Clinical Trials Of Novel Therapies Research Articles

Flow inefficiencies in non-obstructive HCM revealed by kinetic energy and hemodynamic forces on 4D-flow CMR.

Patients with non-obstructive hypertrophic cardiomyopathy (HCM) exhibit myocardial changes which may cause flow inefficiencies not detectable on echocardiogram. We investigated whether left ventricular (LV) kinetic energy (KE) and hemodynamic forces (HDF) on 4D-flow cardiovascular magnetic resonance (CMR) can provide more sensitive measures of flow in non-obstructive HCM. Ninety participants (70 with non-obstructive HCM and 20 healthy controls) underwent 4D-flow CMR. Patients were categorized as phenotype positive (P+) based on maximum wall thickness (MWT) ≥ 15 mm or ≥13 mm for familial HCM, or pre-hypertrophic sarcomeric variant carriers (P-). LV KE and HDF were computed from 4D-flow CMR. Stroke work was computed using a previously validated non-invasive method. P+ and P- patients and controls had comparable diastolic velocities and LV outflow gradients on echocardiography, LV ejection fraction, and stroke volume on CMR. P+ patients had greater stroke work than P- patients, higher systolic KE compared with controls (5.8 vs. 4.1 mJ, P = 0.0009), and higher late diastolic KE relative to P- patients and controls (2.6 vs. 1.4 vs. 1.9 mJ, P < 0.0001, respectively). MWT was associated with systolic KE (r = 0.5, P < 0.0001) and diastolic KE (r = 0.4, P = 0.005), which also correlated with stroke work. Systolic HDF ratio was increased in P+ patients compared with controls (1.0 vs. 0.8, P = 0.03) and correlated with MWT (r = 0.3, P = 0.004). Diastolic HDF was similar between groups. Sarcomeric variant status was not associated with KE or HDF. Despite normal flow velocities on echocardiography, patients with non-obstructive HCM exhibited greater stroke work, systolic KE and HDF ratio, and late diastolic KE relative to controls. 4D-flow CMR provides more sensitive measures of haemodynamic inefficiencies in HCM, holding promise for clinical trials of novel therapies and clinical surveillance of non-obstructive HCM.

Racial/ethnic representation and disparities in preclinical cancer models.

1601 Background: Patient-derived xenograft models (PDXs) recapitulate tumor characteristics credibly and have become a standard for preclinical inquiries that form the basis of clinical trials of novel therapies in oncology. While ample evidence reveals racial/ethnic disparities in cancer care delivery and clinical research, limited data exists regarding racial composition of available PDXs. We sought to define the extent of racial/ethnic representation and disparities among existing PDXs. Methods: Data regarding available PDXs was gathered from the publicly accessible CancerModels.org website ( https://www.cancermodels.org/overview ). Seven members of the research team were involved in data extraction. Information on race/ethnicity (White, Black, Hispanic, Asian), sex, age, and cancer type were recorded. The primary objective was to determine the racial/ethnic composition of PDX models and compare this to racial/ethnic demographics of cancer patients, for which we used US population-based cancer estimates calculated using National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER Incidence Data, 11/2022 Submission (1975 - 2020), SEER 22 registries). Descriptive statistics were used. Proportions were compared using Fischer’s exact test or Chi-squared tests with Yates' correction (odds-ratio [OR] and 95% confidence intervals [95%CI] or Woolf logit interval) were reported. Results: We reviewed 4597 unique PDXs across 33 SEER cancer sites spanning 11 oncology sub-specialties. Of these, 55% models were derived from males and age groups were (years): &lt; 20: 6%; 20-70: 69% and ≥ 70: 25%. Most common cancer sites represented were colorectal (26%), lung (12%), breast (9%), melanoma (9%) and leukemia (7%). Race/ethnicity was not reported in 3395 (73.9%) cases. Racial/ethnic composition of the remaining models was Whites (80.9%), Blacks (7.3%), Hispanics (6.4%) and Asians (5.4%). Compared with their respective proportion of US cancer incidence (69.9%, 10.9%, 13.2% and 5.9%, respectively), these models were over-representative for Whites (OR: 1.82, 95%CI: 1.6-2.1, P &lt; 0.001) and under-represented Blacks (OR: 0.64, 95%CI: 0.5-0.8, P &lt; 0.001) and Hispanics (OR: 0.45, 95%CI: 0.4-0.6, P &lt; 0.001) but not Asians (OR: 0.89, 95%CI: 0.7-1.2, P = 0.43). Similar trends were seen in subgroups focused by cancer site. Among colorectal (N = 1201) models, race/ethnicity was reported for 17.2% of cases and Blacks (OR: 0.52; 55.7% of expected; P = 0.014) and Hispanics (OR: 0.57; 60.8% of expected; P = 0.015) were underrepresented compared to Whites (OR: 1.82; 116% of expected; P &lt; 0.001). Conclusions: Race/ethnicity are infrequently reported for PDX models. Minority races/ethnicities (Blacks and Hispanics) are underrepresented in preclinical models compared to their burden of cancer incidence. There is a need to develop a diverse repertoire of preclinical models to ensure inclusivity and guide equitable research.

