Testing In Clinical Trials Research Articles

Litten appointed director of NIAAA's DTR

Raye Z. Litten, Ph.D., has been appointed director of the Division of Treatment and Recovery (DTR) at the National Institute on Alcohol Abuse and Alcoholism (NIAAA). Litten joined NIAAA in 1989 and previously served as associate director of the Division of Treatment and Recovery Research, acting director of the Division of Medications Development, and acting director of the Division of Treatment and Recovery Research. As DTR Director, Litten leads a broad program of extramural clinical research that focuses on improving treatments for alcohol use disorder (AUD), increasing the use and uptake of such treatments in real‐world settings, and understanding the process of recovery from AUD. During his tenure at NIAAA, Litten has been instrumental in expanding NIAAA's medications development research program. He helped establish the NIAAA's Clinical Investigations Group, a network of clinical sites that conducts proof‐of‐concept, phase II clinical trials of promising AUD medications. He also was key in establishing NIAAA's human laboratory program to efficiently screen compounds for safety and effectiveness prior to clinical trial testing, helping to overcome the “valleys of death” in medications development. Litten has also worked to promote the combined use of behavioral and medication treatments and to strengthen NIAAA's biomarkers and health services research portfolios. “I am grateful for this opportunity to continue to play an active role in this vital part of NIAAA's portfolio of research and research translation,” said Litten, who also praised the agency's newly published definition of recovery (see page 5).

FRI064 - Performance of the Enhanced Liver Fibrosis (ELF) test in real world practice versus clinical trials of non-alcoholic steatohepatitis

FRI064 - Performance of the Enhanced Liver Fibrosis (ELF) test in real world practice versus clinical trials of non-alcoholic steatohepatitis

Habituating to pandemic anxiety: Temporal trends of COVID-19 anxiety over sixteen months of COVID-19

The impact of COVID-19 anxiety on mental health and its association with preventive measures is well-established. We aimed to study how COVID-19 anxiety and its dimensions vary over time (16 months) in a sample of individuals (N = 2717) suffering from mental distress in the pandemic context that participated in a randomized clinical trial testing psychosocial interventions in Brazil. Results showed that pandemic anxiety reduced over time. COVID-19 influences fear of others being infected and concerns about mental health being affected by COVID-19 were more significant than the fear of being infected or the physical health influenced by COVID-19. A similar temporal effect was not found for burnout, and this effect was not correlated with the number of COVID-related deaths. Habituation to pandemic anxiety or higher intolerance of uncertainty at the beginning of the pandemic is putative mechanisms for the patterns observed in the data. They might have implications for mental health interventions in the pandemic scenario and motivational strategies for prevention. Trial registration numberPlataforma Basil (CAAE: 30608420.5.0000.5327), ClinicalTrials.gov (NCT04632082; November 17, 2020).

Nonproportional Hazards—An Evaluation of the MaxCombo Test in Cancer Clinical Trials

The Cross-PhRMA working group has proposed using the MaxCombo test in place of the log-rank test to evaluate treatment differences based on time-to-event endpoints, particularly if nonproportional hazards are expected. Despite demonstrating improved power and overall Type I error control, concerns about using this test for inferential purposes remain. We evaluated the MaxCombo test by reanalyzing data from six cancer clinical trials submitted to the U.S. Food and Drug Administration. Interpretation of the MaxCombo test results is not clear when the Kaplan–Meier curves crossed or had early separation. In addition, we note difficulty in interpretation of the results from the MaxCombo test when the source cause of deviation from proportionality of the survival distributions is due to underlying factors such as differential treatment effect of subgroups or intercurrent events. We illustrate these concerns based on the case examples.

Abstract 805: RECAP (REpair CAPacity) identifies a subset of breast cancers unable to form RAD51 foci which are undetected by DNA-based BRCAness tests

