Multiple Clinical Trials Research Articles

Timing of ctDNA Analysis Aimed at Guiding Adjuvant Treatment in Colorectal Cancer.

Multiple clinical trials are investigating ctDNA to guide adjuvant chemotherapy (ACT) in colorectal cancer. Timely ACT initiation necessitates early ctDNA testing, but the impact of postoperative cell-free DNA (cfDNA) and ctDNA dynamics remains unclear, particularly with cost-reducing input caps employed in some assays. This study investigates ctDNA detection at day 14 versus day 30, comparing whole-sample analysis with capping the cfDNA input, and evaluates single and dual timepoint assessments for ACT allocation. From 2019 to 2023, 611 patients with stage I to III colorectal cancer were enrolled. Blood was collected preoperatively and postoperatively on ∼day 14 and ∼day 30. The cfDNA levels were assessed using digital PCR, and ctDNA was assessed using tumor-informed digital PCR or targeted sequencing analyzing all cfDNA from 8 mL of plasma. Despite elevated cfDNA in 85% of day 14 samples, performance was comparable between the two timepoints (sensitivity, 31% vs. 32% and specificity, both 98%). A 50-ng cfDNA input cap reduced ctDNA detection probability, affecting 78% of day 14 samples and 65% of day 30 samples. At both timepoints, ctDNA detection was prognostic of recurrence (day 14; HR, 9.0, 95% confidence interval, 5.5-14.8 and day 30: HR, 12.5, 95% confidence interval, 7.6-20.4). In 74% of ctDNA-positive recurrence patients, both samples had ctDNA detected. An increase in the ctDNA level from day 14 to day 30 was associated with a shorter time to recurrence (Pearson R = -0.63, P = 0.003). Combining the timepoints would increase sensitivity (36%) and allow earlier ACT start in 80% of patients. Early ctDNA sampling is feasible and highly prognostic. Supplemental later testing may improve sensitivity while allowing early ACT initiation for most ctDNA-positive patients.

Clinical research progress of stem cell therapy for decompensated cirrhosis and liver failure

Chronic liver disease remains a severe threat to human health. Furthermore, if left untreated promptly and effectively, it may gradually develop into end-stage liver disease, including decompensated cirrhosis and liver failure. Currently, mesenchymal stem cell technology is acting as a kind of an emerging treatment method, and multiple clinical trials have confirmed its promising application prospects in the treatment of decompensated cirrhosis and liver failure. Hence, stem cell therapy may offer a novel therapeutic option for these patients. This article summarizes the clinical research progress of stem cell therapy for decompensated cirrhosis and liver failure and analyzes present challenges and application prospects.

Network Meta-Analysis With Individual Participant-Level Data of Time-to-Event Outcomes Using Cox Regression.

The accessibility of individual participant-level data (IPD) enhances the evaluation of moderation effects of patient covariates. It facilitates the provision of accurate estimation of intervention effects and confidence intervals by incorporating covariate correlations across multiple clinical trials. With a time-to-event outcome, Cox regression can be applied for network meta-analysis (NMA) using IPD. However, there lacks comprehensive reviews and comparisons of the specifications and assumptions of these Cox models and their impact on the interpretation of hazard ratios, effect moderation, and trial heterogeneity in IPD-NMA. In this paper, we examine various Cox models for IPD-NMA and compare different approaches to modeling trial, treatment, and covariate effects. We employ multiple graphical tools and statistical tests to assess proportional hazard assumptions and discuss their implications. Additionally, we explore the application of extended Cox models when the proportional hazard assumption is violated. Practical guidance on interpreting and reporting NMA results is provided. A simulation study is conducted to compare the performance of different models. We illustrate the methods to conduct IPD-NMA through a real data example.

Investigational New Drug-enabling studies to use genetically modified mesenchymal stromal cells in patients with critical limb ischemia.

