US Trial Research Articles

US and Digital Breast Tomosynthesis in Women with Focal Breast Complaints: Results of the Breast US Trial (BUST).

Background Digital breast tomosynthesis (DBT) followed by targeted US is commonly performed to evaluate women with localized breast complaints. However, the added value of DBT in addition to targeted US is unknown. Omitting DBT may be cost-effective and improve patient comfort but may miss potential breast cancer. Purpose To assess whether an imaging protocol consisting of targeted US alone may be feasible for the diagnostic work-up of women with localized symptoms and to assess the supplemental value of DBT in this reversed setting. Materials and Methods This prospective study enrolled consecutive women aged 30 years or older with focal breast complaints in three hospitals in the Netherlands between September 2017 and June 2019. In all participants, first, targeted US was evaluated, and if needed, biopsy was performed, followed by DBT. The primary outcome was the frequency of breast cancer detected with DBT when US was negative. Secondary outcomes were frequency of cancer detected with DBT elsewhere in the breast and combined overall sensitivity of US plus DBT. The reference standard was 1 year follow-up or histopathologic examination. Results There were 1961 women (mean age ± SD, 47 years ± 12) enrolled. Based on initial US alone, 1587 participants (81%) had normal or benign findings and 1759 (90%) had a definitive accurate diagnosis. In total, 204 breast cancers were detected during initial work-up. The frequency of malignancy was 10% (192 of 1961 participants) with US (US sensitivity, 98.5% [95% CI: 96, 100]; US specificity, 90.8% [95% CI: 89, 92]). DBT depicted three unobserved malignant lesions at the complaint site and 0.41% (eight of 1961 participants) of incidental malignant findings in participants without symptomatic cancer. Conclusion Compared with combined US and DBT, US was accurate as a stand-alone breast imaging modality in the assessment of focal breast complaints. The rate of cancer detection of cancers elsewhere in the breast with DBT is comparable to cancer detection rate of screening mammography. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Newell in this issue.

Sacroiliac joint manipulation helps to improve pain pressure threshold in chronic piriformis syndrome: a 6-week randomized controlled trial US

Background: Piriformis syndrome (PS) has negative impact on the daily activities of the patients and lead to disability. There is an anatomical association of piriformis muscle with sacroiliac joint (SIJ). So manual therapy including manipulation of SI joint may be the option for relieving the symptoms of PS Objective: To investigate the effectiveness of Sacroiliac joint manipulation in improving pain pressure threshold in patients with chronic piriformis syndrome. Materials and Methods: A randomized clinical trial (NCT04603703) was conducted at Max Rehab and Physical Therapy Centre G8-Markaz, Islamabad, Pakistan. A total of n=30 patients were randomly divided into Experimental group (n=15) and control group (n=15). Both groups received conventional physical therapy including therapeutic ultrasound, moist hot pack, piriformis muscle stretching, myofascial release of paraspinal muscles, gluteal strengthening, sciatic neurodynamics. The experimental group additionally received sacroiliac joint manipulation. The outcome measures were pain, straight leg raise (SLR), pain pressure threshold and piriformis muscle length. The total time frame of the treatment was 3 days per week for 6 weeks and pre and post intervention assessment was done. Result: The mean age of participants was 40.46 ±10.513 years. Pain, SLR, pain pressure threshold and piriformis length was significantly improved (p<0.001) in both the experimental and control group after 6th week intervention. Between group comparison there was no significant difference between the groups after 6-week intervention regarding the pain, SLR and piriformis muscle length, except pain pressure threshold which was significantly improved in experimental group as compared to control group (67.7±18.42 vs 52.51±15.26, p=0.020) . Conclusion: Addition of the sacroiliac joint thrust manipulation technique and conventional physical therapy alone were equally effective in decreasing pain intensity and normalizing length of Piriformis and Straight leg raise. But SIJ manipulation showed promising results on pain pressure threshold. Keywords: Articular, physical therapy modalities, piriformis muscle syndrome, pain threshold, range of motion, sacroiliac joint.

Equipping Active Travel Advocates with Digital Mobility Data and Tools: An Evaluation of a US Trial Program

Shared micromobility services that offer bikes and scooters on demand are complementing walking, cycling, and public transport to expand the role of active mobility in urban transportation. However, on-demand services are often introduced at a faster pace than streets are redesigned to protect the safety of users. The lack of safe street infrastructure limits the potentiail mode shift to micromobility and the associated benefits. Active travel advocacy groups can make a critical difference, but they generally lack access to data resources.In 2020, Spin, a shared micromobility company, launched an initative called Mobility Data for Safer Streets (MDSS). This involved equipping six advocacy organizations in five US cities with a suite of mobility data tools to support their efforts to make streets safer. This research sought to understand how access to mobility data can help active travel advocates be more effective and was assessed via interviews with awardees throughout the 15-month program. Access to data improved advocates' effectiveness in working with the local government, garnering community support, supporting underserved communities, and advocating safe streets for all road users in their work. The MDSS model can be replicated to empower advocates or other stakeholders to advance collective understanding of active travel and influence supportive planning and policy.

