Trials Network Research Articles

Alliance A022101: A pragmatic randomized phase III trial evaluating total ablative therapy for patients with limited metastatic colorectal cancer—Evaluating radiation, ablation, and surgery (ERASur).

TPS236 Background: For patients with oligometastatic colorectal cancer (CRC), aggressive local therapy of isolated metastases, particularly in the liver, has been associated with long-term progression-free survival and overall survival (OS) primarily based on retrospective evidence. However, in patients with limited metastatic CRC that is deemed inoperable or those with additional disease outside of the liver or lungs, the role of local ablative therapies, including microwave ablation (MWA) and stereotactic body radiation therapy (SBRT), to render patients disease free is less clear. Further, despite the long history of treating oligometastatic CRC with local therapy, which is provider biased and not evidence based, questions remain regarding the benefit of extending the paradigm of metastatic directed therapy to patients with more extensive disease. This trial seeks to use a pragmatic multimodality approach that mirrors the current clinical dilemma. This study is designed to evaluate the safety and efficacy of adding total ablative therapy (TAT) of all sites of disease to standard of care systemic treatment in those with limited metastatic CRC. Methods: A022101 is a National Clinical Trials Network randomized phase III study planned to enroll 364 patients with newly diagnosed metastatic CRC (BRAF wild-type, microsatellite stable) with ≤4 sites of metastatic disease on baseline imaging. Liver-only metastatic disease is not permitted, and lesions must be amenable to any combination of surgical resection, MWA, and/or SBRT with SBRT required for at least one lesion. Patients receive first-line systemic therapy for 4-6 months and are then randomized 1:1, stratified by number of metastatic organ sites (1-2 vs. 3-4), timing of metastatic disease diagnosis (de novo vs. secondary), and presence of metastatic disease outside the liver and lungs in at least one site. Patients in Arm 1 will receive TAT which consists of treatment of all metastatic sites with SBRT ± MWA ± surgical resection followed by standard of care systemic therapy. Patients in Arm 2 will continue with standard of care systemic therapy alone. The primary endpoint is OS. Secondary endpoints include event-free survival, treatment-related toxicities, and local recurrence with exploratory biomarker analyses. The study needs 346 evaluable patients combined in the 2 arms to demonstrate an improvement in OS with a hazard ratio of 0.7 to provide 80% power with a one-sided alpha of 5%. The trial utilizes a group sequential design with two interim analyses (25% and 50% of events) for futility. The trial activated in January 2023 and recruitment is ongoing. Support: U10CA180821, U10CA180882; https://acknowledgments.alliancefound.org. U10CA180820 (ECOG-ACRIN); U10CA180868 (NRG); U10CA180888 (SWOG). Clinical trial information: NCT05673148 .

Incorporating patient-reported outcome data into a predictive calculator for allogeneic hematopoietic cell transplantation recipients.

The Center for International Blood and Marrow Transplant Research (CIBMTR) provides a 1-year overall survival calculator to estimate outcomes for individual patients before they undergo allogeneic hematopoietic cell transplantation (HCT) to inform risk. The calculator considers pre-HCT clinical and demographic characteristics, but not patient-reported outcomes (PROs). Because pre-HCT PRO scores have been associated with post-HCT outcomes, the authors hypothesized that adding PRO scores to the calculator would enhance its predictive power. Clinical data were obtained from the CIBMTR and the Blood and Marrow Transplant Clinical Trials Network. The PRO measures used were the 36-Item Short Form Survey (SF-36) and the Functional Assessment of Cancer Therapy-Bone Marrow Transplantation. One thousand thirty-three adult patients were included. When adjusted for clinical characteristics, the SF-36 physical component score was significantly predictive of 1-year survival (hazard ratio [HR], 0.88; 95% confidence interval [CI], 0.81-0.95; p=.0015), whereas the mental component score was not (HR, 1.02; 95% CI, 0.95-1.10; p=0.6396). The baseline single general health question on the SF-36 was also significantly associated with mortality (HR, 1.91 for those reporting fair/poor health vs. good, very good, or excellent health; 95% CI, 1.33-2.76; p=.0005). The addition of PRO scores to the calculator did not result in a significant change in the model's predictive ability. Self-reported pre-HCT scores were strongly predictive of self-reported health status (odds ratio, 3.35; 95% CI, 1.66-6.75; p=.0007) and quality of life (odds ratio, 3.24; 95% CI, 1.93-5.41; p<.0001) after HCT. The authors confirmed the significant, independent association of pre-HCT PRO scores with overall survival, although adding PRO scores to the survival calculator did not improve its performance. They also demonstrated that a single general health question was as accurate as the full measure for predicting survival, an important finding that may reduce respondent burden and promote its inclusion in routine clinical practice. Validation of these findings should be performed.

SNMMI Clinical Trials Network Research Series for Technologists: An Introduction to Conducting Theranostic Clinical Trials.

This article is intended to introduce nuclear medicine technologists (NMTs) to the nuances of radiopharmaceutical therapy clinical trials. Here, we outline the potential roles and responsibilities of the NMT in clinical trials and provide context on different aspects of radionuclide therapy. The regulatory process involving investigational therapeutic radiopharmaceuticals is seldom taught to NMT students, nor is it included in the entry-level nuclear medicine certification examinations. Often, NMTs must spend significant time preparing for therapeutic clinical trials on their own, using multiple academic sources, seeking advice from various health care professionals, and reviewing numerous trial-specific manuals to recognize the detailed requirements. The emergence of theranostics has spurred an increase in the development of therapeutic radiopharmaceuticals. Investigators with a robust nuclear medicine background are required to help develop successful therapeutic clinical trials, and well-informed NMTs are crucial to the success of such trials. This article follows a series of previous publications from the Society of Nuclear Medicine and Molecular Imaging Clinical Trials Network research series for technologists and is intended to guide the investigational radiopharmaceutical landscape.

