppression. The median number of cycles administered as an inpatient was 3 (range 2-10). Conclusions: Within experienced tertiary centres tebe could be safely administered outside of a clinical trial setting. Median time on treatment greatly exceeds progression free survival, likely due to unique response characteristics and limited access to subsequent therapy. Identifying features that enrich for clinical benefit remain necessary for optimising tebe use.

Lung Cancer Yield Among Those Undergoing Lung Cancer Screening in Community-based Healthcare Systems

Purpose: Lung cancer screening (LCS) via low-dose computed tomography (LDCT) for those with a high risk of lung cancer based on age and smoking history has been recommended in the United States for almost a decade, but performance of LCS in community-based settings is unclear. We aimed to estimate the proportion of those screened who were diagnosed with lung cancer across five healthcare systems in the United States. Methods: Study participants were LCS-eligible individuals who received care and a baseline LCS LDCT within the five healthcare systems in the Population-based Research to Optimize the Screening Process Lung Consortium (PROSPR-Lung). We collected data on LDCT utilization and results, as well as patient characteristics and smoking history, via electronic health records. LCS LDCT findings were categorized using Lung-RADS [negative (1), benign (2), probably benign (3), or suspicious (4)]. Lung cancer diagnoses occurring within 12 months of a baseline LDCT were ascertained via cancer registry data. Our preliminary analyses, presented here, includes estimates of lung cancer yield, overall, and by Lung-RADS category, among those receiving a baseline LDCT 2014–2018. Data collection through 2021 is underway and final analyses will include data through 2021. Results: There were 8,682 patients with a baseline scan included in analyses. Of these, 47% were female, 52% were ages 65+, and the ethnic and racial distribution was: 4% Hispanic, 2% Hawaiian/Pacific Islander, 4% Asian, 14% Black, and 74% White. There were 142 (1.6%) patients diagnosed with lung cancer within 12-months of their baseline LDCT. Among those with negative LCS LDCT findings, Lung-RADS 1 (n = 1,987) or Lung-RADS 2 (n = 5,232), there were 1 and 8 lung cancer diagnoses, respectively. Among those with positive LCS LDCT findings, Lung-RADS 3 (n = 906), Lung-RADS 4/4A (n = 363), or Lung-RADS 4B/4X (n = 194), 10 (1%), 35 (10%), and 88 (45%) were diagnosed with lung cancer, respectively. Conclusions: The proportion of those diagnosed with lung cancer within 12 months of a baseline LDCT within community settings is similar to clinical trials settings, and use of Lung-RADS categorization in community settings appropriately stratifies patients into those with a low- vs. high-risk of prevalent lung cancer.

Effect of tecovirimat on healing time and viral clearance by emulation of a target trial in patients hospitalized for mpox.

Tecovirimat is a treatment option for severe mpox, although randomized clinical trials are ongoing. The aim of the study is to assess the effect of tecovirimat on healing time and the extent of viral clearance by target trial emulation using observational data. Clinical and virological data of patients hospitalized for mpox were collected. Samples from the upper respiratory tract (URT) were grouped in two time points: T1 (median 6 days from symptoms onset) and T2 (median 5 days from T1). Patients were followed-up until recovery. Average treatment effect (ATE) in patients untreated versus treated with tecovirimat was estimated on time to healing and variation in viral load in URT, using a weighted and cloning analysis. Among the 41 patients included, 19 completed a course of tecovirimat. The median time from symptoms onset to hospitalization and to drug-starting was 4 days and 10 days, respectively. No improvement in healing time in treated versus untreated was observed. No difference by treatment group in time to viral clearance was detected by ATE fitted in a subset of 13 patients after controlling for confounders. We found no evidence for a large effect of tecovirimat in shortening healing time and viral clearance. While awaiting the results of randomized studies, the use of tecovirimat should be restricted to the clinical trial setting.

More than just 'free heroin': Caring whilst navigating constraint in the delivery of diamorphine assisted treatment.