Abstract Number ‐ 16: Thrombectomy alone versus Bridging intravenous alteplase in the US population: a pseudo‐randomized controlled trial

Introduction Recent randomized controlled trials (RCT) failed to demonstrate non‐inferiority of skipping IV tPA in patients with planned endovascular therapy (EVT). None of these studies included patients from the US due to regulatory challenges. Given practice patterns vary relative to Asia and Europe, we sought to address this topic using a validated alternative to RCTs, fuzzy regression discontinuity design (RDD). Methods From our prospectively maintained multi‐center registry we identified patients with LVO AIS treated with EVT with and without IV tPA treatment from 1/2018 ‐ 9/2021. We used the time cutoff for IV tPA as our discontinuity and assumed subjects on either side of the cutoff have markedly different probabilities of receiving the treatment but are similar in other relevant characteristics. The primary outcome was good functional outcome defined as 90‐day mRS 0–2 and it was compared between these two populations immediately adjacent to the cutoff using local linear regressions. Results Among 694 patients with LVO AIS who received EVT, median age was 69 [IQR 59‐79], 50%, were female, 44% White, 24% Black, and 14% Hispanic. 51% received IV tPA, with median onset to treatment time of 109 min [IQR 79‐160]. We observed a sharp drop (47%) in the probability of tPA around the cutoff time of 4 hours (allowing 30 minutes for in‐hospital evaluation), while there were no significant differences in other relevant features at the cutoff, validating the underlying RDD assumptions (Figure A). Overall, 33% of patients achieved good functional outcomes and there were no significant differences around the cutoff time (Figure B). In fuzzy RDD, there was no evidence of an association of receiving tPA with good functional outcome with regression discontinuity of only 1.0% (p = 0.98)There were no significant differences in rates of hemorrhage in patients treated with or without IV tPA (22% vs 21%, p = 0.68). Conclusions Our study provides the highest quality US‐based evidence supporting the findings of the outside US trials, demonstrating no benefit of skipping IV tPA in patients with planned EVT.

Leveraging published randomized controlled trials to inform clinical trial design: a simulation-based study of laminectomy versus laminectomy and fusion.

The US-based Spinal Laminectomy versus Instrumented Pedicle Screw (SLIP) trial reported improvement in disability following laminectomy with fusion versus laminectomy alone for patients with lumbar spondylolisthesis. Despite using similar methods, a concurrent Swedish trial investigating the same question did not reach the same conclusion. The authors performed a simulation-based analysis to elucidate potential causes of these divergent results. The mean and standard deviation of the preoperative and 2-year postoperative Oswestry Disability Index (ODI) scores for each study group (laminectomy with fusion and laminectomy alone) were collected from the spondylolisthesis stratum of the Swedish trial and used to create a MATLAB simulator using linear transformations to predict postoperative ODI distributions. Applying this simulator to both varied and published preoperative ODI distributions from the SLIP trial, the authors simulated the results of the US-based trial using treatment effects from the Swedish study and compared simulated US results to those published in the SLIP trial. Simulated US results showed that as preoperative disability increased, the difference in postoperative ODI scores grew between treatment groups and increasingly favored laminectomy alone (p < 0.0001). In 100 simulations of a similarly sized US trial, the average mean change in ODI scores postoperatively was significantly higher than was published for laminectomy alone in the SLIP trial (-21.3 vs -17.9), whereas it was significantly lower than published for fusion (-16.9 vs -26.3). The expected benefit of surgical treatments for spondylolisthesis varied according to preoperative disability. Adapting Swedish-estimated treatment effects to the US context mildly overapproximated the improvement in postoperative disability scores for laminectomy, but more severely underapproximated the improvement reported for laminectomy and fusion in the SLIP trial. The observed heterogeneity between these studies is influenced more by patient response to fusion than response to laminectomy. This analysis paves the way for future studies on the impact of preoperative treatment group heterogeneity, differences in surgical methods, and empirical design on reported clinical benefits. Although bayesian reanalysis of published randomized controlled trial data is susceptible to biases that typically limit post hoc analyses, the authors' method offers a simple and cost-effective approach to improve the understanding of published clinical trial results and their implications for future studies.