Impact of trial eligibility criteria on enrollment to KRASG12C inhibitor trials in patients with non-small cell lung cancer.

11012 Background: Clinical trials of novel therapies should enroll a population that reflects patients (pts) who might receive the drug upon FDA approval. In 2017 ASCO proposed modifications to common eligibility criteria (EC) to increase the generalizability of trial findings. Despite this, barriers to trial enrollment in the recent era of molecularly-targeted therapies are not well-characterized. We examined a cohort of non-small cell lung cancer (NSCLC) pts with KRAS G12C mutations to determine whether EC for trials of KRAS G12C inhibitors allowed enrollment of patients seen as part of routine care at an academic medical center. Methods: We extracted EC for Phase I-III trials among six KRAS G12C inhibitors: sotorasib, adagrasib, LY3537982 , divarasib, JDQ443 and RMC-6291. We retrospectively reviewed pts with NSCLC and G12C mutations detected on universal, NGS-based testing of NSCLCs at Columbia University Irving Medical Center (CUIMC) from 2020 to 2023. We defined dates of disease progression and evaluated pts for clinical trial eligibility for each line of treatment. Pts were deemed trial-eligible if they met all EC, borderline if they had 1 laboratory value &lt; 20% from cutoff, or ineligible. The association between baseline factors including self-reported race, sex, and age with rates of eligibility were evaluated with chi-squared tests. Results: EC criteria for 14 trials were characterized. EC were similar across trials regardless of agent or phase and did not substantially change over time; 1 Phase III trial had expanded EC from the Phase I/II trials. Of 1172 patients with NSCLC, we identified 185 pts with G12C mutations (15%), including 69 pts with advanced or metastatic disease. Of these, 19% (13/69) would have been eligible for any G12C trial, 15% (10/69) were borderline, and 67% (46/69) were ineligible. 9% (6) would have qualified for only 1 of the trials. The most common reasons for ineligibility were poor performance status (54% [30/56]), excluded comorbidities (25% [14/56]), and renal dysfunction (27% [15/56]). Among patients who received therapy after FDA accelerated approval (N = 22), only 23% (5) would have been eligible for the related Phase III trial. Conclusions: Our findings suggest that most patients with KRAS G12C mutations would not have been eligible for relevant trials, including &gt; 75% of patients who received KRAS G12C inhibitors off-trial after accelerated FDA approval. EC did not expand after early phase trials demonstrated evidence of safety. These data should guide sponsor and FDA considerations in the development of trial protocols for targeted therapies, as fewer barriers to trial participation would enable trials to be completed more quickly and would improve the generalizability of trial results.

International exchange on the clinical practice and research of rheumatic skin diseases: A report of the 5th International Conference of Cutaneous Lupus Erythematosus.

The 5th International Conference of Cutaneous Lupus Erythematosus was held in Tokyo, Japan on May 9 and 10, 2023. The latest topics on the pathogenesis, diagnosis, assessment, and treatment of cutaneous lupus erythematosus, dermatomyositis, and scleroderma (systemic sclerosis, morphea) were presented by experts in each field and new developments discussed. In these rheumatic skin diseases, many clinical trials of novel therapies targeting cytokines, signaling molecules, plasmacytoid dendritic cells, B cells, and other molecules are currently underway, and standardization of outcome assessment was discussed. In addition, the selection of the therapeutic agents available for the diversity of each case is becoming more important, together with the ongoing pathophysiological analysis of the diseases. The achievements of this conference will further promote the development of clinical practice and research in rheumatic skin diseases through international exchange among researchers. We hope that by reporting a summary of the conference in this manuscript, we can share its contents with readers.

