A crisis in clinical research.

The clinical research pipeline is critical to ensuring continued development of novel treatments that can offer patients with cancer safe and effective options. Unfortunately, progress has slowed since the COVID-19 pandemic due to uncovered, systemic inefficiencies across critical processes. Towards initiating discussion on how to reinvigorate clinical research, the Society for Immunotherapy of Cancer (SITC) hosted a virtual summit that characterized issues and formed potential solutions. This commentary serves to highlight the crisis facing clinical research as well as stimulate field-wide discussion on how to better serve patients into the future.

Developing an international consensus Reporting guideline for intervention Fidelity in Non-Drug, non-surgical trials: The ReFiND protocol.

BACKGROUND: Inadequate reporting of fidelity to interventions in trials limits the transparency and interpretation of trial findings. Despite this, most trials of non-drug, non-surgical interventions lack comprehensive reporting of fidelity. If fidelity is poorly reported, it is unclear which intervention components were tested or implemented within the trial, which also hinders research reproducibility. This protocol describes the development process of a reporting guideline for fidelity of non-drug, non-surgical interventions (ReFiND) in the context of trials. METHODS: The ReFiND guideline will be developed in six stages. Stage one: a guideline development group has been formed to oversee the guideline methodology. Stage two: a scoping review will be conducted to identify and summarize existing guidance documents on the fidelity of non-drug, non-surgical interventions. Stage three: a Delphi study will be conducted to reach consensus on reporting items. Stage four: a consensus meeting will be held to consolidate the reporting items and discuss the wording and structure of the guideline. Stage five: a guidance statement, an elaboration and explanation document, and a reporting checklist will be developed. Stage six: different strategies will be used to disseminate and implement the ReFiND guideline. DISCUSSION: The ReFiND guideline will provide a set of items developed through international consensus to improve the reporting of intervention fidelity in trials of non-drug, non-surgical interventions. This reporting guideline will enhance transparency and reproducibility in future non-drug, non-surgical intervention research.

Implementation Science to Achieve Equity in Heart Failure Care: A Scientific Statement From the American Heart Association.

Guideline-directed medical therapies and guideline-directed nonpharmacological therapies improve quality of life and survival in patients with heart failure (HF), but eligible patients, particularly women and individuals from underrepresented racial and ethnic groups, are often not treated with these therapies. Implementation science uses evidence-based theories and frameworks to identify strategies that facilitate uptake of evidence to improve health. In this scientific statement, we provide an overview of implementation trials in HF, assess their use of conceptual frameworks and health equity principles, and provide pragmatic guidance for equity in HF. Overall, behavioral nudges, multidisciplinary care, and digital health strategies increased uptake of therapies in HF effectively but did not include equity goals. Few HF studies focused on achieving equity in HF by engaging stakeholders, quantifying barriers and facilitators to HF therapies, developing strategies for equity informed by theory or frameworks, evaluating implementation measures for equity, and titrating strategies for equity. Among these HF equity studies, feasibility was established in using various educational strategies to promote organizational change and equitable care. A couple include ongoing randomized controlled pragmatic trials for HF equity. There is great need for additional HF implementation trials designed to promote delivery of equitable guideline-directed therapy.

Treatment-free survival outcomes from the phase II study of nivolumab and salvage nivolumab/ipilimumab in advanced clear cell renal cell carcinoma (HCRN GU16-260-Cohort A).