Abstract Background: Germline BRCA1/2 mutation status is currently used as predictive biomarker for response to Poly-(ADP-Ribose)-Polymerase (PARP) inhibitors in breast cancer (BC) patients. However, non-germline BRCA1/2 mutated tumors and homologous recombination repair deficient (HRD) tumors with unknown etiology are probably also PARP inhibitor-sensitive. Various HRD biomarkers have been proposed and their clinical validity and utility are under investigation. We recently described the functional REpair CAPacity (RECAP) test as a real-time method to select HRD tumors based on their inability to form RAD51 foci. Here, we investigated whether this functional test defines a similar group of HRD tumors as DNA-based tests for primary and metastatic BCs. Materials and Methods: A cohort (n=71; 52 primary and 19 metastatic BCs) enriched for HRD tumors was selected based on the RECAP test, consisting of 26 RECAP-HRD (37%), 9 RECAP-HR intermediate (HRi; 13%) and 36 RECAP-HR proficient (HRP; 51%) tumors. Whole genome sequencing (WGS) was carried out on matched germline and tumor DNA samples for 38 primary BCs and the 19 metastatic lesions, for which material was available. Three samples were excluded due to a low purity score (<0.2), thus WGS data was present for 54 tumors. The tumors were subjected to DNA-based HRD tests: CHORD and BRCA1/2-like classifier algorithms. Concordance between different HRD tests was reached when a tumor was classified as HRD/HRi or HRP by both tests. Results: The RECAP test identified all bi-allelic BRCA deficient samples (n=15) in this cohort as HRD/HRi. Within the remaining non-BRCA RECAP-HRD/HRi samples, there were no pathogenic mutations in other relevant genes that could explain the HRD status of these tumors. In the RECAP-HR proficient tumors no bi-allelic BRCA1/2 deficiencies were identified. The RECAP status partially correlated with the DNA-based HRD test outcomes using the HRDetect, CHORD and BRCA1/2-like classifier algorithms (70% concordance for RECAP-CHORD and RECAP-BRCA1/2-like classifier, and 66% for CHORD-BRCA1/2-like classifier). However, RECAP identified additional samples unable to form RAD51 foci. The discordance among the tests were evenly distributed among the primary and metastatic BCs. Conclusions: The difference between RECAP and other HRD tests in BC patients is relatively large (30-34% discordance), implying that RECAP may be identifying deficiencies in other components of DNA repair which could also result in PARP inhibitor sensitivity. Therefore, direct comparison of these HRD tests in clinical trials will be required to evaluate the optimal predictive test for clinical decision making. Citation Format: Titia G. Meijer, Luan Nguyen, Arne van Hoeck, Marjolijn M. Ladan, Nicole S. Verkaik, Kirsten Ruigrok-Ritstier, Carolien H. van Deurzen, Harmen J. van de Werken, Esther H. Lips, Sabine C. Linn, Yasin Memari, Helen Davies, Serena Nik-Zainal, Roland Kanaar, John W. Martens, Edwin Cuppen, Agnes Jager, Dik C. van Gent. RECAP (REpair CAPacity) identifies a subset of breast cancers unable to form RAD51 foci which are undetected by DNA-based BRCAness tests [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 805.

Abstract CT522: Feasibility and safety of a novel CD19 CAR T cell therapy in adults with R/R B-NHL

Abstract Genetically engineered chimeric antigen receptor (CAR) T cells have exhibited distinct effectiveness against chemotherapy refractory CD19 expressing B cell malignancies in both adults and children. This phase I clinical trial tests a novel anti-CD19 CAR T cell product in adults with relapsed/refractory (R/R) B-cell Non-Hodgkin’s Lymphoma (B-NHL). The CAR construct is comprised of the short chain variable regions of the anti-CD19 monoclonal antibody FMC63, the TNFRSF19-derived transmembrane domain, the 4-1BB costimulatory domain, and the CD3-zeta signaling domain. CD19 CAR T cells were manufactured utilizing the CliniMACS Prodigy® T Cell Transduction Process (CD3/CD28 TransAct™ reagent) allowing for highly automated production, with IL-7 and IL-15 used for T cell expansion for 8-12 days. To date, 7 patients have been treated with an average dose of 1.2 ± 0.2 x 108 CAR T cells. The histology includes marginal zone lymphoma (n=1), follicular lymphoma Grade IIIA (n=1), transformed lymphoma (n=3), follicular lymphoma low grade (n=2), and diffuse large B-cell lymphoma (n=1). One patient required a second apheresis due to poor cell expansion. Despite heterogeneity in disease subtype and leukapheresis product quality, CAR T production and expansion have been consistent with final transduction efficiencies between 14-45%, cell viability between 88-91%, and an overall average yield of 3.2 ± 0.3 x 109 cells before harvest, allowing for product banking. No safety-related out of specifications (OOS) events have occurred, however, 2 patients had OOS product infused due to low transduction efficiency (both at 14% rather than the ≥ 20% release criteria). Two patients experienced Grade 2 CRS, 1 patient experienced Grade 2 neurotoxicity; otherwise, no new safety signals were detected. Disease response was assessed on Days 90, 180, 270, and 360 post-infusion. The assessments were based on 2014 Lugano criteria. Even with 2 OOS products, Day 90 scans showed a complete metabolic remission (CMR) in 6 evaluable patients to date. Of the 6 patients with CMR, 1 patient progressed at Day 180 and the others remain in remission (median f/u = 12 months). Flow cytometry was utilized to measure CAR T cell peak expansion and persistence in 5 patients. Peak CAR T cell expansion (2.9-44.4% of CD3 cells) ranged from Day 5 to 15. Cell persistence was detected for the 5 patients through at least Day 180. ddPCR is currently in development to perform persistence testing in parallel. Additionally, cytokine concentrations including INFγ, IL-10, IL-12p70, IL-13, IL1β, IL-2, IL-4, IL-6, IL-8, and TNFα were evaluated over the first 30 days. Overall, 7 patients diagnosed with 5 different B-NHL subtypes have been treated with the CD19 CAR T cell product. Manufacturing was successful for all patients with no safety related OOS, and no new post-infusion safety signals detected. To date, 6 out of 7 patients are alive, 5 with CMR and with CD19 CAR T cell persistence through at least 180 days. Citation Format: Manali Kamdar, Cheri Adams, Steven Bair, Boro Dropulic, Jonathon Gutman, Bradley Haverkos, Kimberly Jordan, Rebecca Mallo, Russell Marians, Felicia Mast, Lindsey Murphy, Andrew Roth, Matthew Seefeldt, Andrew Worden, Mike Kadan, Ying Xiong, Dina Schneider, Rimas Orentas, Terry Fry, Michael Verneris. Feasibility and safety of a novel CD19 CAR T cell therapy in adults with R/R B-NHL [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 CT522.

