Abstract 10169: Changes in Cytokine Responses by Treatment with Tocilizumab After Out-of-Hospital Cardiac Arrest - A Sub Study of the IMICA Trial

Background: Out-of-hospital cardiac arrest (OHCA) patients are at high risk of morbidity and mortality attributable to the post-cardiac arrest syndrome, in which systemic inflammation is a major component. Cytokines are involved in many processes, including inflammation. In the IMICA trial, treatment with the interleukin 6 receptor (IL-6R) antagonist tocilizumab in resuscitated comatose OHCA patients reduced systemic inflammation as characterized by a greatly reduced CRP response and lower levels of leukocytes as compared to placebo. Markers of myocardial injury were also reduced by treatment. Aim: To investigate changes in cytokine levels induced by blocking the IL-6-mediated signaling with tocilizumab after OHCA by employing a broad cytokine panel. Methods: We randomized 80 patients to a single infusion of tocilizumab 8 mg/kg or placebo after admission. Blood samples were drawn at 0, 24, 48, and 72 hours. Cytokines were measured using a 17-plex cytokine assay: G-CSF, GM-CSF, IFN-γ, MCP-1, MIP-1β, TNF-α, IL- 1β, 2, 4-8, 10, 12, 13, and 17. Data were log2 transformed and analyzed by constrained linear mixed models. Results: Most cytokines had temporal changes after OHCA. However, only for IL- 5, 6 (Figure) and 17 were the treatment-by-time interactions significant, all p<0.05. Circulating IL-5 and in particular IL-6 was markedly increased by inhibition of the IL-6R with tocilizumab as compared to the placebo group. For IL-17 the changes were less pronounced and only differed between groups at 72 hours. Conclusions: Treatment with the IL-6R antagonist, tocilizumab, did not alter the cytokine responses in general, however, IL-5 and IL-6 were markedly increased. Experimental data suggests that IL-5 may play a role in cardiac recovery after ischemia. Blockage of the IL-6R greatly increased the IL-6 levels, and as the CRP response was greatly reduced by tocilizumab, a response strongly associated with IL-6, it can be demonstrated that the function of IL-6 was blunted.

VinCaP: a phase II trial of vinflunine in locally advanced and metastatic squamous carcinoma of the penis

Background We investigated the first-line activity of vinflunine in patients with penis cancer. Cisplatin-based combinations are commonly used, but survival is not prolonged; many patients are unfit for such treatment or experience toxicity that outweighs clinical benefit. Methods Twenty-five patients with inoperable squamous carcinoma of the penis were recruited to a single-arm, Fleming–A’Hern exact phase II trial. Treatment comprised 4 cycles of vinflunine 320 mg/m2, given every 21 days. Primary endpoint was clinical benefit rate (CBR: objective responses plus stable disease) assessed after 4 cycles. Seven or more objective responses or disease stabilisations observed in 22 evaluable participants would exclude a CBR of <15%, with a true CBR of >40% being probable. Results Twenty-two participants were evaluable. Ten objective responses or disease stabilisations were confirmed. CBR was 45.5%, meeting the primary endpoint; partial response rate was 27.3%. Seven patients received >4 cycles of vinflunine. Dose reduction or treatment delay was required for 20% of cycles. In all, 68% of patients experienced at least one grade 3 adverse event. Two deaths on treatment were not caused by disease progression. Conclusions Pre-specified clinical activity threshold was exceeded. Toxicity was in keeping with experience in other tumours. Vinflunine merits further study in this disease. Trial registration NCT02057913.

Clinical activity and safety of the anti-PD-1 monoclonal antibody dostarlimab for patients with recurrent or advanced dMMR endometrial cancer

This document provides a short summary of the GARNET trial which was published in JAMA Oncology in October 2020. At the end of this document, there are links to websites where you can find more information about this study. The trial enrolled adult participants with advanced solid tumors. This report is restricted to patients with a particular type of endometrial cancer that has a deficient mismatch repair (dMMR) status. Patients received a trial treatment called dostarlimab (also known by the brand name Jemperli). In the US, dostarlimab is approved as a single therapy in adult patients with dMMR recurrent or advanced endometrial cancer that has progressed on or after platinum-based chemotherapy. In the EU, dostarlimab is approved as a single therapy in adult patients with recurrent or advanced dMMR/microsatellite instability–high (MSI-H) endometrial cancer that has progressed on or after treatment with a platinum-containing regimen. The GARNET trial looked at dostarlimab given intravenously to patients with dMMR endometrial cancer from 7 countries. The trial showed that dostarlimab was successful in shrinking the tumor in 42% of these patients. In general, the percentage of participants who experienced medical problems (referred to as side effects) was low and within expectations for this type of treatment. ClinicalTrials.gov NCT number: NCT02715284 . To read the full Plain Language Summary of this article, click on the View Article button above and download the PDF. Link to original article here .