BACKGROUND: As part of a partitioned survival analysis, treatment-free survival (TFS) can characterize the overall survival time patients spend between the cessation of immunotherapy and the start of subsequent therapy; both with and without toxicity. Significant TFS was reported for the nivolumab/ipilimumab arms of the CheckMate 067 and 214 trials for patients with advanced melanoma or renal cell carcinoma (aRCC), respectively, where immunotherapy was often halted for toxicity rather than a predefined treatment endpoint. We therefore sought to assess TFS in the HCRN GU16-260 trial, which was designed to reduce toxicity and cap immunotherapy duration. METHODS: Data were analyzed from 128 patients with clear-cell aRCC treated with first-line nivolumab monotherapy for up to 2 years. Salvage nivolumab/ipilimumab for up to 1 year was provided to eligible patients with disease progression at any point or stable disease at 48 weeks (29% of patients). TFS was defined as the area between Kaplan-Meier curves for a time from registration to protocol therapy cessation and for a time from registration to subsequent systemic therapy initiation or death, estimated from 36-month mean times. The time on or off protocol treatment with grade 3+treatment-related adverse events (TRAEs) was also captured. RESULTS: At 36 months from enrollment, 68.3% of patients were alive: 96.8% of International Metastatic RCC Database Consortium (IMDC) favorable-risk patients and 56.6% of those with intermediate/poor-risk, respectively. The 36-month mean time on protocol therapy was 11.5 months including 0.6 months with grade 3+TRAEs (16.0 months for favorable-risk patients and 9.6 months for intermediated/poor-risk patients). The 36-month mean TFS for the whole population was 9.4 months (12.9 months including 1.5 months with grade 3+TRAEs for favorable-risk and 8.0 months including 1.0 months with grade 3+TRAEs for intermediate/poor-risk). At 36 months, 65.6% of favorable-risk patients and 27.1% of intermediate/poor-risk patients were alive and subsequent systemic treatment-free. CONCLUSIONS: Nivolumab monotherapy with salvage nivolumab/ipilimumab in non-responders is an active treatment approach in treatment-naïve patients with aRCC and, similar to nivolumab/ipilimumab in CheckMate 214, results in substantial TFS and toxicity-free TFS. TFS was greatest in patients with favorable-risk disease, supporting the use of an immunotherapy-only regimen in this population.

Society for Immunotherapy of Cancer (SITC) recommendations on intratumoral immunotherapy clinical trials (IICT): from premalignant to metastatic disease.

BACKGROUND: Intratumorally delivered immunotherapies have the potential to favorably alter the local tumor microenvironment and may stimulate systemic host immunity, offering an alternative or adjunct to other local and systemic treatments. Despite their potential, these therapies have had limited success in late-phase trials for advanced cancer resulting in few formal approvals. The Society for Immunotherapy of Cancer (SITC) convened a panel of experts to determine how to design clinical trials with the greatest chance of demonstrating the benefits of intratumoral immunotherapy for patients with cancers across all stages of pathogenesis. METHODS: An Intratumoral Immunotherapy Clinical Trials Expert Panel composed of international key stakeholders from academia and industry was assembled. A multiple choice/free response survey was distributed to the panel, and the results of this survey were discussed during a half-day consensus meeting. Key discussion points are summarized in the following manuscript. RESULTS: The panel determined unique clinical trial designs tailored to different stages of cancer development-from premalignant to unresectable/metastatic-that can maximize the chance of capturing the effect of intratumoral immunotherapies. Design elements discussed included study type, patient stratification and exclusion criteria, indications of randomization, study arm determination, endpoints, biological sample collection, and response assessment with biomarkers and imaging. Populations to prioritize for the study of intratumoral immunotherapy, including stage, type of cancer and line of treatment, were also discussed along with common barriers to the development of these local treatments. CONCLUSIONS: The SITC Intratumoral Immunotherapy Clinical Trials Expert Panel has identified key considerations for the design and implementation of studies that have the greatest potential to capture the effect of intratumorally delivered immunotherapies. With more effective and standardized trial designs, the potential of intratumoral immunotherapy can be realized and lead to regulatory approvals that will extend the benefit of these local treatments to the patients who need them the most.

Oral PD-L1 inhibitor GS-4224 selectively engages PD-L1 high cells and elicits pharmacodynamic responses in patients with advanced solid tumors.

BACKGROUND: Checkpoint inhibitors targeting the programmed cell death 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) pathway are effective therapies in a range of immunogenic cancer types. Blocking this pathway with an oral therapy could benefit patients through greater convenience, particularly in combination regimens, and allow flexible management of immune-mediated toxicities. METHODS: PD-L1 binding activity was assessed in engineered dimerization and primary cell target occupancy assays. Preclinical antitumor activity was evaluated in ex vivo and in vivo human PD-L1-expressing tumor models. Human safety, tolerability, pharmacokinetics, and biomarker activity were evaluated in an open-label, multicenter, sequential dose-escalation study in patients with advanced solid tumors. Biomarkers evaluated included target occupancy, flow cytometric immunophenotyping, plasma cytokine measurements, and T-cell receptor sequencing. RESULTS: GS-4224 binding caused dimerization of PD-L1, blocking its interaction with PD-1 and leading to reversal of T-cell inhibition and increased tumor killing in vitro and in vivo. The potency of GS-4224 was dependent on the density of cell surface PD-L1, with binding being most potent on PD-L1-high cells. In a phase 1 dose-escalation study in patients with advanced solid tumors, treatment was well tolerated at doses of 400-1,500 mg once daily. Administration of GS-4224 was associated with a dose-dependent increase in plasma GS-4224 exposure and reduction in free PD-L1 on peripheral blood T cells, an increase in Ki67 among the PD-1-positive T-cell subsets, and elevated plasma cytokines and chemokines. CONCLUSIONS: GS-4224 is a novel, orally bioavailable small molecule inhibitor of PD-L1. GS-4224 showed evidence of expected on-target biomarker activity, including engagement of PD-L1 and induction of immune-related pharmacodynamic responses consistent with PD-L1 blockade. TRIAL REGISTRATION NUMBER: NCT04049617.

