Clinical Trials For Treatment Research Articles

Retracted and republished from: "The current state of research on influenza antiviral drug development: drugs in clinical trial and licensed drugs".

Influenza viruses (IVs) threaten global human health due to the high morbidity, infection, and mortality rates. Currently, the influenza drugs recommended by the Food and Drug Administration are oseltamivir, zanamivir, peramivir, and baloxavir marboxil. These recommended antivirals are currently effective for major subtypes of IVs as the compounds target conserved domains in neuraminidase or polymerase acidic (PA) protein. However, this trend may gradually change due to the selection of antiviral drugs and the natural evolution of IVs. Therefore, there is an urgent need to develop drugs related to the treatment of influenza to deal with the next pandemic. Here, we summarized the cutting-edge research in mechanism of action, inhibitory activity, and clinical efficacy of drugs that have been approved and drugs that are still in clinical trials for influenza treatment. We hope this review will provide up-to-date and comprehensive information on influenza antivirals and generate hypotheses for screens and development of new broad-spectrum influenza drugs in the near future.

The Implementation of Recommender Systems for Mental Health Recovery Narratives: Evaluation of Use and Performance.

Recommender systems help narrow down a large range of items to a smaller, personalized set. NarraGive is a first-in-field hybrid recommender system for mental health recovery narratives, recommending narratives based on their content and narrator characteristics (using content-based filtering) and on narratives beneficially impacting other similar users (using collaborative filtering). NarraGive is integrated into the Narrative Experiences Online (NEON) intervention, a web application providing access to the NEON Collection of recovery narratives. This study aims to analyze the 3 recommender system algorithms used in NarraGive to inform future interventions using recommender systems for lived experience narratives. Using a recently published framework for evaluating recommender systems to structure the analysis, we compared the content-based filtering algorithm and collaborative filtering algorithms by evaluating the accuracy (how close the predicted ratings are to the true ratings), precision (the proportion of the recommended narratives that are relevant), diversity (how diverse the recommended narratives are), coverage (the proportion of all available narratives that can be recommended), and unfairness (whether the algorithms produce less accurate predictions for disadvantaged participants) across gender and ethnicity. We used data from all participants in 2 parallel-group, waitlist control clinical trials of the NEON intervention (NEON trial: N=739; NEON for other [eg, nonpsychosis] mental health problems [NEON-O] trial: N=1023). Both trials included people with self-reported mental health problems who had and had not used statutory mental health services. In addition, NEON trial participants had experienced self-reported psychosis in the previous 5 years. Our evaluation used a database of Likert-scale narrative ratings provided by trial participants in response to validated narrative feedback questions. Participants from the NEON and NEON-O trials provided 2288 and 1896 narrative ratings, respectively. Each rated narrative had a median of 3 ratings and 2 ratings, respectively. For the NEON trial, the content-based filtering algorithm performed better for coverage; the collaborative filtering algorithms performed better for accuracy, diversity, and unfairness across both gender and ethnicity; and neither algorithm performed better for precision. For the NEON-O trial, the content-based filtering algorithm did not perform better on any metric; the collaborative filtering algorithms performed better on accuracy and unfairness across both gender and ethnicity; and neither algorithm performed better for precision, diversity, or coverage. Clinical population may be associated with recommender system performance. Recommender systems are susceptible to a wide range of undesirable biases. Approaches to mitigating these include providing enough initial data for the recommender system (to prevent overfitting), ensuring that items can be accessed outside the recommender system (to prevent a feedback loop between accessed items and recommended items), and encouraging participants to provide feedback on every narrative they interact with (to prevent participants from only providing feedback when they have strong opinions).

Positive impacts of psychological pain treatments: Supplementary analyses of a randomized clinical trial.

Clinical trials often focus on symptom reduction as a primary outcome, overlooking positive psychology factors of potential importance although many individuals can and do live well with pain. The Patient-Reported Outcomes Measurement Information System (PROMIS) Psychosocial Illness Impact-Positive (PIIP) scale assesses perceptions of adaptive psychosocial functioning (e.g., coping and meaning-making) after illness onset. This study evaluated the effects of hypnosis (HYP), mindfulness meditation (MM), and pain psychoeducation (ED) on PIIP scores, using data from a completed randomized clinical trial (RCT) of complementary and integrative chronic pain interventions. We hypothesized that treatment effects on PIIP would mirror the RCT's primary pain intensity outcome, such that HYP and MM, relative to ED, would lead to greater improvements in PIIP during trial follow-up. Our sample included 262 Veterans who completed the PROMIS PIIP Short-Form 8a at pre- and posttreatment and at 3- and 6-month follow-up. Linear regression was used to test between-group differences in PIIP at each time point, controlling for baseline PIIP, average pain intensity, and baseline perceptions of prepain psychosocial functioning. There were no significant between-group differences in PIIP at posttreatment or 3-month follow-up. However, group differences emerged at 6-month follow-up: individuals randomized to MM and HYP showed improved PIIP relative to those randomized to ED. Positive psychosocial outcomes are a mostly untapped territory in clinical trials of pain interventions. The present work highlights the potential benefits of including positive psychology concepts in both research and clinical contexts, emphasizing the importance of understanding human flourishing in the presence of illness and disability. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Tumor Suppressor MicroRNAs in Clinical and Preclinical Trials for Neurological Disorders.