In 2020, drug related deaths in the United Kingdom (UK) reached the highest rate in over 25 years, with hospitalisations and deaths particularly impacting people who use illicit opioids such as heroin. Treatment systems are increasingly required to be innovative to engage the most vulnerable at risk from premature morbidity and mortality. Heroin Assisted Treatment (HAT) is an alternative treatment modality for people for whom more traditional forms of opioid substitution therapy, such as methadone, have been ineffective. Middlesbrough, a town in the North-East England, was home to the first service in the UK to implement HAT outside of a clinical trial setting which closed for operation in November 2022. Qualitative in-depth interviews with patients and health care providers (n=17) involved in the delivery of HAT were undertaken during 2021. This paper focuses on the health care provider interviews, the majority of which took place remotely. Interviews were audio recorded and thematically analysed. Health care providers navigated multiple layers of constraint during HAT implementation and delivery. We explore this in relation to three themes: 1) Negotiating risk and safety within treatment 2) More than a prescription: care beyond diamorphine 3) Internal and external delivery barriers and impact on treatment acceptability, identity and longevity. Negotiating and managing risks of polysubstance use was a complex task. Benefits regarding access to holistic care, improved therapeutic and social relationships were recognised by practitioners. The rigorous delivery schedule was the biggest barrier to engagement. Outside the treatment room, socio-structural factors posed additional challenges. Despite some operational complexities, health care providers viewed HAT as an effective method of engaging a high risk population with drug treatment services, with holistic benefits for clients over and above the treatment of opioid dependency. Findings will inform advocacy and innovation for future HAT interventions in England.

The Europa Uomo Patient Reported Outcome Study 2.0—Prostate Cancer Patient-reported Outcomes to Support Treatment Decision-making

BackgroundTo further strengthen the voice of patients, Europa Uomo initiated the Europa Uomo Patient Reported Outcome Study 2.0 (EUPROMS 2.0) in October 2021. ObjectiveTo collect the self-reported perspective of prostate cancer (PCa) patients on physical and mental well-being after PCa treatment outside a clinical trial setting to inform future fellow patients about the impact of PCa treatment. Design, setting, and participantsEuropa Uomo invited PCa patients to complete a cross-sectional survey including the validated EQ-5D-5L, EORTC-QLQ-C30, and the EPIC-26 questionnaires. Furthermore, the nine-item Shared Decision Making Questionnaire (SDM-Q-9) and diagnostic clinical scenarios were included. Outcome measurements and statistical analysisDescriptive statistics was used to assess the demographic and clinical characteristics and to analyze the patient-reported outcome data. Results and limitationsBetween October 25, 2021 and January 17, 2022, 3571 men from 30 countries completed the EUPROMS 2.0 survey. The median age of respondents was 70 yr (interquartile range 65–75 yr). Half of the respondents underwent one treatment, most often radical prostatectomy. Men who are treated actively experience lower health-related quality of life than men on active surveillance, mainly regarding sexual function, fatigue, and insomnia. Lower urinary incontinence levels were seen for men who underwent radical prostatectomy (single treatment or in combination with other treatments). Of the respondents, 42% indicated that the determination of the prostate-specific antigen (PSA) value was part of a routine blood test; 25% wanted to undergo screening/early detection for PCa, and 20% indicated that the determination of the PSA value had a clinical reason. ConclusionsA large sample of 3571 international patients has contributed patient experience after PCa treatment in the EUPROMS 2.0 study, confirming that treatment for PCa mainly affects urinary incontinence, sexual function, fatigue, and insomnia. Such information can be used to direct toward a better patient-doctor relationship, to offer patients ready access to responsible information and a better understanding of their disease and treatment. Patient summaryThrough the EUPROMS 2.0 survey, Europa Uomo has strengthened the voice of the patient. Such information can be used to inform future prostate cancer (PCa) patients about the impact of PCa treatment and to engage them in informed and shared decision-making.