Preclinical evaluation and first-in-dog clinical trials of PBMC-expanded natural killer cells for adoptive immunotherapy in dogs with cancer.

BACKGROUND: Natural killer (NK) cells are cytotoxic cells capable of recognizing heterogeneous cancer targets without prior sensitization, making them promising prospects for use in cellular immunotherapy. Companion dogs develop spontaneous cancers in the context of an intact immune system, representing a valid cancer immunotherapy model. Previously, CD5 depletion of peripheral blood mononuclear cells (PBMCs) was used in dogs to isolate a CD5dim-expressing NK subset prior to co-culture with an irradiated feeder line, but this can limit the yield of the final NK product. This study aimed to assess NK activation, expansion, and preliminary clinical activity in first-in-dog clinical trials using a novel system with unmanipulated PBMCs to generate our NK cell product. METHODS: Starting populations of CD5-depleted cells and PBMCs from healthy beagle donors were co-cultured for 14 days, phenotype, cytotoxicity, and cytokine secretion were measured, and samples were sequenced using the 3'-Tag-RNA-Seq protocol. Co-cultured human PBMCs and NK-isolated cells were also sequenced for comparative analysis. In addition, two first-in-dog clinical trials were performed in dogs with melanoma and osteosarcoma using autologous and allogeneic NK cells, respectively, to establish safety and proof-of-concept of this manufacturing approach. RESULTS: Calculated cell counts, viability, killing, and cytokine secretion were equivalent or higher in expanded NK cells from canine PBMCs versus CD5-depleted cells, and immune phenotyping confirmed a CD3-NKp46+ product from PBMC-expanded cells at day 14. Transcriptomic analysis of expanded cell populations confirmed upregulation of NK activation genes and related pathways, and human NK cells using well-characterized NK markers closely mirrored canine gene expression patterns. Autologous and allogeneic PBMC-derived NK cells were successfully expanded for use in first-in-dog clinical trials, resulting in no serious adverse events and preliminary efficacy data. RNA sequencing of PBMCs from dogs receiving allogeneic NK transfer showed patient-unique gene signatures with NK gene expression trends in response to treatment. CONCLUSIONS: Overall, the use of unmanipulated PBMCs appears safe and potentially effective for canine NK immunotherapy with equivalent to superior results to CD5 depletion in NK expansion, activation, and cytotoxicity. Our preclinical and clinical data support further evaluation of this technique as a novel platform for optimizing NK immunotherapy in dogs.

Phase 1a dose escalation study of ivonescimab (AK112/SMT112), an anti-PD-1/VEGF-A bispecific antibody, in patients with advanced solid tumors.