Mesenchymal stromal cells (MSCs) have been tested in multiple clinical trials to treat peripheral artery disease, especially the more severe form called critical limb ischemia. However, MSCs have often not met the expected efficacy endpoints. We developed a more potent therapeutic by genetically modifying MSCs to overexpress Vascular Endothelial Growth Factor (VEGF-A165). Here, we report preclinical studies submitted to the Food and Drug Administration (FDA) as part of our Investigational New Drug submission package. In vitro studies included the characterization of cell banks, transcriptome and secretome analysis, and in vitro potency assays. In vivo studies using immune-deficient NSG mice include dose-finding efficacy studies using a Matrigel plug model, cell retention studies, measurements of circulating VEGF, and toxicology studies to rule out severe adverse events. Our results suggest both the safety and efficacy of MSC/VEGF and support a first-in-human clinical trial to test this new combined cell/gene therapy.

Relationship between undetectable PSA nadir and outcomes for patients with metastatic hormone-sensitive prostate cancer (mHSPC) in IRONMAN, the International Registry for Men with Advanced Prostate Cancer.

65 Background: Intensified androgen deprivation therapy (ADT) with an androgen receptor pathway inhibitor (ARPI) and/or docetaxel has led to improved outcomes for metastatic hormone-sensitive prostate cancer (mHSPC) in multiple clinical trials. Achievement of an undetectable PSA nadir has been associated with improved clinical outcomes, but real-world data across treatment regimens are limited. Methods: We evaluated PSA response and outcomes for patients with mHSPC treated with ADT monotherapy (mono), ADT + ARPI, and ADT + docetaxel in the International Registry for Men with Advanced Prostate Cancer (IRONMAN). All patients with mHSPC enrolled in IRONMAN between 2017 and August 2023 in the United States, Canada, Spain, and England were included. Patients treated with triplet therapy were excluded due to small numbers. Undetectable PSA nadir, defined as PSA <0.2 ng/mL, was evaluated at 6 and 12 months after treatment start. In this real-world study, relapse was defined as meeting one of the following criteria: PSA progression (≥25% PSA increase from nadir and absolute increase >2 ng/mL), treatment change preceded by new metastasis location, or change to a neuroendocrine prostate cancer regimen. Rates of relapse were calculated using Kaplan Meier estimates, with confidence intervals based on standard errors calculated using the Greenwood formula. Results: Among 1,377 eligible patients, treatment was most commonly ADT + ARPI (n=775) followed by ADT mono (n=375) and ADT + docetaxel (n=227). In the overall population, PSA nadir <0.2 ng/mL was achieved in 40% (n=554) at 6 months and 51% (n=702) at 12 months. Rates of PSA nadir <0.2 ng/mL at 6 months were: 51% for ADT + ARPI, 27% for ADT mono, and 26% for ADT + docetaxel. At 12 months, rates of PSA nadir <0.2 ng/mL increased to: 63% for ADT + ARPI, 38% for ADT mono, and 32% for ADT + docetaxel. During a median follow-up of 18 months, 291 patients (21%) experienced disease relapse; 19% experienced PSA progression. The percentage of patients in each treatment group with disease relapse at months 12, 24, and 36 of treatment are shown (Table); treatment groups are divided by whether patients had achieved PSA nadir <0.2 ng/mL in 6 months. Conclusions: In this non-randomized, real-world registry, patients with mHSPC who achieved a PSA nadir <0.2 ng/mL had a lower relapse rate than patients who did not, regardless of treatment. Percentage (95% CI), [number at risk] of patients with relapse at timepoint. Treatment Month 6 Month 12 Month 24 Month 36 ADT Monotherapyn=375 PSA <0.2 ng/mL 0%(0, 0)[60] 1.7%(0, 5.0)[31] 11%(0, 24)[15] PSA ≥0.2 ng/mL 18%(11, 24)[80] 41%(30, 51)[38] 45%(33, 55)[19] ADT + ARPIn=775 PSA <0.2 ng/mL 2.2%(0.6, 3.8)[288] 9.7%(5.9, 13)[166] 18%(12, 24)[76] PSA ≥0.2 ng/mL 21%(16, 26)[178] 42%(35, 49)[81] 50%(42, 58)[37] ADT + Docetaxeln=227 PSA <0.2 ng/mL 8.2%(0.2, 16)[44] 22%(8.9, 33)[29] 36%(18, 50)[14] PSA ≥0.2 ng/mL 34%(25, 43)[69] 62%(50, 72)[21] 73%(59, 82)[12]

