Research Sponsors Research Articles

Abstract 4108: Safety and feasibility of personalized neoantigen DC vaccines in postoperative esophagus squamous cell carcinoma: A Phase 1b trial

Abstract Background: Immunotherapy, currently stands at the forefront of esophagus squamous cell carcinoma (ESCC) research. Yet, the landscape of post-surgical adjuvant therapy, particularly for patients resistant or unresponsive to initial immunotherapy, remains unexplored. Addressing this, our prospective study evaluates the efficacy of a personalized neoantigen-loaded dendritic cell vaccine (Neo-DCVac) as a novel adjuvant in ESCC patients after neoadjuvant immunochemotherapy (nICT). Methods: Neo-DCVac, designed for 12 ESCC patients post-radical mastectomy following nICT. The vaccine regimen included five doses at weeks 1, 2, 4, 6, and 8, followed by bi-monthly boosts for a year. The primary endpoints were safety and immune response post-vaccination, with 1- and 2-year overall survival (OS) and progression-free survival as secondary endpoints. The T-cell response to neoantigen peptides was evaluated using ELISPOT, flow cytometry, ELISA, and single-cell sequencing to investigate the vaccine's mechanism of action. Results: From April 2021 to October 2023, a total of 12 ESCC patients were enrolled. The occurrence of all-grade AEs was 38.5% (5/12), all of grade 1-2, with no dose-limiting toxicities. No treatment interruptions or treatment-related deaths were observed. Till October 27 2023, the median follow-up was 31.2 months. Survival analysis revealed 1-year and 2-year disease-free survival (DFS) and overall survival(OS) rates of 88.3%, 66.7%, and 100.0%, 91.7%, respectively. Patients with diver genes had a longer median DFS (not reached) compared with patients without diver genes (10.8 months, P = 0.001). Post-vaccine immunization, all patients showed a marked increase in peripheral blood T cell subtypes (CD3, CD4, CD8), with significant neoantigen peptide response in 75% (9/12) as evidenced by ELISPOT and ELISA tests. Single-cell sequencing coupled with CoNGA analysis revealed a distinct MAIT cell population, displaying 65 clonotypes and 146 cells with consistent GEX profiles and TCR sequences. GLIPH2 analysis on Neo-Vac immunotherapy patients identified shared peptide-MHC specificities, notably in patient ES0-01, and similar patterns in patients ES0-04 and ES0-07, suggesting T cell expansion and neoantigen-specific responses post-vaccination. Conclusions: The neoantigen DC vaccine demonstrated favorable safety and exhibited notable efficacy in ESCC. Clinical trial information: NCT05023928. Research Sponsor: No. Citation Format: Yueyun Chen, Hua-Shan Shi, Yang Hu, Yong Yuan, Yu-Shang Yang, Heng Xu, Li Yang, Zhen-Yu Ding. Safety and feasibility of personalized neoantigen DC vaccines in postoperative esophagus squamous cell carcinoma: A Phase 1b trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4108.

Abstract 6022: Investigating the mechanisms behind salivary gland tissue sparing in response to ultra-high dose-rate FLASH proton radiotherapy

Abstract Background: Radiotherapy (RT) is a primary treatment for cancers of the head and neck. However, although highly efficacious in eliminating tumors, incidental damage to underlying tissue remains a major limitation of RT. In the case of head and neck cancer, damage to the otherwise healthy salivary glands is often unavoidable even at low dosages, leaving patients with lifelong xerostomia and other comorbidities. FLASH Proton RT (F-PRT) is a form of ultra-high dose RT and has been reported to spare healthy tissues while retaining its tumor-controlling efficacy. The first system to deliver dosimetrically identical FLASH Proton RT (F-PRT; 60- 110 Gy/sec) or Standard Proton RT (S-PRT; 0.5-1 Gy/sec) using double-scattered protons was designed by our group. Aim: In this study, we aimed to investigate the effect of F-PRT on radiation-induced salivary gland dysfunction and the potential mechanism of this sparing effect by analyzing the effects of FLASH on two distinct salivary gland cell types: acinar and ductal cells. Methods: The head and neck area of C57BL/6 mice were irradiated with a single dose of 16 Gy of F-PRT (128Gy/s) or S-PRT (0.95 Gy/s). Radiation-induced xerostomia was studied by measuring the saliva flow rate of mice at 5, 10, 14, and 28 days post-PRT. Expression of AQP5, SOX9, and Keratin- 18, 19 was studied at 2, 5, 10, 14, and 28 days post irradiation by both immunofluorescence and protein immunoblotting. Results: Following irradiation with a single dose of 16 Gy, saliva flow was reduced by both treatments. However, the F-PRT-treated mice showed a significant improvement in salivary flow at 14 and 28 days post-irradiation, compared to those treated with S-PRT. Expression of AQP5 was significantly downregulated at 2, 5, 10 and 14 days post irradiation with S-PRT while F-PRT-treated mice showed a significant restoration of the AQP5 expression during the same time points. Expression of SOX9 showed no significant differences between S-PRT and F-PRT treated mice at earlier time points (2, 14 days), however, there was a significant difference in expression of SOX9 between the irradiated and unirradiated group. The difference in expression of SOX9 was visible from day 28 post-irradiation, where the F-PRT treated group showed increased expression compared to S-PRT. Conclusion: Our findings demonstrate that F-PRT reduces radiation-induced hyposalivation and reinstates the expression of AQP5 in the acinar cells of the submandibular gland of mice. Furthermore, it demonstrates that on day 28 post-irradiation, F-PRT-treated mice displayed more SOX9-expressing progenitor cells in the submandibular salivary glands compared to S-PRT. Acknowledgements: This work was supported by a Sponsored Research Agreement from IBA to Drs. C. Koumenis and L. Dong. Citation Format: George S. Morcos, Priyanka Chowdhury, Michele M. Kim, Khayrullo Shoniyozov, James Metz, Lei Dong, Constantinos Koumenis. Investigating the mechanisms behind salivary gland tissue sparing in response to ultra-high dose-rate FLASH proton radiotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6022.