Cancers and neurological disorders are two major types of diseases in humans. We developed the concept called the "Aberrant Cell Cycle Disease (ACCD)" due to the accumulating evidence that shows that two different diseases share the common mechanism of aberrant cell cycle re-entry. The aberrant cell cycle re-entry is manifested as kinase/oncoprotein activation and tumor suppressor (TS) inactivation, which are associated with both tumor growth in cancers and neuronal death in neurological disorders. Therefore, some cancer therapies (e.g., kinase/oncogene inhibition and TS elevation) can be leveraged for neurological treatments. MicroRNA (miR/miRNA) provides a new style of drug-target binding. For example, a single tumor suppressor miRNA (TS-miR/miRNA) can bind to and decrease tens of target kinases/oncogenes, producing much more robust efficacy to block cell cycle re-entry than inhibiting a single kinase/oncogene. In this review, we summarize the miRNAs that are altered in both cancers and neurological disorders, with an emphasis on miRNA drugs that have entered into clinical trials for neurological treatment.

A review of perioperative treatment strategies with immunotherapy and tyrosine kinase inhibitors in resectable and stage IIIA-N2 non-small cell lung cancer.

Stage IIIA-N2 non-small cell lung cancer (NSCLC) is a heterogeneous group with different potential therapeutic approaches. Treatment is typically multimodal with either surgical resection after neoadjuvant chemotherapy and/or radiation or concurrent chemotherapy and radiation if unresectable. Despite the multimodal treatment and early stage, cure rates have traditionally been low. The introduction of immunotherapy changed the treatment landscape for NSCLC in all stages, and the introduction of immunotherapy in early-stage lung cancer has improved event free survival and overall survival. Tyrosine Kinase inhibitors (TKIs) have also improved outcomes in early-stage mutation-driven NSCLC. Optimal treatment choice and sequence is increasingly becoming based upon personalized factors including clinical characteristics, comorbidities, programmed death-ligand 1 (PD-L1) score, and the presence of targetable mutations. Despite encouraging data from multiple trials, the optimal multimodal sequence of stage IIIA-N2 NSCLC treatment remains unresolved and warrants further investigation. This review article summarizes recent major clinical trials of neoadjuvant and adjuvant treatment including stage IIIA-N2 NSCLC with a focus on immunotherapy and TKIs.

Views of Service Users, Their Family or Carers, and Health Care Professionals on Telerehabilitation for People With Neurological Conditions in Ghana: Qualitative Study.

Up to 50% of people in low- and middle-income countries do not receive the rehabilitation they require. Telerehabilitation has the potential to improve access to neurorehabilitation services especially in low- and middle-income countries. Although there are reports of the barriers and facilitators to telerehabilitation in such settings, almost all are anecdotal. Furthermore, family or carers have a significant influence on the adoption and success of telerehabilitation, but their views have not been reported. This study aimed to investigate the views of service users, their family or carers, and health care professionals (HCPs) on telerehabilitation for people with neurological conditions in Ghana. Two focus groups were held at Komfo Anokye Hospital in Kumasi, Ghana: one in person for service users (n=11) and their family or carers (n=9), conducted in the Ghanaian language of Twi, and one hybrid for HCPs (n=18) conducted in English. The mean (SD) age of the service users was 59.8 (8.6) years; 5 users had a stroke and 6 had Parkinson disease. The HCP group consisted of 7 speech and language therapists, 3 physiotherapists, 3 occupational therapists, 3 medical staff, 1 nurse, and 1 industry representative. Focus groups were semi-structured and explored previous experiences of telerehabilitation, perceived benefits and challenges, and solutions to overcome these challenges. Focus groups were audio transcribed, and the service user transcript was translated into English. The resulting transcripts were analyzed using thematic analysis. Overall, participants were positive about the role of telerehabilitation but recommended hybrid delivery, with in-person rehabilitation in the early stages and telerehabilitation in the later stages. In relation to telerehabilitation in Ghana, there were 3 main themes: benefits, challenges or barriers, and implementation. Benefits included the convenience and lower cost for service users, the higher dose of therapy possible, and increased access for people in remote areas. However, challenges included lack of a stable internet connection, cost of phones and data packages, and low levels of literacy. Implementation issues included cultural relevance, information governance, and the platform used to deliver telerehabilitation, with most participants being familiar with WhatsApp. Telerehabilitation has the potential to be a useful method of delivering rehabilitation to people with neurological conditions in Ghana, especially in a hybrid rehabilitation model with telerehabilitation augmenting in-person sessions. However, many people were unaware of telerehabilitation, and challenges such as a reliable internet connection, cultural relevance, and costs need to be addressed. Clinical trials of low-cost telerehabilitation interventions contextualized to the specific user group are required.