Abstract WP156: Thrombectomy Alone Versus Bridging Intravenous Alteplase In The US Population: A Pseudo-randomized Controlled Trial

Introduction: Recent randomized controlled trials (RCT) failed to demonstrate non-inferiority of skipping IV tPA in patients with planned endovascular therapy (EVT). None of these studies included patients from the US due to regulatory challenges. Given practice patterns vary relative to Asia and Europe, we sought to address this topic using a validated alternative to RCTs, fuzzy regression discontinuity design (RDD). Methods: From our prospectively maintained multi-center registry we identified patients with LVO AIS treated with EVT with and without IV tPA treatment from 1/2018 - 9/2021. We used the time cutoff for IV tPA as our discontinuity and assumed subjects on either side of the cutoff have markedly different probabilities of receiving the treatment but are similar in other relevant characteristics. The primary outcome was good functional outcome defined as 90-day mRS 0-2 and it was compared between these two populations immediately adjacent to the cutoff using local linear regressions. Results: Among 694 patients with LVO AIS who received EVT, median age was 69 [IQR 59-79], 50%, were female, 44% White, 24% Black, and 14% Hispanic. 51% received IV tPA, with median onset to treatment time of 109 min [IQR 79-160]. We observed a sharp drop (47%) in the probability of tPA around the cutoff time of 4 hours (allowing 30 minutes for in-hospital evaluation), while there were no significant differences in other relevant features at the cutoff, validating the underlying RDD assumptions (Figure A). Overall, 33% of patients achieved good functional outcomes and there were no significant differences around the cutoff time (Figure B). In fuzzy RDD, there was no evidence of an association of receiving tPA with good functional outcome with regression discontinuity of only 1.0% (p=0.98) Conclusion: Our study provides the highest quality US-based evidence supporting the findings of the outside US trials, demonstrating no benefit of skipping IV tPA in patients with planned EVT.

Comprehensive comparisons of ocular biometry: A network-based big data analysis

PurposeTo systematically compare and rank ocular measurements with optical and ultrasound biometers based on big data.MethodsPubMed, Embase, the Cochrane Library and the US trial registry (www.ClinicalTrial.gov) were used to systematically search trials published up to October 22nd, 2020. We included comparative studies reporting the following parameters measured by at least two devices: axial length (AL), flattest meridian keratometry (Kf), steepest meridian keratometry (Ks), mean keratometry (Km), astigmatism (AST), astigmatism vectors J0 and J45, anterior chamber depth (ACD), aqueous depth (AQD), central corneal thickness (CCT), corneal diameter (CD) and lens thickness (LT). A network-based big data analysis was conducted using STATA version 13.1.ResultsAcross 129 studies involving 17,181 eyes, 12 optical biometers and two ultrasound biometers (with both contact and immersion techniques) were identified. A network meta-analysis for AL and ACD measurements found that statistically significant differences existed when contact ultrasound biometry was compared with the optical biometers. There were no statistically significant differences among the four swept-source optical coherence tomography (SS-OCT) based devices (IOLMaster 700, OA-2000, Argos and ANTERION). As for Ks, Km and CD, statistically significant differences were found when the Pentacam AXL was compared with the IOLMaster and IOLMaster 500. There were statistically significant differences for CCT when the OA-2000 was compared to Pentacam AXL, IOLMaster 700, Lenstar, AL-Scan and Galilei G6.ConclusionFor AL and ACD, contact ultrasound biometry obtains the lower values compared with optical biometers. The Pentacam AXL achieves the lowest values for keratometry and CD. The smallest value for CCT measurement is found with the OA-2000.

Inflammation in Diabetic Kidney Disease: Focus on New Therapeutic Considerations

Diabetic kidney disease (DKD) is the most common cause of end-stage renal disease (ESRD) in the U.S. and worldwide. A role of chronic low-grade inflammation in the microvascular complications in diabetic patients has now been widely accepted, and anti-inflammatory therapies for DKD are being actively pursued. Such therapies may be especially useful in the treatment of patients with chronic kidney disease (CKD) with normal to only moderately increased albuminuria, a DKD phenotype which is becoming more frequent. Current pharmacologic treatment for DKD includes inhibitors of the renin-angiotensin-aldosterone system (RAAS) and the sodium-glucose co-transporter 2 (SGLT2) in the proximal tubule. Both classes of agents are known to reduce blood pressure but also are thought to have anti-inflammatory, antioxidant, and anti-fibrotic effects independent of their hemodynamic actions. Large clinical trials with experimental agents such as bardoxolone and selonsertib that target inflammation and oxidative stress in DKD have been carried out or are in progress. The non-specific phosphodiesterase inhibitor pentoxifylline (PTX) is also being studied in a large US trial to see if this FDA-approved drug may be able to be repurposed to treat DKD. Other agents have also shown promising effects in small clinical trials but require further large-scale investigation.