Development and evaluation of objective trial performance metrics for multisite clinical studies: Experience from the AlcHep Network

BackgroundRecruitment and retention are critical in clinical studies but there are limited objective metrics of trial performance. We tested if development of trial performance metrics will allow for objective evaluation of study quality. Performance metrics were developed using data from the observational cohort (OBS) and randomized clinical trial (RCT) arms of the prospective Alcoholic Hepatitis Network. MethodsYield-rate (%YR; eligible/screened), recruitment index (RI; mean recruitment time/patient), completion index (CI; average number of days to complete the follow-up/patient), and protocol adherence index (AI; average number of deviations/subject recruited) were determined. Results2250 patients (1168 for OBS; 1082 for RCT) were screened across 8 sites. Recruitment in the RCT (57% target) was similar to that in the OBS (59% target). Of those screened, 743 (63.6%) subjects in the OBS and 147 (13.6%) subjects in the RCT were enrolled in the study. In OBS study, 253 (34.1%) subjects, and in the RCT, 68 (46.3%) subjects, completed the study or reached a censoring event. Across all sites (range), YR for OBS was 63.6% (41.3–98.3%) and for RCT was 13.6% (5.5–92.6%); RI for OBS was 1.66 (8.79–19.85) and for RCT was 4.05 (19.76–36.43); CI for OBS was 4.87 (22.6–118.3) and for RCT was 8.75 (27.27–161.5); and AR for OBS was 0.56 (0.08–1.04) and for RCT was 1.55 (0.39–3.21. Factors related to participants, research design, study team, and research sponsors contributed to lower performance metrics. ConclusionsObjective measures of clinical trial performance allow for strategies to enhance study quality and development of site-specific improvement plans.Trial registration number: ClinicalTrials.gov NCT4072822 NCT 3850899.

Abstract IA031: Equitable access to clinical trials: The role of community healthcare systems

Abstract Approximately 85% of US cancer care is delivered in community healthcare systems, most of which have no formal affiliation with academic programs and do not identify the research mission as a core responsibility. Therefore, most community-based cancer programs are research deserts. Yet there is strong evidence to support the oft-cited statement: 'the best treatment is a clinical trial.' In this age of rapid-fire discovery and clinical trials driven by deep knowledge of cancer biology and drug chemistry, coupled with close regulatory oversight, clinical trials carry much smaller risk for participants than ever before. In the end, clinical trials provide access to tomorrow's treatment, today. The socio-ecological model of healthcare recognizes that most problems and solutions reside at the levels of the individual, clinician, organization and social policy. As the number of actors sequentially diminishes from the individual to the social policy levels, the potential enduring impact of interventions sequentially rises. Interventions directly targeting the individual level are least efficient, those that target key social policies have the greatest enduring impact. So with the wicked challenge of inequitable clinical trials access. We will focus on the institutional level in my solutions-oriented discussion of equitable access to clinical trials. Using the NCI's Minority-Underserved NCORP progam and the Baptist Memorial Health Care Corporation as living examples, we will review intervention frameworks, objectively analyze the barriers to clinical trials access, and provide a pragmatic discussion of stakeholder-centered approaches to building clincial trials infrastructure in the places where people routinely seek care. We propose approaches to integrate clincal research as a core component of cancer care delivery in community healthcare systems and make the case that key external stakeholders, including patient advocacy groups, sponsors of research and healthcare policymakers must meet the target population where they reside. That connection can only happen by building clinical trials infrastructure and manpower within community healthcare systems. Citation Format: Ray U. Osarogiagbon. Equitable access to clinical trials: The role of community healthcare systems [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 IA031.

Abstract C063: OSE279, a PD-1 blocking monoclonal antibody, as future backbone of a bifunctional checkpoint inhibitor platform: Preclinical characterization and early clinical results of a First-In-Human (FIH) study in subjects with advanced malignancies

