UNASSIGNED: There is interest in using treatment breaks in oncology, to reduce toxicity without compromising efficacy.
UNASSIGNED: A Phase II/III multicentre, open-label, parallel-group, randomised controlled non-inferiority trial assessing treatment breaks in patients with renal cell carcinoma.
UNASSIGNED: Patients with locally advanced or metastatic renal cell carcinoma, starting tyrosine kinase inhibitor as first-line treatment at United Kingdom National Health Service hospitals.
UNASSIGNED: At trial entry, patients were randomised (1 : 1) to a drug-free interval strategy or a conventional continuation strategy. After 24 weeks of treatment with sunitinib/pazopanib, drug-free interval strategy patients took up a treatment break until disease progression with additional breaks dependent on disease response and patient choice. Conventional continuation strategy patients continued on treatment. Both trial strategies continued until treatment intolerance, disease progression on treatment, withdrawal or death.
UNASSIGNED: To determine if a drug-free interval strategy is non-inferior to a conventional continuation strategy in terms of the co-primary outcomes of overall survival and quality-adjusted life-years.
UNASSIGNED: For non-inferiority to be concluded, a margin of ≤ 7.5% in overall survival and ≤ 10% in quality-adjusted life-years was required in both intention-to-treat and per-protocol analyses. This equated to the 95% confidence interval of the estimates being above 0.812 and -0.156, respectively. Quality-adjusted life-years were calculated using the utility index of the EuroQol-5 Dimensions questionnaire.
UNASSIGNED: Nine hundred and twenty patients were randomised (461 conventional continuation strategy vs. 459 drug-free interval strategy) from 13 January 2012 to 12 September 2017. Trial treatment and follow-up stopped on 31 December 2020. Four hundred and eighty-eight (53.0%) patients [240 (52.1%) vs. 248 (54.0%)] continued on trial post week 24. The median treatment-break length was 87 days. Nine hundred and nineteen patients were included in the intention-to-treat analysis (461 vs. 458) and 871 patients in the per-protocol analysis (453 vs. 418). For overall survival, non-inferiority was concluded in the intention-to-treat analysis but not in the per-protocol analysis [hazard ratio (95% confidence interval) intention to treat 0.97 (0.83 to 1.12); per-protocol 0.94 (0.80 to 1.09) non-inferiority margin: 95% confidence interval ≥ 0.812, intention to treat: 0.83 > 0.812 non-inferior, per-protocol: 0.80 < 0.812 not non-inferior]. Therefore, a drug-free interval strategy was not concluded to be non-inferior to a conventional continuation strategy in terms of overall survival. For quality-adjusted life-years, non-inferiority was concluded in both the intention-to-treat and per-protocol analyses [marginal effect (95% confidence interval) intention to treat -0.05 (-0.15 to 0.05); per-protocol 0.04 (-0.14 to 0.21) non-inferiority margin: 95% confidence interval ≥ -0.156]. Therefore, a drug-free interval strategy was concluded to be non-inferior to a conventional continuation strategy in terms of quality-adjusted life-years.
UNASSIGNED: The main limitation of the study is the fewer than expected overall survival events, resulting in lower power for the non-inferiority comparison.
UNASSIGNED: Future studies should investigate treatment breaks with more contemporary treatments for renal cell carcinoma.
UNASSIGNED: Non-inferiority was shown for the quality-adjusted life-year end point but not for overall survival as pre-defined. Nevertheless, despite not meeting the primary end point of non-inferiority as per protocol, the study suggested that a treatment-break strategy may not meaningfully reduce life expectancy, does not reduce quality of life and has economic benefits. Although the treating clinicians\' perspectives were not formally collected, the fact that clinicians recruited a large number of patients over a long period suggests support for the study and provides clear evidence that a treatment-break strategy for patients with renal cell carcinoma receiving tyrosine kinase inhibitor therapy is feasible.
UNASSIGNED: This trial is registered as ISRCTN06473203.
UNASSIGNED: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment Programme (NIHR award ref: 09/91/21) and is published in full in Health Technology Assessment; Vol. 28, No. 45. See the NIHR Funding and Awards website for further award information.
Treatment breaks in cancer are of significant interest to patients and health professionals. Renal cell carcinoma is the most common type of kidney cancer. Sunitinib and pazopanib are both targeted treatments. They were commonly used to treat advanced kidney cancer but often cause side effects, sometimes requiring use of a reduced dose or even stopping treatment. The STAR trial was designed to see whether planned treatment breaks made patients with advanced kidney cancer being treated with sunitinib and pazopanib feel better, without substantially affecting how well the treatment worked. After 24 weeks of treatment, patients took sunitinib and pazopanib either as they normally would or in the alternative way with planned treatment breaks. Treating patients in this way was continued until drug-related side effects stopped treatment, patients’ disease worsened while taking treatment or the patient died. The trial compared how well the different treatment strategies worked in terms of how long patients lived and their quality of life over that time. This trial is the largest United Kingdom trial in advanced renal cell carcinoma. Patients took part from 60 United Kingdom centres between 2012 and 2017. It was funded by the National Institute for Health and Care Research Health Technology Assessment Programme and run by the Leeds Clinical Trials Research Unit. In total, 920 patients took part. Four hundred and sixty-one patients were allocated to continue treatment and 459 were allocated to start at least one treatment break. Treatment breaks lasted on average 87 days. The length of time patients lived in both arms of the trial appeared similar, but this cannot be concluded due to insufficient information. Being allocated to have treatment breaks rather than continuing treatment did not negatively impact a patient’s quality of life. Additionally, allocating patients to have treatment breaks was shown to have significant cost savings compared to just continuing treatment. Importantly planned treatment breaks were shown to be feasible.

