Cohort Enrollment Research Articles

Predictors of British Isles Lupus Assessment Group-based outcomes in patients with systemic lupus erythematosus: Analysis from the Systemic Lupus International Collaborating Clinics Inception Cohort.

We aimed to identify factors associated with a significant reduction in SLE disease activity over 12months assessed by the BILAG Index. In an international SLE cohort, we studied patients from their 'inception enrolment' visit. We also defined an 'active disease' cohort of patients who had active disease similar to that needed for enrolment into clinical trials. Outcomes at 12months were; Major Clinical Response (MCR: reduction to classic BILAG C in all domains, steroid dose of ≤7.5mg and SLEDAI ≤ 4) and 'Improvement' (reduction to ≤1B score in previously active organs; no new BILAG A/B; stable or reduced steroid dose; no increase in SLEDAI). Univariate and multivariate logistic regression with Least Absolute Shrinkage and Selection Operator (LASSO) and cross-validation in randomly split samples were used to build prediction models. 'Inception enrolment' (n = 1492) and 'active disease' (n = 924) patients were studied. Models for MCR performed well (ROC AUC = .777 and .732 in the inception enrolment and active disease cohorts, respectively). Models for Improvement performed poorly (ROC AUC = .574 in the active disease cohort). MCR in both cohorts was associated with anti-malarial use and inversely associated with active disease at baseline (BILAG or SLEDAI) scores, BILAG haematological A/B scores, higher steroid dose and immunosuppressive use. Baseline predictors of response in SLE can help identify patients in clinic who are less likely to respond to standard therapy. They are also important as stratification factors when designing clinical trials in order to better standardize overall usual care response rates.

The USnational registry for childhood interstitial and diffuse lung disease: Report of study design and initial enrollment cohort.

Childhood interstitial and diffuse lung disease (chILD) encompasses a broad spectrum of rare disorders. The Children's Interstitial and Diffuse Lung Disease Research Network (chILDRN) established a prospective registry to advance knowledge regarding etiology, phenotype, natural history, and management of these disorders. This longitudinal, observational, multicenter registry utilizes single-IRB reliance agreements, with participation from 25 chILDRN centers across the U.S. Clinical data are collected and managed using the Research Electronic Data Capture (REDCap) electronic data platform. We report the study design and selected elements of the initial Registry enrollment cohort, which includes 683 subjects with a broad range of chILD diagnoses. The most common diagnosis reported was neuroendocrine cell hyperplasia of infancy, with 155 (23%) subjects. Components of underlying disease biology were identified by enrolling sites, with cohorts of interstitial fibrosis, immune dysregulation, and airway disease being most commonly reported. Prominent morbidities affecting enrolled children included home supplemental oxygen use (63%) and failure to thrive (46%). This Registry is the largest longitudinal chILD cohort in the United States to date, providing a powerful framework for collaborating centers committed to improving the understanding and treatment of these rare disorders.

TRLS-06. A PHASE 1, SAFETY AND DOSE ESCALATION STUDY OF BXQ-350 IN COMBINATION WITH RADIATION IN PEDIATRIC PATIENTS WITH DIFFUSE MIDLINE GLIOMA OR DIFFUSE INTRINSIC PONTINE GLIOMA

Abstract This trial (NCT04771897) is currently enrolling at 3 US sites; as of January 2023, a total of 8 patients have been enrolled. Enrollment of cohort 1 (2.4 mg/kg and 54 Gy) and cohort 2 (3.2 mg/kg and 54 Gy) are completed. Enrollment in the expansion cohort is on-going. To date, no dose-limiting toxicity has been observed and the combination of BXQ-350 plus radiation has been well tolerated. BXQ-350 is a nanovesicle formulation of Saposin C that induces apoptosis of cancer cells and an anti-tumoral immune response by lowering Sphingosine-1-Phosphate and increasing ceramides concentrations. Saposin C is a human protein encoded by the Psap gene and is an allosteric activator of enzymes involved in sphingolipid/ceramide metabolism. The significance of sphingolipid metabolism in brain cancers has been demonstrated and enzymes involved in sphingolipid metabolism are being investigated as novel therapeutic targets for adult and pediatric brain cancers. BXQ-350 was investigated in a Phase 1 dose-escalation safety study in pediatric brain cancer patients (NCT03967093); results showed that it was well-tolerated, a MTD was not established, and the safety profile warranted the investigation of combination studies at the highest dose tested (3.2 mg/kg). Additionally, results from a Phase 1 safety and dose escalation study in adult patients with advanced solid malignancies (NCT02859857) indicated that BXQ-350 was well tolerated and showed single agent activity with evidence of modulating sphingolipid metabolism and favorably influencing the tumor microenvironment. The primary objective of this dose-escalation study is to describe the safety profile and to determine the maximum tolerated dose of BXQ-350 in combination with radiation. BXQ-350 is administered intravenously concurrently with radiation therapy followed by adjuvant BXQ-350 until disease progression. Multiple secondary parameters are included to characterize BXQ-350’s pharmacokinetic parameters and efficacy profile and to investigate potential biomarkers.

A phase 1, first-in-human, open label, escalation and expansion study of ORM-5029, a highly potent GSPT1 degrader targeting HER2, in patients with HER2-expressing advanced solid tumors.