The National Israeli Registry for Oculo-Pharyngeal Muscular Dystrophy (IsrO-PMD): rationale and design

BackgroundOculo-pharyngeal muscular dystrophy (OPMD) is a rare disease, caused by trinucleotide repeat expansion in the PABPN1 gene, inherited in an autosomal dominant (AD) manner. Its main features are eyelid ptosis and dysphagia, which manifest at the end of the fifth decade of life. Other symptoms include proximal muscle weakness and bulbar muscle weakness. Although OPMD is prevalent worldwide, a higher prevalence has been reported in the Jewish population from Bukhara. Currently, no specific drugs are available for OPMD.ObjectiveOur National Israeli Registry for Oculo-Pharyngeal Muscular Dystrophy (IsrO-PMD) study aims to provide a framework for the assessment and documentation of the natural history of the diseases as we as a multi-disciplinary management of patients with OPMD. The IsrO-PMD may be the cornerstone of future clinical trials for novel therapies for OPMD.MethodsThe IsrO-PMD is a national prospective registry that involves non-interventional data collection based on the Global Rare Diseases Patient Registry (GRDPR) and data repository standard. Inclusion criteria are clinical diagnosis of OPMD and positive genetic testing. Patients who meet inclusion criteria will be examined using a series of multi-disciplinary investigations and questionnaires including periodic follow-up examinations. Specific attention is given to comprehensive neurological, swallowing, and ophthalmological evaluations.DiscussionThe establishment of this national registry will enhance our understanding of the natural history of OPMD, establish quality care benchmarks, and develop treatment strategies in addressing the multi-system pathophysiology of the disease and associated comorbidities. Our registry provides a foundation for the use of new cutting-edge treatments as they become available.

The Present and Future of Neoadjuvant and Adjuvant Therapy for Locally Advanced Gastric Cancer.

Gastric cancer is a highly prevalent and lethal disease worldwide. Given the insidious nature of the presenting symptoms, patients are frequently diagnosed with advanced, unresectable disease. However, many patients will present with locally advanced gastric cancer (LAGC), which is often defined as the primary tumor extending beyond the muscularis propria (cT3-T4) or having nodal metastases (cN+) disease and without distant metastases (cM0). LAGC is typically treated with surgical resection and perioperative chemotherapy. The treatment of LAGC remains a challenge, given the heterogeneity of this disease, and the optimal multimodal treatment regimen may be different for different LAGC subtypes. However, many promising treatments are on the horizon based on knowledge of molecular subtypes and key biomarkers of LAGC, such as microsatellite instability, HER2, Claudin 18.2, FGFR2, and PD-L1. This review will expand upon the discussion of current standard neoadjuvant and adjuvant therapies for LAGC and explore the ongoing and future clinical trials for novel therapies, with information obtained from searches in PubMed and ClinicalTrials.gov.

Social Cognition in Behavioral Variant Frontotemporal Dementia and Pathological Subtypes: A Narrative Review.

Behavioral variant frontotemporal dementia (bvFTD) belongs to the spectrum of frontotemporal lobar degeneration (FTLD) and is characterized by frontal dysfunction with executive deficits and prominent socioemotional impairments. Social cognition, such as emotion processing, theory of mind, and empathy may significantly impact daily behavior in bvFTD. Abnormal protein accumulation of tau or TDP-43 are the main causes of neurodegeneration and cognitive decline. Differential diagnosis is difficult due to the heterogeneous pathology in bvFTD and the high clinicopathological overlap with other FTLD syndromes, especially in late disease stages. Despite recent advances, social cognition in bvFTD has not yet received sufficient attention, nor has its association with underlying pathology. This narrative review evaluates social behavior and social cognition in bvFTD, by relating these symptoms to neural correlates and underlying molecular pathology or genetic subtypes. Negative and positive behavioral symptoms, such as apathy and disinhibition, share similar brain atrophy and reflect social cognition. More complex social cognitive impairments are probably caused by the interference of executive impairments due to increasing neurodegeneration. Evidence suggests that underlying TDP-43 is associated with neuropsychiatric and early social cognitive dysfunction, while patients with underlying tau pathology are marked by strong cognitive dysfunction with increasing social impairments in later stages. Despite many current research gaps and controversies, finding distinct social cognitive markers in association to underlying pathology in bvFTD is essential for validating biomarkers, for clinical trials of novel therapies, and for clinical practice.