Challenges in designing and running smouldering myeloma interventional clinical trials.

Challenges in designing and running smouldering myeloma interventional clinical trials.

Impact of Broadening Trial Eligibility Criteria on the Inclusion of Patients With Brain Metastases in Cancer Clinical Trials: Time Series Analyses for 2012-2022.

In October 2017, an ASCO, Friends of Cancer Research (FoCR), and US Food and Drug Administration (ASCO/FoCR/FDA) task force recommended that common eligibility criteria be modified to make trials more inclusive. We examined whether patterns of exclusions regarding patients with brain metastases changed over time in relation to these recommendations. Trial eligibility criteria were abstracted from ClinicalTrials.gov for phase I-III US-based interventional clinical trials for patients with advanced breast, colorectal, lung, or melanoma cancers from January 2012 to December 2022. Trials were examined to determine whether patients with brain metastases were not excluded, conditionally excluded (ie, excluded in some circumstances), or wholly excluded. An interrupted time series analysis with multinomial logistic regression was used to determine whether the ASCO/FoCR/FDA recommendations were associated with changes in brain metastases criteria. We evaluated N = 3,077 trials. Patients with brain metastases were not excluded in 506 trials (16.4%), conditionally excluded in 2,263 trials (73.5%), and wholly excluded in 308 trials (10.0%). In the postrecommendation period, we estimated a 68% increase in the odds of brain metastases not excluded compared with conditionally excluded (odds ratio, 1.68 [95% CI, 1.06 to 2.66], P = .03). The proportion of trials in which patients with brain metastases were not excluded increased (from 11.5% v 17.3%) and conditionally excluded decreased (from 82.3% to 75.2%, P = .03). We found no difference in the proportion of trials in which patients with brain metastases were wholly excluded (7.5% v 6.2%, P = .42). The ASCO/FoCR/FDA task force recommendations were associated with a shift in patterns of brain metastases exclusion criteria from conditionally excluded to not excluded. These findings demonstrate that the cancer clinical trial community has begun to change the way trials are written to be more inclusive.

Effect of vitamin E supplementation on bilirubin levels in infants with hyperbilirubinemia: a double-blind randomized clinical trial.

The effect of vitamin E supplementation on bilirubin levels in infants was previously explored, but the results were inconclusive. To examine the effect of vitamin E supplementation on bilirubin levels in term infants in the neonatal intensive care unit (NICU). This interventional double-blind randomized clinical trial was conducted in the Sanandaj Besat Hospital NICU. Enrolled newborns were between 37 and 42 weeks and 6 days of gestation and required phototherapy according to American Academy of Pediatrics clinical guidelines. A total of 138 infants were randomly assigned to vitamin E (n=68) or placebo (n=70) groups. In addition to phototherapy, the vitamin E group received 0.5 mL (5 IU) of supplemental vitamin E daily, whereas the placebo group received 0.5 mL of oral dextrose daily. STATA 17 was used for the data analysis. Changes in bilirubin levels at 24 hours postintervention did not differ significantly from baseline in either group. Vitamin E supplementation did not significantly reduce total bilirubin levels at 24 hours postintervention (mean difference [MD], -0.18; P=0.204; 95% confidence interval [CI], -1.39 to 1.02). However, the vitamin E group exhibited lower total bilirubin levels than the placebo group at 48 hours postintervention (MD, 0.18; P=0.365; 95% CI, -0.89 to 1.27) and 72 hours (MD, 0.36; P=0.356; 95% CI, -2.34 to 1.61), although the differences were not statistically significant. A subgroup analysis revealed that female infants experienced a greater reduction in total bilirubin levels than male infants. Infants administered vitamin E versus placebo demonstrated similar reductions in bilirubin levels and hospital stays. Although the average bilirubin changes did not differ significantly between groups, the vitamin E group showed a more noticeable reduction over time, indicating a positive effect of vitamin E supplementation on serum bilirubin reduction. Trial registration: IRCT20220806055625N2 (registered December 26, 2022; http://irct.ir/trial/67135).