Abstract Background: Anti-PD-1 antibodies have shown significant clinical activity with favorable safety. Bispecific anti-PD-1 antibodies are being developed. OSE279 is a humanized S228P-immunoglobulin (Ig)G4 monoclonal bivalent antibody directed against PD-1 which will be further used as the anti-PD-1 backbone component of a bifunctional checkpoint inhibitor BiCKI® platform. Methods: We performed preclinical assessments of OSE279 that support development in humans. A FIH study investigating OSE279 is ongoing, evaluating 2 Dose Levels (DLs) of 100 and 300 mg given q3w and 1 DL of 600 mg q6w, according to BOIN design, in subjects with refractory malignancies, with no standard treatments, for which anti-PD1/PDL1 have shown efficacy but are not locally available, or rare tumors with reported activity of anti-PD1, or PDL1 positive tumors. Primary objective is to determine the MTD and/or Recommended Phase 2 Doses (RP2D). Secondary objectives are efficacy, safety, PK and PD profiles. DLT period is 21 days. Results: Preclinical investigations showed that OSE279 has antagonist activity against PD1, blocking the binding of PD1 ligands (IC50 308 ± 170 ng/mL). OSE279 blocked PDL1-induced SHP1 phosphorylation in a cell-based assay (IC50=14.19 ng/mL) and promoted reactivation of primary T cell effector functions leading to interleukin 2 and Interferon γ secretion in MLR assay. OSE279 showed potent antitumor activity in syngeneic models of colon cancer, hepatocarcinoma and mesothelioma implanted in immunocompetent Human PD1 Knock-in mice, with long-term response and survival. OSE279 showed good affinity to hFcRn receptor predicting good half-life in humans. Simulations showed that trough Receptor Occupancy (RO) would be 94.1±36.9% and 98.3±36.8% at 100 mg and 300 mg, respectively. NOAEL was determined in monkey at 100 mg/kg for 1 month. In the FIH study as of June 2023, 9 subjects were treated, with 8 tumor types. Median age was 60y (range 43-70), 6/9 patients (67%) were female, median number of prior metastatic lines was 2 (range 1-6). 300 mg was declared RP2D for a q3w regimen; a new cohort is exploring 600 mg q6w. One (with HCC) of seven patients in DL2 (300 mg) had a DLT of gr3 hepatitis. Treatment-Related Adverse Events (TRAEs) occurred in 8 patients (88.9%). Serious TRAEs (pneumonitis gr2, hepatitis gr3) occurred in 2 patients (22.2%). A confirmed PR was observed in HCC after one dose of OSE279 300mg. SD was reported in 3 patients. PK profile showed good exposure and dose-proportionality. RO was maintained and within the boundaries of simulation. Conclusions: OSE279 preclinical data showed comparable efficacy and safety profiles to the EMA/FDA approved anti-PD1 antibodies. In FIH study, OSE279 showed a manageable safety profile with preliminary signs of efficacy in the first 9 patients treated. A RP2D of 300 mg q3w was selected. 600 mg q6w is being evaluated (data available by October 2023). PK and PD profiles were according to modelling. Expansion cohorts are planned. Clinical trial information: NCT 05751798. Research Sponsor: OSE Immunotherapeutics. Citation Format: Philippe Cassier, Carlos Gomez-Roca, Nuria Kotecki, Christophe Massard, Sophie Postel-Vinay, Aurore Morello, Mylène Déramé, Caroline Chevalier, Laurie Cordonnier, Constant Josse, Silvia Comis, Nicolas Poirier, Marie Robert. OSE279, a PD-1 blocking monoclonal antibody, as future backbone of a bifunctional checkpoint inhibitor platform: Preclinical characterization and early clinical results of a First-In-Human (FIH) study in subjects with advanced malignancies [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 C063.

Abstract C114: Dose escalation results from a first-in-human, phase I/II study of GB263T, a novel EGFR/cMET/cMET trispecific antibody, in patients with advanced EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC)

Abstract Background: GB263T, a novel trispecific antibody directed against EGFR and cMET, adopts the design of two humanized VHH antibodies that recognize two different cMET epitopes, in which a conformational change induced by the first VHH binding exposes the second epitope for the second VHH to bind. Sequential binding of the two VHH antibodies to cMET increases tumor specificity, which results in widening of the safety window. In vitro studies show that GB263T induces better antigen-antibody molecular endocytosis, more completely blocks the signal transduction pathway, and has better ADCC activity compared to a benchmark. In addition, GB263T has demonstrated promising pre-clinical activity in models with various EGFR/cMET alterations, including those with high medical need. Here, we report updated dose escalation results of the first-in-human phase I/II study of GB263T in patients (pts) with advanced EGFRm NSCLC (NCT05332574). Methods: This multicenter (China and Australia), phase I/II study was conducted using an accelerated titration method followed by a traditional 3+3 design for dose escalation. Pts with EGFRm NSCLC with prior EGFR TKI and platinum-based chemotherapy were enrolled. GB263T was given at 140-1680 mg (5 dose cohorts) IV weekly for the first two 28-day cycles and biweekly thereafter. Objectives were to evaluate the safety and tolerability, determine the maximum tolerated dose (MTD) and the recommended Phase 2 dose (RP2D), assess the pharmacokinetics, immunogenicity, and preliminary efficacy of GB263T. Results: As of July 5, 2023, 13 pts were treated: 140mg (n=1), 420mg (n=1), 840mg (n=3), 1260mg (n=3), 1680mg (n=5). The enrolment of the 1680mg cohort is ongoing. All pts had received previous third-generation EGFR-TKI and platinum-based chemotherapy. Median number of prior lines of systemic therapy was 3 (range 1-7). One patient at 1680mg experienced DLT (grade 3 oral mucositis, which has resolved after symptomatic treatment). The most common treatment-related adverse events (TRAEs) were rash (61.5%), infusion related reaction (38.5%), fatigue (30.8%) and myalgia (23.1%), and all are mild (grade 1/2). Only one patient developed ≥grade 3 TRAE (grade 3 oral mucositis). There were no treatment-related discontinuations. Among 10 response-evaluable pts, two achieved partial response (PR) and four achieved stable disease (SD) with tumor shrinkage observed in 3/4 SD pts. The disease control rate (DCR) is 60%. The objective response rate (ORR) at the therapeutic dose range (1260-1680mg) is 40% (2/5). Two PR pts and 2/4 SD pts remained on treatment at data cutoff. Conclusions: Results to date demonstrate a good safety profile with promising efficacy at the therapeutic dose range (1260-1680mg). Continued dose escalation and clinical investigation of GB263T is ongoing.Clinical trial information: NCT05332574. Research Sponsor: Genor Biopharma Co. Ltd. Citation Format: Jin-Ji Yang, Nick Pavlakis, Fan Xie, Tong Li, Yi-Long Wu. Dose escalation results from a first-in-human, phase I/II study of GB263T, a novel EGFR/cMET/cMET trispecific antibody, in patients with advanced EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC) [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 C114.