Biosimilars of anti‐vascular endothelial growth factors for ophthalmic disease – Clinical trial status 2022

AbstractPurpose: Diabetic Macular Œdema (DME) and Age‐related Macular Degeneration (nAMD) are the leading causes of vision loss in developed nations. Anti‐Vascular Endothelial Growth Factor (aVEGF) has revolutionized the treatment of both conditions, but access is limited by costs. Biosimilars of aVEGF can cut costs, but prescriber concerns over the lack of clinical data can slow uptake. This paper reports all biosimilar aVEGF in development for Europe and the USA, and pools the results of clinical confirmatory trials to provide statistically greater reassurance in the similarity of outcomes.Methods: Biosimilars in the clinical development phase were identified from US and EU trial registries.Results: There are 13 biosimilars of ranibizumab and aflibercept in final clinical comparative trial stage of development in Europe and the USA, recruiting 6126 patients. Five studies of intravitreal bevacizumab biosimilars are recruiting 772 patients. Equivalence outcomes are typically based on Best‐Corrected Visual Acuity (BCVA) with 90% confidence limits of −3 to +3 letters between reference and biosimilar medicines. Completed trials to date with 1166 participants analysed together show BCVA outcomes of ≤1 letter between Originator Reference Products and Biosimilars; for serious adverse events the risk ratio is 1.17, with 95% confidence intervals of 0.85–1.63, p = 0.32.Conclusions: Biosimilars of aVEGF are expected soon. There are likely sufficient brands expected to create meaningful price competition. To date, the EU/US regulatory pathway is delivering biosimilars with close equivalence of safety and efficacy outcomes.

Disparities in the Inclusion of Racial and Ethnic Minority Groups and Older Adults in Prostate Cancer Clinical Trials

Prostate cancer (PCa) is marked by disparities in clinical outcomes by race, ethnicity, and age. Equitable enrollment in clinical trials is fundamental to promoting health equity. To evaluate disparities in the inclusion of racial and ethnic minority groups and older adults across PCa clinical trials. MEDLINE, Embase, and ClinicalTrials.gov were searched to identify primary trial reports from each database's inception through February 2021. Global incidence in age subgroups and US population-based incidence in racial and ethnic subgroups were acquired from the Global Burden of Disease and Surveillance, Epidemiology, and End Results 21 incidence databases respectively. All phase 2/3 randomized PCa clinical trials were eligible for age disparity analyses. Trials recruiting exclusively from the US were eligible for primary racial and ethnic disparity analyses. This study was reported in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines. Data were pooled using a random-effects model. Enrollment incidence ratios (EIRs), trial proportions (TPs) of participants 65 years or older or members of a racial and ethnic subgroup divided by global incidence in the corresponding age group, or US population-based incidence in the corresponding racial and ethnic subgroup, were calculated. Meta-regression was used to explore associations between trial characteristics and EIRs and trends in EIRs during the past 3 decades. Of 9552 participants among trials reporting race, 954 (10.8%) were African American/Black, 80 (1.5%) were Asian/Pacific Islander, and 8518 (78.5) were White. Of 65 US trials, 45 (69.2%) reported race and only 9 (13.8%) reported data on all 5 US racial categories. Of 286 global trials, 75 (26.2%) reported the enrollment proportion of older adults. Outcomes by race and age were reported in 2 (3.1%) and 41 (15.0%) trials, respectively. Black (EIR, 0.70; 95% CI, 0.59-0.83) and Hispanic (EIR, 0.70; 95% CI, 0.59-0.83) patients were significantly underrepresented in US trials. There was no disparity in older adult representation (TP, 21 143 [71.1%]; EIR, 1.00; 95% CI, 0.95-1.05). The representation of Black patients was lower in larger trials (meta-regression coefficient, -0.06; 95% CI, -0.10 to -0.02; P = .002). The results of this meta-analysis suggest that Black and Hispanic men are underrepresented in trials compared with their share of PCa incidence. The representation of Black patients has consistently remained low during the past 2 decades.

Long-Term Follow-Up Evaluation of Efficacy in Alpha-Emitting Radiation Therapy on Recurrent and Locally Advanced Squamous Cell Carcinomas in Multi-Center Clinical Study

<h3>Purpose/Objective(s)</h3> Diffusing Alpha-emitter Radiation Therapy (DaRT) represents a novel method to deliver alpha particles intratumorally via the decay of Radium-224. Early results demonstrated the feasibility, safety, and efficacy of DaRT with an associated 100% overall response rate at six weeks and a favorable toxicity profile. The purpose of the study was to report the long-term tumor control outcomes of DaRT for the treatment of locally advanced and recurrent squamous cancers (SCC) of the skin and head and neck. <h3>Materials/Methods</h3> This retrospective study evaluated the outcomes of patients with histologically-confirmed SCC of the skin and head and neck who either previously failed or were medically unfit for definitive therapy. For this study, 28 lesions in 23 patients were eligible and treated per protocol. Treatment was delivered via a percutaneous interstitial technique with placement of the radioactive DaRT to encompass the tumor volume with margin. Tumor control was assessed using serial radiographic imaging or clinical assessments. The median follow-up time was 28 months following treatment. <h3>Results</h3> Complete response to the Ra-224 DaRT treatment was observed in 22 lesions (22/28; 79%); 6 lesions (6/28, 21%) manifested a partial response. Among the 22 lesions with a CR, 9 (41%) developed a subsequent local relapse at the site of DaRT implantation at a median time of 6.2 months (range: 2.8-35.4 months). The 2-year local progression-free survival (PFS) probability at the implanted site was 50% (95% Confidence Interval, CI: 28-68%) for complete responders. The 2-year overall survival rates post-DaRT implantation was 65% (95% CI: 42%-81%) among all patients and was 77% (95% CI: 50%-91%) among complete responders. <h3>Conclusion</h3> Despite prior therapy among these recurrent, locally advanced tumors, Ra-224 DaRT treatment was well tolerated and associated with excellent 2-year tumor control outcomes. A pivotal US trial for marketing approval is already underway.