What patients want to know about genetic testing for kidney disease.

Previously, genetic kidney disease was often recognised when family members shared clinical features. Now, many genetic kidney diseases are diagnosed when testing demonstrates a pathogenic variant in a gene associated with the disease. Detection of a genetic variant also identifies the mode of inheritance, and suggests family members at risk. The genetic diagnosis has additional advantages for patients and their doctors even when no specific treatment is available since it often indicates likely complications in other organs, the clinical course, and management strategies. Generally, informed consent is required for genetic testing because the result provides "certainty" with implications for the patient, and their family, and possibly for employment, and for life and medical insurance, as well as having social, ethical, and financial consequences. Patients want to be provided with a copy of their genetic test result in a format that is comprehensible and to have the result explained. Their at-risk family members should be sought out and offered genetic testing too. Patients who allow the sharing of their anonymised results in registries help advance everyone's understanding of these diseases and expedite a diagnosis in other families. Patient Support Groups not only help normalise the disease but also educate patients, and update them on recent advances and new treatments. Some registries encourage patients to themselves submit their genetic variants, clinical features and response to treatment. More and more often, patients may volunteer for clinical trials of novel therapies including some that depend on a genetic diagnosis or variant type.

Danazol Treatment for Thrombocytopenia in Myelodysplastic Syndromes: Can an "Old-fashioned" Drug be Effective?

Danazol Treatment for Thrombocytopenia in Myelodysplastic Syndromes: Can an "Old-fashioned" Drug be Effective?

Abstract 114: Changes In Quantitative Susceptibility Mapping On Magnetic Resonance Imaging During Prospective Follow-Up Of Cavernous Angiomas With Symptomatic Hemorrhage In Trial Readiness Project

Background: Quantitative susceptibility mapping (QSM) is a measure of iron content, and ≥6% increase in QSM has been correlated with new hemorrhage in previously stable cavernous angiomas. Longitudinal changes in QSM are not known in cavernous angiomas with symptomatic hemorrhage (CASH) with high rates of rebleeding and are the targets of novel pharmacotherapies. In a prospective multisite Trial Readiness project (clinicaltrials.gov NCT03652181), QSM is longitudinally assessed. Methods: Trial eligible subjects with CASH in the prior year and not undergoing lesion resection or radiation, were enrolled. Mean QSM of CASH lesion was acquired at baseline and at 1 and 2 year planned follow-ups. Relative change in mean lesional QSM during each follow-up year was assessed, and any symptomatic hemorrhage (SH), asymptomatic changes (AC; defined as subclinical bleed or growth) in the lesion during the same epoch. Results: Paired QSM assessments were completed to date in 99 CASH lesions (67 year 1, and 32 year 2) and are reported herein. Four SH and 6 ACs occurred during 1 st follow-up year, and 3 SH during 2 nd year. QSM increased in 54 lesion-years, decreased in 44, and remained stable in 1. The % lesional QSM change in year 1 was significantly higher than that observed in year 2 (mean +9.33, SD 37.52 vs. +5.20; SD= 24.86; p=0.05; Spearman correlation ρ -0.36). CAs with clinical SH or AC had a significantly higher % QSM change than lesions without (mean +28.03, SD 17.77 vs. +4.97, SD= 34.75; p=0.0014). All 13 lesions with SH/AC demonstrated a QSM increase ≥6% while 31 of 86 (36%) lesions with no clinical events had a ≥6% QSM increase. Conclusion: QSM change of ≥6% is present in every CASH lesion manifesting a new SH or AC (100% specificity), and is more common than clinical events (3.4X higher sensitivity). The biomarker can hence be used as a more sensitive categorical outcome than SH or AC in clinical trials of novel therapies aimed at bleeding in CASH lesions. Effect of an intervention on % QSM change may also be proposed as a time-averaged difference between 2 arms using a repeated measures analysis implemented as an unadjusted linear mixed model. These results are the basis of application for certification by the U.S F.D.A. of QSM as a monitoring biomarker of drug effect in CASH.

P268 Development and validation of a novel composite index for the assessment of endoscopic and histologic disease activity in pouchitis: The Atlantic pouchitis index.