Nutrition considerations for patients with persistent critical illness: A narrative review.

Critically ill patients experience high rates of malnutrition and significant muscle loss during their intensive care unit (ICU) admission, impacting recovery. Nutrition is likely to play an important role in mitigating the development and progression of malnutrition and muscle loss observed in ICU, yet definitive clinical trials of nutrition interventions in ICU have failed to show benefit. As improvements in the quality of medical care mean that sicker patients are able to survive the initial insult, combined with an aging and increasingly comorbid population, it is anticipated that ICU length of stay will continue to increase. This review aims to discuss nutrition considerations unique to critically ill patients who have persistent critical illness, defined as an ICU stay of >10 days. A discussion of nutrition concepts relevant to patients with persistent critical illness will include energy and protein metabolism, prescription, and delivery; monitoring of nutrition at the bedside; and the role of the healthcare team in optimizing nutrition support.

Abstract 4438: Time restricted eating improves antitumor immune responses via modulation of insulin-like growth factor 1 in patients with head and neck cancer

Abstract Background- Treatment of metastatic head and neck cancer remains an area of unmet need with median survival less than a year. We tested the efficacy of a novel circadian aligned fasting intervention called “time restricted eating” (TRE), to improve ICB response in tumor bearing head and neck syngeneic mice models (MOC1), and showed significant reduction in tumor growth, which we then recapitulated in a pilot, open labeled, interventional clinical trial in 30 metastatic head and neck cancer patients. We noted significant improvement in median progression free survival (5 months vs not reached (NR), HR-0.2, p-0.0008) and overall survival (8 months vs NR, HR-0.00000045) in patients observing TRE vs those who did not. The favorable effect of TRE was mediated via modulation of gut microbiome, microbial tryptophan metabolome, and insulin signalling, specifically reduction in circulating insulin-like growth factor 1 (IGF1). We hypothesized that IGF1 mediates ICB resistance via protecting tumor cells from cytotoxic T cell activity. Methods- We performed in vitro luciferase cytotoxicity assays using HLA-A2+NY-ESO+ squamous cell cancer 4 (SCC-4) human cancer cells as targets, and HLA-A2-restricted NY-ESO-1-specific T cell receptor (TCR) -transduced T cells. We co-cultured the tumor cells and the T cells for 24 hours under different conditions of IGF-1 concentration (100 ng, 50 ng, and 10 ng) and T cell-to-tumor cell ratio (1:5, 1:10, and 1:20). We also treated the tumor cells with IGF-1 alone to assess its direct cytotoxic effect. Results We observed that IGF-1 impaired the ability of the T cells to kill the tumor cells in a dose-dependent manner, while IGF-1 had no cytotoxic effect on the tumor cells in the absence of T cells. Conclusion- While the role of IGF1 in treatment resistance has been described, its role and mechanism in antitumor immune response is largely unknown. We, for the first time demonstrate the role of IGF1 in impairing T cell mediated antitumor activity in a dose dependent fashion, thus contributing to ICB resistance. Further work will help us develop alternative strategies to modulate IGF1 and improve ICB resistance, in patients who are unable to tolerate TRE. Citation Format: Mostafa Eysha, Carmen A. Galindo, Jameel Muzaffar, Jessica Mine, Ricardo Chauriogonzalez, Mariam Baig, Luis Lopez-bailon, Muhammad Alhomsi, Mahmoud Hathout, Jiangbo Wang, Wanyu Zhang, Daliya Rizvi, Angie Huang, Kate Lee, Daniel Kye, Amit Sen, Jose Conejo-Garcia, Shahla Bari. Time restricted eating improves antitumor immune responses via modulation of insulin-like growth factor 1 in patients with head and neck cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4438.

Abstract 7623: Biomarker study to personalized neoadjuvant chemotherapy using preoperative gastric cancer specimens of biopsy from the COMPASS trial, a phase II randmazed controlled trial