BACKGROUND: Studies showed that vascular endothelial growth factor (VEGF) inhibitors could improve therapeutic efficacy of PD-1/PD-L1 antibodies by transforming the immunosuppressive tumor microenvironment (TME) into an immunoresponsive TME. Ivonescimab is a first-in-class, humanized tetravalent bispecific antibody targeting PD-1 and VEGF-A simultaneously. Here, we report the first-in-human, phase 1a study of ivonescimab in patients with advanced solid tumors. METHODS: Patients with advanced solid tumors were treated with ivonescimab 0.3, 1, 3, 10, 20 or 30 mg/kg intravenously every 2 weeks using a 3+3+3 dose escalation design. Dose expansion occurred at 10 and 20 mg/kg in selected tumor types. The primary objective was to assess the safety and tolerability, and to determine the maximum tolerated dose (MTD). The secondary objectives included pharmacokinetics, pharmacodynamics and preliminary antitumor activity based on Response Evaluation Criteria in Solid Tumors V.1.1. RESULTS: Between October 2, 2019 and January 14, 2021, a total of 51 patients were enrolled and received ivonescimab. Two dose-limiting toxicities were reported at 30 mg/kg. The MTD of ivonescimab was 20 mg/kg every 2 weeks. Grade≥3 treatment-related adverse events (TRAEs) occurred in 14 patients (27.5%). The most common TRAEs of any grade were rash (29.4%), arthralgia (19.6%), hypertension (19.6%), fatigue (17.6%), diarrhea (15.7%) and pruritus (11.8%). The most common grade≥3 TRAEs were hypertension (7/51, 13.7%), alanine aminotransferase increased (3/51, 5.2%), aspartate aminotransferase increased (2/51, 3.9%) and colitis (2/51, 3.9%). Of 47 patients who had at least one postbaseline assessment, the confirmed objective response rate was 25.5% (12/47) and disease control rate was 63.8% (30/47). Among 19 patients with platinum-resistant ovarian cancer, 5 patients (26.3%) achieved partial response (PR). Efficacy signals were also observed in patients with mismatch repair proficient (pMMR) colorectal cancer, non-small cell lung cancer, and both MMR deficient and pMMR endometrial cancer. CONCLUSIONS: Ivonescimab demonstrated manageable safety profiles and promising efficacy signals in multiple solid tumors. Exploration of alternative dosing regimens of ivonescimab monotherapy and combination therapies is warranted. TRIAL REGISTRATION NUMBER: NCT04047290.

Final results of urelumab, an anti-CD137 agonist monoclonal antibody, in combination with cetuximab or nivolumab in patients with advanced solid tumors.

BACKGROUND: Resistance to immune checkpoint inhibitors and targeted treatments for cancer is common; thus, novel immunotherapy agents are needed. Urelumab is a monoclonal antibody agonist that binds to CD137 receptors expressed on T cells. Here, we report two studies that evaluated urelumab in combination with cetuximab or nivolumab in patients with select, advanced solid tumors. METHODS: CA186-018: Patients with metastatic colorectal cancer or metastatic squamous cell carcinoma of the head and neck (SCCHN) were treated in a dose-evaluation phase with urelumab 0.1 mg/kg (urelumab-0.1) every 3 weeks (Q3W)+cetuximab 250 mg/m2 (cetuximab-250) weekly; and in a dose-expansion phase with urelumab 8 mg flat dose (urelumab-8) Q3W+cetuximab-250 weekly. CA186-107: The dose-escalation phase included patients with previously treated advanced solid tumors (or treated or treatment-naive melanoma); patients received urelumab 3 mg flat dose (urelumab-3) or urelumab-8 every 4 weeks+nivolumab 3 mg/kg (nivolumab-3) or 240 mg (nivolumab-240) every 2 weeks. In the expansion phase, patients with melanoma, non-small cell lung cancer, or SCCHN were treated with urelumab-8+nivolumab-240. Primary endpoints were safety and tolerability, and the secondary endpoint included efficacy assessments. RESULTS: CA186-018: 66 patients received study treatment. The most frequent treatment-related adverse events (TRAEs) were fatigue (75%; n=3) with urelumab-0.1+cetuximab-250 and dermatitis (45%; n=28) with urelumab-8+cetuximab-250. Three patients (5%) discontinued due to TRAE(s) (with urelumab-8+cetuximab-250). One patient with SCCHN had a partial response (objective response rate (ORR) 5%, with urelumab-8+cetuximab-250).CA186-107: 134 patients received study treatment. Fatigue was the most common TRAE (32%; n=2 with urelumab-3+nivolumab-3; n=1 with urelumab-8+nivolumab-3; n=40 with urelumab-8+nivolumab-240). Nine patients (7%) discontinued due to TRAE(s) (n=1 with urelumab-3+nivolumab-3; n=8 with urelumab-8+nivolumab-240). Patients with melanoma naive to anti-PD-1 therapy exhibited the highest ORR (49%; n=21 with urelumab-8+nivolumab-240). Intratumoral gene expression in immune-related pathways (CD3, CD8, CXCL9, GZMB) increased on treatment with urelumab+nivolumab. CONCLUSIONS: Although the addition of urelumab at these doses was tolerable, preliminary response rates did not indicate an evident additive benefit. Nevertheless, the positive pharmacodynamics effects observed with urelumab and the high response rate in treatment-naive patients with melanoma warrant further investigation of other anti-CD137 agonist agents for treatment of cancer. TRIAL REGISTRATION NUMBERS: NCT02110082; NCT02253992.

