Design Of Clinical Studies Research Articles

The Bioactivity and Phytochemicals of Muscari comosum (Leopoldia comosa), a Plant of Multiple Pharmacological Activities.

Leopoldia comosa (LC), popularly known as Muscari comosum, spontaneously grows in the Mediterranean region and its bulbs are used as a vegetable. Traditionally, they are also used to treat various diseases and conditions, which has inspired the study of the pharmacological activities of different parts of LC. These studies revealed the numerous biological properties of LC including antioxidant, anti-inflammatory, anti-diabetes, anti-obesity, anti-cancer, anti-Alzheimer's disease, antibacterial, and immune stimulant. High antioxidant activity compared to other non-cultivated plants, and the potential role of antioxidant activity in other reported activities make LC an excellent candidate to be developed as an antioxidant plant against important associated diseases. The presence of a diverse class of phytochemicals (n = 85), especially flavonoids and homoisoflavones, in LC, also imparts significance to the nutraceutical candidature of the plant. However, limited animal studies and the lack of a directional approach have limited the further design of effective clinical studies for the development of LC. The current study is the first attempt to comprehensively compile information regarding the phytochemicals and pharmacological activities of LC, emphasize the targets/markers targeted by LC, important in other activities, and also highlight the current gaps and propose possible bridges for the development of LC as a therapeutic and/or supplement against important diseases.

Morphological assessment of actin and desmin expression at different cold myocardial ischemia times: observational study

Background. Heart transplantation is currently the treatment of choice for patients in terminal stages of chronic heart failure. The critical shortage of donor organs and the growing need for heart transplantation necessitate the expansion of donor selection criteria, including the estimated ischemia time of the donor heart. Despite numerous studies, the issue remains regarding the safe cold ischemia time; no definite limit to the acceptable preservation time is known and no relevant pathomorphological data are available on the state of the donor heart myocardium at different time parameters. Objective. To comparatively assess the features of cardiomyocyte pathomorphology and expression of protein markers (actin and desmin) in the myocardium of a donor heart prior to the main stage of orthotopic heart transplantation. Methods. The work adopted the design of an observational clinical study, which was prospective in nature. The study used intraoperative myocardial biopsy specimens of the left atrial appendage from donors aged up to 60 years, following cold ischemia of the transplant in Bretschneider solution (Dr. Franz Köhler Chemie GmbH, Germany) lasting up to 240 minutes (Group 1, n = 10) and over 240 minutes (Group 2, n = 7). The nature of pathomorphological myocardial transformation in the left atrial appendage of the donor heart was determined at different cold ischemia times. Histological myocardial sections were stained with hematoxylin and eosin according to standard procedures. After that, they were further studied using light and polarization microscopy; the immunohistochemical method was used to analyze the expression of actin and desmin. Morphometry was performed using the ImageJ 1.48v software (USA). In the analysis of actin and desmin amount, the area of DAB(3,3′-diaminobenzidine)-positive products of the immunohistochemical reaction was estimated as a percentage of the image area. The volume density of immunohistochemically detectable actin and desmin was determined using 20 images at a magnification of 40×10. In order to study the intensity of the immune reaction, a semiquantitative method was used, which involved counting the number of cells in 25 randomly selected fields of view. The types of myocardial contracture damage were assessed via polarization microscopy. Results. Patients included in the first and second groups were comparable in terms of mean age and anthropometric indices. The mean age of patients amounted to 50 [44;59] years in Group 1 and 50 [49;50] years in Group 2, р = 0.193. The body mass index was 25 [22;27] in Group1 and 25 [21;31] in Group 2, р = 0.288. Both groups showed male predominance: 8 (80%) in Group 1 and 6 (85.7%) in Group 2, р = 0.256. The comprehensive morphological assessment of ischemic myocardial damage at different cold ischemia times revealed the uniformity and reversibility of changes in cellular structures (in both groups) that take the form of I–II class contractures, lysis changes in individual cardiomyocytes (only in Group 2), preserved immunohistochemical reactions to actin and desmin in both groups at their average intensity and the complete absence of areas showing no reaction to desmin, which gives an idea about the degree of preservation of their macromolecular structure. Conclusion. The obtained study results showed that due to having a balanced elemental composition that determines the metabolic protection of cells and their ionic balance, the Bretschneider solution effectively protects the donor heart during its transportation, with the myocardial cold ischemia lasting up to 240 min and more.