Prognostic performance of the IABP-SHOCK II Risk Score among cardiogenic shock subtypes in the critical care cardiology trials network registry

BackgroundRisk stratification has potential to guide triage and decision-making in cardiogenic shock (CS). We assessed the prognostic performance of the IABP-SHOCK II score, derived in Europe for acute myocardial infarct-related CS (AMI-CS), in a contemporary North American cohort, including different CS phenotypes. MethodsThe Critical Care Cardiology Trials Network (CCCTN) coordinated by the TIMI Study Group is a multicenter network of cardiac intensive care units (CICU). Participating centers annually contribute ≥2 months of consecutive medical CICU admissions. The IABP-SHOCK II risk score includes age >73 years, prior stroke, admission glucose >191 mg/dl, creatinine >1.5 mg/dl, lactate >5 mmol/l, and post-PCI TIMI flow grade <3. We assessed the risk score across various CS etiologies. ResultsOf 17,852 medical CICU admissions 5,340 patients across 35 sites were admitted with CS. In patients with AMI-CS (n=912), the IABP-SHOCK II score predicted a >3-fold gradient in in-hospital mortality (low risk = 26.5%, intermediate risk =52.2%, high risk = 77.5%, p<0.0001; c-statistic=0.67; Hosmer-Lemeshow p=0.79). The score showed a similar gradient of in-hospital mortality in patients with non-AMI-related CS (n=2,517, p<0.0001) and mixed shock (n=923, p<0.001), as well as in left ventricular (<0.0001), right ventricular (p = 0.0163) or biventricular (<0.0001) CS. The correlation between the IABP-SHOCK II score and SOFA was moderate (r2=0.17) and the IABP-SHOCK II score revealed a significant risk gradient within each SCAI Stage. ConclusionsIn an unselected international multicenter registry of patients admitted with CS, the IABP- SHOCK II score only moderately predicted in-hospital mortality in a broad population of CS regardless of etiology or irrespective of right, left, or bi-ventricular involvement.

The role of randomization inference in unraveling individual treatment effects in early phase vaccine trials.

Randomization inference is a powerful tool in early phase vaccine trials when estimating the causal effect of a regimen against a placebo or another regimen. Randomization-based inference often focuses on testing either Fisher's sharp null hypothesis of no treatment effect for any participant or Neyman's weak null hypothesis of no sample average treatment effect. Many recent efforts have explored conducting exact randomization-based inference for other summaries of the treatment effect profile, for instance, quantiles of the treatment effect distribution function. In this article, we systematically review methods that conduct exact, randomization-based inference for quantiles of individual treatment effects (ITEs) and extend some results to a special case where naïve participants are expected not to exhibit responses to highly specific endpoints. These methods are suitable for completely randomized trials, stratified completely randomized trials, and a matched study comparing two non-randomized arms from possibly different trials. We evaluate the usefulness of these methods using synthetic data in simulation studies. Finally, we apply these methods to HIV Vaccine Trials Network Study 086 (HVTN 086) and HVTN 205 and showcase a wide range of application scenarios of the methods. R code that replicates all analyses in this article can be found in first author's GitHub page at https://github.com/Zhe-Chen-1999/ITE-Inference.

Interhospital Variation in Admissions Managed With Critical Care Therapies or Invasive Hemodynamic Monitoring in Tertiary Cardiac Intensive Care Units: An Analysis From the Critical Care Cardiology Trials Network Registry.

Wide interhospital variations exist in cardiovascular intensive care unit (CICU) admission practices and the use of critical care restricted therapies (CCRx), but little is known about the differences in patient acuity, CCRx utilization, and the associated outcomes within tertiary centers. The Critical Care Cardiology Trials Network is a multicenter registry of tertiary and academic CICUs in the United States and Canada that captured consecutive admissions in 2-month periods between 2017 and 2022. This analysis included 17 843 admissions across 34 sites and compared interhospital tertiles of CCRx (eg, mechanical ventilation, mechanical circulatory support, continuous renal replacement therapy) utilization and its adjusted association with in-hospital survival using logistic regression. The Pratt index was used to quantify patient-related and institutional factors associated with CCRx variability. The median age of the study population was 66 (56-77) years and 37% were female. CCRx was provided to 62.2% (interhospital range of 21.3%-87.1%) of CICU patients. Admissions to CICUs with the highest tertile of CCRx utilization had a greater burden of comorbidities, had more diagnoses of ST-elevation myocardial infarction, cardiac arrest, or cardiogenic shock, and had higher Sequential Organ Failure Assessment scores. The unadjusted in-hospital mortality (median, 12.7%) was 9.6%, 11.1%, and 18.7% in low, intermediate, and high CCRx tertiles, respectively. No clinically meaningful differences in adjusted mortality were observed across tertiles when admissions were stratified by the provision of CCRx. Baseline patient-level variables and institutional differences accounted for 80% and 5.3% of the observed CCRx variability, respectively. In a large registry of tertiary and academic CICUs, there was a >4-fold interhospital variation in the provision of CCRx that was primarily driven by differences in patient acuity compared with institutional differences. No differences were observed in adjusted mortality between low, intermediate, and high CCRx utilization sites.

Data cleaning and harmonization of clinical trial data: Medication-assisted treatment for opioid use disorder.