Early switch from intravenous to oral antibiotic therapy in patients with cancer who have low-risk neutropenic sepsis: the EASI-SWITCH RCT.

Background: Neutropenic sepsis is a common complication of systemic anticancer treatment. There is variation in practice in timing of switch to oral antibiotics after commencement of empirical intravenous antibiotic therapy. Objectives: To establish the clinical and cost effectiveness of early switch to oral antibiotics in patients with neutropenic sepsis at low risk of infective complications. Design: A randomised, multicentre, open-label, allocation concealed, non-inferiority trial to establish the clinical and cost effectiveness of early oral switch in comparison to standard care. Setting: Nineteen UK oncology centres. Participants: Patients aged 16 years and over receiving systemic anticancer therapy with fever (≥ 38°C), or symptoms and signs of sepsis, and neutropenia (≤ 1.0 × 109/l) within 24 hours of randomisation, with a Multinational Association for Supportive Care in Cancer score of ≥ 21 and receiving intravenous piperacillin/tazobactam or meropenem for < 24 hours were eligible. Patients with acute leukaemia or stem cell transplant were excluded. Intervention: Early switch to oral ciprofloxacin (750 mg twice daily) and co-amoxiclav (625 mg three times daily) within 12-24 hours of starting intravenous antibiotics to complete 5 days treatment in total. Control was standard care, that is, continuation of intravenous antibiotics for at least 48 hours with ongoing treatment at physician discretion. Main outcome measures: Treatment failure, a composite measure assessed at day 14 based on the following criteria: fever persistence or recurrence within 72 hours of starting intravenous antibiotics; escalation from protocolised antibiotics; critical care support or death. Results: The study was closed early due to under-recruitment with 129 patients recruited; hence, a definitive conclusion regarding non-inferiority cannot be made. Sixty-five patients were randomised to the early switch arm and 64 to the standard care arm with subsequent intention-to-treat and per-protocol analyses including 125 (intervention n = 61 and control n = 64) and 113 (intervention n = 53 and control n = 60) patients, respectively. In the intention-to-treat population the treatment failure rates were 14.1% in the control group and 24.6% in the intervention group, difference = 10.5% (95% confidence interval 0.11 to 0.22). In the per-protocol population the treatment failure rates were 13.3% and 17.7% in control and intervention groups, respectively; difference = 3.7% (95% confidence interval 0.04 to 0.148). Treatment failure predominantly consisted of persistence or recurrence of fever and/or physician-directed escalation from protocolised antibiotics with no critical care admissions or deaths. The median length of stay was shorter in the intervention group and adverse events reported were similar in both groups. Patients, particularly those with care-giving responsibilities, expressed a preference for early switch. However, differences in health-related quality of life and health resource use were small and not statistically significant. Conclusions: Non-inferiority for early oral switch could not be proven due to trial under-recruitment. The findings suggest this may be an acceptable treatment strategy for some patients who can adhere to such a treatment regimen and would prefer a potentially reduced duration of hospitalisation while accepting increased risk of treatment failure resulting in re-admission. Further research should explore tools for patient stratification for low-risk de-escalation or ambulatory pathways including use of biomarkers and/or point-of-care rapid microbiological testing as an adjunct to clinical decision-making tools. This could include application to shorter-duration antimicrobial therapy in line with other antimicrobial stewardship studies. Trial registration: This trial is registered as ISRCTN84288963. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 13/140/05) and is published in full in Health Technology Assessment; Vol. 28, No. 14. See the NIHR Funding and Awards website for further award information.