Clinical and biomarker results from a phase II trial of combined cabozantinib and durvalumab in patients with chemotherapy-refractory colorectal cancer (CRC): CAMILLA CRC cohort

CAMILLA is a basket trial (NCT03539822) evaluating cabozantinib plus the ICI durvalumab in chemorefractory gastrointestinal cancer. Herein, are the phase II colorectal cohort results. 29 patients were evaluable. 100% had confirmed pMMR/MSS tumors. Primary endpoint was met with ORR of 27.6% (95% CI 12.7-47.2%). Secondary endpoints of 4-month PFS rate was 44.83% (95% CI 26.5-64.3%); and median OS was 9.1 months (95% CI 5.8-20.2). Grade≥3 TRAE occurred in 39%. In post-hoc analysis of patients with RAS wild type tumors, ORR was 50% and median PFS and OS were 6.3 and 21.5 months respectively. Exploratory spatial transcriptomic profiling of pretreatment tumors showed upregulation of VEGF and MET signaling, increased extracellular matrix activity and preexisting anti-tumor immune responses coexisting with immune suppressive features like T cell migration barriers in responders versus non-responders. Cabozantinib plus durvalumab demonstrated anti-tumor activity, manageable toxicity, and have led to the activation of the phase III STELLAR-303 trial.

A basket trial design based on constrained hierarchical Bayesian model for latent subgroups

ABSTRACT It is well known a basket trial consisting of multiple cancer types has the potential of borrowing strength across the baskets defined by the cancer types, leading to an efficient design in terms of sample size and trial duration. The treatment effects in those baskets are often heterogeneous and categorized by the cancer types being sensitive or insensitive to the treatment. Hence, the assumption of exchangeability in many existing basket trials may be violated, and there is a need to design trials without this assumption. In this paper, we simplify the constrained hierarchical Bayesian model for latent subgroups (CHBM-LS) for two classifiers to deal with the potential heterogeneity of treatment effects due to the single classifier of the cancer type. Different baskets are aggregated into subgroups using a latent subgroup modeling approach. The treatment effects are similar and exchangeable to facilitate information borrowing within each latent subgroup. Applying the simplified CHBM-LS approach to the real basket trials where baskets defined by only cancer types shows better performance than other available approaches. Further simulation study also demonstrates this CHBM-LS approach outperforms other approaches with higher statistical power and better-controlled type I error rates under various scenarios.

A generalized calibrated Bayesian hierarchical modeling approach to basket trials with multiple endpoints.

A basket trial simultaneously evaluates a treatment in multiple cancer subtypes, offering an effective way to accelerate drug development in multiple indications. Many basket trials are designed and monitored based on a single efficacy endpoint, primarily the tumor response. For molecular targeted or immunotherapy agents, however, a single efficacy endpoint cannot adequately characterize the treatment effect. It is increasingly important to use more complex endpoints to comprehensively assess the risk-benefit profile of such targeted therapies. We extend the calibrated Bayesian hierarchical modeling approach to monitor phase II basket trials with multiple endpoints. We propose two generalizations, one based on the latent variable approach and the other based on the multinomial-normal hierarchical model, to accommodate different types of endpoints and dependence assumptions regarding information sharing. We introduce shrinkage parameters as functions of statistics measuring homogeneity among subgroups and propose a general calibration approach to determine the functional forms. Theoretical properties of the generalized hierarchical models are investigated. Simulation studies demonstrate that the monitoring procedure based on the generalized approach yields desirable operatingcharacteristics.

Considerations for master protocols using external controls

ABSTRACT There has been an increasing use of master protocols in oncology clinical trials because of its efficiency to accelerate cancer drug development and flexibility to accommodate multiple substudies. Depending on the study objective and design, a master protocol trial can be a basket trial, an umbrella trial, a platform trial, or any other form of trials in which multiple investigational products and/or subpopulations are studied under a single protocol. Master protocols can use external data and evidence (e.g. external controls) for treatment effect estimation, which can further improve efficiency of master protocol trials. This paper provides an overview of different types of external controls and their unique features when used in master protocols. Some key considerations in master protocols with external controls are discussed including construction of estimands, assessment of fit-for-use real-world data, and considerations for different types of master protocols. Similarities and differences between regular randomized controlled trials and master protocols when using external controls are discussed. A targeted learning-based causal roadmap is presented which constitutes three key steps: (1) define a target statistical estimand that aligns with the causal estimand for the study objective, (2) use an efficient estimator to estimate the target statistical estimand and its uncertainty, and (3) evaluate the impact of causal assumptions on the study conclusion by performing sensitivity analyses. Two illustrative examples for master protocols using external controls are discussed for their merits and possible improvement in causal effect estimation.