Promising Safety and Efficacy of Trovocabtagene Autoleucel (C-CAR088) Followed ASCT in Ultra High-Risk Multiple Myeloma (UHR-MM) Patients Who Failed or Had Suboptimal Response to Standard First Line Triplet Based Therapy

Background: The prognosis of MM has improved significantly nowadays. However, patients with ultra-high-risk features (UHR-MM) had dismal outcomes even treated with standard front-line therapy. This study (NCT05632380) explores the potential of new CAR-T therapy in addressing the unmet need of these patients. Trovocabtagene autoleucel (trovo-cel), an anti-BCMA CAR T-cell manufactured by Cellular Biomedicine Group, Inc., showed deep and lasting responses with a good safety profile in relapsed or refractory multiple myeloma (R/R MM). Hereby, we are reporting a phase I, open-label, single-arm study, assessing the feasibility of trovo-cel followed ASCT in UHR-MM patients who failed or had suboptimal responses to the first-line standard therapy. Methods: Eligible patients are 18-70 years old, transplant-eligible and confirmed as UHR-MM defined as follows: 1) Genetic ultra-high risk: del(17p)≥60%; or ≥2 high-risk cytogenetic abnormalities including TP53 mutation, del(17p)/P53 deletion, t(4;14), t(14;16), t(14;20), 1q21 gain/ amplification, and did not reach CR or better response after 4 cycles standard first-line therapy; 2) Primary refractory: <MR after 2 cycles or <PR after 4 cycles standard first-line therapy; 3) Early relapse: lost best response within 6 months from the standard first-line therapy; 4) primary PCL history and < CR after 4 cycles standard first-line therapy. Standard first-line therapy should be a potent standard triplet-based regimen including one PI, one IMIDs, and glucocorticoid. Quadruplet or quintuplet regimens might be used. Prior ASCT, BCMA-targeted therapy, or CAR-T treatment are excluded. Patients undergo conditioning (melphalan alone or plus fludarabine) followed by ASCT on Day 0 and trovo-cel 3.0 or 6.0×10 6 cells/kg single intravenous infusion on Day 3. Maintenance is allowed after 3 months post-transplantation per investigator's decision. Results: As of July 24, 2023, 8 UHR-MM patients completed ASCT and trovo-cel infusion. Five patients received melphalan and 3 received fludarabine combining melphalan pretreatment. Trovo-cel was administrated at 3 × 10 6 cells/kg for all 8 patients. The median age of patients was 54.5 years (range: 39-66). The median number of prior lines of therapy was 2 (range: 1-2), with VRD exposure rate of 100%. Seven patients (87.5%) had received daratumumab, with six having been treated with dara-based quadruplet or quintuplet therapy as a front setting. Two patients (25%) had genetic ultra-high risk features, four patients (50%) had primary refractory myeloma, two (25%) had early relapse myeloma, and three patients (37.5%) had primary PCL history, two (25%) had extramedullary disease. Five patients (62.5%) received bridging and 6 received maintenance therapy. The combination of ASCT and Trovo-cel was well tolerated. With a median follow-up of 184 days (range: 13-332 days), no unexpected adverse events was observed. Among evaluable 7 patients, six (85.7%) had experienced grade 1 CRS and fully recovered. Two patients (28.6%) received tocilizumab and glucocorticoid for CRS. No ICANS event was reported. As expected, hematological toxicities are the most common AEs. All 7 patients achieved hematopoietic reconstitution successfully, with a median time of 14 days for ANC (≥0.5×10 9/L) and 13 days for PLT (≥20×10 9/L) post ASCT. The ORR was 100%, with 6 CR with MRD negative (NGF, 10 -5) (85.7%), 1 VGPR (14.3%). Robust CAR T-cell expansion was observed in blood of all patients. The median time of peak of CAR-T expansion (T max) was 7 days (range 4~7), the median peak CAR-T copy number (C max) was 891,963 copies /μg gDNA and the median AUC 0~28day was 6,009,475.5 copies /μg gDNA/day. The PK profile is similar to trovo-cel single agent treatment 1] but with earlier peak of CAR-T expansion. Conclusion: The preliminary results of this clinical trial show a promising safety and efficacy profile of trovo-cel followed ASCT in UHR-MM patients. Although the follow-up time is relatively limited, we are looking forward to a consistently good safety and efficacy outcome in long-term follow-up and in more patients recruited later. Research Sponsor: Institute of Hematology & Blood Diseases Hospital Collaborator: Cellular Biomedicine Group, Inc.

Good clinical practices in the bioanalytical laboratory.

Despite the existence of good clinical practice guidelines, the way in which they are applied to the bioanalytical laboratory remains unclear. Aspects of patient confidentiality, informed consent and subject withdrawal; addressing unblinding associated with sample analysis, including repeat analysis and incurred sample reanalysis; or the differences in responsibilities between the sponsor and contract research organization are not articulated by the US FDA within the bioanalytical setting, and for most bioanalytical laboratories this remains a gap in their standard operating procedures. The aim of this article is to identify and clarify the aspects of the good clinical practices that are applicable to the bioanalytical laboratory when conducting bioanalysis with clinical samples, and to address potential gaps in the bioanalytical laboratory when it comes to clinical sample bioanalysis.

SNMMI Clinical Trials Network Research Series for Technologists: Imaging Contract Research Organizations, Nuclear Medicine Technologists, and the Role They Play in Medical Imaging Research.

Clinical imaging research is a fast-growing, complex, and integral part of drug and therapy discovery and development. Research sponsors rely on outside vendors to manage their trials and deliver results they hope will demonstrate the efficacy of their product. Specialized vendors known as imaging contract research organizations have teams of highly trained and specialized professionals who lend their expertise to all aspects of imaging research management, of which nuclear medicine technologists are key team members. This article is part of the Clinical Trials Network Research Series for Technologists and will help provide an overview of an imaging research study from initiation to data delivery and the roles that nuclear medicine technologists and other imaging professionals play.

Opportunities and challenges for decentralised clinical trials in sub-Saharan Africa: a qualitative study

IntroductionDigital health has gained traction in research and development, and clinical decision support systems. The COVID-19 pandemic accelerated the adoption of decentralised clinical trials (DCTs) as a mitigation and efficiency...