Abstract Background Several instruments have been used in clinical trials of pouchitis to define eligibility criteria and outcome measures but have not been formally validated. A need remains for a validated pouchitis instrument that is suitable for use in novel drug development. We developed and internally validated the novel composite Atlantic pouchitis index (API) for the assessment of endoscopic and histologic disease activity in patients with pouchitis. Methods Paired baseline and week 10 endoscopic videos and histologic images were obtained from 98 patients with chronic antibiotic-refractory pouchitis who participated in a randomised placebo-controlled trial of alicaforsen enema (ClinicalTrials.gov identifier: NCT02525523). For each pair, 4 endoscopists and 3 pathologists scored 59 items. These items included 51 component items from 11 indices (4 endoscopic, 4 histologic, 3 composite) identified in a prior systematic review and 8 additional items identified in a prior Research and Development/University of California Los Angeles appropriateness methodology exercise. The reliability of all measures was assessed using intraclass correlation coefficients (ICCs) and interpreted according to Landis and Koch benchmarks (slight, 0.00-0.20; fair, 0.21-0.40; moderate, 0.41-0.60; substantial, 0.61-0.80; almost perfect, 0.81-1.00). Responsiveness was evaluated using the area under the receiver operating characteristic curve (AUC). The API was developed using linear regression with a 100-mm visual analogue scale (VAS) of pouchitis activity as an anchor. Results Among all measures assessed for reliability and responsiveness, the simple endoscopic score for Crohn’s disease (SES-CD) and the Robarts histopathology index (RHI) were selected for inclusion in the API. The total API score ranges from 0 to 69, with higher scores indicating more severe disease activity, and can be calculated as API = (3 × SES-CD [0 to 12]) + (1 × RHI [0 to 33]). The API demonstrated almost perfect intra-rater reliability (ICC, 0.88 [95% CI: 0.81, 0.92]), substantial inter-rater reliability (ICC, 0.72 [95% CI: 0.60, 0.79]), and a high correlation with the VAS (r = 0.84 [95% CI: 0.76, 0.89]). Index responsiveness in detecting meaningful improvements in disease activity was higher for the API (AUC, 0.95 [95% CI: 0.89, 0.98]) than for existing endoscopic indices (∆AUC, 0.09-0.24; P≤0.005) (Table). Conclusion The novel API is a composite index of endoscopic (SES-CD) and histologic disease activity (RHI) that is reliable and significantly more responsive than existing endoscopic pouchitis scoring systems. The API is a promising tool for use in clinical trials of novel therapies for pouchitis. Further validation is needed in independent datasets.

Pharmacological neuroprotection and clinical trials of novel therapies for neonatal peri-intraventricular hemorrhage: a comprehensive review.

Peri-intraventricular hemorrhage (PIVH) is a serious condition for preterm infants, caused by traumatic or spontaneous rupture of the germinal matrix (GM) capillary network in the cerebral ventricles. It is a common source of morbidity and mortality in neonates, and risk correlates with earlier delivery, low birth weight, maternal-fetal infection, and vital sign derangements, among others. PIVH typically occurs in the first 72h of life, and symptoms, when present, manifest most commonly within the first week of life. Prevention remains the primary goal in management, predominantly via prolonging of gestation. Current therapy protocols are center-dependent without consistent consensus guidelines, but infant positioning, homeostatic stabilization, and neuroprotection offer potential options. In this update of pharmacologic neuroprotective therapies for PIVH, we highlight commonly utilized therapies and review the investigative literature. Further multi-institutional clinical trials and basic research studies are required.

Hypomethylating Therapy Does Not Improve Outcome of Therapy-Related Myeloid Neoplasm Including TP53 Mutated and Complex Karyotype Subgroups