Abstract 2153: ATR inhibition augments the efficacy of the lurbinectedin in small cell lung cancer

Abstract Small cell lung cancer (SCLC) is a recalcitrant disease with only a 9% five-year survival rate. SCLCs display intertumoral heterogeneity; high neuroendocrine (NE) tumors evolve with treatment and time in a largely MYC driven manner to a chemotherapy resistant non-NE state. Lurbinectedin, an RNA Pol-II inhibitor which causes DNA damage through binding ERCC5 was approved as second line therapy in 2020, with an overall response rate of 35% in patients with relapsed SCLC. However, these responses are short-lived and the majority of patient still succumb to their disease. A trial testing the combination of lurbinectedin and doxorubicin failed to improve survival compared with standard-of-care. We assessed lurbinectedin in combination with 43 other agents in SCLC cells. The top synergistic hit was the clinically relevant ATR inhibitor berzosertib which was 4-fold more synergistic than doxorubicin. Compared with lurbinectedin alone, the combination with berzosertib caused a 3.5-fold increase in DNA damage while significantly reducing the ability of cells to sense this damage by inhibiting γH2AX induction. This led to continued DNA replication even in the presence of lurbinectedin induced DNA damage, causing mitotic catastrophe and cell death. The combination was highly synergistic in 6 of 9 SCLC cell lines tested. Synergy was inversely correlated with p21 RNA and protein expression. The canonical role of p21 is to inhibit G1/S transition, and we found that thymidine induced G1 arrest inhibited synergy, while p21 knock-down increased the synergy. Interestingly, we observed synergy was inversely correlated with NE differentiation. In a high NE high p21 mouse model of SCLC, lurbinectedin alone was highly effective, with the combination showing little improvement. Conversely in a non-NE low p21 mouse model, lurbinectedin treatment alone was less effective, however the addition of berzosertib was synergistic and significantly improved efficacy. Overall, this work demonstrated berzosertib augments lurbinectedin efficacy in the recalcitrant non-NE SCLC subsets, and supported the development of a clinical trial testing lurbinectedin and berzosertib in SCLC patients NCT04802174. Citation Format: Christopher William Schultz, Yang Zhang, Haiqing Fu, Yasuhisa Murai, Darawalee Wangsa, Devon Atkinson, Liton Saha, Brian Elenbaas, Chien-Fei Lee, Astrid Zimmerman, Thomas Ried, Frank Zenke, Zoe Weaver, Rajaa Elmeskini, Yves Pommier, Anish Thomas. ATR inhibition augments the efficacy of the lurbinectedin in small cell lung cancer [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 2153.

AACR Cancer Disparities Progress Report 2022.

AACR Cancer Disparities Progress Report 2022.

Sodium-Glucose Co-Transporter-2 Inhibitors and Cardiac Outcomes Among Patients Treated With Anthracyclines

BackgroundSodium-glucose co-transporter-2 (SGLT2) inhibitors improve outcomes among patients with established heart failure. Despite supportive basic science studies, there are no data on the value of SGLT2 inhibitors among patients treated with anthracyclines. ObjectivesThis study sought to test the cardiac efficacy and overall safety of SGLT2 inhibitors in patients treated with anthracyclines. MethodsThis study identified 3,033 patients with diabetes mellitus (DM) and cancer who were treated with anthracyclines. Cases were patients with cancer and DM who were on SGLT2 inhibitor therapy during anthracycline treatment (n = 32). Control participants (n = 96) were patients with cancer and DM who were also treated with anthracyclines, but were not on an SGLT2 inhibitor. The primary cardiac outcome was a composite of cardiac events (heart failure incidence, heart failure admissions, new cardiomyopathy [>10% decline in ejection fraction to <53%], and clinically significant arrhythmias). The primary safety outcome was overall mortality. ResultsAge, sex, ethnicity, cancer type, cancer stage, and other cardiac risk factors were similar between groups. There were 20 cardiac events over a median follow-up period of 1.5 years. The cardiac event incidence was lower among case patients in comparison to control participants (3% vs 20%; P = 0.025). Case patients also experienced lower overall mortality when compared with control participants (9% vs 43%; P < 0.001) and a lower composite of sepsis and neutropenic fever (16% vs 40%; P = 0.013). ConclusionsSGLT2 inhibitors were associated with lower rate of cardiac events among patients with cancer and DM who were treated with anthracyclines. Additionally, SGLT2 inhibitors appeared to be safe. These data support the conducting of a randomized clinical trial testing SGLT2 inhibitors in patients at high cardiac risk treated with anthracyclines.