Who’s asking? Social platform and research sponsors’ identity biases in guests’ hospitality experience-reviews: a case study of Spanish hotels

ABSTRACT The study here assesses the systematic variability of service performance assessments in customer reviews placed in alternative online social media platforms in the travel industry as well as responses to the firm’s requests for customer evaluations. The research includes an empirical study conducted by a national (Spanish) hotel chain of nine corporately-owned properties (hotels). Data-analyses were performed of data collected for the nine hotels from TripAdvisor and Booking.com, as well as internal data from the hotel chain’s customer data files. The findings support the general conclusion that hotel reviews on different social media platforms vary in systematic ways. TripAdvisor reviews consistently include the largest share of detractors across all social media platforms in this study, ranging from 11 to 51%. This study contributes useful benchmarks for the relative differences in performances in customer experience assessments across different social media platforms.

How Much Evidence Is Enough? Research Sponsor Experiences Seeking Regulatory Acceptance of Digital Health Technology-Derived Endpoints

Introduction: Digital health technologies (DHTs) provide opportunities for real-time data collection and assessment of patient function. However, use of DHT-derived endpoints in clinical trials to support medical product labelling claims is limited. Methods: From November 2020 through March 2021, the Clinical Trials Transformation Initiative (CTTI) conducted a qualitative descriptive study using semi-structured interviews with sponsors of clinical trials that used DHT-derived endpoints. We aimed to learn about their experiences, including their interactions with regulators and the challenges they encountered. Using applied thematic analysis, we identified barriers to and recommendations for using DHT-derived endpoints in pivotal trials. Results: Sponsors identified five key challenges to incorporating DHT-derived endpoints in clinical trials. These included (1) a need for additional regulatory clarity specific to DHT-derived endpoints, (2) the official clinical outcome assessment qualification process being impractical for the biopharmaceutical industry, (3) a lack of comparator clinical endpoints, (4) a lack of validated DHTs and algorithms for concepts of interest, and (5) a lack of operational support from DHT vendors. Discussion/Conclusion: CTTI shared the interview findings with the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) and during a multi-stakeholder expert meeting. Based on these discussions, we provide several new and revised tools to aid sponsors in using DHT-derived endpoints in pivotal trials to support labelling claims.

Neoadjuvant low-dose radiotherapy, tislelizumab, combined with albumin-bound paclitaxel and cisplatin in resectable locally advanced head and neck squamous cell carcinoma (NeoRTPC02): The first-stage result from an open label, single-arm, two stage, phase II clinical trial.

6078 Background: Neoadjuvant immunotherapy and chemotherapy has been explored in phase I/II clinical studies in head and neck squamous cell carcinoma (HNSCC), confirming its safety and efficacy. However, the pathological complete response (pCR) / major pathological response (MPR) rate still needed for improvement. Recent studies revealed that low dose radiotherapy can overcome immunosuppressive tumors by reversing immune desertification when combining immunotherapy. Here, we conducted this clinical trial to explore the efficacy and safety of neoadjuvant low-dose radiotherapy, PD-1 inhibitor, combined with chemotherapy in resectable locally advanced head and neck squamous cell carcinoma. Methods: This was an open-label, single-arm, phase II clinical trial. Patients with untreated, histologically confirmed HNSCC staging III-IVB were included. The eligible patients were scheduled to be administrated neoadjuvant low-dose radiotherapy (1GY/1F, D1, D2, D8, D15, Q3W), PD-1 inhibitor tislelizumab (200 mg D1, Q3W), combined with albumin-bound paclitaxel (100mg/m2, D1, D8, D15, Q3W) and cisplatin (25mg/m2, D1, D8, D15, Q3W) for two cycles. Radically surgical resection was planned to conduct 3-4 weeks after neoadjuvant therapy. The primary endpoint was pCR rate. The second endpoints consisted of MPR rate, objective response rate (ORR), R0 resection rate, safety, non-surgery-delay rate and quality of life. 25 patients will finally be enrolled in this study. Simon's two-stage design was adopted, and 10 patients should be included in the first stage. If 2 or more of the first 10 patients reached pCR, the second stage would be successfully entered. Results: By Jan 10, 2023, 10 patients were enrolled. 7 out of 10 patients successfully received the study regimen and finished the operation on schedule. Our primary endpoint of first stage was met. 4/7 (57%) patients achieved pCR at the primary site , 3/7 (43%) patients achieved MPR. The pCR/MPR rate was 100%. R0 resection rate was 100%. Totally 9 patients underwent MRI scan pre and post neoadjuvant therapy, and the assessment per RESCIST criteria were as follow: 0/9 (0%) CR, 6/9 (66%) PR, 3/9 (33%) SD. The treatment-related adverse events (TRAEs) were manageable. The most shared adverse events of grade 1/2 were anorexia (89%), anemia (89%) and nausea (66%). No surgical delay was observed. Conclusions: Neoadjuvant low-dose radiotherapy, tislelizumab, combined with albumin-bound paclitaxel and cisplatin contributed to an outstanding pCR/MPR rate of 100% (pCR rate of 57% and MPR rate of 43%) at present, and was generally tolerated in locally advanced HNSCC. The second stage is ongoing. Clinical trial information: NCT05343325 . Research Sponsor: BeiGene Co., Ltd. and CSPC Co., Ltd.

A first-in-human phase I, dose-escalation and dose-expansion study of SY-5007, a highly potent and selective RET inhibitor, in Chinese patients with advanced RET positive solid tumors.