Several large-scale, pragmatic clinical trials on opioid use disorder (OUD) have been completed in the National Drug Abuse Treatment Clinical Trials Network (CTN). However, the resulting data have not been harmonized between the studies to compare the patient characteristics. This paper provides lessons learned from a large-scale harmonization process that are critical for all biomedical researchers collecting new data and those tasked with combining datasets. We harmonized data from multiple domains from CTN-0027 (N = 1269), which compared methadone and buprenorphine at federally licensed methadone treatment programs; CTN-0030 (N = 653), which recruited patients who used predominantly prescription opioids and were treated with buprenorphine; and CTN-0051 (N = 570), which compared buprenorphine and extended-release naltrexone (XR-NTX) and recruited from inpatient treatment facilities. Patient-level data were harmonized and a total of 23 database tables, with meticulous documentation, covering more than 110 variables, along with three tables with "meta-data" about the study design and treatment arms, were created. Domains included: social and demographic characteristics, medical and psychiatric history, self-reported drug use details and urine drug screening results, withdrawal, and treatment drug details. Here, we summarize the numerous issues with the organization and fidelity of the publicly available data which were noted and resolved, and present results on patient characteristics across the three trials and the harmonized domains, respectively. A systematic harmonization of OUD clinical trial data can be accomplished, despite heterogeneous data coding and classification procedures, by standardizing commonly assessed characteristics. Similar methods, embracing database normalization and/or "tidy" data, should be used for future datasets in other substance use disorder clinical trials.

Posttraumatic Stress Disorder Symptoms and Incarceration: The Impact on Sexual Risk-Taking, Sexually Transmitted Infections, and Depression Among Black Sexual Minority Men in HIV Prevention Trials Network (HPTN) 061.

Black men and people belonging to sexual minority groups are disproportionately impacted by criminal legal involvement and sexually transmitted infections (STIs). Traumatic experiences are often associated with later criminal legal involvement, depression symptoms, sexual risk behavior, and STIs. Research on the joint influence of trauma and incarceration on STI risk among racial and/or sexual minority people is limited. This study tested the association between post-traumatic stress disorder (PTSD) symptoms and incarceration on sexual risk behavior and STI among Black sexual minority men, a population that may be at higher risk for contracting STIs. Using data from the HIV Prevention Trials Network 061 Study, a longitudinal study of adult Black sexual minority men in six U.S. cities (N = 855), we tested associations between past six-month incarceration and subsequent sexual risk behavior, STI, and depression symptoms, for those with and without pre-incarceration PTSD symptoms. PTSD symptoms were elevated among participants who reported Hispanic ethnicity, having sex with both men and women, and previous incarceration. Although there were not significant differences between recent incarceration and sexual risk for those with and without PTSD, incarceration was linked to some sexual risk behaviors regardless of PTSD symptoms. Among people with PTSD symptoms, there was a higher prevalence of sexual risk and depression symptoms, regardless of incarceration. These findings suggest a potentially compounding influence of PTSD symptoms and incarceration on sexual risk and infection among Black sexual minority men.

Minding the gaps: assessing and addressing clinical research core competencies across a network of Canadian cancer centres.

The Canadian Cancer Clinical Trials Network (3CTN, the Network), established in 2014 to address the decline in academic cancer clinical trials' (ACCT) activity, has successfully achieved incremental year-over-year accrual targets as well as implemented recognized performance measures and supports for improving efficiency and quality of trial activities at member sites across Canada. As part of efforts to address ongoing challenges of staff recruitment, retention, and turnover in academic institutions that have been more recently exacerbated by the pandemic, the Network's Performance Strategy Sub-Committee (PSC) oversaw surveys of site clinical research professionals intended to capture workforce development status and identify knowledge gaps using the Joint Task Force Core Competency Framework (JTF CCF) as the standard basis for assessment. Accountable to the 3CTN Management Committee, the PSC consists of clinical research operations experts across Canada responsible for overseeing implementation and monitoring progress of this initiative. Staff at 3CTN's adult sites evaluated and reported trial personnel core competencies and gaps according to each domain/leveled competency statement of the framework. The most frequently noted competency gaps were in the domains of: Investigational Product Development and Regulation (28%); Scientific Concepts and Research Design (16%); and Study and Site Management (14%). Reported data was compiled and represented in the 3CTN Core Competency Report, developed as a web-based, interactive tool enabling members and stakeholders to filter data to enumerate and quantify workforce competency gaps at their site, within their node of affiliated sites, or across the national Network. Concurrently, an environmental scan and review of education resources was conducted and reviewed by the PSC. Embedded links to curated learning and development resources were incorporated into the report and associated with each domain/leveled competency statement to provide ready access to high-quality learning and development resources where needed. In the remaining years of its current strategic plan, 3CTN will continue to monitor, develop collaborative initiatives to target prioritized clinical research competency gaps and create opportunities for ongoing assessment and reporting by sites to capture changes in workforce core competencies over time.

Demographics of Youth With Newly Diagnosed Acute/Recent HIV Infection in Adolescent Trials Network 147: Early Treatment of Acute HIV Infection

PurposeGay, bisexual, and other cisgender men who have sex with men, and racial minority youth are at elevated risk of acquiring HIV infection. The Adolescent Trials Network 147 recruited youth with acute/recent HIV-infection for early antiretroviral treatment. The cohort make-up is described here. MethodsTreatment-naïve, recently identified HIV + youth, aged 12–24 years, from Los Angeles and New Orleans were recruited from community centers, clinics, social media, and a high-risk seronegative cohort (n = 1,727, the Adolescent Trials Network 149) using point-of-care assays. Acute HIV infection was determined by Fiebig staging. HIV RNA viral load (VL) and CD4 cell counts, along with demographic and behavioral data were assessed at enrollment. ResultsBetween July 2017 and July 2021, 103 newly diagnosed youth were enrolled, initiating antiretroviral treatment within a week. Mean age was 20.8 years (standard deviation: 2.4); 90.3% identified as cis male, 83.5% were single or in casual relationships, 71.8% were gay, bisexual, and other cisgender men who have sex with men; 60.2% were Black. One-fourth (24.3%) reported homelessness ever; 10.7% within last 4 months. At enrollment, median plasma VL was 37,313 HIV RNA copies/ml (interquartile range: 5,849–126,162) and median CD4 count 445.5 cells/mm3 (interquartile range: 357–613). 40% of youth reported acute retroviral symptoms before or at enrollment. Acutely infected, seroconverting youth had the highest VL. Sexually transmitted coinfections were present at enrollment in 56% of the cohort, with syphilis being most frequent (39%). DiscussionEarly identification and treatment of HIV can increase positive HIV outcomes. A high sexually transmitted infection burden was present in recently HIV-infected youth. Acute retroviral symptoms were not reported by most participants, demonstrating that broad universal HIV screening is needed for identification of recent infection in youth.