Functional RECAP (REpair CAPacity) assay identifies homologous recombination deficiency undetected by DNA-based BRCAness tests

Germline BRCA1/2 mutation status is predictive for response to Poly-[ADP-Ribose]-Polymerase (PARP) inhibitors in breast cancer (BC) patients. However, non-germline BRCA1/2 mutated and homologous recombination repair deficient (HRD) tumors are likely also PARP-inhibitor sensitive. Clinical validity and utility of various HRD biomarkers are under investigation. The REpair CAPacity (RECAP) test is a functional method to select HRD tumors based on their inability to form RAD51 foci. We investigated whether this functional test defines a similar group of HRD tumors as DNA-based tests. An HRD enriched cohort (n = 71; 52 primary and 19 metastatic BCs) selected based on the RECAP test (26 RECAP-HRD; 37%), was subjected to DNA-based HRD tests (i.e., Classifier of HOmologous Recombination Deficiency (CHORD) and BRCA1/2-like classifier). Whole genome sequencing (WGS) was carried out for 38 primary and 19 metastatic BCs. The RECAP test identified all bi-allelic BRCA deficient samples (n = 15) in this cohort. RECAP status partially correlated with DNA-based HRD test outcomes (70% concordance for both RECAP-CHORD and RECAP-BRCA1/2-like classifier). RECAP selected additional samples unable to form RAD51 foci, suggesting that this functional assay identified deficiencies in other DNA repair genes, which could also result in PARP-inhibitor sensitivity. Direct comparison of these HRD tests in clinical trials will be required to evaluate the optimal predictive test for clinical decision making.

Development of combination strategies for focal adhesion kinase inhibition in diffuse gastric cancer.

e16057 Background: Diffuse gastric cancer (DGC) is an aggressive and frequently lethal pathological subtype of gastric cancer (GC). Since DGC often lacks genomic aberrations that indicate clear candidate therapeutic targets, it has been challenging to develop target therapies for this GC subtype. Our previous study highlighted the contribution of focal adhesion kinase (FAK) in the tumorigenesis of DGC, and the potential for small molecule FAK inhibitors to have efficacy in DGC. Currently, FAK inhibitors are under active clinical evaluation in several tumor types. To date, FAK inhibitor monotherapy has been tolerated in the clinic, but has shown only modest clinical efficacy in cancer treatment, which inspired us to explore targets for the combination with FAK inhibitors in DGC. Methods: We constructed the engineered murine DGC model of Cdh1-/- RHOAY42C/+ organoids, with Cdh1 (E-Cadherin) loss and RHOA Y42C mutation, in our previous study. Using this DGC organoids model, we performed genome-scale libraries of open reading frames (ORF) screen to identify candidate mechanisms of resistance to FAK inhibitors (defactinib or PF-573228). For the top hits found in ORF screen, further validations were performed in Cdh1-/- RHOAY42C/+ organoids and human DGC cell lines of NUGC4 and SNU668 to check whether they could function as candidates for the combination with FAK inhibitors. Besides, we used Digiwest, a high-throughput protein analysis assay, to investigate pathway alterations of Cdh1-/- RHOAY42C/+ organoids treated with FAK inhibitors (defactinib or PF-573228). We then explored whether the activated pathways were the candidates for the drug combination. Zero Interaction Potency (ZIP) model was used to measure the synergistic effect between the drugs. The combination strategies were also tested in vivo. Results: We identified that cyclin-dependent kinase 6 (CDK6) promotes FAK inhibitors (defactinib and PF-573228) resistance according to ORF screen, and CDK4/6 inhibitor, Palbociclib, enhances the efficacy of defactinib for DGC models. Furthermore, we demonstrated that FAK inhibitors (defactinib and PF-573228) treatment in DGC models leads to compensatory activation of MAPK pathway in DGC, and the RAF/MEK dual inhibitor VS-6766 effectively enhances the antitumor efficacy of FAK inhibitors in vitro and in vivo. Conclusions: These data suggest that combinations of FAK inhibitors with MAPK inhibitors or CDK4/6 inhibitors are promising treatment strategies for DGC that warrant further testing in clinical trials.