Palliative Care Interventions for Persons With Neurodegenerative Disease: A Scoping Review of Clinical Trial Study Design Features.

Background: Within palliative care research, best practice guidelines to conduct scientifically rigorous clinical trials for neurodegenerative diseases are underexplored. This patient population experiences unique challenges, including fluctuations in cognitive capacity, care partner (CP) and proxy involvement, and high adverse events (AEs), that necessitate special consideration when designing clinical trials. Objective: The objective of this study was to describe and identify clinical trial design features that have been documented in studies involving a neuropalliative intervention for persons with neurodegenerative diseases, highlighting features that have been adapted for this unique patient population. Design: We conducted a scoping review of clinical trials with a neuropalliative intervention for persons with neurodegenerative disease. We searched Cochrane, Web of Science, EMBASE, Scopus, and PubMed (MEDLINE) databases for articles published in English between 1950 and 2023. Two reviewers screened, extracted, and synthesized data from the included articles. A third reviewer adjudicated instances of conflict. The data were analyzed using a thematic framework approach. Results: Of 1025 texts, 44 articles were included. Seven study design features were analyzed: (1) consent, (2) proxies and CPs, (3) recruitment strategies, (4) retention strategies, (5) choice of comparator, (6) AEs, and (7) internal validity. This scoping review found disparities in study design features around structured consent, proxies and CPs, comparators, and AEs. Conclusions: To date, neuropalliative care clinical trials have had varied study designs and the majority of research has focused on dementia. Research guideline development for high-quality neuropalliative care clinical trials is greatly needed across the range of neurodegenerative diseases. To increase the scientific rigor of clinical trials and neuropalliative care, we recommend a standardized capacity assessment for consent, defining conditions for the CP, proxy, and AEs, systematizing appropriate comparators, and outlining preemptive recruitment and retention strategies to address the broader unpredictable challenges of palliative care research.

Protocol for a randomized, placebo-controlled, double-blind phase IIa study of the safety, tolerability, and symptomatic efficacy of the ROCK-inhibitor Fasudil in patients with Parkinson's disease (ROCK-PD).

The Rho-kinase (ROCK) inhibitor Fasudil has shown symptomatic and disease-modifying effects in Parkinson's disease (PD) models in vitro and in vivo. In Japan, Fasudil has been approved for the treatment of subarachnoid haemorrhage since 1995 and shows a favourable safety profile. To investigate the safety, tolerability, and symptomatic efficacy of ROCK-inhibitor Fasudil in comparison to placebo in a randomized, national, multicenter, double-blind phase IIa study in patients with PD. We plan to include 75 patients with at least 'probable' PD (MDS criteria), Hoehn and Yahr stages 1-3, and age 30-80 years in 13 German study sites. Patients must be non-fluctuating and their response to PD medication must have been stable for 6 weeks. Patients will be randomly allocated to treatment with the oral investigational medicinal product (IMP) containing either Fasudil in two dosages, or placebo, for a total of 22 days. As primary analysis, non-inferiority of low/high dose of Fasudil on the combined endpoint consisting of occurrence of intolerance and/or treatment-related serious adverse events (SAEs) over 22 days will be assessed in a sequential order, starting with the lower dose. Secondary endpoints will include tolerability alone over 22 days and occurrence of treatment-related SAEs (SARs) over 22 and 50 days and will be compared on group level. Additional secondary endpoints include efficacy on motor and non-motor symptoms, measured on established scales, and will be assessed at several timepoints. Biomaterial will be collected to determine pharmacokinetics of Fasudil and its active metabolite, and to evaluate biomarkers of neurodegeneration. After positive evaluation by the competent authority and the ethics committee, patient recruitment started in the 3rd quarter of 2023. ROCK-PD is registered with Eudra-CT (2021-003879-34) and clinicaltrials.gov (NCT05931575). Results of this trial can pave way for conducting extended-duration studies assessing both symptomatic efficacy and disease-modifying properties of Fasudil.

The Finkelstein-Schoenfeld Test: A Note on Some Overlooked Issues Concerning Power.

In this note, we express our viewpoint regarding power considerations, via simulation studies, in clinical study design using hierarchical composite endpoint and Finkelstein-Schoenfeld test.