Neutropenic sepsis, or infection with a low white blood cell count, can occur following cancer treatment. Usually patients receive treatment with intravenous antibiotics (antibiotics delivered into a vein) for two or more days. Patients at low risk of complications from their infection may be able to have a shorter period of intravenous antibiotics benefitting both patients and the NHS. The trial compared whether changing from intravenous to oral antibiotics (antibiotics taken by mouth as tablets or liquid) 12­24 hours after starting antibiotic treatment ('early switch') is as effective as usual care. Patients could take part if they had started intravenous antibiotics for low-risk neutropenic sepsis. Patients were randomly allocated to 'early switch' or to usual care. The main outcome measured was treatment failure. Treatment failure happened if fever persisted or recurred despite antibiotics, if patients needed to change antibiotics, if they needed to be re-admitted to hospital or needed to be admitted to intensive care within 14 days or died. We had originally intended that 628 patients would take part, but after review of the design of the study the number needed to take part was revised to 230. We were not able to complete the trial as planned as unfortunately only 129 patients took part. As the trial was smaller than expected we were not able to draw conclusions as to whether 'early switch' is no less effective than usual care. Our findings suggest that 'early switch' might result in a shorter time in hospital initially; however, treatment failure was more likely to occur, meaning some patients had to return to hospital for further antibiotics. There were no differences in side effects and no serious complications from treatment or treatment failure (such as intensive care admission or death) among the 65 patients in the 'early switch' group. Patients were satisfied with 'early switch'. Early switch may be a treatment option for some patients with low-risk neutropenic sepsis who would prefer a shorter duration of hospital admission but accept a risk of needing hospital re-admission.

Efficacy, safety, and biomarker analyses of bintrafusp alfa, a bifunctional fusion protein targeting TGF-ß and PD-L1, in patients with advanced non-small cell lung cancer.

BACKGROUND: Bintrafusp alfa, a first-in-class bifunctional fusion protein targeting transforming growth factor-ß (TGF-ß) and programmed cell death ligand 1, has demonstrated encouraging efficacy as second-line treatment in patients with non-small cell lung cancer (NSCLC) in a dose expansion cohort of the phase 1, open-label clinical trial (NCT02517398). Here, we report the safety, efficacy, and biomarker analysis of bintrafusp alfa in a second expansion cohort of the same trial (biomarker cohort). METHODS: Patients with stage IIIb/IV NSCLC who were either immune checkpoint inhibitor (ICI)-naïve (n=18) or ICI-experienced (n=23) were enrolled. The primary endpoint was the best overall response. Paired biopsies (n=9/41) and peripheral blood (n=14/41) pretreatment and on-treatment were studied to determine the immunological effects of treatment and for associations with clinical activity. RESULTS: Per independent review committee assessment, objective responses were observed in the ICI-naïve group (overall response rate, 27.8%). No new or unexpected safety signals were identified. Circulating TGF-ß levels were reduced (>97%; p<0.001) 2 weeks after initiation of treatment with bintrafusp alfa and remained reduced up to 12 weeks. Increases in lymphocytes and tumor-associated macrophages (TAMs) were observed in on-treatment biospies, with an increase in the M2 (tumor trophic TAMs)/M1 (inflammatory TAMs) ratio associated with poor outcomes. Specific peripheral immune analytes at baseline and early changes after treatment were associated with clinical response. CONCLUSIONS: Bintrafusp alfa was observed to have modest clinical activity and manageable safety, and was associated with notable immunologic changes involving modulation of the tumor immune microenvironment in patients with advanced NSCLC.

Public involvement in Australian clinical trials: A systematic review.

BACKGROUND: Public involvement enhances the relevance, quality, and impact of research. There is some evidence that public involvement in Australian research lags other countries, such as the United Kingdom. The purpose of the systematic review was to establish the rates and describe the characteristics of public involvement in Australian clinical trials. METHODS: We reviewed evidence of public involvement in all Australian randomised controlled trials published in the first 6 months of 2021. To determine the quality of public involvement, we used the five-item short-form version of the Guidance of Reporting Involvement Patients and the Public, version 2. RESULTS: In total, 325 randomised controlled trials were included, of which 17 (5%) reported any public involvement. Six trials reported public involvement in setting the research aim and seven in developing study methods. The authors of one study reflected on the overall role and influence of public involvement in the research. CONCLUSION: Rate of public involvement in Australian clinical trials is seemingly substantially lower than those reported in countries with similar advanced public health care systems, notably the United Kingdom. Our observations may be explained by a lack of researcher skills in how to involve the public and the failure by major funding agencies in Australia to mandate public involvement when deciding on how to award grant funding.

¿Ensayos clínicos de superioridad, equivalencia o no inferioridad? / ¿Clinical trials of superiority, non-inferiority or equivalence?