Retention and critical outcomes among new methadone maintenance patients following extended take-home reforms: a retrospective observational cohort study

Approximately 1800 opioid treatment programs (OTPs) in the US dispense methadone to upwards of 400,000 patients with opioid use disorder (OUD) annually, operating under longstanding highly restrictive guidelines. OTPs were granted novel flexibilities beginning March 15, 2020, allowing for reduced visit frequency and extended take-home doses to minimize COVID exposure with great variation across states and sites. We sought to use electronic health records to compare retention in treatment, opioid use, and adverse events among patients newly entering methadone maintenance in the post-reform period in comparison with year-ago, unexposed, controls. Retrospective observational cohort study across 9 OTPs, geographically dispersed, in the National Institute of Drug Abuse (NIDA) Clinical Trials Network. Newly enrolled patients between April 15 and October 14, 2020 (post-COVID, reform period) v. March 15-September 14, 2019 (pre-COVID, control period) were assessed. The primary outcome was 6-month retention. Secondary outcomes were opioid use and adverse events including emergency department visits, hospitalizations, and overdose. 821 individuals were newly admitted in the post-COVID and year-ago control periods, average age of 38.3 (SD 11.1), 58.9% male. The only difference across pre- and post-reform groups was the prevalence of psychostimulant use disorder (25.7% vs 32.9%, p=0.02). Retention was non-inferior (60.0% vs 60.1%) as were hazards of adverse events in the aggregate (X2 (1)=0.55, p=0.46) in the post-COVID period. However, rates of month-level opioid use were higher among post-COVID intakes compared to pre-COVID controls (64.8% vs 51.1%, p<0.001). Moderator analyses accounting for stimulant use and site-level variation in take-home schedules did not change findings. Policies allowing for extended take-home schedules were not associated with worse retention or adverse events despite slightly elevated rates of measured opioid use while in care. Relaxed guidelines were not associated with measurable increased harms and findings could inform future studies with prospective trials. USDHHSNIDACTNUG1DA013035-15.

Abstract B040: NCI 10129: A Phase 2 Study of the PARP inhibitor Olaparib (AZD2281) in IDH1 and IDH2 mutant advanced solid tumors

Abstract Introduction: Cholangiocarcinoma (CCA) is a highly aggressive malignancy with mutations in Isocitrate dehydrogenase (IDH) identified in approximately 15% of patients. Neomorphic mutations in IDH 1/2 result in accumulation of the oncometabolite 2-hydroxyglutarate (2G), which has been implicated in tumor progression via inhibitory effects on alpha ketoglutarate. Moreover, the mutant IDH dependent accumulation of 2HG results in homologous recombination deficiency (HRD) and renders these cells exquisitely sensitive to Poly (ADP-Ribose) polymerase (PARP) inhibitors. NCI 10129 evaluated the efficacy of olaparib for IDH mutated solid tumors, and here we present the CCA cohort. Methods: NCI 10129 is a 3 arm, open label phase 2 clinical trial performed in the NCI National Clinical Trials Network evaluating olaparib 300 mg twice daily for IDH mutated solid tumors refractory to standard treatment. Patients with CCA were enrolled in 2 cohorts 1) IDHi pre-treated CCA and 2) IDHi untreated CCA. The primary endpoint was overall response rate (ORR) and secondary endpoints includes progression-free survival (PFS), and overall survival (OS). An exploratory analysis measured the impact of circulating 2HG levels, circulating tumor DNA, and tumor genomics on patient outcomes. Results: Thirty patients with CCA enrolled on NCI10129 (15 each IDHi pre-treated and IDHi treatment naïve), 18 patients received ≥ 2 prior systemic treatments, and 23 patients had IDH1 mutations and 7 patients IDH2 mutations. There were no objective responses seen in the first 15 CCA patients in either cohort and enrollment was closed. The median PFS was 2.4 months 95% CI (1.9 - 6.5) and median OS 12.9 months 95% CI (6.3 – not reached). The IDHi pre-treated cohort had improved median OS compared to IDHi treatment naïve (15.3 vs 7.3, P = 0.04). There were 8/30 (27%) patients with clinical benefit (CB) as defined by PFS &amp;gt; 6 months. Patients with CB had lower baseline mean D-2HG levels compared to those without CB (1.4 umol/L vs 5.9 umol/L, p = 0.02). Whole exome sequencing revealed the study population to be enriched for HRD by sum scores and HRD mutational signatures without alternative HRD mutations other than IDH1/2. No improvement in survival was noted based on HRD status. RNA sequencing Gene Set Enrichment Analysis revealed that cell cycle and interferon alpha pathways were activated in patients with CB (p &amp;lt; 0.01). Olaparib was tolerable with the majority of adverse events grade 1-2. Conclusion: Olaparib did not result in objective responses in IDH mutated CCA. However, a subgroup of patients did demonstrate prolonged PFS comparable to historical controls for refractory CCA as well that seen with targeted agents such as IDHi. Exploratory analysis revealed this subgroup to be enriched for lower baseline 2HG levels. Serial ctDNA analysis is ongoing and will be presented. Given the CB subgroup and OS data, additional clinical trials leveraging the HRD properties of IDH mutations is warranted. Future studies may benefit from DNA damage combination therapies thereby enhancing potency. Citation Format: Michael Cecchini, Mary Jo Pilat, Nataliya Uboha, Nilofer S Azad, May Cho, Elizabeth J Davis, Jordi Rodon Ahnert, Gabriel Tinoco, Geoff I Shapiro, Simon Khagi, Benjamin Powers, Roman Groisberg, Jan Drappatz, Li Chen, Biswajit Das, Xun Bao, Jing Li, Abhijit Patel, Monica Niger, Deborah Doroshow, Diane Durecki, Scott Boerner, Ranjit Bindra, Percy Ivy, Yu Shyr, Patricia LoRusso. NCI 10129: A Phase 2 Study of the PARP inhibitor Olaparib (AZD2281) in IDH1 and IDH2 mutant advanced solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B040.