Abstract Background and Aim: The results of COMPASS, a randomized phase II trial, suggest that preoperative adjuvant chemotherapy (NAC) regimen or course for locally advanced gastric cancer (GC) does not affect overall survival (OS). However, we hypothesized that some NAC regimens may be more effective for OS on a case-by-case basis. Furthermore, we searched for biomarkers, assuming that further improvement in the outcome of locally advanced GC could be expected if appropriate NAC regimens could be selected using biomarkers before treatment initiation. Materials and Methods: RNA was extracted from endoscopic biopsy specimens of primary tumors collected prior to NAC administration in COMPASS patients, and real-time polymerase chain reaction (PCR) of 127 genes was performed to identify genes with significant (P < 0.05) interaction P values for survival with each regimen and stratified OS with each regimen. Genes were identified and biomarkers were searched at the protein level using immunohistochemical analysis. Results: The THBS1, MSI1, and IGF2BP3 genes were identified as genes whose expression levels significantly (P < 0.05) stratified survival for each regimen and had significant (P < 0.05) interaction P values. Furthermore, a strong correlation was observed between each gene and THBS1, MSI1, and IGF2BP protein expression by immunohistochemical analysis, confirming that protein expression levels by immunohistochemical analysis are also useful as biomarkers. Conclusion: Using endoscopic biopsy specimens prior to NAC for locally advanced GC, biomarkers were identified to select NAC regimens over predicted OS. The results of this study may guide the conduct of clinical trials of individualized treatment of NAC using biomarkers. Citation Format: Takashi Oshima. Biomarker study to personalized neoadjuvant chemotherapy using preoperative gastric cancer specimens of biopsy from the COMPASS trial, a phase II randmazed controlled trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7623.

The Impact of COVID-19 on Health Behavior Engagement and Psychological and Physical Health Among Active Duty Military Enrolled in a Weight Management Intervention: An Exploratory Study.

The COVID-19 pandemic profoundly affected the health and well-being of people globally. Some studies suggest individuals with overweight or obesity may have been more adversely impacted by pandemic restrictions. Additionally, military personnel may have been more vulnerable to stress during the pandemic because of job demands (e.g., work in close quarters). Our research group was conducting a randomized clinical trial of a weight management intervention in active duty military personnel with overweight or obesity when the COVID-19 pandemic struck. Thus, we collected additional pandemic-related data from participants enrolled during the COVID-19 pandemic and conducted exploratory analyses to understand how the pandemic affected their stress levels and perceived abilities to engage in health behaviors like exercise and healthy eating. The aims of this exploratory study were to: (1) assess associations between pandemic-related stress and health behaviors with body fat percentage (BF%) and psychological and physical health, and (2) explore how pandemic-related stress and health behaviors affected BF% during and after the intervention. A total of 29 active duty Navy personnel (55% female, 69% White) were enrolled after the onset of pandemic restrictions and completed measures assessing pandemic-related stress and health behaviors as well as measures of general psychological and physical health before the intervention. BF% was collected at 5 timepoints, including baseline, during, and following the intervention. Bivariate correlations assessed associations at baseline. Linearmixed-effects longitudinal models explored how pandemic-related stress and health behaviors affected BF%. Post-hoc analyses evaluated the effects of pandemic factors on BF% at each timepoint. Most participants perceived of the pandemic as increasing stress and detracting from their abilities to engage in health behaviors (i.e., exercise and healthy eating). Higher pandemic stress was significantly associated with reporting exercise and healthy eating as more difficult, worse overall health, and more anxiety and general stress. Reporting exercise as harder during the pandemic also was associated with more psychological distress at baseline. A linearmixed- effects model controlling for age, sex, and number of intervention sessions attended revealed endorsing "exercise as harder" was associated with higher BF%. Post-hoc regression analyses revealed rating "exercise as harder" significantly predicted higher BF% 3 months post-intervention (B = 0.65, P = .01), whereas pandemic stress was not significantly associated with higher BF% at 3 month (B =0.14, P = .08) or 6 month (B = 0.21, P = .09) follow-up. As expected, most participants perceived of the pandemic as heightening stress and interfering with engagement in health behaviors. It is possible that pandemic-related stress may have exacerbated weight gain-promoting behaviors and/or interfered with achievement of desired weight management outcomes. Outside the context of the pandemic, it may be beneficial for healthcare providers to screen individuals for stress and perceptions of ease of engagement in health behaviors before enrollment in a weight management intervention. Further, tailoring interventions to mitigate stress and promote perceptions of ease in engaging in health behaviors may promote better weight management outcomes.

Abstract 6559: Clinical validity of post-surgery circulating tumor DNA testing in stage III colon cancer patients treated with adjuvant chemotherapy: The PROVENC3 study