A Multicenter Prospective Trial of Diffusing Alpha-Emitter Radiation Therapy for Recurrent or Unresectable Cutaneous Cancers: Early Results from a Pilot Feasibility Study in the United States

<h3>Purpose/Objective(s)</h3> Recurrent or unresectable cutaneous cancers may have limited treatment options. Diffusing alpha-emitter Radiation Therapy (DaRT, AlphaTau Medical, Tel Aviv, Israel) is a novel method of treating solid tumors using alpha-particle interstitial radiotherapy. A prior study conducted outside the United States demonstrated the feasibility, safety and efficacy of DaRT in patients with squamous cell carcinoma of the skin or mucosa of the head and neck. In this prospective multicenter trial conducted in the United States, we tested the hypothesis that DaRT for recurrent and unresectable cutaneous cancers was feasible, and also characterized preliminary safety and efficacy. <h3>Materials/Methods</h3> Patients with malignant skin or soft tissue tumors were recruited if they had limited treatment options, including recurrent disease, unresectable tumors, or those with metastases which could not be rendered disease-free with surgery. After baseline patient and tumor assessment, pre-treatment planning was performed. Patients underwent temporary DaRT placement to deliver a physical dose of 10 Gy to the tumor. Patients were followed for adverse events and tumor response 6, 12 and 24 weeks after removal. The primary objectives were to determine the feasibility of the procedure (based on successful implantation of DaRT device in the tumor) as well as the safety (based on adverse events (AEs) graded by CTCAE V5.0). Secondary objectives included response (based on RECIST V1.1 criteria), among others. <h3>Results</h3> Ten patients were recruited to the study and all successfully underwent the DaRT procedure, confirming feasibility. Median patient age was 72 years (range 57-92 years), with 6 men and 4 women participating. Six patients had recurrent disease, 4 were deemed unresectable and none had metastases. Tumors were located on the nose, chin, eyelid, scalp, neck, trunk, and extremities. The baseline mean tumor volume was 3.4 cm³ (range 0.65-12.65 cm³). Mean prescription dose coverage of the gross tumor volume was 91%, with all tumors having ≥85% coverage. No device-related grade 3 AEs were noted. Common AEs were grade 1-2 erythema, edema, and pruritis. At 12 weeks following treatment, there was a 100% complete response (CR) rate. Nine out of the ten CRs were confirmed by CT imaging. <h3>Conclusion</h3> This trial demonstrated the feasibility, and preliminary safety and efficacy of DaRT in the treatment of recurrent or unresectable cutaneous cancers. The favorable safety profile and high response rate are promising. A pivotal US trial for marketing approval is expected to be underway by the time of this presentation.

Efficacy and Safety of Ketamine vs Electroconvulsive Therapy Among Patients With Major Depressive Episode

Whether ketamine is as effective as electroconvulsive therapy (ECT) among patients with major depressive episode remains unknown. To systematically review and meta-analyze data about clinical efficacy and safety for ketamine and ECT in patients with major depressive episode. PubMed, MEDLINE, Cochrane Library, and Embase were systematically searched using Medical Subject Headings (MeSH) terms and text keywords from database inception through April 19, 2022, with no language limits. Two authors also manually and independently searched all relevant studies in US and European clinical trial registries and Google Scholar. Included were studies that involved (1) a diagnosis of depression using standardized diagnostic criteria, (2) intervention/comparator groups consisting of ECT and ketamine, and (3) depressive symptoms as an efficacy outcome using standardized measures. Data extraction was completed independently by 2 extractors and cross-checked for errors. Hedges g standardized mean differences (SMDs) were used for improvement in depressive symptoms. SMDs with corresponding 95% CIs were estimated using fixed- or random-effects models. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline was followed. Efficacy outcomes included depression severity, cognition, and memory performance. Safety outcomes included serious adverse events (eg, suicide attempts and deaths) and other adverse events. Six clinical trials comprising 340 patients (n = 162 for ECT and n = 178 for ketamine) were included in the review. Six of 6 studies enrolled patients who were eligible to receive ECT, 6 studies were conducted in inpatient settings, and 5 studies were randomized clinical trials. The overall pooled SMD for depression symptoms for ECT when compared with ketamine was -0.69 (95% CI, -0.89 to -0.48; Cochran Q, P = .15; I2 = 39%), suggesting an efficacy advantage for ECT compared with ketamine for depression severity. Significant differences were not observed between groups for studies that assessed cognition/memory or serious adverse events. Both ketamine and ECT had unique adverse effect profiles (ie, ketamine: lower risks for headache and muscle pain; ECT: lower risks for blurred vision, vertigo, diplopia/nystagmus, and transient dissociative/depersonalization symptoms). Limitations included low to moderate methodological quality and underpowered study designs. Findings from this systematic review and meta-analysis suggest that ECT may be superior to ketamine for improving depression severity in the acute phase, but treatment options should be individualized and patient-centered.