9111 Background: RET gene fusions have been identified as oncogenic drivers in 1-2% of non-small-cell lung cancer (NSCLC) and 10-20% of papillary thyroid carcinomas. Activating RET mutations occur in 50-60% of medullary thyroid cancer (MTC). Recently, selective RET TKIs, selpercatinib and pralsetinib, were approved for RET positive solid tumors by FDA. SY-5007 is a highly potent RET inhibitor that selectively targets RET fusions and mutations. This study is to investigate the safety, PK characteristics and preliminary efficacy of SY-5007 in Chinese patients with advanced RET-altered solid tumors. Methods: In this first-in-human phase I study, eligible patients previously treated and with positive RET were enrolled. In the dose escalation phase, following 3+3 design, the patients were administered orally with SY-5007 20 mg once daily, or 20, 40, 80, 120, 160, 200 mg twice daily in a 28-day cycle. The expansion doses (160 and 200 mg twice daily) were executed in a dose expansion phase to determine a recommended phase II dose (RP2D). Then three cohorts ( RET fusion-positive NSCLC or thyroid cancers and RET mutant MTC) at RP2D were expanded in eligible patients. Primary endpoints included safety, tolerability, MTD, DLTs. Secondary endpoints included PK and preliminary antitumor activity of SY-5007 per RECIST v1.1. Results: As of Feb.06, 2023, a total of 60 patients including 55 RET fusion NSCLC and 5 RET mutant solid tumors were enrolled into dose escalation cohorts (n = 17) and dose expansion cohorts (n = 43).Totally, 55 (91.7%) patients experienced treatment-related adverse events (TRAEs) including increased aspartate aminotransferase (50.0%), increased alanine aminotransferase (41.7%), diarrhea (41.7%), etc. Grade ≥3 TRAEs were observed in 22 (36.7%) patients including hypertension (15%), diarrhea (5%), increased alanine aminotransferase (3.3%), etc. PK study showed SY-5007 was absorbed rapidly, exposure of SY-5007 increased in a dose-dependent manner at doses between 20 and 160 mg twice daily, and it was saturated at 160 mg twice daily. In 50 evaluable patients, the overall ORR and DCR was 62.0% (95% CI, 47.2-75.4) and 94.0 % (95% CI, 83.5-98.8), respectively. 29 patients (24 NSCLC, 4 MTC) received SY-5007 at 160 mg twice daily, 27 of 28 (96.4%) evaluable patients showed tumor regression, ORR and DCR was 72.4% (95% CI, 52.8-87.3) and 89.7% (95% CI, 72.7-97.8), respectively. For NSCLC patients, the ORR and DCR was 75.0% (95% CI, 53.3-90.2) and 91.7% (95% CI, 73.0-99.0), respectively. Conclusions: SY-5007 was well tolerated in patients. Preliminary antitumor activity was also observed in patients with advanced RET-fusion positive NSCLS and RET mutant MTC. The pivotal Phase II clinical study of SY-5007 in NSCLC patients is ongoing. Research Sponsor: Shouyao Holdings (Beijing) Co., Ltd. Clinical trial information: NCT05278364 .

Validation of a transthoracic impendance sensor for screening of sleep apnea in CIED patients: a pooled analysis of AIRLESS and UPGRADE

Abstract Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): Scientific grant support from the Boston Scientific Investigator Sponsored Research (ISR) Committee, Boston Scientific, St. Paul, MN, USA. Background/Introduction Cardiac implantable electronic devices and their integrated thoracic impedance sensors, meant to detect sleep apnea, are available for over a decade now. Despite its usage in daily clinical practice, there is only limited data on its diagnostic accuracy. Purpose To further validate an apnea sensor by using polysomnography (PSG) and investigate subgroups with potential differences in diagnostic accuracy. Methods AIRLESS and UPGRADE were prospective investigator driven trials meant to validate an apnea sensor. Patients, who either fulfilled the criteria for implantation of an implantable cardioverter-defibrillator (ICD), cardiac resynchronization therapy (CRT) or upgrading to CRT according to current guidelines were eligible for enrolment. Sleep apnea and its severity, measured by apnea-hypopnea index (AHI), were exclusively assessed by PSG. PSG was conducted in a time interval of 1 to 3 months post implantation of the device. For direct comparison, the apnea sensor derived respiratory disturbance index (RDI) was used from the identical night. Bivariate correlations (spearman coefficient) as well as the Bland-Altmann method were applied to assess diagnostic accuracy of the apnea sensor. Results Overall, 80 patients were analysed, out of whom the majority (n = 35, 43.8%) were diagnosed with central sleep apnea. Sixteen (20.0%) patients received a conventional ICD system, whereas 21 (26.3%) were implanted a CRT-P and 43 (53.8%) a CRT-D. Atrial fibrillation was known in 50.0% (n=40) of patients, 45 patients suffered from periodic leg movement syndrome (PLMS, 56.3%). In the overall cohort, the sensor derived RDI correlated significantly with the AHI (r = 0.61, p < 0.001) with a mean difference (MD) of -12.6 (95% CI -38.2 – 13.0). The sensor did specifically perform well in patients without atrial fibrillation (r = 0.80, p < 0.001; MD -9.0, 95% CI -30.4 – 12.5), while the presence of PLMS did not affect the accuracy of measurements (PLMS: r = 0.60, p = 0.007, MD -16.1, 95% CI -43.9 – 11.8 vs. no PLMS: r = 0.62, p = 0.001, MD -9.9, 95% CI -32.8 – 12.9). Furthermore, the RDI was found to correlate well in patients with central sleep apnea (r = 0.61, p = 0.013), although similar overestimation was observed (MD -11.6, 95% CI -35.4 – 12.2) as in other subgroups. Conclusion In an exclusive heart failure cohort, the apnea sensor did correlate well with the PSG derived AHI. Although similar correlation is found in most subgroups, there remains to be a decent overestimation of events.