Introduction: Therapy related myeloid neoplasm (t-MN) is a rare but devastating complication of cytotoxic therapy used for management of unrelated malignancy or autoimmune diseases. Therapeutic options for t-MN are limited and although hypomethylating agents (HMA) are frequently used, the benefit of it in t-MN is unclear. There are no prospective trials of HMA in t-MN and published experience is based on retrospective analysis of small number of cases (n=42 to 54). The aim of this study was to assess the efficacy of HMA therapy in t-MN patients and evaluate predictors for it.Methods: t-MN patients managed with first line HMA therapy were analyzed. This study was approved by the participating institutional review board. Criteria for inclusion were a pathologically confirmed diagnosis of t-MN based on WHO 2016 criteria, age >18 years, and ≥1 cycle of decitabine or azacitidine.Patient characteristics were summarized by frequency (percentage). Overall survival was calculated from the time of starting azacitidine to last follow up or death date using Kaplan-Meier analysis. Multivariable analysis was performed using Cox proportional hazard model. Statistical analysis was performed using R program and significance was defined as P<0.05.Results: Of the 554 t-MN patients analyzed, 184 (33%) patients were treated with HMA as the first line therapy and were included in the study. Median age at t-MN diagnosis was 70 (IQR 64-75) years and 112 (60%) patients were male. At the time of diagnosis, 84% (n=154) and 16% (n=30) patients were classified as t-MDS and t-AML and 47% (87/184) and 46% (49/107) of the evaluable patients had complex karyotype and TP53 somatic mutations (TP53 Mut) respectively. Azacitidine (n=145, 79%) was most frequently used HMA followed by decitabine (n=39, 21%). Median survival of the whole cohort since t-MN diagnosis was 13.2 months.At the time of analysis further treatment details were available for 78 patients and outcome of these patients were compared with primary MDS (p-MDS) and oligoblastic AML managed at the same institute. Completion of six-cycles of HMA (50% vs. 62%; P=0.07) and overall response rate (47 vs. 50%, P=0.22) was not significantly different between t-MN and p-MDS. However, median OS of t-MN was significantly poor compared to p-MDS (10 vs. 20 months, P=0.0004; Figure 1A).In t-MN patients treated with HMA as the first-line agent, median OS was significantly shorter in t-AML compared to t-MDS (7 vs.10 months, P=0.04; Figure 1B). Median OS was significantly shorter in patients with TP53 Mut and complex karyotype (Figure 1C-D). In Cox proportional hazard analysis, t-AML and complex karyotype were independently associated with poor outcome.Conclusion: This study demonstrates significantly poor outcome of t-MN patients treated with HMA therapy as first line. The outcome is particularly poor in t-AML and patients with complex karyotype and TP53 Mut. Hence there is urgent need for clinical trials of novel therapies for t-MN. [Display omitted] DisclosuresSharplin: Kite Gilead: Honoraria; Novartis: Other: Travel Support. Ross: Keros Therapeutics: Consultancy, Honoraria; Bristol Myers Squib: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hiwase: Novartis: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees.

Utility of Blue Light Cystoscopy for Post-bacillus Calmette-Guérin Bladder Cancer Recurrence Detection: Implications for Clinical Trial Recruitment and Study Comparisons.

The utility of blue light cystoscopy (BLC) in patients receiving bacillus Calmette-Guérin (BCG) during post-treatment cystoscopy is not well understood. Our objective was to determine if BLC improves recurrence detection in patients with non-muscle invasive bladder cancer (NMIBC) undergoing BCG. Using the prospective multi-institutional Cysview® Registry (2014-2019), patients with NMIBC who received BCG within 1 year prior to BLC were identified. Primary outcomes were recurrences and whether lesions were detected on white light cystoscopy (WLC), BLC or both. We calculated the percentage of cystoscopies with recurrences that were missed with WLC alone. The cystoscopy-level BLC false-positive rate was the proportion of cystoscopies with biopsies only due to BLC suspicious lesions without recurrence. Of 1,703 BLCs, 282 cystoscopies were in the analytic cohort. The overall recurrence rate was 45.0% (127). With only WLC, 13% (16/127) of recurrences would have been missed as 5.7% (16/282) of cystoscopies performed had recurrence only identified with BLC. Among 16 patients with recurrence missed with WLC, 88% (14) had carcinoma in situ. The cystoscopy-level BLC false-positive rate was 5% (15). BLC helped detect recurrences after recent BCG that would have been missed with WLC alone. Providers should consider BLC for high-risk patients undergoing BCG and should discuss the risk of false-positives with these patients. As clinical trials of novel therapies for BCG-unresponsive disease increase and there are no clear guidelines on BLC use for post-treatment cystoscopies, it is important to consider how variable BLC use could affect enrollment in and comparisons of these studies.