BACKGROUND: Tryptase, a mast cell protease, has been identified as a potential therapeutic target in managing patients with refractory asthma. We assessed the efficacy, safety, pharmacokinetics, and pharmacodynamics of MTPS9579A, an anti-tryptase antibody, in a phase 2a randomized trial for patients with uncontrolled asthma and a phase 1c trial to understand activity within the lower respiratory tract.
METHODS: Phase 2a patients (n = 134) received 1800 mg MTPS9579A or placebo intravenously every 4 weeks for 48 weeks. The primary endpoint was time to the first composite exacerbation event. Phase 1c patients (n = 27) received one intravenous dose of 300 or 1800 mg MTPS9579A or placebo. Both trials measured MTPS9579A concentrations and effects on tryptase in serum and nasal lining fluid; phase 1c also analyzed bronchial lining fluid.
RESULTS: MTPS9579A did not meet the primary endpoint (hazard ratio = 0.90; 95% CI: 0.55-1.47; p = 0.6835); exacerbation rates in the placebo group were low. Serum and nasal MTPS9579A pharmacokinetics and tryptase levels were consistent with data from healthy volunteers. However, in phase 1c patients, compared to nasal levels, MTPS9579A bronchial concentrations were 6.8-fold lower, and bronchial active and total tryptase levels were higher (119-fold and 30-fold, respectively). Pharmacokinetic/pharmacodynamic modeling predicted intravenous doses of 3800 mg every 4 weeks would be necessary to achieve 95% active tryptase inhibition from baseline.
CONCLUSIONS: The MTPS9579A dose tested in the phase 2a study was insufficient to inhibit tryptase in bronchial lining fluid, likely contributing to the observed lack of efficacy.