Abstract CT195: Interim safety results from SEPION/AIO-PAK-0118: A multicenter, Phase I/II study of sequential epigenetic and immune targeting in combination with nab-paclitaxel/gemcitabine in patients with advanced pancreatic ductal adenocarcinoma

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) remains a hard-to-treat cancer entity with limited therapeutic options. We aim to enhance the anti-tumor and pro-immunogenic effect of standard-of-care nab-paclitaxel/gemcitabine (GnP) by concomitant epigenetic targeting followed by immune-modulating maintenance therapy in patients (pts) with treatment-naive metastatic PDAC. This phase 1/2, open-label, multicenter, dose-escalation/dose-expansion study evaluates the safety and tolerability of azacitidine (AZA) and romidepsin (ROM) in combination with GnP and the potential of immune-modulating consolidation with durvalumab and lenalidomide after three cycles of either GnP or GnP plus epigenetic targeting. Here we report interim results of the dose escalation. Methods: In part 1A, dose escalation of three regimen ROM/GnP (arm A), AZA/GnP (arm B) and ROM/AZA/GnP (arm C) for determination of the recommended dose for expansion (RDE) is performed with a 3 + 3 dose escalation scheme using fixed dose levels. For dose expansion (part 1B), one of the treatment arms (Arm C over B over A) is continued using a Simon two-stage design to a maximum of 35 patients. The efficacy of the sequential programmed death-ligand (PD-L)1 blockade in combination with low-dose lenalidomide is evaluated in study part 2 (consolidation part) for pts with controlled disease (DCR) after 3 cycles of part 1 therapy. Evaluation of the consolidation concept in part 2 requires a sufficient DCR based on the statistical considerations. Thus, in addition to pts in part 1A and 1B, pts treated with GnP alone are additionally recruited (standard arm), so that at least 41 pts with controlled disease after 3 cycles of therapy are available for part 2. Key eligibility includes metastatic PDAC (stage IV), ECOG 0-1 and no prior chemotherapy or radiotherapy therapy for stage IV PDAC. Primary objectives include safety and tolerability of AZA and/or ROM in combination with GnP followed by sequential immune targeting with PD-L1 blockade in combination with low-dose lenalidomide. Results: In October 2022, 76 pts were enrolled, of which 67 pts were treated with at least one dose of study medication. The median age in the treated population was 62.8 years (range: 33 - 83), 32 (47.8 %) were female, 80.6 %/13.4 % were included with ECOG 0/1. In part 1A, an RDE of 2mg/m² for ROM (N=3, dose level L-1) and 30mg/m² for AZA (N=6, dose level L1) was established, respectively. The combined administration of AZA (30 mg/m²), ROM (2 mg/m²) and GnP (arm C) led to severe DLTs, namely neutropenia, non-hematologic toxicities (> grade2) and ROM related non-hematologic toxicities (≥ grade2) in all three patients. Given the best safety profile, Arm B was chosen for the expansion part 1B. Conclusions: ROM in combination with GnP showed considerable toxicity at dose level L1 as did the combination of ROM (dose level L-1) and AZA (dose level L1) with GnP. The combination of 30 mg/m2 AZA with GnP was feasible and chosen for further expansion. Dose expansion (part 1B) and sequential immunotherapy consolidation (part 2) are ongoing. Clinical trial information: NCT04257448. Research Sponsor: GWT-TUD GmbH. Citation Format: Jens T. Siveke, Marianne Sinn, Stefan Boeck, Gabriele Siegler, Thomas Seufferlein, Joerg Trojan, Dirk Waldschmidt, Alexander Koenig, Dorothea Schipp, Ines Winkler, Sven Thorsten Liffers, Volker Kunzmann. Interim safety results from SEPION/AIO-PAK-0118: A multicenter, Phase I/II study of sequential epigenetic and immune targeting in combination with nab-paclitaxel/gemcitabine in patients with advanced pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT195.

Did Ghana Do Enough? A Scientometric Analysis of COVID-19 Research Output from Ghana within the African Context

The COVID-19 pandemic has generated worldwide research efforts to provide knowledge about the disease. Yet little is known about how Ghana contributed to this critical knowledge production. This scientometric analysis was conducted to ascertain Ghana's COVID-19 research output within the African context to gain understanding and identify potential future directions. The study retrieved relevant research, spanning 2019 to 2022, from the Scopus database in December 2022. The retrieved data were assessed using various established indices, including collaboration patterns, productive institutions, citation patterns, and major research sponsors, among others. Ghana came seventh in Africa with a total of 1112 publications. For international collaborations, the United States and the United Kingdom were the major partners, while South Africa was the main African collaborator with Ghana. Out of the top 21 most productive authors, 85.7% were males and 14.3% were females, demonstrating a great gender gap in research output in Ghana. Although Ghana has made some contributions to the global COVID-19 research output, there are few intra-continental research collaborations, which limits Africa's overall research output. Our study demonstrates a critical need for the Ghanaian government to prioritize research and funding and address barriers to women's research productivity.