Comparator Data Characteristics and Testing Procedures for the Clinical Performance Evaluation of Continuous Glucose Monitoring Systems.

Comparing the performance of different continuous glucose monitoring (CGM) systems is challenging due to the lack of comprehensive guidelines for clinical study design. In particular, the absence of concise requirements for the distribution of comparator (reference) blood glucose (BG) concentrations and their rate of change (RoC) that are used to evaluate CGM performance, impairs comparability. For this article, several experts in the field of CGM performance testing have collaborated to propose characteristics of the distribution of comparator measurements that should be collected during CGM performance testing. Specifically, it is proposed that at least 7.5% of comparator BG concentrations are <70 mg/dL (3.9 mmol/L) and >300 mg/dL (16.7 mmol/L), respectively, and that at least 7.5% of BG-RoC combinations indicate fast BG changes with impending hypo- or hyperglycemia, respectively. These proposed characteristics of the comparator data can facilitate the harmonization of testing conditions across different studies and CGM systems and ensure that the most relevant scenarios representing real-life situations are established during performance testing. In addition, a study protocol and testing procedure for the manipulation of glucose levels are suggested that enable the collection of comparator data with these characteristics. This work is an important step toward establishing a future standard for the performance evaluation of CGM systems.

Olaparib in Patients With Pancreatic Cancer With BRCA1/2 Mutations: Results From the Targeted Agent and Profiling Utilization Registry Study

PURPOSE Targeted Agent and Profiling Utilization Registry (TAPUR) is a phase II basket trial evaluating the antitumor activity of commercially available targeted agents in patients with advanced cancer and genomic alterations known to be drug targets. Results of a cohort of patients with advanced pancreatic cancer with BRCA1/ 2 mutations treated with olaparib are reported. METHODS Eligible patients had advanced pancreatic cancer, measurable disease, Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, and no standard treatment options available. Genomic testing was performed in Clinical Laboratory Improvement Amendments–certified, College of American Pathologists-accredited site selected laboratories. Simon's two-stage design was used with a primary end point of disease control (DC), defined as objective response (OR) or stable disease of at least 16 weeks duration (SD16+) according to RECIST v1.1. Secondary end points included OR, progression-free survival (PFS), overall survival (OS), duration of response, duration of stable disease, and safety. RESULTS Thirty patients with BRCA1/ 2 mutations were enrolled from November 2016 to August 2019. The median number of reported previous therapies was 3 (range, 1-10). Two patients were not evaluable and excluded from efficacy analyses. Two patients with complete response, three with partial response and three with SD16+, were observed for DC and OR rates of 31% (90% CI, 18 to 40; P = .04) and 18% (95% CI, 6 to 37), respectively. The median PFS was 8 (95% CI, 8 to 15) weeks, and the median OS was 38 (95% CI, 21 to 65) weeks. Three patients had at least one drug-related grade 3 adverse event or serious adverse event of anemia, fever, or oral mucositis. CONCLUSION Olaparib showed antitumor activity in patients with advanced pancreatic cancer with BRCA1/ 2 mutations extending findings of recent studies of olaparib in patients with this disease.

Sunitinib in Patients With Breast Cancer With FGFR1 or FGFR2 Amplifications or Mutations: Results From the Targeted Agent and Profiling Utilization Registry Study.

The Targeted Agent and Profiling Utilization Registry Study is a phase II basket trial evaluating the antitumor activity of commercially available targeted agents in patients with advanced cancer and genomic alterations known to be drug targets. Results from cohorts of patients with metastatic breast cancer (BC) with FGFR1 and FGFR2 alterations treated with sunitinib are reported. Eligible patients had measurable disease, Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, and no standard treatment options. Simon's two-stage design was used with a primary end point of disease control (DC), defined as objective response (OR) or stable disease of at least 16 weeks duration (SD16+) according to RECIST v1.1. Secondary end points included OR, progression-free survival, overall survival, duration of response, duration of stable disease, and safety. Forty patients with BC with FGFR1 (N = 30; amplification only n = 26, mutation only n = 1, both n = 3) or FGFR2 (N = 10; amplification only n = 2, mutation only n = 6, both n = 2) alterations were enrolled. Three patients in the FGFR1 cohort were not evaluable for efficacy; all patients in the FGFR2 cohort were evaluable. For the FGFR1 cohort, two patients with partial response and four with SD16+ were observed for DC and OR rates of 27% (90% CI, 13 to 100) and 7% (95% CI, 1 to 24), respectively. The null hypothesis of 15% DC rate was not rejected (P = .169). No patients achieved DC in the FGFR2 cohort (P = 1.00). Thirteen of the 40 total patients across both cohorts had at least one grade 3-4 adverse event or serious adverse event at least possibly related to sunitinib. Sunitinib did not meet prespecified criteria to declare a signal of antitumor activity in patients with BC with either FGFR1 or FGFR2 alterations. Other treatments and clinical trials should be considered for these patient populations.