Oncology patients’ experiences in experimental medicine cancer trials: a qualitative study

ObjectivesThe study aimed to explore patients’ experiences of experimental cancer medicine (ECM) clinical trials.DesignThe study’s design was qualitative. Two focus groups with patients were undertaken followed by semistructured interviews, to explore patients’ experiences of ECM clinical trials. Interviews and focus groups were audiorecorded and transcribed verbatim. Data were analysed using thematic analysis.SettingA regional cancer centre (tertiary care) in North-West England.ParticipantsTwelve patients (aged 52–79) participated in one of the two focus groups and 22 patients (aged 42–83) participated in interviews.Primary outcome measurePatients’ experiences of an ECM trial.ResultsFour main themes were identified from the analysis: decision making, information needs, the experience of trial participation and impact of trial participation. Subthemes are presented in the manuscript.ConclusionTo make fully informed decisions about trial participation, patients required the simplification of trial information and wanted more information about side effects, their response to trial treatment and the overall trial progress throughout the trial. Patients highlighted the need for improvement for the support provided to their family and friends.

Single pill combinations present a proven fast track in practice to reach the target blood pressure

Objective To assess the efficacy of ambulatory blood pressure (BP) lowering with perindopril/amlodipine (dual SPC arm) and perindopril/amlodipine/indapamide (triple SPC arm) in newly diagnosed and uncontrolled hypertensive patients. Design and method: 450 adults with essential hypertension were assessed in the interventional, open-label, prospective, international, multicentre PRECIOUS trial. Treatment duration was 16 weeks, divided into four treatment periods. ABPM was performed at the baseline and end of the study (prior to the visit 1 and 5), with a validated automated portable BP-measuring device (Mobil-O-Graph PWA) worn on the non-dominant arm for a 24-hour period, measuring BP in 20 minutes interval during the day and 30 minutes interval during the night. At inclusion, naïve or patients uncontrolled on previous mono or dual therapy (other than perindopril/amlodipine (P/A)) were assigned to dual SPC arm with initial dose of 4/5 mg P/A. Those uncontrolled on previous dual or triple therapy were assigned to triple SPC arm with initial dose of 4/5/1.25 mg perindopril/amlodipine/indapamide (P/A/I). If office BP control was not reached, the initial dose was up titrated in 4-week intervals to 8/5 mg, 8/10 mg P/A or 8/10/2.5 mg P/A/I in dual SPC arm and to 8/5/2.5 mg, or 8/10/2.5 mg P/A/I in triple SPC arm. Results After 16 weeks of treatment the decrease in average ambulatory BP was −16.1/−10.8 mmHg (from 142.8/92.6 mmHg to 125.1/80.8 mmHg) in dual SPC arm and −21.8/−13.5 mmHg (from 147.3/93.3 mmHg to 124.2/79.0 mmHg) in triple SPC arm. The relative reductions in ambulatory BP were −11.1%/−11.3% in dual and −14.5%/−14.2% in triple SPC arm. The absolute as well as relative ABPM reductions were higher for the awake-time BP. All ambulatory BP reductions were statistically significant in both arms (p&lt;0.001). 71% of patients reached the normal 24h SBP levels and 45.6% the normal 24h DBP levels. At the end of the trial, the mean dose of perindopril was 6.4±2.0 mg and of amlodipine 6.5±2.3 mg in dual SPC arm. In triple SPC arm, the mean dose of perindopril was 6.66±1.89 mg, of amlodipine 6.51±2.30 mg, and of indapamide 2.08±0.59 mg. Treatment tolerability was good. 85% of patients experienced no adverse events; the recorded ones were clinically irrelevant. Conclusions Applying dual (perindopril/amlodipine) and triple (perindopril/amlodipine/indapamide) SPC treatment strategy resulted in a significant and fast BP reduction, measured by ABPM, in naïve and in patients uncontrolled on previous therapy. In even 71% of patients normal 24h SBP was reached. It seems that adding long acting diuretic in triple SPC enhanced drug efficacy even though the patients in the triple SPC arm had a more resistant hypertension. FUNDunding Acknowledgement Type of funding sources: None.

Out of Compassion of Out of Rights? A Story about an Amyotrophic Lateral Sclerosis (ALS) Human Clinical Trial

This article examines the intersection of compassion and rights, and how the two concepts are constituted and wielded in the context of human clinical trials. Doron, an ALS patient who was recruited to a clinical trial, believed that he had the right to post-trial treatment according to the wording of an informed consent form he signed before joining the trial. However, the biotech company sponsoring the trial instead offered him ‘compassionate use’ access, i.e., access at its discretion rather than as a legal obligation on its part. I argue that under a ‘bioeconomy of value’, the human clinical trial regime has been subordinated to two competing discourses: that of compassion and that of patients’ rights. Both are interpreted and deployed differently by the different stakeholders, namely the patient, the biotech company, and the medical establishment. I argue that the adoption, by bioeconomy actors, of a social value discourse of compassion is designed to preserve a hierarchy that deprives the patient of their power and their rights. Simultaneously, this practice highlights the power of the biotech industry as a moral partner and ‘saviour’ in its relationship with patient organisations and its role as a medical–scientific actor in the Israeli healthcare system.