PARP Inhibitors in the Treatment of Ovarian Cancer

Introduction Ovarian cancer is a leading cause of cancer mortality globally due to late-stage diagnosis and limited treatment options. PARP inhibitors have shown promise as effective treatments for recurrent and various stages of ovarian cancer. Aim of the Study This study reviews the efficacy and application of PARP inhibitors in ovarian cancer treatment over the past 15 years, focusing on literature from the PubMed database post-2009 and considering FDA and EMA guidelines. Review methods A literature review was conducted using the PubMed database, focusing on studies published after 2009. The review also incorporated recommendations from the FDA and the European Medicines Agency regarding the use of PARP inhibitors in ovarian cancer treatment. Results The findings highlight the substantial impact of PARP inhibitors on ovarian cancer treatment, improving PFS and overall outcomes. Olaparib, niraparib, and rucaparib have become integral to ovarian cancer management, offering effective options for patients with BRCA mutations or homologous recombination deficiencies. These inhibitors have been validated in multiple clinical trials, underscoring their robustness and effectiveness. Combination therapies, such as olaparib with bevacizumab, further enhance therapeutic outcomes, showcasing the potential for synergistic effects. Summary PARP inhibitors represent a significant advancement in ovarian cancer treatment, offering improved survival outcomes for patients with specific genetic profiles. Their integration into standard care protocols underscores their importance and efficacy, providing valuable therapeutic options in the fight against ovarian cancer. Key Words: PARP inhibitors, ovarian cancer, ovarian cancer treatment

A novel CD28 x Nectin-4 costimulatory bispecific antibody for advanced bladder cancer.

810 Background: Effective T-cell activation is driven by multiple signals. CD3 bispecific antibodies (bsAbs) stimulate T-cell activation through the TCR. CD3 bsAbs demonstrate durable responses in hematological malignancies, but multiple clinical trials suggest that signaling through CD3 alone is insufficient to treat solid tumors. Recent results suggest that a robust T-cell response in solid tumors can be achieved by tumor-targeted costimulatory bsAbs that promote sustained T-cell activity. Bladder cancer is the tenth most prevalent cancer worldwide with suboptimal progression free survival in the locally advanced and metastatic setting. Efficacy of checkpoint inhibitors (CPI) in metastatic urothelial cancer (mUC) patients indicates the presence of tumor antigen-specific T-cell activity, and thus, treatment with a costimulatory bsAb as a single agent may elicit a durable and robust anti-tumor response. Here we describe RNDO-564, a novel CD28 x Nectin-4 bispecific molecule. RNDO-564 was developed preclinically with optimal potency to provide robust anti-tumor activity and safety by localizing co-stimulatory activity to the site of the tumor and avoiding super-agonist activity. Methods: High throughput antibody discovery was completed on CD28 and Nectin-4. A panel of agonistic bispecific CD28 antibodies was generated by combining high affinity Nectin-4 binders with CD28 binders of varying potencies using knobs-in-hole technology. Bispecific antibodies were tested for their ability to enhance T-cell mediated cytotoxicity and cytokine release on tumor cell lines expressing varying levels of Nectin-4 in the presence of suboptimal signal 1. Lead candidates were then tested for efficacy using in vivo syngeneic mouse models. Results: Affinity tuning of CD28 agonistic activity was performed by testing a diverse panel of CD28 effector arms to identify optimal costimulatory activity that lacked super agonist activity. One of these CD28 binders was paired with a high affinity Nectin-4 binder to generate RNDO-564. With an affinity tuned CD28 arm and a high affinity Nectin-4 arm driving localization to tumor cells, RNDO-564 exhibited potent and specific cytotoxicity and cytokine release to Nectin-4 expressing tumor cells in vitro. In vivo , RNDO-564 alone and in combination with an anti-PD-1 mAb resulted in dose-dependent tumor growth inhibition in signal 1-proficient syngeneic models, indicating clinical potential for both monotherapy and combination activity. In addition, RNDO-564 was well-tolerated in non-human primates and had normal pharmacokinetics after a single dose infusion. Conclusions: RNDO-564 has a high affinity Nectin-4 binding arm and an affinity-tuned CD28 arm optimized for activity in metastatic bladder cancer. A phase 1 study is planned to evaluate the safety, tolerability, PK/PD, and clinical activity of RNDO-564 alone and in combination with CPI in mUC.