Landscape and Saturation Analysis of Mutations Associated With Race in Cancer Genomes by Clinical Sequencing.

Differences in cancer genomes between racial groups may impact tumor biology and health disparities. However, the discovery of race-associated mutations is constrained by the limited representation and sample size of different racial groups in prior genomic studies. We evaluated the influence of race on the frequency of gene mutations using the Genomics, Evidence, Neoplasia, Information, Exchange database, a large genomic dataset aggregated from clinical sequencing. Matched cohort analyses were used to identify histology-specific race-associated mutations including increased TERT promoter mutations in Black and Asian patients with gliomas and bladder cancers, and a decreased frequency of mutations in DNA repair pathway genes and subunits of the SWI/SNF chromatin complex in Asian and Black patients across multiple cancer types. The distribution of actionable mutations in oncogenes was also race-specific, demonstrating how targeted therapies may have a disparate impact on racial groups. Down-sampling analyses indicate that larger sample sizes are likely to discover more race-associated mutations. These results provide a resource to understand differences in cancer genomes between racial groups which may inform the design of clinical studies and patient recruitment strategies in biomarker trials.

P998 Phase 2 basket design study evaluating the efficacy and safety of an anti-TL1A antibody (TEV-48574) in moderate to severe ulcerative colitis or Crohn's Disease (RELIEVE UCCD)

Abstract Background TEV-48574 is a human antibody that targets tumor necrosis factor (TNF)-like ligand 1A, also known as TNF superfamily member 15 (TNFSF15). TEV-48574 is being evaluated in the first basket design trial in IBD. The basket design is uniquely suited for the efficient assessment of TEV-48574 as evidence suggests that TL1A signaling plays a key role in both ulcerative colitis (UC) and Crohn’s disease (CD). TL1A signaling is not a primary driver but an amplifier of inflammation; thus, targeting TL1A should mitigate excessive immune responses while leaving baseline immunity intact. Originating in oncology trials, the basket trial design has emerged as a new efficient approach for testing treatment efficacy in different disease indications with potentially common molecular mechanisms. The basket design approach allows the evaluation of multiple indications in a single study design that provides adequate support for initiation of confirmatory studies. Additionally, the basket design allows for shared sites and institutional review boards, data collection and analyses under consistent conditions. Herein, we describe the phase 2b basket trial evaluating TEV-48574 in UC and CD (clinicaltrials.gov NCT05499130), currently ongoing along with a long-term extension study (LTE)(NCT05668013). Methods In this double-blind placebo-controlled global study, TEV-48574 or placebo is administered subcutaneously to adults (n = 240) diagnosed with moderate-to-severe IBD (UC (n = 120) or CD (n = 120)). Patients who meet pre-specified inclusion/exclusion criteria are randomized to either one of two TEV-48574 dose regimens or placebo in a 1:1:1 ratio (stratified by diagnosis (UC or CD) and previous exposure to advanced IBD therapy(biologics and small molecules)) for 14 weeks. Patients who complete the 14-week induction period have the option to enter the LTE, consisting of a 44-week maintenance period for responders and a re-induction period for non-responders. Primary efficacy endpoints are induction of clinical remission (a modified Mayo Score of ≤2 points for UC), and endoscopic response (a reduction in Simple Endoscopic Score for Crohn's Disease (SES-CD) of ≥ 50% from baseline) for CD, at week 14. A Bayesian approach will be used to compute posterior probabilities for the response endpoints within each indication. Additional endpoints include safety assessments, measures of clinical response, biomarkers, pharmacokinetics, and immunogenicity. Results Conclusion TEV-48574 is a potential novel treatment option for patients with UC and CD that may have dual antifibrotic and anti-inflammatory effects. The phase 2 basket study design offers an efficient approach to advance TEV-45874to confirmatory phase 3 studies.

Levetiracetam modulates brain metabolic networks and transcriptomic signatures in the 5XFAD mouse model of Alzheimer's disease.