(500) What Do Women Want? Vibrators To Be Prescribed by Their Doctors

Abstract Introduction Traditionally vibrator use has been a taboo topic that is rarely discussed between patient and physician. Nevertheless, the vibrator industry has flourished the past several years with vibrators now available at mainstream retailers. While these devices are readily available to the public, the role of medical professionals in regards to vibrator use and female pelvic health is not well known. Objective The purpose of this study was to describe the interest among women responding to a clinical trial for female sexual wellness and the use of vibrator. Methods We reviewed the responses to a female sexual wellness clinical trial posted on various medical platforms (clinicaltrials.gov, Medscape, Medege, Medpage). Using qualitative content analysis, we reviewed the inquiries made by women interested in participating in the study. Those women who were ineligible for the study due to their geographical location but desired to have an in depth discussion were offered telephone calls. Results A total of 260 emails and 12 voice mails were received from 148 women within a two-week time frame who had inquired about the female sexual wellness study and vibrators. The locations of the respondents included 31 states within the United States and Canada. The average age of the respondents was 60 years, and 62 (42%) of the women worked in the medical field (medical doctors, osteopathic doctors, and registered nurses). Five women (3.3%) received a link about the study from their male partners. The most common conditions that women were hoping to improve with vibrator use in descending order: sexual dysfunction (dyspareunia, desire/libido, orgasm), urinary incontinence, prolapse/pelvic floor, and menopause. Conclusions Our review demonstrated that women are interested in vibrators, particularly in a clinical trial setting, and are seeking to use them for multiple conditions including FSD and pelvic floor disorders. Clinicians should consider discussing vibrator use with patients, as it normalizes vibrator use. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Abbvie, Coloplast, Sprout Pharmaceuticals.

Revealing the immune cell subtype reconstitution profile in patients from the CLARITY study using deconvolution algorithms after cladribine tablets treatment

Immune Cell Deconvolution methods utilizing gene expression profiling to quantify immune cells in tissues and blood are an appealing alternative to flow cytometry. Our objective was to investigate the applicability of deconvolution approaches in clinical trial settings to better investigate the mode of action of drugs for autoimmune diseases. Popular deconvolution methods CIBERSORT and xCell were validated using gene expression from the publicly available GSE93777 dataset that has comprehensive matching flow cytometry. As shown in the online tool, ~ 50% of signatures show strong correlation (r > 0.5) with the remainder showing moderate correlation, or in a few cases, no correlation. Deconvolution methods were then applied to gene expression data from the phase III CLARITY study (NCT00213135) to evaluate the immune cell profile of relapsing multiple sclerosis patients treated with cladribine tablets. At 96 weeks after treatment, deconvolution scores showed the following changes vs placebo: naïve, mature, memory CD4+ and CD8+ T cells, non-class switched, and class switched memory B cells and plasmablasts were significantly reduced, naïve B cells and M2 macrophages were more abundant. Results confirm previously described changes in immune cell composition following cladribine tablets treatment and reveal immune homeostasis of pro- vs anti-inflammatory immune cell subtypes, potentially supporting long-term efficacy.

Access Denied: Disparities in Thyroid Cancer Clinical Trials

For thyroid cancer clinical trials, the inclusion of participants from diverse patient populations is uniquely important given existing racial/ethnic disparities in thyroid cancer care. Since 2011, a paradigm shift has occurred in the treatment of advanced thyroid cancer with the approval of multiple systemic therapies by the US Food and Drug Administration based on their use in the clinical trials setting. Although these clinical trials recruited patients from up to 164 sites in 25 countries, the inclusion of racial/ethnic minority patients remained low. In this mini-review, we provide an overview of barriers to accessing cancer clinical trials, framed in the context of why patients with thyroid cancer may be uniquely vulnerable. Multilevel interventions and increased funding for thyroid cancer research are necessary to increase access to and recruitment of under-represented patient populations into thyroid cancer clinical trials.

The amyotrophic lateral sclerosis-health index (ALS-HI): development and evaluation of a novel outcome measure