Unleashing the potential of a low CpG Passer transposon for superior CAR-T cell therapy.

To date, the non-viral vector Chimeric Antigen Receptor (CAR) T cell preparation platform, exemplified by transposons, has demonstrated significant potential in tumor immunotherapy and yielded positive results in multiple clinical trials. Nonetheless, non-methylated CpG sequences within plasmid DNA can elicit an inflammatory response via Toll-like receptor 9 (TLR9) during CAR-T cell preparation, adversely affecting transgene expression. Additionally, de novo DNA methylation programs promote T cell exhaustion, which poses a significant limitation for CAR-T cell therapy applications. High-throughput liquid protein chip and CBA analyses were utilized to determine the expression levels of inflammatory factors. Flow cytometry and luciferase reporter assays were employed for mutation screening. BALB/c mice and M-NSG mice were used to evaluate the inflammatory response and efficacy of LCG CAR-T in vivo, with TIL grouping detected via immunohistochemistry. In this study, we modified the newly discovered Passer (JL) transposon to construct a low-CpG content transposon for CAR-T cell (LCG CAR-T cell) preparation. In vitro experiments demonstrated that LCG CAR-T cells prepared using this new transposon exhibited stronger cytotoxicity. In animal models, LCG CAR-T cells significantly inhibited tumor growth and increased the populations of CD4+CAR-T cells and tumor-infiltrating lymphocytes. Furthermore, LCG CAR-T cells modulated pro-inflammatory cytokine release, thereby reducing in vivo inflammatory responses and surpassing the effects observed with unmodified CAR-T cells. Collectively, our results demonstrate the high safety and efficacy of non-viral, low CpG Passer transposon CAR-T cells, offering new avenues for improving CAR-T cell efficacy while minimizing in vivo inflammation.

Combination therapy as a new standard of care in diabetic and non-diabetic chronic kidney disease.

A range of therapies now exists to reduce the risk of kidney failure and cardiovascular events in people with type 2 diabetes, including renin-angiotensin system blockade, sodium-glucose cotransporter 2 (SGLT2) inhibitors, non-steroidal mineralocorticoid receptor antagonists, and glucagon-like peptide-1 receptor agonists. With multiple clinical trials underway, it is likely that at least some of these therapies-as well as additional agents such as endothelin receptor antagonists-will further demonstrate kidney-protective effects in people with CKD who do not have diabetes in the near future. For conditions such as IgA nephropathy, several therapies have recently been approved or are being evaluated in late phase trials. Thus combination therapy is emerging as a new standard for diabetic and non-diabetic chronic kidney disease (CKD). This approach is supported by randomized data suggesting that each therapeutic class offers independent and additive benefits in diabetic kidney disease, regardless of background therapy. Notably, the reduction in hyperkalaemia and fluid retention with SGLT2 inhibitors may enhance the tolerability and safety of other treatments. In this review, we present the rationale for combination therapy with evidence-based kidney therapies in diabetic and non-diabetic CKD. We also summarize randomized evidence supporting a multi-medicine approach, address safety considerations, review ongoing trials, and propose frameworks for implementing treatments aligned with patient risk to optimize person-centred care and reduce long-term risks of kidney failure and related complications.

A Review of the Therapeutic Effects of Garlic in Lowering Blood Pressure: A Comprehensive Analysis of Recent Mechanisms and Existing Clinical Data

Hypertension is a medical condition characterized by an elevation in systolic blood pressure equal to or greater than 140 mmHg and/or diastolic blood pressure equal to or greater than 90 mmHg. Hypertension elevates the likelihood of developing cerebrovascular disease and mortality. The administration of conventional antihypertensive drugs frequently leads to the occurrence of adverse effects. Moreover, a significant proportion of the population in developing nations, approximately 70%, currently favors the utilization of herbal remedies as opposed to conventional pharmaceuticals. Garlic is a herbal plant known for its antihypertensive properties. This review specifically examines the current mechanisms by which garlic acts as an antihypertensive, and presents the clinical evidence available to date regarding garlic's effectiveness in lowering blood pressure. The present mechanism by which garlic acts as an antihypertensive agent involves its anti-inflammatory, vasorelaxant, antioxidant, anti-apoptotic effects, enhancement of microbiota activities, and improvement of heart function. The antihypertensive effect of garlic is derived from its organosulfur content. Based on multiple clinical trials, the majority of studies have found that administering interventions in the form of capsules containing garlic or aged black garlic extract leads to a decrease in blood pressure. Garlic has anti-hypertensive effects, especially in the form of aged black garlic extract.