Subcritical epileptiform activity is associated with impaired cognitive function and is commonly seen in patients with Alzheimer's disease (AD). The anti-convulsant, levetiracetam (LEV), is currently being evaluated in clinical trials for its ability to reduce epileptiform activity and improve cognitive function in AD. The purpose of the current study was to apply pharmacokinetics (PK), network analysis of medical imaging, gene transcriptomics, and PK/PD modeling to a cohort of amyloidogenic mice to establish how LEV restores or drives alterations in the brain networks of mice in a dose-dependent basis using the rigorous preclinical pipeline of the MODEL-AD Preclinical Testing Core. Chronic LEV was administered to 5XFAD mice of both sexes for 3 months based on allometrically scaled clinical dose levels from PK models. Data collection and analysis consisted of a multi-modal approach utilizing 18F-FDG PET/MRI imaging and analysis, transcriptomic analyses, and PK/PD modeling. Pharmacokinetics of LEV showed a sex and dose dependence in Cmax, CL/F, and AUC0-∞, with simulations used to estimate dose regimens. Chronic dosing at 10, 30, and 56 mg/kg, showed 18F-FDG specific regional differences in brain uptake, and in whole brain covariance measures such as clustering coefficient, degree, network density, and connection strength (i.e., positive and negative). In addition, transcriptomic analysis via nanoString showed dose-dependent changes in gene expression in pathways consistent 18F-FDG uptake and network changes, and PK/PD modeling showed a concentration dependence for key genes, but not for network covariance modeling. This study represents the first report detailing the relationships of metabolic covariance and transcriptomic network changes resulting from LEV administration in 5XFAD mice. Overall, our results highlight non-linear kinetics based on dose and sex, where gene expression analysis demonstrated LEV dose- and concentration-dependent changes, along with cerebral metabolism, and/or cerebral homeostatic mechanisms relevant to human AD, which aligned closely with network covariance analysis of 18F-FDG images. Collectively, this study show cases the value of a multimodal connectomic, transcriptomic, and pharmacokinetic approach to further investigate dose dependent relationships in preclinical studies, with translational value toward informing clinical study design.

Face Recognition Characteristics in Patients with Age-Related Macular Degeneration Determined Using a Virtual Reality Headset with Eye Tracking.

Face recognition is one of the most serious disabilities of patients with age-related macular degeneration (AMD). Our purpose was to study face recognition using a novel method incorporating virtual reality (VR) and eye tracking. Eighteen patients with AMD (seven male; median age 83 years; 89% with bilateral advanced AMD) and nineteen healthy controls (five male; median age 68 years) underwent the face recognition test IC FACES (Synthesius, Ljubljna, Slovenia) on a VR headset with built-in eye tracking sensors. Analysis included recognition accuracy, recognition time and fixation patterns. Additionally, a screening test for dementia and imaging with fundus autofluorescence and optical coherence tomography was performed. AMD patients had significantly lower face recognition accuracy (42% vs. 92%; p < 0.001) and longer recognition time (median 4.0 vs. 2.0 s; p < 0.001) in comparison to controls. Both parameters were significantly worse in patients with lower visual acuity. In both groups, eye-tracking data revealed the two classical characteristics of the face recognition process, i.e., fixations clustering mainly in the nose-eyes-mouth triangle and starting observation in the nasal area. The study demonstrates usability of a VR headset with eye tracking for studying visual perception in real-world situations which could be applicable in the design of clinical studies.

1877 Recruitment to a phase 3, RCT in Parkinson’s: strategies and association between participant characteristics and PI specialty