This Issue's Featured Solutions

Inside Precision MedicineVol. 9, No. 3 MarketplaceFree AccessThis Issue's Featured SolutionsPublished Online:18 Jun 2022https://doi.org/10.1089/ipm.09.03.18AboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail Custom Reagents and Services For Molecular DiagnosticsAt Fortis Life Sciences, we know what it takes to succeed. We first work with you to understand your specific challenges and then our experts will design, develop, manufacture, and validate complete assay solutions for your molecular diagnostic assay.Decision SupportGenomOncology's precision oncology solutions enhance decision support by combining proprietary technologies, curation processes, data-delivery systems, and public and licensed annotation sets, with internal clinical dataOLINK® TARGETOlink® Target allows for more focused studies on a specific area of disease or key biological processes, targeting 96 or 48 biomarkers. The Target readout uses qPCR.Companion Diagnostic (CDx) ServicesQ2 Solutions® has a venerable track record of successfully supporting drug developers and in-vitro diagnostic (IVD) companies in many global CDx programs, from the early stages of biomarker validation through clinical trials testing and commercialization.FiguresReferencesRelatedDetails Volume 9Issue 3Jun 2022 InformationCopyright © GEN PublishingTo cite this article:This Issue's Featured Solutions.Inside Precision Medicine.Jun 2022.69-69.http://doi.org/10.1089/ipm.09.03.18Published in Volume: 9 Issue 3: June 18, 2022PDF download

Trial in progress: Durvalumab and olaparib for the treatment of prostate cancer in men predicted to have a high neoantigen load.

TPS5099 Background: Approximately 30% of patients (pts) treated with definitive surgical and/or radiation therapy for localized prostate adenocarcinoma develop biochemical recurrence (BCR). The optimal time to initiate androgen deprivation therapy (ADT) for such patients is controversial and depends on patient and provider preference, absolute PSA value, and PSA doubling time (PSADT), which has been associated with time to metastasis. Because the time from BCR to metastasis can be long in many cases, strategies allowing pts to avoid ADT while extending metastasis-free survival are desirable. Prior studies have shown that a high tumor neoantigen load correlates with response to anti-PD(L)1. We hypothesized that PARP inhibitor-induced genomic instability may sensitize tumors to anti-PD(L)1 through: i) increasing mutational burden and subsequent tumor neoantigen formation, and/or ii) through activation of other immunogenic pathways (e.g. the STING pathway). This trial investigates an ADT-sparing approach for men predicted to have high neoantigen load and who have BCR prostate cancer. Methods: This is a phase 2 clinical trial testing durvalumab (1500 mg IV every 4 weeks) and olaparib (300 mg PO twice a day) (one cycle = 4 weeks) in men with BCR (PSADT≤10 months) whose tumors are predicted to have high neoantigen load based on: biallelic CDK12 mutations (Cohort A), mismatch repair deficiency (MMRd)/high microsatellite instability (MSI-H) (Cohort B), or loss of function mutations in homologous recombination repair (HRR) genes (Cohort C). Cohorts A and B will receive 3 cycles of durvalumab followed by 3 cycles of the combination of durvalumab and olaparib. Given the proven efficacy of olaparib in prostate cancer patient whose tumors posses an HRR gene mutation, Cohort C will receive 6 full cycles of the combination. Ten patients will be enrolled in each cohort (total n = 30) at two collaborating sites. This study was designed to provide preliminary efficacy data across eligible cohorts, with a primary objective of estimating the proportion of pts with an undetectable PSA at 12 months within each cohort. Secondary objectives include safety, proportion of patients with ≥50% decline in PSA from baseline and quality of life measures. Correlative studies will assess blood and tissue molecular biomarkers for association with outcomes. The study is open with two patients enrolled at the time of abstract submission. Clinical trial information: NCT04336943.

Focal radiation with pulsed systemic therapy of abiraterone, androgen deprivation therapy (ADT), olaparib towards castration-sensitive oligometastatic prostate cancer (FAALCON Trial).