Atezolizumab neutralizing assay development: a novel way of evaluating assay cutpoint after sample pretreatment

Atezolizumab, a biotherapeutic monoclonal antibody directed against PD-L1, has been shown to be efficacious in multiple oncology indications. In clinical trials, a subset of patients developed anti-atezolizumab antibodies, necessitating the development of a neutralizing antibody (NAb) assay. A bead-based sample pretreatment method was developed to reduce high levels of therapeutic in patient serum samples. Untreated sample variability is reduced by this sample pretreatment, based on this, a novel approach was taken for determining an appropriate assay decision threshold (cutpoint). The therapeutic was added to the samples to mimic typical patient samples. The resulting assay was successfully validated and applied to sample analysis from multiple clinical trials.

Network Meta-Analysis of Time-to-Event Endpoints With Individual Participant Data Using Restricted Mean Survival Time Regression.

Network meta-analysis (NMA) extends pairwise meta-analysis to compare multiple treatments simultaneously by combining "direct" and "indirect" comparisons of treatments. The availability of individual participant data (IPD) makes it possible to evaluate treatment effect moderation and to draw inferences about treatment effects by taking the full utilization of individual covariates from multiple clinical trials. In IPD-NMA, restricted mean survival time (RMST) models have gained popularity when analyzing time-to-event outcomes because RMST models offer more straightforward interpretations of treatment effects with fewer assumptions than hazard ratios commonly estimated from Cox models. Existing approaches estimate RMST within each study and then combine by using aggregate-level NMA methods. However, these methods cannot incorporate individual covariates to evaluate the effect moderation. In this paper, we propose advanced RMST NMA models when IPD are available. Our models allow us to study treatment effect moderation and provide a comprehensive understanding about comparative effectiveness of treatments and subgroup effects. The methods are evaluated by an extensive simulation study and illustrated using a real NMA example about treatments for patients with atrialfibrillation.

Tumor-infiltrating lymphocytes in HER2-positive breast cancer: potential impact and challenges.

Tumor-infiltrating lymphocytes in HER2-positive breast cancer: potential impact and challenges.

Abstract TP302: Single and Combination Antithrombotics for Secondary Prevention in Embolic Stroke of Undetermined Source: Secondary Analysis of the CASPR Registry

Background: Multiple randomized clinical trials failed to show benefit of anticoagulation over antiplatelets in the secondary prevention for embolic stroke of undetermined source (ESUS). However, the benefit of combination antithrombotic regimens remains unexplored in the same patient population. Methods: This is a subgroup analysis of a multicenter retrospective observational cohort of consecutive adult patients with ESUS (n=27 sites, 2015-2024). Comparisons were made between patients treated with single (SAPT) or dual antiplatelet therapy (DAPT), exclusive anticoagulation (AC) (direct oral anticoagulant, vitamin K antagonist, low molecular weight heparin) and combination anticoagulation and antiplatelet therapy initiated within the first 7 days of index stroke. The primary composite outcome of recurrent ischemic stroke, major bleeding, or death was assessed using unadjusted and adjusted Cox proportional hazards regression. Secondary outcomes were individual outcomes of recurrent ischemic stroke, major bleeding, or death. Results: Of the 2201 included patients, 1456 (66.1%) were on SAPT, 527 (23.9%) were on DAPT, 195 (8.8%) were on exclusive AC and 23 (1.0%) were on AC+AP (all of which were on DAPT). Patients treated with AC+AP were older (median 66 years [IQR 51-78]), more likely to have history of hypertension, stroke, hyperlipidemia, PFO and left atrial enlargement. Compared to SAPT, all treatment strategies were associated with similar risk of the primary outcomes in the unadjusted and adjusted cox regression. Similarly, there was no difference in individual outcomes including recurrent stroke, major bleeding and death in the adjusted cox regression. However, there was an increased risk of major bleeding with AC+AP in the unadjusted cox regression (HR 4.0, [95% CI 1.2-12.8], p=0.02) but not in the adjusted model when compared to SAPT. Also, DAPT was associated with lower risk of death than SAPT in the unadjusted model (HR 0.61 [95% CI 0.4-0.8],p=0.005) but not the adjusted model. Additionally, when adjusted by the HASBLED score, there was no difference in major bleeding when AC+AP was compared to SAPT. Conclusion: Over 90% of ESUS patients in this cohort were prescribed SAPT or DAPT. Antithrombotic therapy with DAPT, exclusive AC, or AC+AP was not associated with any lower risk of recurrent ischemic stroke, major bleeding and death compared with SAPT in an unselected cohort of ESUS patients.

