BioReliance (United States)

ABSTRACT BackgroundThe United States (U.S.) Food and Drug Administration (FDA) conducts Good Clinical Practice (GCP) inspections to evaluate regulatory compliance, assess clinical trial conduct, and verify data integrity in support of marketing applications. To date, there has been no comprehensive assessment of the geographic distribution or extent of such inspections conducted during the marketing application review. MethodsWe conducted a retrospective analysis of FDA GCP inspection records involving clinical investigators (CIs), sponsors, and contract research organizations (CROs) associated with marketing applications submitted during fiscal years 2016 to 2018. ResultsA total of 1,275 GCP inspections were performed in support of 347 marketing applications during the study period. Inspections covered CIs (86%), sponsors (10%), and CROs (4%). On average, three CIs were inspected for each application. Most CI inspections (63%) were conducted within the U.S., with the remainder primarily in Europe. Of the 347 applications, 36% had sponsor inspections and 15% CRO inspections; the majority of these were conducted in the U.S. (>80%). Approximately 4% of U.S.-based and 2% of non-U.S.-based CIs were inspected. CI inspections covered about 10% of enrolled trial participants overall (14% U.S. vs. 8% non-U.S.) and included review of approximately 5% of source records (8% U.S. vs. 3% non-U.S.). ConclusionsWhile the total number of inspections and source records reviewed varied by year, the distribution of inspection types, participant coverage, and source document review percentages remained consistent. Most inspections were conducted in the U.S., where CI inspections also covered a higher proportion of participants and source data.

2596 Background: Tifcemalimab, a humanized IgG4 antibody against BTLA, showed a tolerable safety profile and preliminary single-agent anti-tumor activity in pretreated pts with advanced malignancies. Here we report the dose escalation and cohort expansion study of tifcemalimab in combination with toripalimab (anti-PD-1) in pts with pretreated advanced malignancies. Methods: Eligible pts with advanced malignancies refractory to standard therapies were enrolled in the dose escalation and the cohort expansion phases of this study (NCT04137900). During dose escalation, tifcemalimab was administered at escalating doses of 20, 70, 200 and 500 mg in combination with 240 mg toripalimab given intravenously once every three weeks (Q3W) until disease progression or intolerable toxicity. Dose-limiting toxicity (DLT) was evaluated. Study objectives included safety and efficacy. During cohort expansion, the combination of tifcemalimab (200mg Q3W) and toripalimab (240 mg Q3W) were further evaluated in five indication-specific cohorts (melanoma, non-small cell lung cancer [NSCLC], renal cell carcinoma [RCC], urothelial carcinoma [UC] and lymphoma) for safety and efficacy. Results: By December 16, 2023, a total of 16 pts received study treatment during dose escalation and 69 pts were treated during cohort expansion from 18 participating sites from the US. Pts were heavily pretreated with a median of 4 prior lines of therapy. The median age was 65 (range 32-85) years, 69% of pts were male. As of December 16, 2023, the median follow-up was 11.4 weeks. No DLT was observed during dose escalation. Treatment-emergent adverse event (TEAEs) occurred in 92% pts, 44% experienced grade 3 or higher TEAEs, including 2 (2%) treatment-related Grade 5 events. The most common TEAEs included: fatigue (27%), diarrhea (17%), nausea (17%), anemia (15%), arthralgia (15%), decreased appetite (15%), and dyspnea (15%). TEAE led to discontinuation of study drug in 6% of pts. Nineteen percent of pts experienced immune-related AEs. No new safety signal was identified outside the known risk profiles of tifcemalimab and toripalimab. Among 14 evaluable pts in the dose escalation phase, 8 had stable disease. Among 57 evaluable pts in the cohort expansion phase, 1 complete response (lymphoma), 6 partial responses (2 melanoma, 2 RCC, 1 NSCLC, 1 UC) and 17 stable disease were observed. The ORRs were 5%, 11%, 17%, 18% and 33% in the NSCLC, melanoma, UC, RCC and lymphoma cohorts respectively. All responders were refractory to prior immunotherapy and all responses were still ongoing by the cutoff date. Conclusions: Tifcemalimab in combination with toripalimab showed preliminary efficacy in immunotherapy-refractory pts with a manageable safety profile. Phase II combination studies in various advanced solid tumors are ongoing. Clinical trial information: NCT04137900 .