Brief Report: Dolutegravir Plasma Protein Binding and Unbound Concentrations During Pregnancy and Postpartum.

Clinical interpretation of the reduced dolutegravir (DTG) plasma concentrations reported during pregnancy is complicated by its high plasma protein binding. Plasma proteins significantly decrease during pregnancy, and understanding changes in DTG protein binding and its therapeutically active unbound concentrations are necessary to evaluate the impact of pregnancy changes on DTG pharmacokinetics. Retrospective assessment of plasma samples from pregnant women living with HIV enrolled in the International Maternal Pediatric Adolescent AIDS Clinical Trials Network P1026s study receiving 50 mg DTG film-coated tablets once daily as part of clinical care. Unbound and total DTG concentrations were determined predose (C0) and at maximum (Cmax) concentrations during the second trimester (2T), third trimester (3T), and postpartum (PP). Percentage unbound was calculated as the ratio of ultrafiltrate unbound DTG concentration to total DTG concentration. Twenty-nine mothers were included for protein binding evaluations; 15, 27, and 23 from the 2T, 3T, and PP, respectively. DTG % unbound for C0 and Cmax were significantly different by stage of pregnancy, with 3T significantly higher compared with PP; 1.02% vs. 0.69% (P = 0.0067) for C0 and 0.76% vs. 0.46% for Cmax (P = 0.0056). Median (IQR) unbound concentrations for C0 were 6.3 (4.7-18.4) for the 2T, 8.0 (5.6-16.9) for the 3T, and 13.3 (8.4-22.7) ng/mL PP, significantly different between 2T and PP (P = 0.0039), but not different between 3T and PP (P = 0.46). Lower total DTG plasma concentrations during pregnancy coincide with temporal decreases in DTG protein binding, resulting in comparable unbound DTG concentrations during the 3T and PP.

Mechanisms of Successful Implementation of Tailored Motivational Interviewing in a Multisite Study of Youth HIV Clinics in the United States.

A recent implementation science stepped-wedge trial of motivational interviewing (MI) in adolescent HIV clinics indicated variable degrees of implementation success. The present mixed-methods study analyzed trajectories of postimplementation MI competence scores and compared postimplementation qualitative interviews among the clinics with the highest levels of provider competency and the lowest levels of competency to further understand mechanisms of successful implementation. Ten HIV clinics in the Adolescent Trials Network for HIV/AIDS Interventions. This study used a sequential explanatory mixed-methods design. Continuous MI competency data from the parent study were structured with repeated measurements nested within providers nested within 10 sites. A mixed-effects regression model rank ordered the clinics by competence scores. Key stakeholders (N = 77) at the 10 randomized clinics completed a 1-hour qualitative interview at 12-month follow-up (immediately postimplementation). Using the phases of reflexive thematic analysis, interviews from the 3 highest competence clinics and the 3 lowest competence clinics were pragmatically analyzed. Thematic analysis suggested 3 central themes that influenced successful evidence-based practice (EBP) implementation. Organizational culture included the leadership, collective effort, and resources that influenced how the organization at large responded to the implementation intervention. Staff attitudes encapsulated individual providers' mindsets and attitudes about MI and the implementation intervention. EBP integration reflected the perception and use of MI by individuals and the organization as a whole. These themes and their subthemes are interconnected and exerted an influence on each other through the implementation process. Findings suggest additional implementation strategies to improve implementation of EBPs. Such mixed-methods research is critical to understanding the mechanisms of successful implementation of EBP and improving future implementation strategies.

Abstract IA029: Expanding access and participation to early phase clinical trials for our underrepresented populations

Abstract The American Society of Clinical Oncology (ASCO) has a firm position that phase I trials provide trials participants potential benefit with improved quality of life, psychological and direct medical benefit. Disproportionate access to novel therapies through early phase clinical trials among underrepresented populations continues to exist. In fact, there is worsening disparity in accrual of patients from racial and ethnic minority groups in phase 1 trials of drugs for metastatic cancer. Access to cutting-edge clinical trials leading to paradigm-changing treatments is critical for cancer care and equity in society, as participation in clinical trials correlates with reduction in mortality. Stark disparities in access and participation to clinical trials impact underserved populations among racial and ethnic minorities, socioeconomically disadvantaged, and geographically isolated populations. The impact of newer therapies, if inadequately studied in underserved populations, may result in poor generalizability of study results and uncertain benefit for these groups. Further, evidence suggests that access to clinical trials narrows the gap in cancer care disparity among patients in urban and rural communities. In response to ethical, clinical, and biologic mandate, the National Cancer Institute’s (NCI) Create Access to Targeted Cancer Therapy for Underserved Populations (CATCH-UP.2020) was created. This congressional mandate was a P30 administrative supplement awarded to eight NCI-designated cancer centers to enhance access to early phase precision medicine Experimental Therapeutics Clinical Trials Network (ETCTN) clinical trials for minority and underserved populations. The purpose of this presentation is to share best practices learned in CATCH-UP.2020 and discuss how this program helped create a roadmap to building a clinical trials ecosystem that allowed expanded access to early phase trials through cross-fertilization of successful tools among the CATCH-UP sites and within ETCTN. In our institution, learned best practices are applied across the spectrum of early phase clinical investigations to help overcome clinical trials disparities using the rural lens. With the goal of bringing precision medicine clinical trials close to home for our underrepresented populations, we aim to accelerate drug development without leaving anyone behind. Citation Format: Joaquina C. Baranda. Expanding access and participation to early phase clinical trials for our underrepresented populations [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr IA029.