FcRn inhibitors: Transformative advances and significant impacts on IgG-mediated autoimmune diseases.

FcRn inhibitors: Transformative advances and significant impacts on IgG-mediated autoimmune diseases.

Principal investigator gender and clinical trial success: Analysis of over 3000 obstetrics and gynecology trials

Principal investigator gender and clinical trial success: Analysis of over 3000 obstetrics and gynecology trials

Immune Resistance in Glioblastoma: Understanding the Barriers to ICI and CAR-T Cell Therapy.

Glioblastoma (GBM) is the most common primary malignant brain tumor, with fewer than 5% of patients surviving five years after diagnosis. The introduction of immune checkpoint inhibitors (ICIs), followed by chimeric antigen receptor (CAR) T-cell therapy, marked major advancements in oncology. Despite demonstrating efficacy in other blood and solid cancers, these therapies have yielded limited success in clinical trials for both newly diagnosed and recurrent GBM. A deeper understanding of GBM's resistance to immunotherapy is essential for enhancing treatment responses and translating results seen in other cancer models. In this review, we examine clinical trial outcomes involving ICIs and CAR-T for GBM patients and explore the evasive mechanisms of GBM and the tumor microenvironment. Multiple clinical trials investigating ICIs in GBM have shown poor outcomes, with no significant improvement in progression-free survival (PFS) or overall survival (OS). Results from smaller case studies with CAR-T therapy have warranted further investigation. However, no large-scale trials or robust studies have yet established these immunotherapeutic approaches as definitive treatment strategies. Future research should shift focus from addressing the scarcity of functional T cells to exploiting the abundant myeloid-derived cells within the tumor microenvironment. Translating these therapies into effective treatments for glioblastoma in humans remains a significant challenge. The highly immunosuppressive nature of GBM and its tumor microenvironment continue to hinder the success of these innovative immunotherapeutic approaches. Targeting the myeloid-derived compartment may lead to more robust and sustained immune responses.

Abstract B003: Landscape of chemoradiation plus immunotherapy trials across multiple locally advanced cancer types: The more, the better?