TPS5113 Background: Molecular imaging (i.e. PSMA directed agents) identifies metastatic prostate cancer at an earlier disease state than conventional imaging resulting in a new clinical entity within metastatic hormone-sensitive prostate cancer (mHSPC): molecular positive HSPC (mpHSPC). Historically, patients in this category with prior local therapy would have been classified as having a biochemical recurrence only, and observation was routine. Approaches to mpHSPC include observation or the use of focal and/or systemic therapies. Focal radiation for mpHSPC may delay the need for systemic therapy, yet many patients require further focal or systemic treatment. Androgen deprivation therapy (ADT) with abiraterone (abi) benefits men with high-risk localized disease and standard mHSPC. mpHSPC hypothetically resides somewhere between these two disease states. Finally, the inhibition of poly(ADP-ribose) polymerase (PARP) with olaparib plus abi shows promise in metastatic castration resistant prostate, suggesting this approach may be worthy of testing in earlier disease states. Methods: FAALCON is a single-site, phase 2 clinical trial testing olaparib with abi, ADT and radiation therapy in oligometastatic mpHSPC. Oligometastatic mpHSPC is defined as up to 5 radiation treatment sites (5 cm maximum size each) and must encompass all visible disease on the molecular scan. Patients must have had their prostate previously treated. The primary endpoint is the percentage of patients without treatment failure 24 months from study start. Treatment failure is defined as one of the following: new or progressive metastases on CT/MRI, new lesions on bone scan without alternate explanation, clinical progression, or a PSA doubling time under 6 months with an absolute final PSA over 1.5 ng/mL. Additional radiation therapy is deemed progression. Select secondary endpoints include time to any subsequent therapy, and percentage of patients with undetectable PSA with a recovered testosterone at multiple timepoints. Correlative work will analyze quality of life and prior prostatic tissue. ADT and abi (1000 mg daily) are given for 6 months, and radiation is completed by day 40. Olaparib (300 mg PO twice daily) is started 2 weeks after radiation completes and continues for the remaining ̃5 months. After therapy completion, patients are monitored by PSA q3 months with imaging based on predetermined PSA cutoffs. Molecular imaging (PSMA-PET) may be offered on study. Historical disease control at 24 months is estimated at 40% from prior molecular guided radiation studies and intermittent ADT. With 80% power and a one-sided 5% type-I error, we can detect a hazard ratio of 0.5 (80% control rate) at 24 months with 26 patients. To account for dropout, 29 patients will be accrued. Clinical trial information: NCT04748042.

A phase 1/2 multicenter investigator-initiated trial of DKN-01 as monotherapy or in combination with docetaxel for the treatment of metastatic castration-resistant prostate cancer (mCRPC).

5048 Background: Dickkopf-1 (DKK1) is a secreted Wnt signaling modulator that is upregulated in prostate cancers with low androgen receptor (AR) expression and co-occurring mutations in Wnt signaling family genes. DKN-01, a potent humanized monoclonal antibody (IgG4) with neutralizing activity against DKK1, delays prostate cancer growth in pre-clinical DKK1-expressing models in an NK cell dependent manner. These data provided the rationale for a prospective clinical trial testing DKN-01 in patients with mCRPC and elevated DKK1. Here, we report the safety and efficacy results of the phase 1 dose escalation cohorts. Methods: This is an investigator-initiated parallel-arm non-randomized phase 1/2 clinical trial testing DKN-01 alone or in combination with docetaxel 75 mg/m2 for men with mCRPC who progressed on ≥1 AR signaling inhibitor. Eligible patients who had progressed on or were intolerant of docetaxel were assigned to the monotherapy cohort whereas taxane-naïve patients were assigned to the DKN-01 plus docetaxel combination cohort. DKK1 status was determined by RNA in-situ expression. The primary endpoint of the phase 1 dose escalation cohorts was safety, characterized by dose-limiting toxicity (DLT). A secondary endpoint of the study was to correlate anti-tumor activity, DKK1 expression (cutoff H-score ≥ 1), and clinical evidence of aggressive variant prostate cancer (AVPC). Results: 13 pts were enrolled in the completed phase 1 portion of this study – 7 patients in the monotherapy cohort and 6 patients in the combination cohort. No DLTs were observed at DKN-01 300mg or 600mg dose levels as monotherapy or in combination with docetaxel. No treatment-related serious adverse events occurred in either cohort. A best overall response of stable disease occurred in 2 out of 7 patients in the monotherapy cohort. In the combination cohort, all 5 evaluable patients had a partial response (PR) – 3 confirmed and 2 unconfirmed. All evaluable combination patients had ≥ 50% reduction in either PSA or CEA. Confirmed PRs in the combination cohort were observed in both DKK1 low (DKK1 H-score &lt; 1) and high expressing tumors (H-score ≥1), including in 2 out of 3 patients with AVPC. Conclusions: DKN-01 600mg was well tolerated and selected as the recommended phase 2 dose as monotherapy and in combination with docetaxel. DKN-01 in combination with docetaxel showed promising clinical activity in prostate cancers regardless of DKK1 expression and was particularly promising in patients with AVPC. Further accrual into the phase 2 portion of this study is ongoing alongside preclinical and correlative studies aiming to investigate the mechanism of action of this combination therapeutic strategy. Clinical trial information: NCT03837353.