MA15.05 Rates of Guideline-Concordant Surgery and Adjuvant Chemotherapy Among Patients in The U.S. ALCHEMIST Study (Alliance)

The standard of care for resectable non-small cell lung cancer (NSCLC) includes anatomic surgical resection with adequate lymph node dissection and adjuvant chemotherapy for appropriate patients. Historically, many patients with early-stage NSCLC have not received such guideline-concordant therapy. Longstanding disparities have also existed in the delivery of quality cancer care by sociodemographic factors such as race and ethnicity. This could impact interpretation of adjuvant therapy trials. In this descriptive analysis, we examined rates of guideline-concordant treatment among patients enrolled in ALCHEMIST, a large U.S.-wide screening trial to facilitate enrollment to targeted adjuvant treatment trials for resectable NSCLC, enrolling at 754 sites. Patients who enrolled in ALCHEMIST (Alliance A151216) from August 18, 2014-April 1, 2019 who did not enroll in a therapeutic adjuvant therapy clinical trial were included; these patients had stage IB-IIIA disease (AJCC 7th edition), with tumors at least 4 cm in size and/or positive lymph nodes. Four outcomes are reported: whether patients (1) had adequate lymph node dissection per National Comprehensive Cancer Network criteria (≥ one N1 nodal station plus ≥ three N2 nodal stations); (2) received any adjuvant chemotherapy; (3) received any cisplatin-based adjuvant chemotherapy; and (4) received at least 4 cycles of adjuvant chemotherapy. Associations between these binary outcomes and sociodemographic variables were explored using unadjusted modified Poisson regression models accounting for trial site-level correlation. 2,834 patients were analyzed; 53.4% had adequate lymph node dissection; 57.1% received any adjuvant chemotherapy; 34.1% received any cisplatin-based adjuvant chemotherapy; and 43.7% received at least four cycles of adjuvant platinum-based chemotherapy. The distribution of treatment by key clinical and demographic characteristics is provided in Table 1; adjuvant chemotherapy was delivered more often to patients who were younger, had more advanced stage, had non-squamous NSCLC, and did not have EGFR-mutant tumors. Rates were similar across categories of race and ethnicity. Many patients with early-stage NSCLC did not receive adequate lymph node dissection or adjuvant chemotherapy despite indications for such treatment, even among patients who consented for testing to inform eligibility for an adjuvant therapy clinical trial. No substantial disparities in treatment were observed by race or ethnicity in this clinical trial cohort, contrary to historical patterns in population-based cohorts. Efforts are needed to optimize utilization of therapies with proven benefit for early-stage NSCLC. These results may inform the generalizability of clinical trials of novel therapies in the adjuvant setting. Support: U10CA180821, U10CA180882; U10CA180820 (ECOG-ACRIN); https://acknowledgments.alliancefound.org; Clinicaltrials.gov Identifier: NCT02194738

Health-related quality of life data collected in chimeric antigen receptor T-cell (CAR-T) therapy clinical trials

IntroductionChimeric antigen receptor T-cell (CAR-T) therapy represents a novel approach to cancer treatment, particularly advanced cancer. Much of the current evidence for the effectiveness of these therapies is associated with considerable uncertainty. This uncertainty poses a challenge for decision-makers and health systems responsible for granting patients access to these therapies. While the stage of development of the technology is a component of this uncertainty, it can be reduced with relevant data collection alongside clinical trials that is meaningful to patients and decision-makers. The objective of this research was to investigate the frequency with which HRQoL data is collected in currently registered clinical trials investigating CAR-T cancer treatment. MethodsWe searched for current CAR-T clinical trials at a registry compiled at United States National Institutes of Health National Library of Medicine (NLM) database. Trials were required to be active, recruiting, or completed. Trials were required to be phase I-IV, listed as ‘interventional’, and specific to cancer treatment. ResultsThere were 424 clinical trials that were included in our analysis. The majority of these trials (76 %) were investigating CAR-T therapy in haematological malignancies. Of the included studies, only 29 (6.8 %) included HRQoL as a primary or secondary outcome measure. Only 25 (5.9 %) trials reported collecting data on overall survival. ConclusionsThis investigation into clinical trials for CAR-T therapies has shown a failure to collect valuable HRQoL data. Sponsors of clinical trials need to appreciate that clinical trials for novel therapies need to collect relevant data that is paramount to informing decision-making and providing access to patients. Policy statementThe effectiveness of innovative cancer therapies, such as CAR-T, remains associated with considerable uncertainty. This uncertainty can be reduced for decision-makers via the collection of critical HRQoL data. Sponsors of clinical trials should be incentivized to collect these data, particularly where the intention is to use that trial for a reimbursement submission and decision..

2021 update on clinical trials in β-thalassemia.