The UK Impact Transplant Trials Network: An Effective National Strategy to Accelerate the Delivery of Randomized Trials in Stem Cell Transplantation

Introduction: Stem cell transplantation (SCT) is an important curative modality in patients with blood cancer whose outcome with chemotherapy is predicted to be poor and is an increasingly important therapy in non-malignant disease. However, even in 2023, 50% of patients are still destined to die after either allogeneic or autologous transplantation, either of relapsed disease or treatment toxicity. In response the transplant community continue to develop innovative strategies designed to improve patient outcome. However, despite the fact that the adoption of new therapies in haemato-oncology is, almost without exception, based on evidence generated by randomized studies fewer than 5% of transplant patients are currently recruited to prospective practice informing trials. Thus, much current transplant practice is based on retrospective registry analyses whose results can often be misleading. There is therefore an urgent need for innovative trial models with the ability to accelerate transplant trial delivery if patient outcomes after SCT are to be improved. Methodology: We reasoned that limited trials capacity at busy centres coupled with the absence of a fit-for-purpose clinical trials network represented potentially tractable barriers to transplant trial recruitment. In 2018 a $5 million grant was secured from UK blood cancer charities in order to directly fund the salaries of research nurses within the IMPACT network covering 11 major UK transplant centres and a linked clinical trials hub. Critically, up-front investment into research nurses at major transplant centres created a catchment region in excess of 20 million. The pre-stated aim of the IMPACT pilot was to recruit 400 patients to 7 new transplant trials over a 4 year period. Results Opened in 2018 the IMPACT network has now randomized 1344 patients to 7 prospective transplant trials over a 5 year period. Trials delivered include COSI, a randomized trial examining the benefit of the addition of Thiotepa to a Fludarabine/Busulphan based conditioning regimen in patients allografted for acute myeloid leukemia (AML) (n=333) and AMADEUS a randomized comparison of the benefit of post-transplant CC486 maintenance (n-326). In conjunction with recruitment to the Pro-DLI trial- a randomized study of prophylactic DLI in patients allografted for high risk AML (n=150)- the IMPACT initiative has resulted in more than 900 patients being recruited to practice informing AML transplant trials over a 5 year period. Importantly, AMADEUS has been designed and delivered in order to generate registration enabling data. Additional trials delivered by the IMPACT network include ALL-RIC the first randomized comparison of reduced intensity conditioning regimens in acute lymphoblastic leukemia (n=102, now in follow-up) and the ongoing MoTD trial a randomized comparison of post-transplant cyclophosphamide GVHD prophylaxis (n=139 to date). Sample return for bolt-on scientific studies has been in excess of 85% allowing prospective analysis of the prognostic significance of pre and post-transplant MRD, molecular determinants of transplant outcome and the biology of disease relapse in patients allografted for AML and ALL. Of note the IMPACT research nurse network demonstrated impressive resilience during the COVID-19 pandemic permitting continued trial delivery despite faltering recruitment to other cancer trials. Conclusions: The funding of a national transplant trials network has transformed recruitment to prospective randomized transplant trials in the UK. The success of the IMPACT pilot, which-out-performed its recruitment metrics by 300%, confirms the importance of innovative trial delivery models in accelerating recruitment to practice informing transplant studies and is a scalable model internationally. At the same time, IMPACT has proved a highly effective mechanism to generate linked translational data with the ability to inform future trial design. Building on similar models in Europe, such as LYSARC, the IMPACT network is now funded by a not-for-profit trials delivery vehicle Accelerating Clinical Trials Ltd (www.act4patients.com) creating a financially sustainable model within the UK for the delivery of a mixed portfolio of industry sponsored and investigator initiated transplant and cell therapy trials.

Rapid Clinical Mutation Screening for AML Using the Genexus Platform

Introduction: The promise of “precision medicine” is using therapeutic agents matched to the inferred biology of a patient's particular disease. In acute myeloid leukemia this approach demands fast and accurate assessment of the mutation and cytogenetic landscape of each AML case. The NCI Myeloid Malignancies Molecular Analysis for Therapy Choice program (“myeloMATCH”) is a precision medicine clinical trial initiative across the NCI National Clinical Trials Network for patients with newly diagnosed acute myeloid leukemia and myelodysplasia. In myeloMATCH the goal is to have cytogenetic and mutation assays performed within 72 hours of central lab receipt, allowing for a rapid assignment of the appropriate clinical trial from the myeloMATCH trial portfolio. Here we report analytic performance of rapid genomic profiling laboratory developed test based on the Thermo Fisher Genexus Oncomine Myeloid Panel GXv2 (NCI Myeloid Assay version 2, or “NMAv2”) which performs rapid sequencing of SNVs, indels, and gene fusions, capturing 1,661 hotspot variants (45 genes) and 779 fusions (35 genes) with a turnaround time of &amp;lt;48 hours from specimen receipt to clinical reporting. Methods: The validation testing was performed by two harmonized laboratories; NCI Molecular Characterization laboratory (MoCha) and Fred Hutch Molecular Oncology (MO). We conducted analytical validation and harmonization experiments for CLIA/CAP and FDA regulatory compliant use in this trial across both accredited clinical laboratories with harmonized workflows. Samples are extracted with AllPrep per manufacture protocol. Library preparation with the Oncomine Myeloid Assay GX v2 and the sequencing reactions are performed on the automated Ion Torrent Genexus System. Sequencing data generated by NMAv2 was analyzed using Ion Torrent Genexus system version 6.6.2.1. The default manufacturer workflow has been customized using a custom designed hotspot browser extensible data (BED) file, sequence variant baseline (SVB) file, fusion target file, torrent variant caller (TVC) version 5.18 and Oncomine extended filter chain (OEFC) version 5.16. In NMA, the default 2.5%, and 3% VAFs were set up for calling hotspot and non-hotspots SNV/indel, 1% VAF for FLT3-ITD and 100 read counts for all fusion, except 2000 read counts for KMT2A-PTD. Results: The validation set included 148 unique samples and comprised of 76 AML/MDS patients (49 peripheral blood, 27 bone marrow aspirate), 51 healthy donor blood, 6 healthy donor bone marrow, 7 cancer cell lines, 5 normal HapMap cell lines, and 3 contrived materials encompassing 364 known mutations (143 SNPs, 132 indels, 27 fusions). 180 runs were completed for this validation (106 at FH and 74 at MoCha) with 89.44% success rate in passing run level metrics. Results of the validation testing are detailed in Table 1. High reproducibility in detecting all reportable variants was observed, with overall &amp;gt;99% mean positive percentage agreement (PPA) across both labs (Figure 1). The limit of detection for each variant type was &amp;lt;0.06% for hotspot SNVs, 0.07% for non-hotspot SNVs, 0.51% for hotspot indels, ~1% for non-hotspot indels, 0.23% for FLT3-ITDs, and 50 minimum reads at 0.1% tumor content for fusions. 99.39% concordance was observed by testing 86 blinded validation sample set with analytically validated orthogonal assays. Conclusions: The NMAv2 has high specificity, sensitivity, accuracy and reproducibility (inter-lab and intra-lab) with sequencing results generated within 48 hours of assay initiation. As such, the assay is well suited for use to rapidly categorize the genomic alteration of AML to support clinical care in patients with active myeloid malignancies, including those patients potentially enrolled in the myeloMATCH program. Table 1: Results of validation experiment results for the NMAv2 Figure 1: Harmonization results for the NMAv2 between MoCha and MO labs, Right Panel = Indel; Left panel = SNV