Abstract Introduction Falls are a common complication of Parkinson’s disease, driven in part by an underlying cholinergic deficit that contributes to gait and cognitive impairment. Phase 2 studies have established that amelioration of this deficit using cholinesterase inhibitors may reduce falls. Methods CHIEF-PD (CHolinesterase Inhibitor to prEvent Falls in Parkinson's Disease) is a phase 3 randomised, double-blind placebo-controlled trial of rivastigmine to prevent falls in Parkinson's disease that recruited from NHS sites. Relationships between the Principal Investigators’ specialty and the participants baseline characteristics were evaluated using linear, logistic and ordinal logistic regression. Cognitive impairment was defined as MoCA ≤26, while falls in the prior 12 months were separated into ordinal quartiles (1-2, 3-5, 6-12, 13+). Results Recruitment to CHIEF-PD commenced in January 2020 and completed in April 2023. Recruitment increased up until the start of the pandemic and thereafter there were 2 peaks. Potential participants were identified through clinic lists, databases, via national and local media and charities. 600 participants were enrolled across 38 sites. Sites enrolled between 1 and 74 participants, each. The median recruitment rate was 19 participants per month (IQR 6-27). 14 (37%) sites had Principal Investigators that were neurologists and 24 (63%) sites had PIs that were geriatricians. Most participants (76%) were over the age of 65 years. Compared with neurologists, geriatricians recruited older patients (difference in means 2.08 (95% CI 0.68, 3.48); p=0.004), with similar levels of cognitive impairment (OR 1.20 (95% CI 0.85, 1.69); p=0.293) and a lower fall rate (OR 0.46 (95% CI 0.34, 0.62); p&amp;lt;0.001) at baseline. Conclusion Recruitment of older participants to a Clinical Trial of an Investigational Medicinal Product (CTIMP) trial throughout the Covid-19 pandemic across 38 UK centres was feasible using multiple strategies. Characteristics of participants varied according to the sub-speciality of the Principal Investigator at the site.

Addition of metastasis-directed therapy to standard-of-care systemic therapy for oligometastatic pancreatic ductal adenocarcinoma (EXTEND): Results of a multicenter, randomized phase II trial.

603 Background: Standard treatment of oligometastatic pancreatic ductal adenocarcinoma (PDAC) consists of multi-agent chemotherapy, although outcomes remain poor. We tested the hypothesis that the addition of comprehensive metastasis-directed therapy (MDT) to standard-of-care systemic therapy would improve progression-free survival (PFS) compared with systemic therapy alone. Methods: The External Beam Radiation to Eliminate Nominal Metastatic Disease (EXTEND) trial is a multicenter phase II basket trial randomizing patients with ≤ 5 solid tumor metastases 1:1 to MDT plus systemic therapy versus systemic therapy alone. Each histology-specific basket was pre-specified and independently powered for the primary endpoint of PFS; here we present results of the pancreatic cancer basket. Progression was defined by radiographic criteria (RECIST v1.1), clinical events, or death. Patients were stratified at randomization by number of metastases (1-2 vs 3-5), number of prior lines of systemic therapy (0-1 vs 2+), and cancer antigen 19-9 (CA-19-9) level (&lt;90U/ml vs ≥90U/ml). Exploratory endpoints included systemic immune response measures. The cutoff date for the primary analysis was September 1, 2023. ClinicalTrials.gov registration: NCT03599765. Results: Between March 2019 and February 2023, 41 patients with oligometastatic PDAC were randomized and 40 were eligible for PFS analysis (MDT arm: 19 patients; control arm: 21 patients). Baseline characteristics were well-balanced between arms. Thirty-one patients experienced progression or death; median follow-up time for censored patients was 9.9 months. The MDT arm had significantly longer PFS compared to the systemic therapy arm (median PFS 10.3 versus 2.5 months; log-rank p=0.006). After stratification, the estimated PFS hazard ratio was 0.43 (95% confidence interval: 0.20, 0.94; p=0.03) for MDT compared with systemic therapy. There were no grade 3 or greater adverse events with at least possible attribution to MDT, and only one grade 2 adverse event possibly related to treatment in the MDT arm occurred. Increased systemic T-cell stimulatory cytokines, CD8+ T-cell activation, CD8+ T-cell proliferation, and T-cell receptor clonal expansion following treatment were associated with the MDT arm compared with the control arm (all p&lt;0.05). Conclusions: Among patients with oligometastatic PDAC, the combination of MDT plus systemic therapy was associated with improved PFS compared with systemic therapy alone. Further exploration in phase III trials is warranted, as is investigation into the potential therapeutic implications of systemic immune activation associated with MDT receipt. Clinical trial information: NCT03599765 .

Nivolumab in patients (pts) with advanced gastrointestinal (GI) cancers with high plasma tumor mutational burden (pTMB): Results from a SCRUM-Japan GOZILA phase II trial.