TPS1114 Background: Targeted protein degradation (TPD) molecules have expanded the therapeutic options through their catalytic mechanism of action (MOA) and ability to degrade “undruggable” proteins. To increase the efficacy versus tolerability window of protein degradation and improve drug delivery, ORM-5029 uses a Dual-Precision TPD (TPD2) approach combining the catalytic mechanism of TPDs with the precision of tumor-targeting therapeutic antibodies. ORM-5029 is a first-in-class human epidermal growth factor receptor 2 (HER2)-targeted antibody-drug conjugate (ADC) comprised of SMol006, a highly potent GSPT1 degrader, conjugated to pertuzumab, a clinically validated antibody. HER2 is overexpressed in cancers such as breast, ovarian and gastric, and associated with early-onset aggressive disease. ORM-5029 is in development for treatment of HER2-expressing solid tumors. The MOA is mediated by targeted uptake of the ADC, release of the TPD payload, and cell death by GSPT1 degradation. ORM-5029 showed robust in vitro and in vivo efficacy in multiple HER2-expressing models with comparable activity to trastuzumab deruxtecan and strong activity in trastuzumab emtansine-refractory models. Methods: This phase 1 first-in-human study evaluates the safety, tolerability, and efficacy of ORM-5029 administered by intravenous infusion in patients (pts) with HER2-expressing advanced solid tumors (NCT05511844). The escalation, guided by the Bayesian Optimal Interval design, explores cohorts of ORM-5029 to identify the maximum tolerated dose (MTD) and/or expansion dose level (EDL). Each cohort will enroll ≥3 breast cancer pts with at least HER2 1+ (HER2 low) or greater by immunohistochemistry or positive by in situ hybridization. Expansion cohort A (HER2+ breast cancer) may enroll in parallel to escalation evaluating doses showing pharmacodynamic activity or efficacy. Up to 10 pts may be enrolled at each dose explored in cohort A. Enrollment into expansion cohort B (up to 21 pts) and cohort C (up to 22 pts) will begin once the EDL has been determined to further assess the safety, tolerability and efficacy of ORM-5029 using a Simon’s optimal 2-stage design. Cohort B will enroll pts with HER2+ breast cancer refractory or intolerant to standard treatment after ≥2 HER2 therapies in the metastatic setting. Cohort C will enroll pts with advanced solid tumors that are refractory or intolerable to standard treatment or for which no standard treatment is available, including HER2+ gastric or gastroesophageal junction adenocarcinoma or tumors with HER2 expression, amplification or mutations (e.g., colorectal, bile duct, ovarian, bladder, non-small cell lung). Study enrollment began in October 2022 in the United States. Escalation cohort 1 was completed without DLT; enrollment in cohort 2 began as of December 2022. Clinical trial information: NCT05511844 .

A phase 1 study to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and immunogenicity of LB4330, a peptide fused to CLDN18.2 antibody targeting the tumor antigen associated CD8+t CELLS in patients with advanced solid tumors.

TPS4196 Background: PD-1/PD-L1-targeted immunotherapies have become critical roles in the treatment for many tumors. However, there is limited progress in pancreatic ductal adenocarcinoma (PDAC). PDAC is low immunogenicity. PDAC microenvironment is immunosuppressive. More than 70% PDACs have few or no CD8+ T cells around the tumor cell or in the tumor microenvironment (TME). Therefore, immunotherapy like PD-1/PD-L1 antibody alone is rarely effective for PDACs. Some cytokine or analogs may activate CD8+ T cells. An analog specifically activating tumor antigen associated (TAA) CD8+ T cells was designed and fused to anti-CLDN18.2 antibody. This specific bi-functional molecule LB4330 has high affinity to human anti-CLDN18.2 (14pM) and CD8+T cells. LB4330, as a novel, first-in-class molecule, may activate TAA CD8+ T cells in TME and has potential in alone or in combination with PD-1/PD-L1 mAb, for the treatment of advanced solid tumors, especially for Claudin 18.2 positive PDAC. Methods: This is a FIH, phase 1 study to evaluate the safety, tolerability, pharmacokinetics and immunogenicity of LB4330 in patients with advanced solid tumors (MEETCD8-001). The planned sample size is approximately 66 patients in two parts: part 1 dose escalation, will evaluate safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and determine the maximum tolerated dose (MTD) and/or the recommended phase 2 dose (RP2D). Part 2 dose expansion will further characterize the safety profile and preliminary tumor response in advanced gastric and gastroesophageal junction adenocarcinoma and PDAC with Claudin 18.2 expression. In dose escalation stage, patients will be recruited with advanced solid tumors who have failed standard treatment, or for whom standard treatment is not available or applicable at this stage. Exclusion criteria include a greater risk for gastric bleeding, irritable bowel syndrome with symptoms, active virus infections. The primary endpoints are incidence of dose limiting toxicities and adverse events, MTD, and recommended phase 2 dose. Secondary objectives will evaluate PK parameters, preliminary antitumor activity, and immunogenicity of LB4330. Tumor response will be assessed per RECIST and iRECIST every 2 cycles. The Phase I study in advanced solid tumors is ongoing. Enrollment in cohort 1 began in Nov 2022. Clinical trial information: NCT05707676 .

A phase 1b study to evaluate the efficacy, safety, and pharmacokinetics of an investigational microbiome therapeutic, SER-155, in adults undergoing hematopoietic stem cell transplantation.