The treatment landscape for patients with β-thalassemia is witnessing a swift evolution, yet several unmet needs continue to persist. Patients with transfusion-dependent β-thalassemia (TDT) primarily rely on regular transfusion and iron chelation therapy, which can be associated with considerable treatment burden and cost. Patients with non-transfusion-dependent β-thalassemia (NTDT) are also at risk of significant morbidity due to the underlying anemia and iron overload, but treatment options in this patient subgroup are limited. In this review, we provide updates on clinical trials of novel therapies targeting the underlying pathology in β-thalassemia, including the α/non-α-globin chain imbalance, ineffective erythropoiesis, and iron dysregulation.

Type-2 airway inflammation in mild asthma patients with high blood eosinophils and high fractional exhaled nitric oxide.

Type‐2 (T2) inflammation is a characteristic feature of asthma. Biological therapies have been developed to target T2‐inflammation in asthma. IL‐13 is a key component of T2‐inflammation in asthma, driving mucus hypersecretion, IgE‐induction, and smooth muscle contraction. Early phase clinical trials for treatments that target T2‐inflammation require biomarkers to assess pharmacological effects. The aim of this study was to examine levels of IL‐13 inducible biomarkers in the airway epithelium of patients with mild asthma compared to healthy controls. Ten patients with mild asthma with high blood eosinophil and high fractional exhaled nitric oxide (FeNO) were recruited, and six healthy subjects. Blood eosinophil and FeNO reproducibility was assessed prior to bronchoscopy. Epithelial brushings were collected and assessed for IL‐13 inducible gene expression. Blood eosinophil and FeNO levels remained consistent in both patients with asthma and healthy subjects. Of the 11 genes assessed, expression levels of 15LOX1, POSTN, CLCA1, SERPINB2, CCL26, and NOS2 were significantly higher in patients with asthma compared to healthy controls. These six genes, present in patients with mild asthma with T2 inflammation, have the potential to be used in translational early phase asthma clinical trials of novel therapies as bronchial epithelial biomarkers.

Monitoring Immune Responses in IgA Nephropathy: Biomarkers to Guide Management.

IgA nephropathy (IgAN) is the commonest biopsy-reported primary glomerulonephritis worldwide. It has an incidence which peaks among young adults, and 30 to 40% of patients’ progress to end stage kidney disease within twenty years of diagnosis. Ten-year kidney survival rates have been reported to be as low as 35% in some parts of the world. The successful management of IgAN is limited by an incomplete understanding of the pathophysiology of IgAN and a poor understanding of how pathophysiology may vary both from patient to patient and between patient groups, particularly across races. This is compounded by a lack of rigorously designed and delivered clinical trials in IgAN. This is slowly changing, with a number of Phase 2 and 3 clinical trials of novel therapies targeting a number of different putative pathogenic pathways in IgAN due to report in the next 5 years. From our current, albeit limited, understanding of the pathophysiology of IgAN it is unlikely a single therapy will be effective in all patients with IgAN. The successful management of IgAN in the future is, therefore, likely to be reliant on targeted therapies, carefully selected based on an individualized understanding of a patient’s risk of progression and underlying pathophysiology. The potential role of biomarkers to facilitate personalization of prognostication and treatment of IgAN is immense. Here we review the progress made over the past decade in identifying and validating new biomarkers, with a particular focus on those that reflect immunological responses in IgAN.

Current Status of Medical Therapy for Inflammatory Bowel Disease: The Wealth of Medications.

Previously, the natural history of Crohn's disease and ulcerative colitis included significant morbidity due to limited treatment options that were not without serious side effects. Early treatment options included corticosteroids as well as mesalamine, thiopurines, and methotrexate. In 1998, monoclonal antibodies to a key inflammatory cytokine, TNFα, became available. Over the next 22years, the field of gastroenterology has seen multiple new treatments emerging for inflammatory bowel disease (IBD) that target different aspects of the inflammatory cascade, significantly changing the therapeutic landscape. Additional monoclonal antibodies are available that target the integrins, which are adhesion proteins that traffic inflammatory leukocytes. Small molecule inhibitors block the inflammatory signals of several cytokines. New therapies that modulate lymphocyte escape from lymphoid tissue are promising. Lastly, stem cell technology has emerged as a platform to successfully treat perianal fistulizing disease. Our aim is to summarize the currently available therapies for IBD beyond steroids, mesalamine, and immune modulators. We highlight the most important clinical trials that have brought these treatments to clinical practice, and we discuss the ongoing clinical trials of novel therapies that have a high probability of eventual regulatory approval.