Assessment of Outcomes of Consolidation Therapy By Number of Cycles of Blinatumomab Received in Newly Diagnosed Measurable Residual Disease Negative Patients with B-Lineage Acute Lymphoblastic Leukemia: In the ECOG-ACRIN E1910 Randomized Phase III National Clinical Trials Network Trial

Introduction: ECOG ACRIN E1910 is a randomized phase III trial that showed that adults with newly diagnosed BCR::ABL1 negative acute lymphoblastic leukemia (ALL) who become MRD negative (&amp;lt;0.01%) after induction chemo who receive blinatumomab with conventional chemotherapy (chemo) have improved survival compared with those who received chemo only (Litzow et al, Blood (2022) 140: Supplement 2, LBA-1). However, not all pts were able to receive all four planned cycles of blinatumomab in consolidation. In this report we assessed outcomes of pts in the blinatumomab arm of the trial who received all 4 cycles of blinatumomab compared to those who received 1-2 cycles. Methods: Patient between the ages of 30 and 70 with newly diagnosed BCR::ABL1 negative B-lineage ALL were enrolled and initially received 2.5 months of combination induction chemo utilizing a BFM-like regimen adapted from the E2993/UKALLXII clinical trial, with pegaspargase (after induction only for patients &amp;gt;=55 years of age) and addition of rituximab for CD20 positive patients. After remission induction (step 1) pts in morphologic complete remission (CR/CRi) received an intensification course of high dose methotrexate with pegaspargase for CNS prophylaxis (step 2). At the conclusion of step 2, remission and MRD status were determined centrally by 6-color flow cytometry with MRD negativity defined as &amp;lt;0.01%. In the primary analysis subset, MRD negative patients were randomized to receive an additional 4cycles of consolidation chemo or 2 cycles of blinatumomab at 28 mcg/day (flat dose) for 28 days each cycle followed by 3 cycles of consolidation chemo, another 4-week cycle of blinatumomab (3rd cycle of blinatumomab) followed by an additional cycle of chemo and then a 4th cycle of blinatumomab (step 3). Following completion of consolidation chemo +/- blinatumomab, pts were given 2.5 years of POMP maintenance therapy timed from the start of the intensification cycle (step 4). Estimates of OS were calculated using the Kaplan-Meier method. Comparison of OS between treatment arms were conducted using the stratified log-rank test and Cox proportional-hazards model with age, CD20 status, rituximab use, and whether pts intend to receive HSCT or not as stratification factors. As the number of cycles needed to optimize outcome has not been studied, an unplanned landmark analysis was used to compare OS of pts in the blinatumomab arm who received all 4 cycles o those who received 1-2 cycles. Time 0 was chosen as 9 months post step 3 randomization (the time that patients were supposed to complete 4 cycles of blina). Four pts who received blinatumomab but died within 9 months post step 3 randomization were therefore excluded from this analysis. Results: The study was activated on December 17, 2013 and closed to enrollment on October 15, 2019. 772 pts were screened for the trial and 488 were enrolled on step 1 induction therapy. The median age of the pts was 51 years (range 30-70). 224 MRD negative pts were randomized, 112 pts to each arm. In the blinatumomab arm 12 pts received 1 cycle (11%), 32 pts received 2 cycles (29%), 4 pts received 3 cycles (4%) and 63 pts received 4 cycles (57%). The OS of pts who received 1-2 cycles of blinatumomab was compared to control (Figure 1) The difference was not significant (hazard ratio 0.62, 95% CI 0.28 to 1.34, p=0.22). Fig 2 compares the survival of those who received 1-2 cycles to those who received 4 cycles ( (HR: 0.39, 95% CI 0.12 to 1.16, p=0.076). Conclusion: The addition of blinatumomab to consolidation chemotherapy resulted in a significantly better overall survival compared to chemotherapy alone in pts with newly diagnosed B-lineage ALL who were MRD negative after intensification. This represents a new standard of care for pts aged 30-70 years with BCR::ABL1 negative ALL. The optimal dose and number of cycles is however unknown. In this unplanned subgroup analysis we demonstrate that a survival benefit can only be confirmed in patients who receive the intended 4 cycles of blinatumomab during consolidation. Further studies will be needed to determine if fewer cycles can provide a similar benefit.