TPS7080 Background: In patients undergoing allogeneic hematopoietic cell transplantation (HCT), loss of gastrointestinal microbial diversity is associated with risk of bloodstream infections (BSI), acute graft-versus-host disease (aGvHD), and death. SER-155 is a rationally designed investigational cultivated microbiome therapeutic, hypothesized to improve clinical outcomes in HCT by restoring colonization resistance to potential pathogens, promoting epithelial barrier integrity, and reducing colonic inflammation. SER-155-001 is a Phase 1b study evaluating the efficacy, safety, and pharmacokinetics (PK) of SER-155 in adults undergoing HCT. Methods: This study will enroll approximately 70 subjects ≥18 years in an open-label Cohort 1 (n = 10) followed by a double-blind, placebo-controlled Cohort 2 (n = 60) randomized 1:1 to SER-155 or placebo. A variety of conditioning regimens, donor types, and GVHD-prophylaxis regimens are included. Exclusion criteria include history of severe colitis or active inflammatory bowel disease or total colectomy, umbilical cord blood or ex vivo T-cell depletion, exposure to fecal microbiota transplant or any live microbial therapeutic within 3 months prior to screening, and evidence of relapse or progression of hematologic malignancy (minimal residual disease is allowed). Following screening, participants in both cohorts receive 2 treatment courses (one before and one after HCT), each comprised of microbiome conditioning with oral vancomycin or placebo followed by SER-155 or placebo, plus a conditional 3rd treatment course if the subject receives antibiotics. Safety outcomes are followed through 52 weeks post HCT. The primary endpoint is the incidence and severity of adverse events, serious adverse events, and adverse events of special interest. Secondary endpoints include rates of BSI, gastrointestinal infections, aGvHD, febrile neutropenia and overall survival. Microbiome related endpoints include engraftment of SER-155 bacterial strains in the gastrointestinal tract (PK endpoint) and fecal microbiome diversity, composition and metabolites. Results: Cohort 1 enrollment is complete, with 13 participants receiving SER-155. In December 2022, the Data and Safety Monitoring Committee supported continuation to Cohort 2 enrollment following review of safety data from Cohort 1. Enrollment in Cohort 2 is underway. Conclusions: This Phase 1b study is designed to assess the safety, and clinical efficacy of SER-155 in allogeneic HCT, expanding the clinical experience of microbiome- directed interventions in allogeneic HCT recipients. Clinical trial information: NCT04995653 .

A phase I study of nelmastobart (hSTC810), an anti-BTN1A1 antibody, in patients with advanced solid tumors.

2633 Background: Butyrophilin 1A1 (BTN1A1) is a novel immune checkpoint that is primarily expressed by tumor cells in a manner that is mutually exclusive with PD-(L)1. BTN1A1 can potentially be targeted to extend new immunotherapeutic treatment options to patients (pts) whose tumors are unresponsive to anti-PD-(L)1 therapy. This phase I study describes the safety and clinical activity of Nelmastobart (hSTC810), a humanized monoclonal antibody targeting BTN1A1, in pts with advanced solid tumors. Methods: Nelmastobart was administered intravenously every 2 weeks across 6 dose levels from 0.3 mg/kg to 15 mg/kg. The primary objectives were to determine the safety profile and maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D). Using a 3+3 design, dose-escalation cohorts were evaluated for dose-limiting toxicities (DLT) during the first 2 cycles. Backfill cohorts were allowed once a dose was deemed safe. Response was assessed using RECIST 1.1 every 4 cycles (8 weeks). Pts were treated until disease progression or unacceptable toxicity. Results: As of January 30, 2023, enrollment in the dose-escalation cohorts is complete. A total of 39 pts with colon (n=14), lung (NSCLC n=3; SCLC n=2), urothelial (n=3), breast, cholangiocarcinoma, melanoma, ovarian, pancreatic (n=2) each, adrenocortical, anal, esophageal, H&N, PEComa, skin, and thymic (n=1) cancers each were treated in the dose-escalation and backfill cohorts. Median duration of therapy for all pts was 8 weeks (maximum 29 weeks). Most common treatment related adverse events (TRAEs) reported were grade 1-2 fatigue (6%), headache (5.9%), and nausea (4.4%); furthermore, there were no TRAEs ≥ 3. No pts was discontinued or required dose reduction due to TRAEs. There were no DLTs across all dose levels and the MTD was not reached. In evaluable pts, one confirmed partial response was observed in MSI-H colon cancer (3 mg/kg) and 13 pts (colon, H&N, lung, melanoma, ovarian, thymic carcinoma) had a best response of stable disease (SD) across multiple dose levels. Median duration of PR/SD pts on study was 17.5 weeks. Interim pharmacokinetics (PK) analysis demonstrated consistent exposure with linear PK. Pharmacodynamic analysis measuring cytokines and cell-based markers is pending and will be presented. Based on the safety, efficacy, and PK, we recommend 15 mg/kg Q2W as the RP2D. Conclusions: Nelmastobart is well-tolerated without DLTs up to the final dose of 15 mg/kg. Current data show evidence of anti-tumor activity and durable SD. Clinical development planning for a phase Ib/II clinical trial is underway to further characterize the therapeutic dose and efficacy in select solid tumors. Clinical trial information: NCT05231746 .

A randomized phase 2 non-inferiority trial of (Z)-endoxifen and exemestane + goserelin as neoadjuvant treatment for premenopausal women with ER+/HER2- breast cancer (EVANGELINE).