Association of Dual Decline in Cognition and Gait Speed With Risk of Dementia in Older Adults

Dual decline in gait speed and cognition has been found to be associated with increased dementia risk in previous studies. However, it is unclear if risks are conferred by a decline in domain-specific cognition and gait. To examine associations between dual decline in gait speed and cognition (ie, global, memory, processing speed, and verbal fluency) with risk of dementia. This cohort study used data from older adults in Australia and the US who participated in a randomized clinical trial testing low-dose aspirin between 2010 and 2017. Eligible participants in the original trial were aged 70 years or older, or 65 years or older for US participants identifying as African American or Hispanic. Data analysis was performed between October 2020 and November 2021. Gait speed, measured at 0, 2, 4, and 6 years and trial close-out in 2017. Cognitive measures included Modified Mini-Mental State examination (3MS) for global cognition, Hopkins Verbal Learning Test-Revised (HVLT-R) for memory, Symbol Digit Modalities (SDMT) for processing speed, and Controlled Oral Word Association Test (COWAT-F) for verbal fluency, assessed at years 0, 1, 3, 5, and close-out. Participants were classified into 4 groups: dual decline in gait and cognition, gait decline only, cognitive decline only, and nondecliners. Cognitive decline was defined as membership of the lowest tertile of annual change. Gait decline was defined as a decline in gait speed of 0.05 m/s or greater per year across the study. Dementia (using Diagnostic and Statistical Manual of Mental Disorders [Fourth Edition] criteria) was adjudicated by an expert panel using cognitive tests, functional status, and clinical records. Cox proportional hazard models were used to estimate risk of dementia adjusting for covariates, with death as competing risk. Of 19 114 randomized participants, 16 855 (88.2%) had longitudinal gait and cognitive data for inclusion in this study (mean [SD] age, 75.0 [4.4] years; 9435 women [56.0%], 7558 participants [44.8%] with 12 or more years of education). Compared with nondecliners, risk of dementia was highest in the gait plus HVLT-R decliners (hazard ratio [HR], 24.7; 95% CI, 16.3-37.3), followed by the gait plus 3MS (HR, 22.2; 95% CI, 15.0-32.9), gait plus COWAT-F (HR, 4.7; 95% CI, 3.5-6.3), and gait plus SDMT (HR, 4.3; 95% CI, 3.2-5.8) groups. Dual decliners had a higher risk of dementia than those with either gait or cognitive decline alone for 3MS and HVLT-R. Of domains examined, the combination of decline in gait speed with memory had the strongest association with dementia risk. These findings support the inclusion of gait speed in dementia risk screening assessments.

The trial to assess chelation therapy 2 (TACT2): Rationale and design

BackgroundIntravenous edetate disodium-based infusions reduced cardiovascular events in a prior clinical trial. The Trial to Assess Chelation Therapy 2 (TACT2) will replicate the initial study design. MethodsTACT2 is an NIH-sponsored, randomized, 2x2 factorial, double masked, placebo-controlled, multicenter clinical trial testing 40 weekly infusions of a multi-component edetate disodium (disodium ethylenediamine tetra-acetic acid, or Na2EDTA)-based chelation solution and twice daily oral, high-dose multivitamin and mineral supplements in patients with diabetes and a prior myocardial infarction (MI). TACT2 completed enrollment of 1000 subjects in December 2020, and infusions in December 2021. Subjects are followed for 2.5 to 5 years. The primary endpoint is time to first occurrence of all-cause mortality, MI, stroke, coronary revascularization, or hospitalization for unstable angina. The trial has >;85% power to detect a 30% relative reduction in the primary endpoint. TACT2 also includes a Trace Metals and Biorepository Core Lab, to test whether benefits of treatment, if present, are due to chelation of lead and cadmium from patients. Design features of TACT2 were chosen to replicate selected features of the first TACT, which demonstrated a significant reduction in cardiovascular outcomes in the EDTA chelation arm compared with placebo among patients with a prior MI, with the largest effect in patients with diabetes. ResultsResults are expected in 2024. ConclusionTACT2 may provide definitive evidence of the benefit of edetate disodiumbased chelation on cardiovascular outcomes, as well as the clinical importance of longitudinal changes in toxic metal levels of participants.

Anti-Obesity Activities of Standardized Ecklonia stolonifera Extract in 3T3-L1 Preadipocytes and High-Fat-Diet-Fed ICR Mice

The purpose of this study was to prepare a clinical trial test material (ESETM, test material of Ecklonia stolonifera extract) to develop a health functional food based on its anti-obesity effect. The anti-obesity effect of ESETM was evaluated in 3T3-L1 adipocytes and obese mice fed a high-fat diet (HFD) to confirm its nonclinical trial effect before application in clinical trial. Adipogenesis is a process of preadipocyte differentiation that causes an increase in the production of reactive oxygen species (ROS) and lipid accumulation. In vitro study results indicated that ESETM outstandingly inhibits the production of ROS and lipid accumulation during adipogenesis and lipogenesis. In vivo, ESETM-treated ICR mice had reduced HFD-induced weight change, food efficiency ratio, adipose tissue weight, liver weight and showed improved serum lipid profiles. Our results show that ESETM inhibits weight change by regulating the adipogenesis, lipogenesis, lipolysis, and thermogenesis pathways.