Objective: The identification of effective therapeutics for ALS necessitates valid and responsive outcome measures to track disease progression and therapeutic gain in clinical trial settings. The Amyotrophic Lateral Sclerosis-Health Index (ALS-HI) is a multifaceted, disease-specific patient-reported outcome measure (PRO) designed to measure ALS symptomatic disease burden in adults with ALS. Methods: Through a national cross-sectional study of individuals with ALS, we identified the most important symptoms in ALS. These symptoms were incorporated into the ALS-HI, a measure that quantifies the multifaceted disease burden in ALS. We performed factor analysis, qualitative patient interviews, test-retest reliability assessment, and known groups analysis to evaluate and validate the ALS-HI. Results: The cross-sectional study included 497 participants with ALS who identified the most important symptoms to include in the ALS-HI. Fifteen participants beta tested the ALS-HI and found it to be clear, easy to use, and relevant. Twenty-one participants engaged in a test-retest reliability study, which indicated the reliability of the instrument (intraclass correlation coefficient = 0.952 for full instrument). The final ALS-HI and its subscales demonstrated a high internal consistency (Cronbach’s α = 0.981 for full instrument) and an ability to differentiate between groups with dissimilar disease severity. Conclusions: This research supports use of the ALS-HI as a valid, sensitive, reliable, and relevant PRO to assess the multifactorial disease burden faced by adults with ALS. The ALS-HI has potential as a mechanism to track disease progression and treatment efficacy during therapeutic trials.

A Personalised 3D-Printed Dental Plaque Removal Mouthguard for Older Adults

ObjectivesThe aim of the present study was to examine the plaque removal effectiveness of a personalised 3D-printed dental plaque removal mouthguard device in a clinical trial setting. MethodsA personalised 3D-printed mouthguard was developed to clean dental plaque using micro-mist. A clinical trial was conducted to examine the plaque removal effectiveness of this device. The clinical trial recruited 55 participants (21 males and 34 females) with an average age of 68.4 years (range, 60–81 years). Dental plaque was dyed by plaque disclosing liquid (Ci). Turesky Modification of the Quigley-Hein Plaque Index (TMQHPI) was used to evaluate the level and rate of plaque formation on the tooth surface. The TMQHPI was recorded and intraoral photos were taken before and after mouthguard cleaning. The plaque removal rate was calculated based on TMQHPI and intraoral photos (pixel-based method) before and after cleaning. ResultsThe personalised 3D-printed micro-mist injection mouthguard can be effective in dental plaque removal on tooth and gingiva, and the effectiveness lies between that of a manual toothbrush and a mouth rinse. The newly proposed pixel-based method can be a practical, high sensitive tool to evaluate the level of plaque formation. ConclusionsUnder the conditions of the present study, we conclude that the personalised 3D-printed micro-mist injection mouthguard can be useful in reducing dental plaque and may be especially suitable for older adults and disabled people.

Comparison of Glucose ORS with and without Rice Based ORS in Treatment of Acute Gastroenteritis from 6 Month to 5 Years

Introduction: Acute gastroenteritis-related diarrhea is a major contributor to pediatric morbidity and mortality. Although the success of various oral rehydration formulations varies and the treatment of choice ultimately depends on the underlying reason, oral rehydration remains crucial for efficient early therapies. Objective: To compare outcome of Glucose ORS with and without rice based ORS in treatment of acute gastroenteritis from 6 month to 5 years in terms of mean stool frequency. Study Design: Randomized clinical trial Settings: The study will be done at department of Peads Ittifaq Hospital Lahore from 9 December 2018 to 19 June 2019. Sample Technique: Non probability consecutive sampling Methodology: Children of both sexes were included in this analysis of gastroenteritis cases between the ages of 6 months and 5 years. They divided into two separate groups. For 48 hours, group A was given G-ORS, whereas group B was given rice soup. Over the course of 48 hours, the typical individual needs to use the washroom. Results: Eighty people took part in the study (forty in each group). There were 25 males in Group A (40.02%), and 26 in Group B (50.98%). The average ages of those in Group A and Group B were very comparable (3.30±1.18 vs. 2.07±1.03 years, p=0.29). The baseline stool frequency of Group A was 4.11±2.33, while that of Group B was 5.01±2.81 (p= 0.51). Group A also had a higher mean weight, at 6.87±1.97, than Group B, at 6.28±2.01. Group A had an average of 2.15±0.77 bowel movements in 48 hours, while Group B had an average of 2.08±0.73 (p=0.91). The mean frequency was 2.170.78 for males, 2.14±0.69 for females, and 2.11±0.72 for both sexes combined (p=0.91). There were no statistically significant differences in age, BMI over 10, or baseline frequency. Practical implication: The purpose of this research was to more exactly explain the authentic benefit of rice-based ORS in comparison to glucose ORS and to evaluate whether or not there is significant differences. Conclusion: Both groups reduced the number of incidences of the confounding variable roughly at the same rate, and there was no statistically significant difference between them either in terms of that reduction or in terms of stratification of any of the study's other confounding variables. Keywords: G-ORS, Gastroenteritis, Stool frequency, Rice soup

Angioimmunoblastic T-cell lymphoma and correlated neoplasms with T-cell follicular helper phenotype: from molecular mechanisms to therapeutic advances.