18P Adoptive cell therapy (ACT) with bispecific gamma delta TCR+ invariant TCR+ NKT-like cells for multiple myeloma (MM): Comparison of preconditioning (PC) on outcome

AVM0703 (AVM) is the subject of an actively enrolling US trial in relapsed/refractory (R/R) no-option Non-Hodgkin’s Lymphoma (NHL), with drug related adverse events limited to grades 1-3 and durable complete (CR) and partial responses (PR) to date. Acute supra-pharmacologic doses (>6 mg/kg) of AVM0703 mobilized endogenous bispecific gdTCR+ invTCR+ Natural Killer T-like cells (AVM_NKT) (PCT/US21/19773) in mice, humanized mice and clinical trial patients1. An ACT model was conducted to verify the direct tumor killing activity of AVM0703 induced novel immune cells (AVM_NKT) and to determine the effect of different PC on tumor killing of the ACT. MOPC315 (Balb/c) MM cells were inoculated into the flank as single cell suspensions. When tumor volume reached ∼400mm3 well-established tumors, mice were PC’d with human equivalent dose (HED) cyclophosphamide-fludarabine (CyFlu HED 500/30 mg/mm2), with Placebo (PL) or with AVM0703 HED 18 mg/kg. ACT splenocytes (3.3M) from mice dosed with PL or AVM were iv injected 48 hours later (PL_ACT had 8,240 AVM_NKT and AVM_ACT had 150,000). The next day (13-16 hours later) the mice were euthanized and remaining live MOPC cells were measured in the tumor, spleen, bone marrow, thymus and blood by flow cytometry. PC was necessary for AVM_ACT effect since there was no difference in live MOPC cells between AVM_ACT versus PL_ACT in mice PC’d with PL. AVM PC was equivalent to CyFlu PC against MOPC in tumor and spleen when AVM_ACT were transferred. Neither AVM nor CyFlu PC (with AVM_ACT) reduced MOPC in blood, bone marrow or thymus compared to PL PC. Repeat daily AVM and CyFlu dosing for PC will be explored in subsequent studies.Table: 18PPCPlaceboAVMAVMCyFluCyFluACTAVMPlaceboAVMPlaceboAVM* P<0.05 versus Placebo PC with Placebo ACTTumor***Spleen***BloodBone marrow*Thymus Open table in a new tab AVM0703 could be a less-toxic PC agent before CarT or other ACT. 1 Blood 2021:138(S1) 4557

404P A quantitative synthesis of disparities in the inclusion of younger adults and racial/ethnic minorities in colorectal cancer clinical trials

Colorectal cancer (CRC) incidence in younger adults has been rising for unclear reasons, and clinical outcomes also differ across racial/ethnic subpopulations. We analyzed all trials for age disparity and trials recruiting from the US for racial/ethnic disparity from primary reports of CRC randomized controlled trials (1990-2021). We calculated enrollment-incidence ratios (EIR), which compare trial enrollment from an age or racial/ethnic subgroup against global estimates of incidence in the corresponding age subgroup (from Global Burden of Disease) or US-population-based incidence in the corresponding racial/ethnic subgroup (from SEER 21). Individual-trial EIRs were pooled using random-effects meta-analyses. Meta-regression was used to explore associations between key trial characteristics and EIR, as well as trends in EIR over the last three decades. Of 411 global trials, 139 trials (33.8%) reported the number of patients within pre-defined age subgroups/categories; among these, patients were most frequently reported as above/below 65 years of age (n = 86; 20.9%). Only 12 trials (2.9%) reported the number of participants younger than 50 years, while even fewer reported the number of participants younger than 45 or 40 years (n = 8; 1.9%). 78 trials (19.0%) reported a subgroup analysis by age. Of 37 US trials, 19 trials (51.4%) reported race and 5 (13.5%) reported ethnicity, with only 2 (5.4 %) reporting data on all 5 U.S. racial categories. Patients aged >65 years were significantly underrepresented (EIR: 0.85 [95% CI: 0.78 - 0.94]). Asians were under-enrolled (EIR: 0.44 [95% CI: 0.36 - 0.52]), as well as Black (EIR: 0.57 [95% CI: 0.49 - 0.66]) and Hispanic patients (EIR: 0.51 [95% CI: 0.39 - 0.67]) with the inclusion of larger, international trials. There were no significant changes in the degree of disparity over the last three decades. Despite rising incidence of CRC in younger adults, clinical trials show infrequent reporting of this age group. Racial ethnic/minorities are significantly underrepresented in colorectal clinical trials based on their share of colorectal cancer incidence.