Abstract Introduction: Surgery followed by adjuvant chemotherapy (ACT) is standard of care in stage III colon cancer. However, only 15-20% of patients benefit from ACT, as half of patients are cured by surgery, and 25-30% still experience a recurrence. Detection of circulating tumor DNA (ctDNA) after resection of the primary tumor is a strong prognostic biomarker in non-metastatic colon cancer and offers a promising approach to better stratify stage III colon cancer patients for ACT treatment decisions. Aim: The PROVENC3 study aims to determine the clinical validity of post-surgery ctDNA detection in patients with stage III colon cancer treated with ACT. Methods: Blood was collected pre-surgery, post-surgery and post-ACT for stage III colon cancer patients treated with ACT. Tumor-informed detection of ctDNA was performed through integrated whole genome sequencing (WGS) analyses of formalin-fixed paraffin-embedded tumor tissue DNA (80x), germline DNA (40x), and plasma cell-free DNA (30x). The primary outcome was time to recurrence (TTR). Results: Results from 209 patients (median follow up: 40 months) show that ctDNA-positive patients post-surgery (n=28) had a higher risk of developing a recurrence than ctDNA-negative patients (HR: 6.3, [95%CI: 3.5-11.3], P<10−8). 38% of patients with a recurrence within 3 years were ctDNA-positive post-surgery. Combination of post-surgery ctDNA status with established clinicopathological risk classification of low-risk (T1-3 and N1) and high-risk (T4 and/or N2) resulted in a 3-year cumulative recurrence risk of 82% for clinical high-risk ctDNA-positive patients compared to 7% for clinical low-risk ctDNA-negative patients (HR 28.9 [95%CI: 10.6-78.2]; P<10−10). Results from 170 patients with post-ACT blood available showed that post-ACT ctDNA-positive patients (n=24) were at a higher risk of developing a recurrence (HR 7.9 [95%CI: 3.5-15.9]; P<10−8) than ctDNA-negative patients. The patients experiencing a recurrence had higher aggregate ctDNA variant allele frequencies than patients not experiencing a recurrence post-surgery or post-ACT (P<0.001 and P<0.001, respectively). Conclusion: Post-surgery ctDNA detection by tumor-informed WGS is a strong prognostic biomarker in stage III colon cancer patients, and improves the current risk stratification. Importantly, the post-surgery ctDNA-positive patients who did not experience a recurrence were likely cured by ACT. These data enable the design of clinical practice-changing ctDNA-guided interventional trials in stage III colon cancer to personalize adjuvant treatment decisions. Citation Format: Carmen Rubio Alarcon, Andrew Georgiadis, Ingrid A. Franken, Haoyue Wang, Sietske C. van Nassau, Suzanna J. Schraa, Dave E. van der Kruijssen, Karlijn van Rooijen, Theodora C. Linders, Pien Delis-van Diemen, Maartje Alkemade, Anne Bolijn, Marianne Tijssen, Margriet Lemmens, Lana Meiqari, Steven L. Ketelaars, Adria Closa Mosquera, Miranda M. van Dongen, Mirthe Lanfermeijer, Birgit I. Lissenberg-Witte, Linda J. Bosch, Teunise Bisschop-Snetselaar, Bregje Adriaans, Amy Greer, David Riley, James R. White, Christopher Greco, Liam Cox, Jesse Fox, Kaitlin Victor, Catherine Leech, Samuel V. Angiuoli, Niels F. Kok, Cornelis J. Punt, Daan van den Broek, Miriam Koopman, Gerrit A. Meijer, Victor E. Velculescu, Jeanine M. Roodhart, Veerle M. Coupé, Mark Sausen, Geraldine R. Vink, Remond J. Fijneman. Clinical validity of post-surgery circulating tumor DNA testing in stage III colon cancer patients treated with adjuvant chemotherapy: The PROVENC3 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6559.

Abstract 6539: RNAi mediated silencing of STAT3 in tumor-associated immune cells induces robust anti-tumor effects in immunotherapy resistant tumors

Abstract Malignant tumors are often associated with an immunosuppressive tumor microenvironment (TME), rendering most of them resistant to standard-of-care immune checkpoint inhibitors (CPIs). Signal transducer and activator of transcription 3 (STAT3), a ubiquitously expressed transcription factor, has well-defined immunosuppressive functions in several leukocyte populations within the TME. Since the STAT3 protein has been challenging to target using conventional pharmaceutical modalities, we investigated the feasibility of applying systemically delivered RNA interference (RNAi) agents to silence its mRNA directly in tumor-associated immune cells. In preclinical murine tumor models, chemically stabilized acetylated small-interfering RNAs (siRNAs) selectively silenced Stat3 mRNA in multiple relevant cell types in TME and tumor-draining lymph nodes (TDLN), reduced STAT3 protein levels, and increased cytotoxic T-cell infiltration. In murine models of CPI-resistant tumors, RNAi-mediated Stat3 silencing resulted in tumor growth inhibition, which was further enhanced and resulted in tumor regressions in combination with CPIs. Our findings suggest that targeting STAT3 directly and reducing STAT3 protein in the suppressive immune cell populations in the TME and TDLN may overcome some of the current limitations of immunotherapy and be of therapeutic benefit especially for cancer patients who failed to respond to standard immunotherapy treatments alone. A human active STAT3 conjugate is currently in Phase 1 clinical trial for treatment of immunotherapy refractory cancer types (NCT06098651). Citation Format: Shanthi Ganesh, Minju Kim, Jenny Lee, Xudong Feng, Harini Sivagurunatha Krishnan, Rene Rijnbrand, Amber Beaudry, Jennifer A. Lockridge, Vinita Uttamsingh, John Hanrahan. RNAi mediated silencing of STAT3 in tumor-associated immune cells induces robust anti-tumor effects in immunotherapy resistant tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6539.