Epistemic affordances in gestalt perception as well as in emotional facial expressions and gestures

Summary Methodological problems often arise when a special case is confused with the general principle. So you will find affordances only for ‚artifacts’ if you restrict the analysis to ‚artifacts’. The general principle, however, is an ‚invitation character’, which triggers an action. Consequently, an action-theoretical approach known as ‚pragmatic turn’ in cognitive science is recommended. According to this approach, the human being is not a passive-receptive being but actively produces those action effects that open up the world to us (through ‚active inferences’). This ‚ideomotor approach’ focuses on the so-called ‚epistemic actions’, which guide our perception as conscious and unconscious cognitions. Due to ‚embodied cognition’ the own body is assigned an indispensable role. The action theoretical approach of ‚enactive cognition’ enables that every form can be consistently processualized. Thus, each ‚Gestalt’ is understood as the process result of interlocking cognitions of ‚forward modelling’ (which produces anticipations and enables prognoses) and ‚inverse modelling’ (which makes hypotheses about genesis and causality). As can be shown, these cognitions are fed by previous experiences of real interaction, which later changes into a mental trial treatment, which is highly automated and can therefore take place unconsciously. It is now central that every object may have such affordances that call for instrumental or epistemic action. In the simplest case, it is the body and the facial expressions of our counterpart that can be understood as a question and provoke an answer/reaction. Thus, emotion is not only to be understood as expression/output according to the scheme ‚input-processing-output’, but acts itself as a provocative act/input. Consequently, artifacts are neither necessary nor sufficient conditions for affordances. Rather, they exist in all areas of cognition—from Enactive Cognition to Social Cognition.

A methodology for the extraction and analysis of real-world radiographic and electronic medical record data to reconstruct treatment arms of historical prostate cancer clinical trials.

5033 Background: Real-world evidence (RWE), including synthetic comparator arms created from historical real-world data (RWD), has the potential to support the safety and efficacy evaluation of new medical products. However, many available RWD sources lack the details necessary to reliably identify patients comparable to clinical trial cohorts or to assess essential oncologic efficacy endpoints. This project demonstrates the ability to extract and analyze RWD to identify patients matching eligibility criteria to four historical clinical trials in metastatic castration-resistant prostate cancer (mCRPC), and calculate outcome measures. Methods: A total of 5,741 patients treated for prostate cancer at multiple institutions (2010-2020) were analyzed in two cohorts using data extracted from the EMR, Tumor Registry, Oncology Information System, and Picture Archiving and Communication System. Of 3,486 patients with prostate cancer in Cohort 1, 422 mCRPC patients were identified: those treated with ADT who achieved castration-level testosterone ( < 50 ng/dL), had evidence of metastatic disease, and exhibited rising PSA (PCWG2). These patients were further matched to four historical clinical trial treatment arms (COU-AA-301: 49, COU-AA-302: 143, AFFIRM: 30, PREVAIL: 79), based on prior chemotherapy and receipt of Abiraterone or Enzalutamide. Overall survival (OS) and time to skeletal related events (SRE) (pathological fracture, spinal compression, surgery to bone, and radiotherapy to bone) were calculated based on diagnosis and procedure codes using the Kaplan-Meier (KM) Estimator. Of 2,255 patients with prostate cancer in Cohort 2, 101 patients received Abiraterone or Enzalutamide and 59 patients had sufficient baseline and follow-up imaging to be scored. Radiographic progression-free survival (rPFS) was calculated from the start of treatment to the time of progression (RECIST 1.1) or loss to follow-up using the KM estimator. Results: In Cohort 1, median OS was 37.7 months (95% CI: 31.5-NR), and median time to SRE was 17.9 months (13.5-22.6). Median OS per patient cohort matched to historical trial treatment arm was COU-AA-301: 23.7 months (10.7-NR), COU-AA-302: 45.9 months (34.9-NR), AFFIRM: 35.3 months (6.34-NR), PREVAIL: 41.5 months (21.9-NR). In Cohort 2, median rPFS was 37.2 months (13.3-NR). Conclusions: The methodology employed in this analysis not only successfully identified a cohort of RWD patients similar to clinical trial-defined patients, but also curated sufficiently reliable data to calculate essential endpoints (e.g., rPFS). At scale, this methodology can be used to generate RWE, including synthetic comparator arms to support clinical trials with radiographic endpoints.