TPS633 Background: Ovarian function suppression (OFS) when combined with tamoxifen or an aromatase inhibitor is the standard of care for premenopausal estrogen receptor positive (ER+) human epidermal growth factor receptor 2 negative (HER2-) breast cancer (BC) based on SOFT (Francis 2022) and TEXT (Pagani 2022) clinical trials and confirmed in a metanalysis (EBCTCG 2022). However, estrogen deprivation in premenopausal women is associated with significant morbidity and up to 40% of premenopausal women with ER+/HER2- BC are intolerant of OFS. For these women, tamoxifen monotherapy is the only FDA approved option. Therefore, there is substantial room to improve endocrine therapy for premenopausal women with ER+/HER2- BC. (Z)-endoxifen is one of the most active anti-estrogen tamoxifen metabolites, with preclinical data demonstrating superiority to tamoxifen and letrozole in aromatase expressing xenograft models and evidence for antitumor activity in early phase clinical trials in patients with prior progression on endocrine therapy including tamoxifen. In addition to its ability to potently block ERa, (Z)-endoxifen at clinically achievable concentrations inhibits protein kinase C beta 1 (PKCβ1), resulting in downstream AKT inhibition and apoptosis. It is hypothesized that (Z)-endoxifen, when delivered as monotherapy at doses that dually target both ERα and PKCβ1, will potently inhibit BC proliferation while obviating the need for OFS in premenopausal women. If successful, this innovative approach could spare women with endocrine sensitive BC from the side effects of OFS. Methods: To further study (Z)-endoxifen in premenopausal women, a multicenter study in the United States, with possible expansion to other countries was designed (EVANGELINE; NCT05607004). This is a Phase 2, open-label, randomized, neoadjuvant study in premenopausal women with Stage IIA or IIB ER+/HER2- BC. Subjects are randomized 1:1 to either exemestane plus goserelin or (Z)-endoxifen. The primary objective is to determine whether the endocrine sensitive disease (ESD) rate (defined as Ki-67 ≤ 10% after 4 weeks of neoadjuvant therapy) with (Z)-endoxifen is non-inferior to exemestane plus goserelin. Subjects will be enrolled with the intent of surgical treatment in the involved breast(s) after completing 6 months of neoadjuvant treatment. Safety, tolerability, response rates and surgical outcomes will be assessed. Disease progression will be monitored throughout study participation. Paired tumor biopsies and blood sampling will allow for a robust biomarker evaluation. Prior to initiating the Treatment Cohort (162 subjects), up to 12 subjects will be enrolled in a pharmacokinetic (PK) Run-in Cohort to identify the optimal dose for the Treatment Cohort. Enrolment in the PK Run-in cohort began in February 2023. Clinical trial information: NCT05607004 .

Case Ascertainment of Sickle Cell Disease Using Surveillance or Single Administrative Database Case Definitions.

In the absence of access to surveillance system data, single-source administrative databases are often used to study health care utilization and health outcomes among people with sickle cell disease (SCD). We compared the case definitions from single-source administrative databases with a surveillance case definition to identify people with SCD. We used data from Sickle Cell Data Collection programs in California and Georgia (2016-2018). The surveillance case definition for SCD developed for the Sickle Cell Data Collection programs uses multiple databases, including newborn screening, discharge databases, state Medicaid programs, vital records, and clinic data. Case definitions for SCD in single-source administrative databases varied by database (Medicaid and discharge) and years of data (1, 2, and 3 years). We calculated the proportion of people meeting the surveillance case definition for SCD that was captured by each single administrative database case definition for SCD, by birth cohort, sex, and Medicaid enrollment. In California, 7117 people met the surveillance case definition of SCD from 2016 through 2018; 48% of this group was captured by the Medicaid case definition and 41% by the discharge case definition. In Georgia, 10 448 people met the surveillance case definition of SCD from 2016 through 2018; 45% of this group was captured by the Medicaid case definition and 51% by the discharge case definition. These proportions differed by years of data, birth cohort, and length of Medicaid enrollment. The surveillance case definition identified twice as many people with SCD as the single-source administrative database definitions during the same period, but trade-offs exist in using single administrative databases for decisions on policy and program expansion for SCD.

The Trial within Cohorts (TwiCs) study design in oncology: experience and methodological reflections

A Trial within Cohorts (TwiCs) study design is a trial design that uses the infrastructure of an observational cohort study to initiate a randomized trial. Upon cohort enrollment, the participants provide consent for being randomized in future studies without being informed. Once a new treatment is available, eligible cohort participants are randomly assigned to the treatment or standard of care. Patients randomized to the treatment arm are offered the new treatment, which they can choose to refuse. Patients who refuse will receive standard of care instead. Patients randomized to the standard of care arm receive no information about the trial and continue receiving standard of care as part of the cohort study. Standard cohort measures are used for outcome comparisons. The TwiCs study design aims to overcome some issues encountered in standard Randomized Controlled Trials (RCTs). An example of an issue in standard RCTs is the slow patient accrual. A TwiCs study aims to improve this by selecting patients using a cohort and only offering the intervention to patients in the intervention arm. In oncology, the TwiCs study design has gained increasing interest during the last decade. Despite its potential advantages over RCTs, the TwiCs study design has several methodological challenges that need careful consideration when planning a TwiCs study. In this article, we focus on these challenges and reflect on them using experiences from TwiCs studies initiated in oncology. Important methodological challenges that are discussed are the timing of randomization, the issue of non-compliance (refusal) after randomization in the intervention arm, and the definition of the intention-to-treat effect in a TwiCs study and how this effect is related to its counterpart in standard RCTs.