98 Background: TMB is a biomarker for immune checkpoint inhibitors (ICIs). Analysis of circulating tumor DNA (ctDNA) has the potential to non-invasively identify pts likely to benefit from ICIs by assessing pTMB. We conducted a phase II basket trial as part of the SCRUM-Japan GOZILA umbrella/basket trial to evaluate the efficacy and safety of nivolumab monotherapy in pts with advanced GI cancers with high pTMB. Methods: Eligibility criteria included histologically confirmed unresectable or recurrent GI cancers; ECOG PS of 0 or 1; refractory or intolerant to the standard therapies; and high pTMB identified by Guardant360 CDx, a 74-gene ctDNA assay. Pts received intravenous nivolumab monotherapy of 360 mg every 3 weeks until progressive disease. The primary endpoint was objective response rate (ORR) per investigator assessment. The pTMB score was calculated by adjustment of mutation count by tumor fraction, and initial pTMB thresholds were determined based on previously reported ORR for ICI treatment for each GI cancer in the cohort. The cohort 2 proceeded only for esophageal cancer, and an ultra-high TMB cohort was created to include pts in the top 2% for pTMB scores. Results: Fifty-one pts with high pTMB in the cohort 1/2 (n=32) and the ultra-high TMB cohort (n=19) were enrolled. The median duration of follow-up was 7.5 months (range, 0.9–51.3). Deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H) was observed in 1 pt in cohort 1/2 and 2 in ultra-high TMB cohort. The ORR was 12.5% and 21.1%, with median duration of response of 14.0 months and not reached, respectively. In an exploratory analysis of the overall population, pts with esophageal cancer had the highest ORR of 33.3% (4/12), followed by pancreatic (1/6, 16.7%) and colorectal cancer (3/27, 11.1%). Of 2 pts with proficient MMR/non-MSI-H colorectal cancer who had a response, 1 had a POLE mutation. Pts with response tended to have higher pTMB score (median, 26 vs. 8). dMMR/MSI-H (HR=0.16; 95% CI, 0.02–1.18), PD-L1 CPS ≥1 (HR=0.55; 95% CI, 0.29–1.01), and absence of liver metastasis (HR=0.36; 95% CI, 1.48–5.14) were significantly associated with longer progression-free survival. Treatment-related grade 3–4 adverse events occurred in 3 pts (9%) in the cohort 1/2 and 3 (16%) in the ultra-high TMB cohort, with no treatment death in either cohort. Conclusions: Nivolumab demonstrated antitumor activity in pretreated pts with advanced GI cancer and high pTMB. These results suggest that the use of pTMB potentially identify patients who may benefit from ICI treatment. Clinical trial information: UMIN000033182 .

Talazoparib (Tala) in patients (pts) with colorectal cancer (CRC) with BRCA1/2 mutations (mut): Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) study.

106 Background: TAPUR is a phase II basket study evaluating antitumor activity of commercially available targeted agents in pts with advanced cancers with specific genomic alterations. Results in a cohort of pts with CRC with BRCA1/2 mut treated with Tala are reported. Methods: Eligible pts had measurable disease, ECOG performance status (PS) 0-2, adequate organ function, and no standard treatment (tx) options. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. Pts received 1 mg of Tala orally daily until disease progression. Primary endpoint was disease control (DC) per investigator defined as complete or partial response or stable disease of at least 16 weeks (wks) duration (SD16+) per RECIST v 1.1. Simon 2-stage design tested the null DC rate of 15% vs. 35% (power = 0.85; α = 0.10). If ≥2 of 10 pts in stage 1 have DC, 18 more pts are enrolled; otherwise, the cohort is closed. If ≥7 of 28 pts have DC, the null DC rate is rejected. Secondary endpoints were objective response (OR), progression-free survival (PFS), overall survival (OS), and safety. Results: 10 pts with advanced CRC and BRCA1 mut (n=3), BRCA2 mut (n=5), or both (n=2) were enrolled from February 2020 to June 2021. Germline or somatic status was not reported in 7 of 10 pts, 2 pts had somatic BRCA2 muts and 1 pt had a germline BRCA2 mut. 2 pts had left sided tumors, 2 had right sided, 3 had rectal tumors, and 3 pts had tumors that were site undetermined. All pts were evaluable for efficacy and toxicity. Table summarizes pt demographics and outcomes. No pts experienced DC, median PFS was 8 wks (95% CI, 6 to 8) and median OS was 24 wks (95% CI, 7 to 43). Co-alterations were observed in the following genes: KRAS (3 pts) and BRAF (2 pts). 2 pts had 3 separate grade 3 adverse events of anemia or fatigue at least possibly related to Tala. Conclusions: Monotherapy Tala did not demonstrate sufficient clinical activity in pts with advanced CRC with BRCA1/2 mut. Other tx should be considered for these pts, including tx offered in clinical trials. Clinical trial information: NCT02693535 . [Table: see text]