Angioimmunoblastic T-cell lymphoma (AITL) is the second most frequent subtype of mature T-cell lymphoma (MTCL) in the Western world. It derives from the monoclonal proliferation of T-follicular helper (TFH) cells and is characterized by an exacerbated inflammatory response and immune dysregulation, with predisposition to autoimmunity phenomena and recurrent infections. Its genesis is based on a multistep integrative model, where age-related and initiator mutations involve epigenetic regulatory genes, such as TET-2 and DNMT3A. Subsequently, driver-mutations, such as RhoA G17V and IDH-2 R172K/S promote the expansion of clonal TFH-cells ("second-hit"), that finally begin to secrete cytokines and chemokines, such as IL-6, IL-21, CXCL-13 and VEGF, modulating a network of complex relationships between TFH-cells and a defective tumor microenvironment (TME), characterized by expansion of follicular dendritic cells (FDC), vessels and EBV-positive immunoblasts. This unique pathogenesis leads to peculiar clinical manifestations, generating the so-called "immunodysplastic syndrome", typical of AITL. Its differential diagnosis is broad, involving viral infections, collagenosis and adverse drug reactions, which led many authors to use the term "many-faced lymphoma" when referring to AITL. Although great advances in its biological knowledge have been obtained in the last two decades, its treatment is still an unmet medical need, with highly reserved clinical outcomes. Outside the setting of clinical trials, AITL patients are still treated with multidrug therapy based on anthracyclines (CHOP-like), followed by up-front consolidation with autologous stem cell transplantation (ASCT). In this setting, the estimated 5-year overall survival (OS) is around 30-40%. New drugs, such as hypomethylating agents (HMAs) and histone deacetylase inhibitors (HDAi), have been used for relapsed/refractory (R/R) disease with promising results. Such agents have their use based on a biological rationale, have significant potential to improve the outcomes of patients with AITL and may represent a paradigm shift in the therapeutic approach to this lymphoma in the near future.

SLE is not a one-size-fits-all disease.

In this Viewpoint we discuss how experimental medicine applied in the setting of clinical trials can address unmet need in the prototypic autoimmune disease systemic lupus erythematosus (SLE) to improve outcomes for patients.

Coxsackievirus A11 is an immunostimulatory oncolytic virus that induces complete tumor regression in a human non-small cell lung cancer

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide. Innovative treatment is required to improve overall survival rates for advanced NSCLC. Oncolytic virotherapy using enteroviruses has emerged as a promising anticancer strategy. To identify a novel, potent virotherapy with an improved safety profile, we assessed the oncolytic activity of 28 enteroviral strains and focused on coxsackievirus A11 (CVA11). CVA11 infection caused extensive oncolytic activity in all three of the examined human NSCLC cell lines, with high intercellular adhesion molecule-1 (ICAM-1) expression associated with greater CVA11-induced cytotoxicity. In vitro inhibition analysis using a pan-caspase inhibitor and western blot detection of cleaved poly (ADP-ribose) polymerase (PARP) indicated that apoptosis partly contributed to CVA11-driven cytotoxicity. CVA11 infection-induced immunogenic cell death in vitro was strongly suggested by substantial calreticulin expression and release of high mobility group box-1 protein (HMGB1). Moreover, in vivo treatment of human NSCLC xenografts with intratumoral CVA11 injection caused complete tumor regression in all treated mice, without significant weight loss. Our findings indicate that novel oncolytic virotherapy utilizing CVA11 may be less toxic and more effective than current treatments for human NSCLC, thus warranting further investigation in clinical trial settings, especially in combination with immunotherapy.

From Meaningful Outcomes to Meaningful Change Thresholds: A Path to Progress for Establishing Digital Endpoints.