Reaming the intramedullary canal during tibial nailing does not affect in vivo intramuscular pH of the anterior tibialis.

Adults with acute tibia shaft fractures (level 1, academic, 2019-2021) were offered enrollment in an observational cohort. During IM nailing, a sterile, validated IpH probe was placed into the anterior tibialis (<5 cm from fracture, continuous sampling, independent research team). IpH before, during, and after reaming was averaged and compared through repeated measures ANOVA. As the appropriate period to analyze IpH during reaming is unknown, the analysis was repeated over periods of 0.5, 1, 2, 5, 10, and 15 minutes prereaming and postreaming time intervals. Sixteen subjects with tibia shaft fractures were observed during nailing. Average time from injury to surgery was 35.0 hours (SD, 31.8). Starting and ending perioperative IpH was acidic, averaging 6.64 (SD, 0.21) and 6.74 (SD, 0.17), respectively. Average reaming time lasted 15 minutes. Average IpH during reaming was 6.73 (SD, 0.15). There was no difference in IpH between prereaming, intrareaming, and postreaming periods. IpH did not differ regardless of analysis over short or long time domains compared with the duration of reaming. Reaming does not affect IpH. Both granular and broad time domains were tested, revealing no observable local impact.

Real-World Experience on the Use of Mepolizumab from the Severe Asthma Registry of the German Asthma Net (MepoGAN-Study).

The German Asthma Net (GAN) operates a Severe Asthma Registry that provides an overview of the clinical presentation and management of patients with severe asthma. Based upon data from the GAN registry, the MepoGAN study aimed to describe clinical profiles and treatment outcomes of patients who were treated with the anti-IL-5 monoclonal antibody mepolizumab (NucalaTM) in routine practice in Germany. The MepoGAN study is a descriptive retrospective non-interventional cohort study. Mepolizumab patients enrolled in the GAN registry were evaluated with results being described in two different data sets: Cohort 1 (n=131) started on mepolizumab when the patients entered the registry. Results were reported after 4 months of therapy. Patients in Cohort 2 (n=220) were on treatment with mepolizumab at the time of enrollment and follow-up data were collected after a further year of treatment. Outcome measures included asthma control, lung function, disease symptoms, OCS use, and exacerbations. Patients enrolled in the registry who started on mepolizumab in Cohort 1 had a mean age of 55 years, were former smokers in 51% of the cases, had a mean blood eosinophil count of 500 cells/μL, and frequently had maintenance OCS use (55%). In this real-world setting, mepolizumab therapy was associated with a clinically relevant reduction in blood eosinophils (-445.7 cells/μL), OCS use (-30%), and improvement in asthma control. Fifty-five percent (vs 10% at baseline) of the patients reported controlled or partially controlled asthma 4 months after starting therapy. In patients who were already treated with mepolizumab at registry enrollment (Cohort 2), asthma control and lung function remained stable after a further year of observation. The GAN registry data confirm the effectiveness of mepolizumab in a real-world setting. Treatment benefits are maintained over time. While the asthma of patients treated in routine practice was more severe, the results observed with mepolizumab are broadly consistent with RCTs.

Novel Metabolic Subtypes in Pregnant Women and Risk of Early Childhood Obesity in Offspring

The in utero metabolic milieu is associated with offspring adiposity. Standard definitions of maternal obesity (according to prepregnancy body mass index [BMI]) and gestational diabetes (GDM) may not be adequate to capture subtle yet important differences in the intrauterine environment that could be involved in programming. To identify maternal metabolic subgroups during pregnancy and to examine associations of subgroup classification with adiposity traits in their children. This cohort study included mother-offspring pairs in the Healthy Start prebirth cohort (enrollment: 2010-2014) recruited from University of Colorado Hospital obstetrics clinics in Aurora, Colorado. Follow-up of women and children is ongoing. Data were analyzed from March to December 2022. Metabolic subtypes of pregnant women ascertained by applying k-means clustering on 7 biomarkers and 2 biomarker indices measured at approximately 17 gestational weeks: glucose, insulin, Homeostatic Model Assessment for Insulin Resistance, total cholesterol, high-density lipoprotein cholesterol (HDL-C), triglycerides, free fatty acids (FFA), HDL-C:triglycerides ratio, and tumor necrosis factor α. Offspring birthweight z score and neonatal fat mass percentage (FM%). In childhood at approximately 5 years of age, offspring BMI percentile, FM%, BMI in the 95th percentile or higher, and FM% in the 95th percentile or higher. A total of 1325 pregnant women (mean [SD] age, 27.8 [6.2 years]; 322 [24.3%] Hispanic, 207 non-Hispanic Black [15.6%], and 713 [53.8%] non-Hispanic White), and 727 offspring with anthropometric data measured in childhood (mean [SD] age 4.81 [0.72] years, 48% female) were included. We identified the following 5 maternal metabolic subgroups: reference (438 participants), high HDL-C (355 participants), dyslipidemic-high triglycerides (182 participants), dyslipidemic-high FFA (234 participants), and insulin resistant (IR)-hyperglycemic (116 participants). Compared with the reference subgroup, women in the IR-hyperglycemic and dyslipidemic-high FFA subgroups had offspring with 4.27% (95% CI, 1.94-6.59) and 1.96% (95% CI, 0.45-3.47) greater FM% during childhood, respectively. There was a higher risk of high FM% among offspring of the IR-hyperglycemic (relative risk, 8.7; 95% CI, 2.7-27.8) and dyslipidemic-high FFA (relative risk, 3.4; 95% CI, 1.0-11.3) subgroups; this risk was of greater magnitude compared with prepregnancy obesity alone, GDM alone, or both conditions. In this cohort study, an unsupervised clustering approach revealed distinct metabolic subgroups of pregnant women. These subgroups exhibited differences in risk of offspring adiposity in early childhood. Such approaches have the potential to refine understanding of the in utero metabolic milieu, with utility for capturing variation in sociocultural, anthropometric, and biochemical risk factors for offspring adiposity.