Perioperative chemotherapy is the standard treatment for locally advanced gastric or gastro-esophageal junction cancer, and the addition of programmed cell death 1 (PD-1) inhibitor is under investigation. In this randomized, open-label, phase 2 study (NEOSUMMIT-01), patients with resectable gastric or gastro-esophageal junction cancer clinically staged as cT3-4aN + M0 were randomized (1:1) to receive either three preoperative and five postoperative 3-week cycles of SOX/XELOX (chemotherapy group, n = 54) or PD-1 inhibitor toripalimab plus SOX/XELOX, followed by toripalimab monotherapy for up to 6 months (toripalimab plus chemotherapy group, n = 54). The primary endpoint was pathological complete response or near-complete response rate (tumor regression grade (TRG) 0/1). The results showed that patients in the toripalimab plus chemotherapy group achieved a higher proportion of TRG 0/1 than those in the chemotherapy group (44.4% (24 of 54, 95% confidence interval (CI): 30.9%-58.6%) versus 20.4% (11 of 54, 95% CI: 10.6%-33.5%)), and the risk difference of TRG 0/1 between toripalimab plus chemotherapy group and chemotherapy group was 22.7% (95% CI: 5.8%-39.6%; P = 0.009), meeting a prespecified endpoint. In addition, a higher pathological complete response rate (ypT0N0) was observed in the toripalimab plus chemotherapy group (22.2% (12 of 54, 95% CI: 12.0%-35.6%) versus 7.4% (4 of 54, 95% CI: 2.1%-17.9%); P = 0.030), and surgical morbidity (11.8% in the toripalimab plus chemotherapy group versus 13.5% in the chemotherapy group) and mortality (1.9% versus 0%), and treatment-related grade 3-4 adverse events (35.2% versus 29.6%) were comparable between the treatment groups. In conclusion, the addition of toripalimab to chemotherapy significantly increased the proportion of patients achieving TRG 0/1 compared to chemotherapy alone and showed a manageable safety profile. ClinicalTrials.gov registration: NCT04250948 .

Abstract Geostatistics provides innovative tools for the radiological characterization of nuclear facilities under decommissioning as well as contaminated sites for remediation. The relevance of this approach relies on the presence of a spatial continuity for radiological contamination. In this case, geostatistics provides reliable activity estimates, uncertainty quantification and risk analysis, which are essential decision-making tools for decommissioning and dismantling projects of nuclear installations. The experimental variogram γ(h) is calculated by averaging, within classes of distance h, the variability contribution of each couple of data; this contribution is usually quantified by the half-squared difference of the measured values. In this paper, a parallel is drawn with an alternative formula of the statistical variance to be able to break down the different variance contribution (sampling duplicates, measurement replicates, spatial variability). The application on one chemical case and one radiological case demonstrates that, the relative uncertainty on the laboratory results (analyses on destructive samples) can be seen as negligible in comparison to the sampling uncertainty on the one hand and the spatial variability on the other hand. In addition, classification of volumes according to a threshold seems to be quite robust in comparison to the relative accuracy of the lab results. The artificial introduction of a systematic bias (± 50% for instance) leads to a corresponding limited impact on contaminated volumes (only ± 10% or ±20%).

<div>AbstractPurpose:<p>Immunotherapy offers a second-line option for patients with metastatic urothelial carcinoma (mUC) who failed standard therapy, but the biomarkers for predicting response remain to be explored. This study aims to evaluate the safety, efficacy, and correlative biomarker of toripalimab in patients with previously treated mUC.</p>Patients and Methods:<p>Patients with mUC received toripalimab 3 mg/kg Q2W. Clinical response was assessed every 8 weeks by an independent review committee per RECIST v1.1. Tumor PD-L1 expression, tumor mutational burden (TMB), and other biomarkers were evaluated.</p>Results:<p>Among the intention-to-treat population (<i>n</i> = 151), 85% of the patients experienced treatment-related adverse event (TRAE) and 20% experienced grade 3 and above TRAE. The objective response rate (ORR) was 26% with a disease control rate (DCR) of 45%. The median duration of response, progression-free survival (PFS), and overall survival (OS) were 19.7 months [95% confidence interval (CI): 13.9–not estimable], 2.3 months (95% CI, 1.8–3.6), and 14.4 months (95% CI, 9.3–23.1), respectively. Both PD-L1<sup>+</sup> and TMB-high (10 mutations/Mb as the cutoff) patients had better ORR than PD-L1<sup>−</sup> patients (42% vs. 17%, <i>P</i> = 0.002) and TMB-low patients (48% vs. 22%, <i>P</i> = 0.014), respectively. The TMB-high group also showed better PFS (12.9 vs. 1.8 months, <i>P</i> < 0.001) and OS (not reached versus 10.0 months, <i>P</i> = 0.018) than the TMB-low group.</p>Conclusions:<p>Toripalimab has demonstrated encouraging clinical activity in the second-line treatment of mUC with a manageable safety profile. PD-L1 expression and TMB were two independent biomarkers in the study.</p></div>

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Summary Before constructing wind turbines in the south of Groix island, overseas measurements of the total magnetic field were conducted to locate the Unexploded Ordnances (UXO) buried since the Second World War. A set of two magnetometers pulled by a boat was used to measure the magnetic field in go-and-return trajectories. The measurements along north and southward trajectories were correlated. However, the magnetometers systematically recorded a relatively higher magnetic field during the northward course. Using both north and southward measurements resulted in a heterogenous dataset, which created azimuthal artifacts on the produced maps. A Gaussian transformation was used to adapt the statistical distribution of the southward measurements to the northward ones and make the dataset homogeneous. Therefore, the azimuthal artifacts were considerably reduced, and potential UXO locations were detected more easily. Exploratory data analysis and mapping steps were done entirely in the Isatis.neo™ geostatistical software.