Following the coronavirus disease-2019 outbreak caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), there is an ongoing need to seek drugs that target COVID-19. First off, novel drugs have a long development cycle, high investment cost, and are high risk. Second, novel drugs must be evaluated for activity, efficacy, safety, and metabolic performance, contributing to the development cycle, investment cost, and risk. We searched the Cochrane COVID-19 Study Register (including PubMed, Embase, CENTRAL, ClinicalTrials.gov, WHO ICTRP, and medRxiv), Web of Science (Science Citation Index, Emerging Citation Index), and WHO COVID-19 Coronaviral Disease Global Literature to identify completed and ongoing studies as of February 20, 2024. We evaluated the pharmacological effects, in vivo and in vitro data of the 16 candidates in the paper. The difficulty of studying these candidates in clinical trials involving COVID-19 patients, dosage of repurposed drugs, etc. is discussed in detail. Ultimately, Metformin is more suitable for prophylactic administration or mildly ill patients; the combination of Oseltamivir, Tamoxifen, and Dexamethasone is suitable for moderately and severely ill patients; and more clinical trials are needed for Azvudine, Ribavirin, Colchicine, and Cepharanthine to demonstrate efficacy.

BACKGROUND: In the phase 2 EMPOWER-CSCC-1 study (NCT02760498), cemiplimab demonstrated antitumor activity against metastatic (mCSCC) and locally advanced cutaneous squamous cell carcinoma (laCSCC).
OBJECTIVE: To report final analysis of weight-based cemiplimab in mCSCC and laCSCC (Groups 1 and 2), fixed-dose cemiplimab in mCSCC (Group 3), and primary analysis of fixed-dose cemiplimab in mCSCC/laCSCC (Group 6).
METHODS: Patients received cemiplimab (3 mg/kg intravenously [IV] every 2 weeks [Groups 1 and 2]) or cemiplimab (350 mg IV [Groups 3 and 6]) every 3 weeks. The primary endpoint was objective response rate (ORR). Duration of response (DOR) and progression-free survival (PFS) are presented per protocol, according to post-hoc sensitivity analyses that only include the period of protocol-mandated imaging assessments.
RESULTS: At 42.5 months, ORR for Groups 1-3 (n=193) was 47.2%, estimated 12-month DOR was 88.3%, and median PFS was 26.0 months. At 8.7 months, ORR for Group 6 (n=165 patients) was 44.8%; median DOR and median PFS were not reached. Serious treatment-emergent adverse event rates (grade ≥3) were Groups 1-3: 31.1% and Group 6: 34.5%.
CONCLUSIONS: Non-randomized study, non-survival primary endpoint.
CONCLUSIONS: EMPOWER-CSCC-1 provides the largest prospective data on long-term efficacy and safety for anti-programmed cell death-1 therapy in advanced CSCC.

The proven efficacy of immunotherapy in fighting tumors has been firmly established, heralding a new era in harnessing both the innate and adaptive immune systems for cancer treatment. Despite its promise, challenges such as inefficient delivery, insufficient tumor penetration, and considerable potential toxicity of immunomodulatory agents have impeded the advancement of immunotherapies. Recent endeavors in the realm of tumor prophylaxis and management have highlighted the use of living biological entities, including bacteria, oncolytic viruses, and immune cells, as a vanguard for an innovative class of live biotherapeutic products (LBPs). These LBPs are gaining recognition for their inherent ability to target tumors. However, these LBPs must contend with significant barriers, including robust immune clearance mechanisms, cytotoxicity and other in vivo adverse effects. Priority must be placed on enhancing their safety and therapeutic indices. This review consolidates the latest preclinical research and clinical progress pertaining to the exploitation of engineered biologics, spanning bacteria, oncolytic viruses, immune cells, and summarizes their integration with combination therapies aimed at circumventing current clinical impasses. Additionally, the prospective utilities and inherent challenges of the biotherapeutics are deliberated, with the objective of accelerating their clinical application in the foreseeable future.