102 AI-Based Molecular Classification of Diffuse Gliomas using Rapid, Label-Free Optical Imaging

Molecular classification has transformed the management of brain tumors by enabling more accurate prognostication and personalized treatment. Access to timely molecular diagnostic testing for brain tumor patients is limited, complicating surgical and adjuvant treatment and obstructing clinical trial enrollment. By combining stimulated Raman histology (SRH), a rapid, label-free, non-consumptive, optical imaging method, and deep learning-based image classification, we are able to predict the molecular genetic features used by the World Health Organization (WHO) to define the adult-type diffuse glioma taxonomy, including IDH-1/2, 1p19q-codeletion, and ATRX loss. We developed a multimodal deep neural network training strategy that uses both SRH images and large-scale, public diffuse glioma genomic data (i.e. TCGA, CGGA, etc.) in order to achieve optimal molecular classification performance. One institution was used for model training (University of Michigan) and four institutions (NYU, UCSF, Medical University of Vienna, and University Hospital Cologne) were included for patient enrollment in the prospective testing cohort. Using our system, called DeepGlioma, we achieved an average molecular genetic classification accuracy of 93.2% and identified the correct diffuse glioma molecular subgroup with 91.5% accuracy within 2 minutes in the operating room. DeepGlioma outperformed conventional IDH1-R132H immunohistochemistry (94.2% versus 91.4% accuracy) as a first-line molecular diagnostic screening method for diffuse gliomas and can detect canonical and non-canonical IDH mutations. Our results demonstrate how artificial intelligence and optical histology can be used to provide a rapid and scalable alternative to wet lab methods for the molecular diagnosis of brain tumor patients during surgery.

Lifetime healthcare expenses across demographic and cardiovascular risk groups: The application of a novel modeling strategy in a large multiethnic cohort study

ObjectiveTo understand the burden of healthcare expenses over the lifetime of individuals and evaluate differences among those with cardiovascular risk factors and among disadvantaged groups based on race/ethnicity and sex. MethodsWe linked data from the longitudinal multiethnic Dallas Heart Study, which recruited participants between 2000 and 2002, with inpatient and outpatient claims from all hospitals in the Dallas-Fort Worth metroplex through December 2018, capturing encounter expenses. Race/ethnicity and sex, as well as five risk factors, hypertension, diabetes, hyperlipidemia, smoking, and overweight/obesity, were defined at cohort enrollment. For each individual, expenses were indexed to age and cumulated between 40 and 80 years of age. Lifetime expenses across exposures were evaluated as interactions in generalized additive models. ResultsA total of 2184 individuals (mean age, 45±10 years; 61% women, 53% Black) were followed between 2000 and 2018. The mean modeled lifetime cumulative healthcare expenses were $442,629 (IQR, $423,850 to $461,408). In models that included 5 risk factors, Black individuals had $21,306 higher lifetime healthcare spending compared with non-Black individuals (P < .001), and men had modestly higher expenses than women ($5987, P < .001). Across demographic groups, the presence of risk factors was associated with progressively higher lifetime expenses, with significant independent association of diabetes ($28,075, P < .001), overweight/obesity ($8816, P < .001), smoking ($3980, P = .009), and hypertension ($528, P = .02) with excess spending. ConclusionOur study suggests Black individuals have higher lifetime healthcare expenses, exaggerated by the substantially higher prevalence of risk factors, with differences emerging in older age.

INFINITY: A multicentre, single-arm, multi-cohort, phase II trial of tremelimumab and durvalumab as neoadjuvant treatment of patients with microsatellite instability-high (MSI) resectable gastric or gastroesophageal junction adenocarcinoma (GAC/GEJAC).