APJS-1 International trial activity of AGITG

The Australasian Gastrointestinal Trials Group (AGITG) is the main cooperative trials group performing multidisciplinary gastrointestinal clinical trials in Australia and New Zealand. The group has a strong history of international collaboration and has undertaken trials with US and European trial groups. More recently AGITG has had more of a focus in the Asian region and has developed strong relationships with several key Asian partners including within Japan. This relationship has developed primarily in the gastric cancer space through the INTEGRATE gastric cancer trials program.

Disparities in positive results and dissemination of randomized controlled trials in immuno-oncology

Background This cross-sectional and longitudinal analysis aimed to demonstrate the disparities in positive results and dissemination patterns of randomized controlled trials (RCTs) in global immuno-oncology (IO). Methods Phase II–IV RCTs with results reported by article publications registered on ClinicalTrials.gov in 2007–2018 studying immune checkpoint inhibitors (ICIs), adoptive cell transfer, cancer vaccines, and immune modulators were included. Results Twenty-eight percent of trials were positive (72 of 258), most of which were pharma-sponsored and focused on ICI and multiple IO therapies in lung cancer, melanoma, and multiple cancer types. The recent period of trial start year, upfront registration, large sample size, high strictness score on corticosteroid/infection-related criteria, and survival endpoints were associated with positive results. Trials from Mainland China had a faster publication timeline of positive results but lacked study diversity or full reporting of negative results compared with US and multinational trials. Compared with phase II trials, phase III–IV trials had a higher average proportion of positive results (28.9% vs. 22.2%) and a more stable change over the past decade (23.65% vs. 49.24%). Positive trials yielded more secondary manuscripts (10 vs. 4), a shorter publication process of approximately two years (P < 0.001), and a superiority in the dissemination of journals with an h-index >90 (P < 0.001) compared with negative trials. Conclusion Disparities in positive result dissemination are widespread in IO RCTs and affected by trial features. We proposed improvements in upfront registration, procedural integrity, and adequate inclusion of rival trials reporting negative results within the earlier two years in future reviews.

Exploring ethnic representativeness in diabetes clinical trial enrolment from 2000 to 2020: a chronological survey

Aims/hypothesisEthnic representativeness of participant enrolment in diabetes RCTs involving multiple ethnicities remains unknown. The aims of this study were to evaluate the status and temporal trend of ethnic representativeness in enrolment to diabetes RCTs, and to assess under-enrolment of non-white ethnic groups and explore trial characteristics associated with under-enrolment.MethodsWe conducted a chronological survey by systematically searching the literature to include eligible RCTs published between January 2000 and December 2020. We assessed temporal trends in enrolment of ethnic groups in the included trials. Univariable logistic regression was used to explore the association between trial characteristics and under-enrolment of non-white groups, using a participant to prevalence ratio of <0.8 to define under-enrolment. This study was registered in PROSPERO (CRD42021229100).ResultsWe included 405 RCTs for analysis (327 multi-country trials, 69 conducted in the USA and nine conducted in the UK). The median enrolment rate of all non-white groups was 24.0% in the overall RCTs. Trials conducted in the USA and the UK had median enrolment rates of 29.0% and 12.0% for all non-white groups, respectively. There was a temporal trend towards increased participation of non-white ethnic groups in the overall RCTs; however, no significant improvement over time was found in the US or UK trials. Non-white groups were under-enrolled in most included trials: 62.3% (43/69) in US trials and 77.8% (7/9) in UK trials. The US trials with a high female proportion were associated with lower odds of under-enrolment of all non-white groups (OR 0.22; 95% CI 0.07, 0.65), while trials receiving funding from industry showed increased odds of under-enrolment (OR 4.64; 95% CI 1.50, 14.35). Outpatient enrolment and intervention duration were significantly associated with under-enrolment of Black participants. Only a small proportion of trials reported subgroup results or explored the effect modification by ethnicity.Conclusions/interpretationA temporal trend towards increased non-white ethnic enrolment was found in diabetes RCTs globally, but not in the USA or the UK. Non-white ethnic groups were under-represented in the majority of diabetes trials conducted in the USA and the UK. Some trial characteristics may be associated with non-white under-enrolment in diabetes trials. These findings provide some evidence for non-white ethnic representativeness in diabetes trials over the past two decades, and highlight the need for more effective strategies and endeavours to alleviate under-enrolment of non-white ethnic groups.Graphical abstract Supplementary InformationThe online version contains supplementary peer-reviewed but unedited material available at 10.1007/s00125-022-05736-z.