Abstract Purpose: Checkpoint inhibitors (ICIs) are being added to standard-of-care chemoradiotherapy in multiple clinical trials. The optimal sequencing of immunotherapy and chemoradiotherapy remains widely debated. Therefore, we compiled available trials and reviewed various aspects that may be associated with outcomes. Methods: We conducted a systematic literature review of randomized controlled Phase 3 trials (RCTs) in PubMed, ClinicalTrials.gov and Google scholar from 1/1/2018 to 11/8/2024. We included all available seminal randomized controlled trials with matured data, encompassing locally advanced non–small and small cell lung carcinomas, head and neck, endometrial and cervical cancers treated with chemoradiotherapy plus ICI. Performance of these trials with different ICI timing was analyzed in a high level and stratified by radiation treatment sites, oncovirus driven histology, anti PD1/PD-L1 agents and treatment discontinuation rate. Results: Eleven seminal randomized clinical trials across 6 different cancer types with 7891 patients were included. Among 5 trials with thoracic RT, 2 trials(PACIFIC and ADRIATIC) with only consolidative design proved PFS superiority over placebo, while PACIFIC-2 and LU-005 with concurrent and maintenance design did not. Moreover, CheckMate-73L failed to prove the superiority of concurrent and maintenance ICI over consolidative ICI. Among 3 head & neck trials all with induction + concurrent + maintenance design, only CONTINUUM trial treating nasopharyngeal cancer with 3 cycles of induction ICI proved EFS superiority. Among 3 gynecological trials all with concurrent + maintenance design, only anti PD-1 agent showed PFS superiority in cervical cancer (KEYNOTE-A18) and dMMR endometrial cancer (KEYNOTE-B21) in pre-planned analysis. The trials with concurrent ICI approaches failed in all non-viral driven cancers (NSCLC, SCLC and overall endometrial), but succeeded in EBV-rich Asian nasopharyngeal cancer (CONTINUUM) and HPV-driven cervical cancer (KEYNOTE-A18 and CALLA post hoc analysis of PD-L1 TAP ≥20%). However, this success was not found in HPV-driven head & neck squamous cell cancer (HPV subgroup of either KEYNOTE-412 or JAVELIN). For consolidative ICI trials in thorax, the treatment discontinuation rate was significantly lower in experimental arm compared to control arm (population weighted p=0.0003), mainly due to less tumor progression. For the trials with concurrent ICI, the treatment discontinuation rate was significantly higher in experimental arm (population weighted p=0.001), mainly due to more adverse events. Conclusion: Despite multifactorial heterogeneity, this review provides insights for designing future trials in locally advanced cancers. Consolidative ICI approaches generally showed superiority in thoracic cancers, while concurrent ICI approaches often failed in non-viral-driven cancers likely due to higher adverse events and discontinuation rates but showed efficacy in EBV-rich nasopharyngeal and HPV-driven cervical cancers. As more trial data matures, the existing trends will be further tested. Citation Format: Bin Gui, Bhupesh Parashar. Landscape of chemoradiation plus immunotherapy trials across multiple locally advanced cancer types: The more, the better? [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr B003.

P0541 Placebo rates in randomised clinical trials of Ulcerative Colitis: An individual patient data meta-analysis

Abstract Background Information on placebo rates is important for designing clinical trials. We aimed to assess placebo rates and associated factors using individual patient data from multiple randomised clinical trials in ulcerative colitis. Methods We conducted a meta-analysis of individual participant-level data from nine randomised trials using Vivli and Yale University Open Data Access data-sharing platforms. Phase 2 and 3 placebo-controlled randomised clinical trials of advanced biologic therapies in adults with moderate-to-severe active ulcerative colitis published since 2010 were included. Pooled placebo rates and 95% CIs were estimated using one-stage and two-stage meta-analytical approach. Significant patient-level factors (P<0.05) associated with placebo rates were identified using regression analyses. The pre-specified primary outcomes were placebo clinical response and remission. Results Outcome data were available for 1,703 patients from nine studies (three induction-only, one maintenance-only, and five including both phases). For induction trials, overall placebo response and remission rates were 33% (95% CI 29-38%) and 9% (95% CI 7-11%), respectively (Figure). Overall placebo response and remission rates in maintenance trials were 28% (95% CI 17%-41%) and 14% (95% CI 9-20%), respectively (Figure). A lower body mass index reduced odds of placebo response and remission, while higher baseline albumin levels and left-sided UC (compared to extensive) increased the odds of these outcomes. A one-point increase in the Mayo Clinic Score and adapted Mayo Clinic Score was associated with a 26% and 27% reduction in the odds of clinical remission. For induction trials, prior exposure to biologics or tumour necrosis factor antagonist therapy was associated with lower odds of both response and remission. Multi-centre trials have lower placebo effect than single-centre trials. Conclusion These results will enable future trials that include placebo to incorporate design elements that enable reduction of placebo rates as well as a precise benchmark for expected rates in clinical trials that do not include placebo.

Optical Coherence Tomography in Huntington's Disease-A Potential Future Biomarker for Neurodegeneration?

Huntington's disease (HD) is a progressive neurodegenerative disorder for which, until now, only symptomatic treatment has been available. Lately, there have been multiple ongoing clinical trials targeting therapeutic agents for preventing disease onset or slowing disease progression in HD. These studies are in constant need of reliable biomarkers for neurodegeneration in HD. In recent years, retinal biomarkers have attracted significant attention in neurodegenerative disorders. Likewise, optical coherence tomography (OCT) is being evaluated as a potential biomarker in HD. In this article, we review the existing literature on OCT as a biomarker for neurodegeneration in HD.