358 Background: In resectable GAC/GEJAC, MSI status is associated with better survival and potential lack of benefit from chemotherapy. Given the high responsiveness of MSI tumors to immunotherapy, neoadjuvant or definitive dual CTLA-4/PD(L)-1 inhibition may allow omission of chemotherapy or surgery. Methods: INFINITY is a multicentre, single-arm, multi-cohort phase II trial (NCT04817826) investigating the activity and safety of tremelimumab+durvalumab as neoadjuvant (Cohort 1) or definitive (Cohort 2) treatment for MSI, mismatch repair deficient (dMMR) and EBV-negative resectable GAC/GEJAC. In Cohort 1, patients (pts) received a 12-week treatment with single high dose tremelimumab 300 mg and durvalumab 1500 mg q4 weeks (T300/D) for 3 cycles followed by surgery. The primary endpoint was pCR rate (ypT0N0) with negative ctDNA after T300/D. Secondary endpoints: disease-free survival, overall survival, quality of life. Exploratory: correlation of pCR with clinical variables, PDL-1 CPS assessed by IHC 22C3, tumor mutational burden (TMB) by Foundation One, liquid biopsies and other biomarkers. Cohort 2 investigates non operative management after same treatment regimen. Results: Overall, 18 pts with MSI/dMMR resectable cT2-4 any N GAC/GEJAC were recruited in Cohort 1. One withdrew consent and 2 achieved a complete clinical-pathological response at radiology and endoscopy (ongoing) and refused surgery. Among 15 evaluable patients, 1 had disease progression and 14 underwent resection. pCR rate was 60% (9/15) and major-complete pathological response (&lt;10% viable cells) was 80%. All pts with pCR had negative ctDNA status pre-surgery. pCR rate was 1/6 (17%) in T4 vs 8/9 (89%) in T2-3 tumors (p=0.011), whereas no correlation was found with baseline N status. PDL-1 CPS was not associated with outcomes and TMB had a non-significant trend of correlation with pCR (median TMB 26 in non-pCR vs 40 in pCR group, p=0.2). Grade≥3 immune-related AEs occurred in 3 pts of safety population (n=18): colitis, pneumonitis, liver toxicity, all resolved with high dose steroids and did not impair surgery. Two pts died after surgery for other reasons than disease or AEs, whereas no disease relapses were observed in remaining pts. QoL and additional translational analyses on RNA-seq, digital spatial profiling and ctDNA monitoring will be presented. Conclusions: Pre-operative T300/D for 3 months was safe and provided promising proof of efficacy in MSI, dMMR GAC/GEJAC pts. These results open the way to investigate NOM in pts with clinical, pathological and molecular (ctDNA minimal residual disease) complete response after T300/D. Enrollment in Cohort 2 has started after IDMC evaluation and protocol. amendment to include only pts with cT2-3 tumors confirmed at staging laparoscopy. Clinical trial information: NCT04817826 .

Trial in progress: A phase 1, first-in-human, open-label, multicenter, dose-escalation and dose-expansion study of ASP3082 in patients with previously treated advanced solid tumors and KRAS G12D mutations.

TPS764 Background: Kirsten rat sarcoma (KRAS) G12D is a point mutation observed in various cancer types including pancreatic ductal cancer, colon adenocarcinoma, and lung cancers. ASP3082 is a novel small-molecule proteolysis-targeting chimeric degrader that binds to, and selectively targets, the KRAS G12D-mutated protein for degradation via recruitment of E3 ubiquitin ligase proteins. In preclinical studies, ASP3082 selectively degraded the KRAS G12D-mutated protein and showed growth inhibitory activity in KRAS G12D-mutated cancer cells but not in KRAS -wildtype cancer cells. Notable antitumor effects of ASP3082 have been demonstrated when intravenously administered weekly in mice xenografted with KRAS G12D-mutated cancer cells. Methods: This first-in-human, open-label, multicenter, phase 1 study evaluates the safety and tolerability of ASP3082 in patients with pancreatic cancer, colorectal cancer, non-small cell lung cancer or other solid tumors. Participants with unresectable, locally advanced, or metastatic solid tumor malignancy with documented KRAS G12D mutation are eligible for enrollment. Part 1 consists of dose-escalation cohorts of 3−12 patients receiving intravenous administration of ASP3082 in a 21-day cycle. Part 2 consists of random assignment of ≤20 patients into 2 cohorts with different ASP3082 dose levels to determine the recommended phase 2 dose. Additional tumor-specific expansion cohorts may enroll ≤20 participants per tumor type. Primary endpoints will evaluate safety and tolerability as noted by dose-limiting toxicities, adverse events, serious adverse events, laboratory test results, electrocardiograms, vital signs, physical exams, and Eastern Cooperative Oncology Group performance status. Secondary endpoints will evaluate objective response rate, duration of response, disease control rate per Response Evaluation Criteria in Solid Tumors version 1.1, pharmacokinetics of single and repeated doses of ASP3082, and changes in KRAS G12D in tumor samples. Exploratory objectives will evaluate potential biomarkers that may correlate with treatment outcomes. Tumor assessment follow-up will continue for ≤45 weeks or until progressive disease. Enrollment in Cohort 1 is complete, and enrollment to Cohort 2 began in September 2022. Clinical trial information: NCT05382559 .

A phase 1b, open-label, safety, pharmacokinetic, and pharmacodynamic study of an anti–super-enhancer triptolide analogue with nab-paclitaxel plus gemcitabine in patients with metastatic adenocarcinoma of the pancreas.