This paper examines the use of digital endpoints (DEs) derived from digital health technologies (DHTs), focusing primarily on the specific considerations regarding the determination of meaningful change thresholds (MCT). Using DHTs in drug development is becoming more commonplace. There is general acceptance of the value of DHTs supporting patient-centric trial design, capturing data outside the traditional clinical trial setting, and generating DEs with the potential to be more sensitive to change than conventional assessments. However, the transition from exploratory endpoints to primary and secondary endpoints capable of supporting labeling claims requires these endpoints to be substantive with reproducible population-specific values. Meaningful change represents the amount of change in an endpoint measure perceived as important to patients and should be determined for each digital endpoint and given population under consideration. This paper examines existing approaches to determine meaningful change thresholds and explores examples of these methodologies and their use as part of DE development: emphasizing the importance of determining what aspects of health are important to patients and ensuring the DE captures these concepts of interest and aligns with the overarching endpoint strategy. Examples are drawn from published DE qualification documentation and responses to qualification submissions under review by the various regulatory authorities. It is the hope that these insights will inform and strengthen the development and validation of DEs as drug development tools, particularly for those new to the approaches to determine MCTs.

Abstract 957: Prediction of patient response to targeted and immunotherapies from the tumor transcriptome in a wide set of indications and clinical trials

Abstract Background: Precision oncology is gradually advancing into mainstream clinical practice, demonstrating significant survival benefits. However, eligibility and response rates remain limited in many cases, calling for better predictive biomarkers. Methods: We present ENLIGHT, a transcriptomics-based computational approach that identifies clinically relevant genetic interactions and uses them to predict a patient’s response to a variety of therapies in multiple cancer types, importantly, without training on previous treatment response data. Consequently, in addition to its ability to predict patients' response to approved and well-studied therapies, ENLIGHT can predict the response to new treatments in early development, even before clinical data has accumulated. Accordingly, we study ENLIGHT in two translationally relevant scenarios: Personalized Oncology (PO), aimed at prioritizing approved treatments to a given patient, and Clinical Trial Design (CTD), selecting the subset of most likely responders in a patient cohort. Results: Evaluating ENLIGHT’s performance on 21 blinded clinical trial datasets spanning 11 indications and 15 different drugs in the PO setting, we show that it can effectively predict a patient’s treatment response across multiple therapies and cancer types, with an overall odds ratio of 2.59 (p=3.41e-8), and a 36% increase in response rate over the baseline (p=3.30e-13). Its prediction accuracy is better than other state-of-the-art transcriptomics-based signatures. Unlike most signatures that are prognostic or provide insights for only very few, specific treatments, ENLIGHT provides matching scores to a broad range of treatments. Quite strikingly, its performance is comparable to that of supervised predictors developed for specific indications and drugs. In combination with the IFN-γ signature, ENLIGHT achieves an odds ratio larger than 4 in predicting response to immune checkpoint therapy. In the CTD scenario, our results show that by excluding non-responders ENLIGHT can enhance clinical trial success for immunotherapies and other monoclonal antibodies, achieving > 90% of the response rate attainable under an optimal exclusion strategy. Conclusion: ENLIGHT is a powerful transcriptomics-based precision oncology pipeline developed by Pangea Biomed that broadly predicts response to both extant and novel targeted and immune therapies, going beyond context-specific biomarkers. Citation Format: Gal Dinstag, Eldad D. Shulman, Efrat Elis, Doreen S. Ben-Zvi, Omer Tirosh, Eden Maimon, Isaac Meilijson, Emmanuel Elalouf, Boris Temkin, Philipp Vitkovsky, Eyal Schiff, Danh-Tai Hoang, Sanju Sinha, Nishanth Ulhas Nair, Joo Sang-Lee, Alejandro A. Schäffer, Ze'ev Ronai, Dejan Juric, Andrea B. Apolo, William L. Dahut, Stanley Lipkowitz, Raanan Berger, Razelle Kurzrock, Antonios Papanicolau-Sengos, Fatima Karzai, Mark R. Gilbert, Kenneth Aldape, Padma S. Rajagopal, Tuvik Beker, Eytan Ruppin, Ranit Aharonov. Prediction of patient response to targeted and immunotherapies from the tumor transcriptome in a wide set of indications and clinical trials [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 957.