La eficacia de una nueva intervención se establece generalmente a través de ensayos clínicos (EC) con asignación aleatoria (AA). Sin embargo, entre otros tantos desafíos metodológicos, el especificar la hipótesis de un EC con AA, sigue siendo un problema complejo de resolver para los investigadores clínicos. En este manuscrito discutimos las características de tres variantes de los EC con AA: EC de superioridad (ECS), EC de no-inferioridad (ECNI), y EC de equivalencia (ECE). Estos tres tipos de EC tienen supuestos diferentes sobre los efectos de una intervención, por lo que plantear hipótesis y definir objetivos requiere conocer algunos supuestos subyacentes a estos EC, incluso hasta elementos relacionados con la estimación del tamaño de muestra para cada cual. El objetivo de este manuscrito fue describir las diferencias metodológicas entre ECS, ECNI y ECE.

Efficacy and effectivity of new interventions are generally established through randomized clinical trials (RCTs). However, among many other methodological challenges, specifying the hypothesis of a RCT remains complex problem for clinical researchers. In this manuscript we discuss the characteristics of three variants of RCTs: superiority RCT (SRCT), non-inferiority RCT (NIRCT), and equivalence RCT (ERCT). These three types of RCT have different assumptions about the effects of an intervention, so setting hypotheses and defining objectives requires knowing some assumptions underlying these RCTs, including elements related to the estimation of the sample size for each one. The aim of this manuscript was to describe methodological differences between SRCT, NIRCT and ERCT.

Ethnic Minority Participation in Clinical Trials from Latin America and the Caribbean: A Scoping Review.

We summarize the clinical trials (CTs) main characteristics, including members of ethnic minorities from Latin America. We carried out a systematic search in six databases. We made a descriptive synthesis of CTs, summarizing the characteristics, interventions, main findings, results, and conclusions reported. 4411 studies were acquired in search strategy, leaving 24 CTs in the final selection. Of these, ten were randomized, four were non-randomized, and the remainder had other designs. Most of the studies were carried out in the population of infants and children (08), ten of the studies included only women, and two studies included men. Nine studies were conducted in Mexico, with the Mayan ethnic minority being mostly evaluated (05). In only 15 it was mentioned that their research was approved by a research ethics committee. Finally, half of the CTs reported funding from international agencies and third reported funding from government agencies. Our results show that that CTs in ethnic minorities are limited and reduced to a few native peoples of the continent.

Adoptive transfer of CMV-specific TCR-T cells for the treatment of CMV infection after haploidentical hematopoietic stem cell transplantation.

BACKGROUND: Cytomegalovirus (CMV) reactivation after unmanipulated haploidentical stem cell transplantation (SCT) frequently occurs, causing life-threatening morbidities and transplantation failure. Pre-emptive therapy upon the detection of CMV viremia using antiviral agents is currently the standard of care but it was associated with significant toxicity. The CMV antigen-specific cytotoxic T lymphocyte therapy was limited by the time-consuming manufacture process and relatively low success rate. More effective and safer approaches for the treatment of CMV reactivation after haploidentical SCT are in urgent need. METHODS: A single-arm, open-label, phase I clinical trial evaluating the safety and efficacy of CMV-targeting T cell receptor-engineered T (CMV-TCR-T) cell therapy as the first-line pre-emptive therapy for patients with CMV reactivation after haploidentical peripheral blood SCT (PBSCT) was conducted in the Chinese PLA General Hospital. Six patients with CMV reactivation after haploidentical SCT were adoptively transferred by one to three doses of SCT donors-derived CMV-TCR-T cells. This trial was a dose-escalation study with doses ranging from 1×103 CMV-TCR-T cells/kg body weight per dose to 5×105 CMV-TCR-T cells/kg per dose. RESULTS: Except for the grade 1 cytokine release syndrome observed in one patient and mild fever in two patients, no other adverse events were observed. Four patients had response within a month after CMV-TCR-T cell infusion without the administration of any antiviral agents. The other two patients who initially did not respond to CMV-TCR-T cell therapy had salvage ganciclovir and foscarnet administration and then had rapid CMV clearance. The CMV-TCR-T cells displayed overall robust expansion and persistence in the peripheral blood after infusion. The CMV-TCR-T cells were first detected in the peripheral blood of these patients 3-7 days after the first dose of CMV-TCR-T infusion, rapidly expanded and persisted for at least 1-4 months, providing long-term protection against CMV reactivation. In one patient, the CMV-TCR-T cells started to expand even when the anti-graft-versus-host disease reagents were still being used, further indicating the proliferation potential of CMV-TCR-T cells. CONCLUSIONS: Our study first showed CMV-TCR-T cell as a highly feasible, safe and effective first-line pre-emptive treatment for CMV reactivation after haploidentical PBSCT. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT05140187).