TPS769 Background: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive malignancies and the leading cause of cancer-related death in the world, although recent advances in chemotherapies for metastatic PDAC provide better clinical outcomes. Triptolide (TPL), a natural compound isolated from the Chinese herb has shown promising antitumor activity though the inhibition of HSP70 in a number of preclinical models including pancreatic cancer. In addition, TPL disrupt super-enhancer networks in pancreatic cancer cells and cancer-associated fibroblasts to reprogram the cellular cross talk and signaling in tumor environment. Minnelide (ML), water soluble, novel prodrug of TPL, was recently reported to show promising activity in patients with gastrointestinal malignancies in phase I trial. Based on the strong synergism with nab-paclitaxel (A) plus gemcitabine (G), we designed this phase 1b study. Methods: Eligible patients will have histologically confirmed PDAC and have failed first-line FOLFIRINOX with adequate organ function and performance status. This study is composed of two parts; dose escalation and dose expansion. In the dose escalation part (phase 1b), different dose levels of ML (0.25 mg to 1.0 mg once a day) in combination with A plus G will be tested with 3+3 subjects recruited in each cohort. Patients in each cohort will receive ML 0.25 to 1.0 mg orally once a day on days 1-5, 8-12 and 15-19 with A 100-125mg/m2 intravenously plus G 800-1000mg/m2 IV on days 1, 8 &amp; 15 of a 28-day cycle. The primary endpoint is to determine the safety of ML with A+G and to determine PFS by Independent Radiological Review (IRR). Once an MTD reaches, a total of 18 patients will be enrolled at MTD level in dose expansion part. The key secondary endpoints are to determine the pharmacokinetics, pharmacodynamics effect, the percentage of patients who achieve an objective confirmed overall response by IRR, maximum tolerated dose and recommended dose for phase 2 of ML in combination of A+G. As of September 2022, the study is just initiated for patient enrollment in first cohort. This study is prospectively registered on ClinicalTrials.gov, NCT05557851. Clinical trial information: NCT05557851 .

Prepregnancy Migraine, Migraine Phenotype, and Risk of Adverse Pregnancy Outcomes.

Migraine is a highly prevalent neurovascular disorder among reproductive-aged women. Whether migraine history and migraine phenotype might serve as clinically useful markers of obstetric risk is not clear. The primary objective of this study was to examine associations of prepregnancy migraine and migraine phenotype with risks of adverse pregnancy outcomes. We estimated associations of self-reported physician-diagnosed migraine and migraine phenotype with adverse pregnancy outcomes in the prospective Nurses' Health Study II (1989-2009). Log-binomial and log-Poisson models with generalized estimating equations were used to estimate relative risks (RRs) and 95% CIs for gestational diabetes mellitus (GDM), preeclampsia, gestational hypertension, preterm delivery, and low birthweight. The analysis included 30,555 incident pregnancies after cohort enrollment among 19,694 participants without a history of cardiovascular disease, diabetes, or cancer. After adjusting for age, adiposity, and other health and behavioral factors, prepregnancy migraine (11%) was associated with higher risks of preterm delivery (RR = 1.17; 95% CI = 1.05-1.30), gestational hypertension (RR = 1.28; 95% CI = 1.11-1.48), and preeclampsia (RR = 1.40; 95% CI = 1.19-1.65) compared with no migraine. Migraine was not associated with low birthweight (RR = 0.99; 95% CI = 0.85-1.16) or GDM (RR = 1.05; 95% CI = 0.91-1.22). Risk of preeclampsia was somewhat higher among participants with migraine with aura (RR vs no migraine = 1.51; 95% CI = 1.22-1.88) than migraine without aura (RR vs no migraine = 1.30; 95% CI = 1.04-1.61; p-heterogeneity = 0.32), whereas other outcomes were similar by migraine phenotype. Participants with migraine who reported regular prepregnancy aspirin use had lower risks of preterm delivery (<2×/week RR = 1.24; 95% CI = 1.11-1.38; ≥2×/week RR = 0.55; 95% CI = 0.35-0.86; p-interaction < 0.01) and preeclampsia (<2×/week RR = 1.48; 95% CI = 1.25-1.75; ≥2×/week RR = 1.10; 95% CI = 0.62-1.96; p-interaction = 0.39); however, power for these stratified analyses was limited. Migraine history, and to a lesser extent migraine phenotype, appear to be important considerations in obstetric risk assessment and management. Future research should determine whether aspirin prophylaxis may be beneficial for preventing adverse pregnancy outcomes among pregnant individuals with a history of migraine.

Factors Associated with Hemodialysis Vascular Access Failure: A retrospective study in Colombia

Introduction: Vascular access (VA) remains a major source of morbidity for hemodialysis patients (HD). Few data sources adequately capture longitudinal patency of the VA. This study aimed to evaluate VA failure and its related factors in HD patients. Methods: A retrospective cohort study of 985 incident hemodialysis patients treated in clinics of BRCS in Colombia, from January 1rst ,2016, until December 3 of the same year, was done. The cohort's enrollment was on day 1 of HD, and with follow-up for up to 15 months. Association among a group of independent variables and time to failure of the VA was performed, and adjusted by baseline variables using a Cox regression model. Results: A total of 985 patients were included in the study, requiring 1774 procedures of vascular access during follow-up. The mean age was 61 ± 15.6 years. At day 1, 15% were dialyzing with an arteriovenous fistula (AVF) or AVG; and at day 90, this proportion had increased to 70%. The rate of vascular access procedure was 1.95 per patients-year, 95% CI 1.86-2.04. The rate of vascular access failure was 0.66 per patients-year, 95% CI 0.61–0.72. Risk factors for failure in AVF/AVG were age &gt; 65 (p= 0.008), diabetes (p= 0.019), female sex (p= 0.002) rural housing (p&lt;0.0001) and higher hemoglobin (p= 0.021). Conclusion: Vascular access failure and the requirement for procedures associated with it are frequent in the dialysis population. Several risk factors, some of them modifiable, are related to vascular access failure.