Abstract 5643: YK-2168, a potent and selective small molecule CDK9 inhibitor

Abstract Objective: Cyclin-dependent kinase 9 (CDK9), which regulates transcriptional elongation, is an attractive therapeutic target for many cancers, especially for cancers driven by transcriptional dysregulation. Specifically, CDK9 mediated transcriptional regulation of short-lived antiapoptotic proteins is critical for the survival of transformed cells. Emerging evidence indicates that selective CDK9 inhibition may provide a therapeutic benefit against certain cancers. We disclose here for the first time a novel CDK9 inhibitor YK-2168 a clinical candidate and its preclinical results. Method: The biochemical activities of YK-2168 for CDK9, CDK1 and CDK2 were measured by literature methods (Tinggui, 2014). The in vitro anti-proliferative activity was evaluated on selected leukemia cell line MV4-11, lymphoma cell line Karpas422 and gastric carcinoma cell line SNU16. The in vivo antitumor activity of YK-2168 was evaluated in cell-derived xenograft (CDX) models of Leukemia (MV4-11) and gastric carcinoma (SNU16), YK-2168 was administered by intravenous (IV) injection. PK/PD was assessed by western blot analysis of pS2-RNA Pol ll CTD expression and cleaved caspase 3 level in the treated tumor tissues. Result: YK-2168 displayed potent selective inhibitory biochemical activity for CDK9 (IC50 : 7.5 nM), but that of CDK1 and CDK2 were modest (IC50 : 466.4 and 361.1 nM), indicative of good selectivity for CDK9. It also showed good anti-proliferative activities in tumor cell lines of different types, MV4-11 potency IC50 of 53.4 nM, Karpas422 potency IC50 of 91.1 nM, and SNU16 potency IC50 of 88.3 nM. YK-2168 showed in vivo antitumor activity in a MV4-11 CDX model with TGI =80 % @10 mpk QW (IV with 4 doses), compared with the same dose of BAY1251152 (TGI =65 % @10 mpk, QW). YK-2168 also showed good regressive antitumor activity in vivo in a SNU16 CDX model with TGI =115 % @10 mpk QW (while BAY1251152 totally inhibited growth with TGI =100%). Western blot analysis of the tumor samples showed that YK-2168 can also inhibit the expression of CDK9 downstream signal proteins and induced apoptosis in a dose-dependent manner. Conclusion: We have discovered a potent and selective small molecule CDK9 inhibitor YK-2168, which showed potent CDK9 inhibition and strong antitumor activity in both in vitro and in vivo preclinical tumor models. These results together with GLP safety results are considered highly promising and warrant moving the compound forward to clinical investigation. In fact, YK-2168 was granted phase I clinical trials in both US and China. Citation Format: Charles Z. Ding, Yingchun Liu, Wang Zhou. YK-2168, a potent and selective small molecule CDK9 inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5643.

Race/ethnicity reporting and representation in US clinical trials: A cohort study

Systemic progress in improving trial representation is uncertain, and previous analyses of minority trial participation have been limited to small cohorts with limited exploration of driving factors. We analyzed detailed trial records from all US clinical trials registered in ClinicalTrials.gov from March 2000 to March 2020. Minority enrollment was compared to 2010 US Census demographic estimates using Wilcoxon test. We utilized logistic regression and generalized linear regression with a logit link to assess the association of possible drivers (including trials' funding source, size, phase, and design) with trials' disclosure of and amount of minority enrollment respectively. Among 20,692 US-based trials with reported results (representing ~4·76 million enrollees), only 43% (8,871/20,692) reported any race/ethnicity data. The majority of enrollees were White (median 79·7%; interquartile range [IQR] 61·9-90·0%), followed by Black (10·0%; IQR 2·5-23·5%), Hispanic/Latino (6·0%; IQR 0·43-15·4%), Asian (1·0%; IQR 0·0-4·1%), and American Indian (0·0%; IQR 0·0-0·2%). Median combined enrollment of minority race/ethnicity groups (Black, Hispanic/Latino, Asian, American Indian, Other/Multi) was below census estimates (27·6%) (p<0·001) however increased at an annual rate of 1·7%. Industry and Academic funding were negatively associated with race/ethnicity reporting (Industry adjusted odds ratio [aOR]: 0·42, 95% confidence interval [CI]: 0·38 to 0·46, p<0.0001; Academic aOR: 0·45, CI: 0·41 to 0·50, p<0.0001). Industry also had a negative association with the proportion of minority ethnicity enrollees (aOR: 0·69, CI: 0·60 to 0·79) compared to US Government-funded trials. Over the past two decades, the majority of US trials in ClinicalTrials.gov do not report race/ethnicity enrollment data, and minorities are underrepresented in trials with modest improvement over time. Stanford Medical Scholars Research Funding, the National Heart, Lung, and Blood Institute, NIH (1K01HL144607) and the American Heart Association/Robert Wood Johnson Medical Faculty Development Program.