Abstract 6351: MUC1*-ADCs are effective against heterogeneous solid tumor cancers

Abstract Purpose: To develop a MUC1*-ADC for the treatment of over 75% of solid tumor cancers. Methods: MUC1* (muk 1 star) is a growth factor receptor created after cleavage and release of the N-terminal portion of MUC1. The targeting antibody, huMNC2, has already demonstrated safety and cancer selectivity in a 1st-in-human CAR-T clinical trial for treatment of metastatic breast cancers. MNC2 is an IgG1 antibody that only recognizes the conformational epitope created when MUC1 is cleaved by specific tumor-associated enzymes. Confocal microscopy and pHlourin2 were employed to measure antibody internalization as a function of time. We conjugated MNC2 to MMAE, MMAF, Dxd and exatecan via several different linkers. MUC1*-ADCs with DARs ranging from 4-8 were tested in vitro and in vivo for efficacy against a panel of solid tumor cancers. Heterogenous MUC1* tumors were made by mixing different ratios of mCherry wild-type cancer cells with GFP MUC1* overexpressed cancer cells. Resulting H scores ranged from 10-280 (max 300). Results: Cancer cells internalized the MUC1* MNC2 antibody within 2 hours. In vitro, MUC1*-ADC IC50s ranged from 1.3nM to 20.0nM, depending on the linker-payload and cancer subtype, wherein the majority had an IC50 of about 10nM. In general, efficacy in animals was seen across multiple cancer sub-types treated with multiple MUC1*-ADCs. Efficacy in animals xenografted with heterogeneous MUC1* tumors showed a dependence on antigen density. Greatest efficacy was observed for breast cancer xenografts with an H Score >10 treated with MNC2-Deruxtecan. However, only pancreatic tumors with higher H Scores were completely eliminated by MNC2-MMAE, MNC2-Deruxtecan and MNC2-exatecan. MNC2-ADC and MNC2-CAR share the same antibody. No off-tumor toxicity was observed in animals treated with MNC2-ADC, which mimicked lack of off-target toxicities for MNC2-CAR T cells in humans. Conclusions: These data, combined with MNC2-CAR T data from our 1st-in-human trial for metastatic breast cancer, supports a conclusion that the MUC1* antibody MNC2 is safe and could have high therapeutic value as a MUC1*-ADC for multiple solid tumors with both high and low antigen density. Citation Format: Cynthia Carol Bamdad, Benoit S. Smagghe, Scott T. Moe, Mark G. Carter, Trevor J. Grant, Kevin R. Yi, Michael J. Nash, Jacy P. Marquez, Natalie K. Miller, Jac-Leen S. Nash, Dan S. Miller, Danica M. Walkley, Andrew K. Stewart. MUC1*-ADCs are effective against heterogeneous solid tumor cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6351.

Abstract 5723: Selectivity profiling of small molecule kinesin inhibitors using microplate-based ATPase activity assay

Abstract Kinesin superfamily proteins (KIFs) are a large family of molecular motor proteins, that share a highly conserved motor domain. KIFs play an important role in cell division and transport of vesicles and organelles within cells. Mitotic kinesins hydrolyze ATP through its ATPase activity to move along the spindle microtubules and carry out several functions during mitosis to facilitate precise chromosome segregation. Altered expressions of several kinesins are shown in various cancers, fueling the aggressive nature of cancers leading to genomic instability. KIF11/Eg5 overexpression is shown in various cancers including hepatic carcinoma, lung, prostate, colorectal, gastric, and pancreatic cancers. Small molecule inhibitors of KIF11/Eg5 and CENP-E are shown to result in mitotic arrest leading to apoptosis in tumor cell lines. Despite the poor clinical outcome of several Eg5 and CENP-E inhibitors entered in clinical trials, targeting kinesins remains an attractive anti-cancer therapeutic approach. Recently, an inhibitor of KIF18A has entered clinical trial for treatment of solid tumors with high chromosomal instability. Here we show development of a microplate based biochemical screening assays for a panel of kinesin motor domain proteins. We summarize kinetic characterization of kinesin proteins and study the selectivity of various previously reported KIF18A, Eg5, CENP-E inhibitors across a kinesin selectivity panel. Citation Format: Brenna P. Lee, Sung Won Oh, Kurumi Y. Horiuchi, Safnas F. AbdulSalam. Selectivity profiling of small molecule kinesin inhibitors using microplate-based ATPase activity assay [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5723.