Out-of-Pocket Costs and Financial Hardship Among Participants of the BMT CTN 1102 Study

Introduction The Blood and Marrow Transplant Clinical Trials Network 1102 study (BMT CTN 1102, NCT02016781) was a multicenter, biologic assignment trial, where patients aged 50-75 with intermediate-2 or high risk de novo myelodysplastic syndrome (MDS) were assigned to reduced-intensity allogeneic hematopoietic cell transplantation (alloHCT) or best supportive care (non-alloHCT) based on donor availability. A parallel economic evaluation was performed alongside BMT CTN 1102. Here, we report on the financial impact of the treatment protocol on patients using a prospective cost diary study conducted within the trial. Methods BMT CTN 1102 enrollees were offered the option to participate in the parallel cost diary study at the same time of primary study enrollment. The cost diary survey instrument, comprised of 19 questions, covered the domains of out-of-pocket (OOP) costs of healthcare and financial hardship indicators. Surveys were distributed at 1- (1M), 7- (7M), and 19-months (19M) after enrollment. Study participants were grouped by actual treatment received, rather than group assignment. Responses were analyzed using univariate Fisher's exact and Wilcoxon rank sum tests for association. Results Out of 216 enrollee invitations, 138 patients (64%) returned at least one survey. Total completed surveys at the 1M, 7M, and 19M timepoints were 103 (39%), 93 (35%), and 71 (27%), respectively. 50 (36%) completed only one survey, while 41 (39%) completed surveys at all three timepoints. Of all respondents, median age was 67.7 years (IQR: 64.8-70.3), 88 (64%) were male, 128 (93%) white, and 126 (91%) were non-Hispanic. Among respondents of the 1M, 7M and 19M surveys, 82 (80%), 78 (84%), 65 (92%) received alloHCT, respectively. Mean OOP costs by category are presented in Table 1. While alloHCT patients experienced higher OOP costs compared to non-alloHCT patients across all categories (outpatient services, prescription medications, and accommodations for healthcare), none of the comparisons were statistically significant. However, total OOP costs were significantly higher among alloHCT patients at 1 and 7 months (mean over past 30 days, 1M: $889 vs. $217, p=0.046; 7M: $678 vs. $349, p=0.03; 19M: $328 vs. $103, p=0.15). Financial hardship indicators are presented in Table 2. While alloHCT patients experienced greater financial hardship compared to non-alloHCT patients across all categories (mobilized reserve funds, borrowed money to pay for care, developed debt due to care), none of the comparisons were statistically significant. However, alloHCT patients were significantly more likely to experience at least one of these factors of financial hardship at 7 months (1M: 38% vs. 19%, p=0.13; 7M: 42% vs. 13%; p=0.04; 19M: 37% vs. 0%, p=0.08). Discussion Patients with MDS who received alloHCT incurred substantially more OOP costs overall compared to patients who did not receive alloHCT, most notably for accommodations related to alloHCT. Similarly, alloHCT patients were more likely to develop financial hardship, including mobilizing reserve funds, borrowing money, and developing debt. These findings demonstrate that treatment-related OOP expenditures associated with alloHCT are substantial and may pose significant burdens for some populations receiving alloHCT. Financial navigation and assistance, which have been shown to help patients address cost burden in solid tumor settings, should be considered for MDS patients prior to alloHCT. Small final sample sizes limited our analyses significantly; further research into OOP costs and financial hardship among larger cohorts of alloHCT patients are necessary to confirm these findings. Acknowledgement Support for this study was provided by grants #U10HL069294 and #U24HL138660 to the Blood and Marrow Transplant Clinical Trials Network from the National Heart, Lung, and Blood Institute and the National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Eye movement desensitisation and reprocessing (EMDR) therapy in prison and forensic services: a qualitative study of lived experience

ABSTRACT Background: Posttraumatic stress disorder (PTSD) is common in people with serious mental illness who come into contact with the criminal justice system. Little evidence exists on EMDR treatment in forensic mental health, with no prior qualitative research exploring lived experience perspectives. Objective: This qualitative study recruited adult forensic mental health patients with PTSD and psychotic disorders, predominantly schizophrenia, who had received EMDR as part of a clinical trial, either in prison or in hospital. We sought to understand their experiences of EMDR therapy while receiving forensic care. Method: Ten in-depth, semi-structured qualitative interviews were undertaken and analysed using thematic analysis. We used an inductive, realist approach, reporting the experiences, meanings, and reality of the participants. Results: Five overarching themes were identified. First, severe trauma was ubiquitous and participants felt Seriously Messed Up by their traumatic experiences, with debilitating and enduring PTSD symptoms contributing to offending and psychosis (‘giving the voices something to feed on’). Second, EMDR was regarded with Early Scepticism. Third, the therapy itself was initially emotionally taxing and Not Easy but participants generally felt safe and persevered. Fourth, they were often surprised and delighted by results (And it Worked!), describing significant symptom reduction and personal transformation. Lastly, EMDR Fits the Forensic Setting, bringing empowerment in a place perceived as disempowering. People reported changes that increased their hope in a violence-free future. Conclusions: The limited research on EMDR in forensic mental health is unfortunate given how common PTSD is in mentally unwell offenders and its potential to impede recovery and contribute to further offending. This first qualitative study found participants experienced positive transformative change, extending beyond symptom reduction. Themes support previously published quantitative outcomes showing EMDR to be safe and effective in this cohort. EMDR was well suited to a forensic setting and was seen as an empowering therapy. Trial registration: Australian New Zealand Clinical Trials Registry identifier: ACTRN12618000683235. Study registration: The study was registered on the Australia and New Zealand Clinical Trials Network, registration number ACTRN12618000683235 (registered prospectively, 24 April 2018), https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id = 374682