Chemoradiotherapy in Muscle-invasive Bladder Cancer: 10-yr Follow-up of the Phase 3 Randomised Controlled BC2001 Trial

BackgroundBC2001, the largest randomised trial of bladder-sparing treatment for muscle-invasive bladder cancer (MIBC), demonstrated improvement in locoregional control by adding fluorouracil and mitomycin C to radiotherapy (James ND, Hussain SA, Hall E, et al. Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med 2012;366:1477–88). There are limited data on long-term recurrence risk. ObjectiveTo determine whether benefit of adding chemotherapy to radiotherapy for MIBC is maintained in the long term. Design, setting, and participantsA phase 3 randomised controlled 2 × 2 factorial trial was conducted. Between 2001 and 2008, 458 patients with T2-T4a N0M0 MIBC were enrolled; 360 were randomised to radiotherapy (178) or chemoradiotherapy (182), and 218 were randomised to standard whole-bladder radiotherapy (108) or reduced high-dose-volume radiotherapy (111). The median follow-up time was 9.9 yr. The trial is registered (ISRCTN68324339). InterventionRadiotherapy: 55 Gy in 20 fractions over 4 wk or 64 Gy in 32 fractions over 6.5 wk; concurrent chemotherapy: 5-fluorouracil and mitomycin C. Outcome measurements and statistical analysisLocoregional control (primary endpoint), invasive locoregional control, toxicity, rate of salvage cystectomy, disease-free survival (DFS), metastasis-free survival (MFS), bladder cancer–specific survival (BCSS), and overall survival. Cox regression was used. The analysis of efficacy outcomes was by intention to treat. Results and limitationsChemoradiotherapy improved locoregional control (hazard ratio [HR] 0.61 [95% confidence interval {CI} 0.43–0.86], p = 0.004) and invasive locoregional control (HR 0.55 [95% CI 0.36–0.84], p = 0.006). This benefit translated, albeit nonsignificantly, for disease-related outcomes: DFS (HR 0.78 [95% CI 0.60–1.02], p = 0.069), MFS (HR 0.78, [95% CI 0.58–1.05], p = 0.089), overall survival (HR = 0.88 [95% CI 0.69–1.13], p = 0.3), and BCSS (HR 0.79 [95% CI 0.59–1.06], p = 0.11). The 5-yr cystectomy rate was 14% (95% CI 9–21%) with chemoradiotherapy versus 22% (95% CI 16–31%) with radiotherapy alone (HR 0.54, [95% CI 0.31–0.95], p = 0.034). No differences were seen between standard and reduced high-dose-volume radiotherapy. ConclusionsLong-term findings confirm the benefit of adding concomitant 5-fluorouracil and mitomycin C to radiotherapy for MIBC. Patient summaryWe looked at long-term outcomes of a phase 3 clinical trial testing radiotherapy with or without chemotherapy for patients with invasive bladder cancer. We concluded that the benefit of adding chemotherapy to radiotherapy was maintained over 10 yr.

Stroke Family Caregiver Life Changes From the COVID-19 Pandemic.

ABSTRACTBACKGROUND: Stroke family caregivers were already struggling with unmet needs and changes in their own lives from providing care. The COVID-19 pandemic added further stress and disruption to their lives. The purpose of this study was to describe life changes in 17 stroke family caregivers specifically resulting from the COVID-19 pandemic. METHODS: This study was conducted as a secondary data analysis from an ongoing randomized controlled clinical trial testing feasibility of the Telehealth Assessment and Skill-Building Kit (TASK III). Using a multimethod design, both quantitative and qualitative data were analyzed to determine caregiver life changes. Quantitative ratings regarding life changes were obtained using 17 items adapted specifically for COVID-19 from the Bakas Caregiving Outcomes Scale. Rigorous content analysis procedures for the qualitative data were guided by a start list of codes based on the 17 items, with additional themes possible. Representative quotes were selected based on author consensus. RESULTS: Findings revealed both negative and positive life changes from the COVID-19 pandemic. Negative life changes included such things as disrupted daily routines, limited access to healthcare providers and resources (eg, food, masks, hand sanitizers), reduced family and social contact and activities, decreased emotional well-being, and problems with performing caregiving activities for the survivor. Positive life changes were increased use of the Internet and videoconferencing, closer relationships with friends, and learning how to access needed resources in new ways. CONCLUSION: Stroke family caregivers experienced both negative and positive life changes specifically as a result of the COVID-19 pandemic. Responses further indicated that COVID-19 affected most caregivers in different ways and an individualized approach is needed in dealing with caregiver life changes.