Abstract 4824: Multi-level intervention to increase minority cancer patient enrollment to clinical treatment trials- Study design considerations and baseline characteristics from the ACTWONDER2S Study

Abstract Introduction: Black/African American (AA) and Hispanic cancer patients are underrepresented in cancer clinical trials (CCTs). Disparities stem from multiple factors, thus, comprehensive, multi-level interventions (MLI) are needed. Presented here is a conceptual framework for selecting the appropriate study design for MLIs using ACTWONDER2S, a multi-level intervention (MLI) aimed to increase Black/AA and Hispanic patient participation into CCTs, as an illustrative example. Baseline characteristics of the ACTWONDER2S target populations are also provided. Methods: ACTWONDER2S integrates community health educator and digital tools into an MLI targeting community residents and physicians in the Moffitt Cancer Center (MCC) catchment area, as well as MCC patients, physicians and CCT coordinators. A literature review of the relative strengths and weakness of 5 candidate designs for MLIs was conducted, and a cluster stratified randomized design was selected. Geospatial analytics were used to identify clusters of census tracts (“priority zones”) with high Black/AA and Hispanic populations for intervention deployment. Baseline characteristics of the priority zones were described using US Census data and other sources. Results: 14 priority zones were identified, which were matched on population characteristics and randomized into intervention (n=7) and control (n=7) zones. There were no statistically significant differences between the intervention and control priority zones in total population size (paired t-test p-value=0.63), proportions of Black/AA (p=0.133) and Hispanic populations p=0.17), and distance (in miles) from MCC (p=0.64). Approximately 35.8% and 16.5% of the intervention priority zones were Hispanic or Black/AA, respectively. Average distance to MCC, cancer cases, referral and CCT enrollment rates were also similar between groups. Conclusion: Decision frameworks for MLI study design selection are lacking. The framework provided here for ACTWONDER2S can be applied to other studies seeking to evaluate MLIs. Furthermore, the randomization of the priority zones produced optimal target populations for testing the efficacy of the MIL within ACTWONDER2S. Citation Format: Dana E. Rollison, Rossybelle P. Amorrortu, Lindsay N. Fuzzell, Melany A. Garcia, Elliott S. Tapia-Kwan, Yayi Zhao, Steven A. Eschrich, Bob R. Gore, Brian S. Mittman, Nathanael B. Stanley, Susan T. Vadaparampil. Multi-level intervention to increase minority cancer patient enrollment to clinical treatment trials- Study design considerations and baseline characteristics from the ACTWONDER2S Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4824.

Dietary composition and time in range in population with type 2 diabetes mellitus-exploring the association using continuous glucose monitoring device.

To understand the association between macronutrient composition of a diet with Time in Range (TIR), Time above Range (TAR) and Time below Range (TBR) derived using a Continuous Glucose Monitoring (CGM) device for 14 days. An exploratory analysis on the baseline data of 50 Type 2 Diabetes Mellitus participants with age 25-55 years, HbA1c upto 8% and on Metformin only) enrolled for an interventional clinical trial was performed. Participants consuming adequate carbohydrates (CHO) of 55 to 60% of total calories had better Average Blood Glucose of 142.0 ± 24.0 mg/dL with a significance of p = 0.03 and Glucose Management Indicator (GMI) of 6.6 ± 0.7% significant at p = 0.01, than those with high CHO intake >60% of the total calories, with Average Blood Glucose - 155.0 ± 13.4 mg/dL and GMI - 7.06 ± 0.4%. Similarly, TIR - 68.2 ± 5.1% and TAR - 23.0 ± 10.8% was significantly better (p = 0.00) among those consuming adequate protein (12-15%) as compared to low protein (≤ 10%) with TIR- 61.0 ± 5.1% & TAR- 32.9 ± 10.3%. A correlation (r = -0.482 & p = 0.00) and simple linear regression analysis (R² = 0.33, F = 7.72, p = 0.000) revealed that when CHO intake increases the TIR decreases whereas TAR increases (r = 0.380 & p = 0.006). We did not find any significant relation between fat intake and TIR, TAR or TBR. Our results suggest that lowering CHO, while increasing protein in the diet may help improve TIR. Further in-depth studies are needed to confirm these findings.

Six-Month Results of the World's First VASC Clinical Trial for Endovascular NTNT Treatment of GSV Through Empty Vein Ablation Using Velex™

Six-Month Results of the World's First VASC Clinical Trial for Endovascular NTNT Treatment of GSV Through Empty Vein Ablation Using Velex™