PD28-09 A MULTI-INSTITUTIONAL ANALYSIS OF HUMAN IN VIVO INTRARENAL PRESSURE DURING URETEROSCOPY

You have accessJournal of UrologyCME1 Apr 2023PD28-09 A MULTI-INSTITUTIONAL ANALYSIS OF HUMAN IN VIVO INTRARENAL PRESSURE DURING URETEROSCOPY Stefanie Croghan, Sorcha O'Meara, Eoghan Cunnane, Connor Cunnane, Muheilan Muheilan, Mutaz Elamin, Kenneth Patterson, Steven Anderson, Jody Khan, James Forde, Rustom Manecksha, Fergal O'brien, Michael Walsh, and Niall Davis Stefanie CroghanStefanie Croghan More articles by this author , Sorcha O'MearaSorcha O'Meara More articles by this author , Eoghan CunnaneEoghan Cunnane More articles by this author , Connor CunnaneConnor Cunnane More articles by this author , Muheilan MuheilanMuheilan Muheilan More articles by this author , Mutaz ElaminMutaz Elamin More articles by this author , Kenneth PattersonKenneth Patterson More articles by this author , Steven AndersonSteven Anderson More articles by this author , Jody KhanJody Khan More articles by this author , James FordeJames Forde More articles by this author , Rustom ManeckshaRustom Manecksha More articles by this author , Fergal O'brienFergal O'brien More articles by this author , Michael WalshMichael Walsh More articles by this author , and Niall DavisNiall Davis More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003313.09AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Elevated intrarenal pressure is a proposed risk factor for adverse clinical outcomes in endourology. However, minimal human data exists on baseline or ureteroscopic pressures within the upper urinary tract. We aimed to quantify in vivo intrarenal pressure in a consecutive patient sample undergoing ureteroscopy and assess for correlation between pressure dynamics and clinical outcome. METHODS: A prospective, multi-institutional study was designed with ethical approval. One hundred consenting adult patients undergoing elective ureteroscopy were included. The Comet™ II Pressure Guidewire (Boston Scientific), was placed retrograde within the renal pelvis under fluoroscopy prior to ureteroscopy. Semi-rigid and/or flexible ureteroscopy/renoscopy was performed according to surgeon’s standard practice. The AVVIGOTM (Boston Scientific) System provided live intrarenal pressure recordings, to which the operating surgeon was blinded. Baseline and ureteroscopic intrarenal pressures were recorded. Thirty-day follow up of clinical outcomes was completed and statistical analysis performed. RESULTS: Analysis of 309 unique pressure traces from 100 consecutive patients (56 male; 44 female) was performed. Mean patient age was 57.21±13.73 years. Ureteroscopy was performed for urolithiasis in 94% (n=94) and for other diagnostic indications in 6% (n=6); 26% (n=26) were pre-stented. The mean resting baseline intrarenal pressure (IRP) was 17.47±10.66 mmHg. Semi-rigid ureteroscopy (URS) was performed with a 6.5-7.5Fr ureteroscope in 30% (n=30), with mean IRP 39.55±17.66 mmHg. Flexible ureterorenoscopy (FURS) with a 9.1-10Fr instrument was performed in 93% (n=93). FURS without a ureteral access sheath (UAS) resulted in mean IRP 38.12±16.33 mmHg. FURS using an 11/13Fr UAS resulted in IRPs (mean±SD) of 30.1±20.48mmHg (gravity irrigation); 43.04±24.87mmHg (pressurised irrigation at 100mmHg); 46.53±25.05mmHg (pressurised irrigation at 150mmHg) and 79.74±61.66 (pressurised irrigation at 200mmHg). Readmission with pyrexia occurred in 4% (n=4); mean procedural IRP in this cohort was significantly higher than controls at 120.25±67.88mmHg versus 41.3±26.4mmHg(p<0.001). CONCLUSIONS: Both baseline intra-renal pressures and ureteroscopic pressures exhibit variability. Intraoperative IRP is related to technical variables. High intrarenal pressure values are positively correlated with postoperative pyrexia, however the complication pressure threshold appears to be higher than previously thought. Source of Funding: Boston Scientific (Investigator Sponsored Research product grant). © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e822 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Stefanie Croghan More articles by this author Sorcha O'Meara More articles by this author Eoghan Cunnane More articles by this author Connor Cunnane More articles by this author Muheilan Muheilan More articles by this author Mutaz Elamin More articles by this author Kenneth Patterson More articles by this author Steven Anderson More articles by this author Jody Khan More articles by this author James Forde More articles by this author Rustom Manecksha More articles by this author Fergal O'brien More articles by this author Michael Walsh More articles by this author Niall Davis More articles by this author Expand All Advertisement PDF downloadLoading ...

List of the academic editors of Al-Qadisiyah journal for engineering sciences for the period from January 2023 to the present

Al-Qadisiyah Journal for Engineering Sciences (QJES) is a scientific Open Access peer-reviewed journal. It publishes papers online and hard copy in all areas of the engineering field, including experimental, theoretical, and computational analysis. The first edition of the QJES was published in 2008. Currently, it is published four times per year at the end of March, June, September, and December at the College of Engineering, the University of Al-Qadisiyah under the Iraqi Ministry of Higher Education and Scientific Research sponsorship. Based on the evaluation of the editorial and advisory members, the QJES provides essential reference materials and critical feedback into basic and practical contributions in different fields of engineering sciences. All submissions to the journal will be subject to peer review from leading experts in the field from inside and outside Iraq. Their impressions and comments will determine the final decision of the paper, whether accepted or rejected.

Measuring the research funding landscape: a case study of BRICS nations

Purpose The purpose of this study is to determine the funding ratio of BRICS nations in various research areas. The leading funding institutions that support research in the developing world have also been researched. Design/methodology/approach This study involves the funding acknowledgment analysis of the data retrieved from the “Clarivate Analytics' InCites database” under “22 specific research areas” to determine whether the publication was funded. Findings This study shows that China achieves the highest funding ratio of 88.6%, followed by Brazil (73.74%), Russia (72.93%) and South Africa (70.94%). However, India has the lowest funding ratio of 58.2%. For the subject areas, the highest funding ratio is by microbiology in Russia (86.6%), India (84.3%) and China (96.9%) and space science in Brazil (93.7%) and South Africa (94.82%). However, economics and business achieves the lowest funding ratio in Brazil (38.6%), India (20.1%) and South Africa (30.24%). Moreover, the regional funding agencies are the leading research sponsors in the BRICS nations. Practical implications This study implies increasing the funding ratio across various research areas, including arts, humanities and social sciences. The nations, particularly India, also need to gear up sponsoring the research to improve the funding ratio for scientific development, bringing overall good. Originality/value This study efforts to show the status of countries and research subjects in terms of funding ratio and reveals the prominent funders working toward scientific growth.