OBJECTIVE: High quality data entry in clinical trial databases is crucial to the usefulness, validity, and replicability of research findings, as it influences evidence-based medical practice and future research. Our aim is to assess the quality of self-reported data in trial registries and present practical and systematic methods for identifying and evaluating data quality.
METHODS: We searched ClinicalTrials.Gov for interventional total knee arthroplasty(TKA) trials between 2000-2015. We extracted required and optional trial information elements and used the CTG\'s variables\' definitions. We performed a literature review on data quality reporting on frameworks, checklists, and overviews of irregularities in healthcare databases. We identified and assessed data quality attributes: consistency, accuracy, completeness, and timeliness.
RESULTS: We included 816 interventional TKA trials. Data irregularities varied widely: 0% to 100%. Inconsistency ranged from 0% to 36%, most often non-randomized labeled allocation were combined with a \"single group\" assignment trial design. Inaccuracy ranged from 0% to 100%. Incompleteness ranged from 0% to 61%: 61% finished TKA trials did not report their outcome. As regard to irregularities in timeliness: 49% of the trials were registered more than 3 months after the start date.
CONCLUSIONS: We found significant variations in the data quality of registered clinical TKA trials. Trial sponsors should be committed to ensuring that the information they provide is reliable, consistent, up-to-date, transparent and accurate. CTG\'s users need to be critical when drawing conclusions based on the registered data. We believe this awareness will increase well-informed decisions about published articles and treatment protocols, including replicating and improving trial designs.

The growing prevalence of MDR and XDR bacterial pathogens is posing a critical threat to global health. Traditional antibiotic development paths have encountered significant challenges and are drying up thus necessitating innovative approaches. Drug repurposing, which involves identifying new therapeutic applications for existing drugs, offers a promising alternative to combat resistant pathogens. By leveraging pre-existing safety and efficacy data, drug repurposing accelerates the development of new antimicrobial therapy regimes. This review explores the potential of repurposing existing FDA approved drugs against the ESKAPE and other clinically relevant bacterial pathogens and delves into the identification of suitable drug candidates, their mechanisms of action, and the potential for combination therapies. It also describes clinical trials and patent protection of repurposed drugs, offering perspectives on this evolving realm of therapeutic interventions against drug resistance.

BACKGROUND: SB16 is a proposed biosimilar to reference denosumab (DEN; brand name: Prolia).
OBJECTIVE: This phase 3 randomized, double-blind, multicenter study evaluated the biosimilarity of SB16 to DEN in women with postmenopausal osteoporosis (PMO; NCT04664959).
METHODS: The study included 457 PMO patients who had a lumbar spine or total hip T-score between -2.5 and -4. Patients were randomized in a 1:1 ratio to receive either 60 mg of SB16 or DEN subcutaneously at Month 0 and Month 6. At Month 12, patients were re-randomized to continue with the assigned treatment or switch from DEN to SB16 up to Month 18. This report includes results up to Month 12.
METHODS: The primary endpoint was the percent change from baseline in lumbar spine bone mineral density (BMD) at Month 12. Secondary endpoints including the percent change from baseline in BMD of the lumbar spine (except for Month 12), total hip and femoral neck; pharmacokinetic, pharmacodynamic (serum C-telopeptide of type I collagen [CTX] and procollagen type I N-terminal propeptide [P1NP]), safety, and immunogenicity profiles were measured up to Month 12.
RESULTS: The least-squares mean differences in percent change from baseline in lumbar spine BMD at Month 12 were 0.33% (90% confidence interval [CI]: -0.25, 0.91) in the full analysis set and 0.39% (95% CI: -0.36, 1.13) in the per-protocol set; both within the pre-defined equivalence margin. The secondary endpoints were comparable between the two treatment groups.
CONCLUSIONS: The reported efficacy, PK, PD, safety, and immunogenicity data support the biosimilarity of SB16 to DEN.

Liver cancer is a global health challenge, causing a significant social-economic burden. Hepatocellular carcinoma (HCC) is the predominant type of primary liver cancer, which is highly heterogeneous in terms of molecular and cellular signatures. Early-stage or small tumors are typically treated with surgery or ablation. Currently, chemotherapies and immunotherapies are the best treatments for unresectable tumors or advanced HCC. However, drug response and acquired resistance are not predictable with the existing systematic guidelines regarding mutation patterns and molecular biomarkers, resulting in sub-optimal treatment outcomes for many patients with atypical molecular profiles. With advanced technological platforms, valuable information such as tumor genetic alterations, epigenetic data, and tumor microenvironments can be obtained from liquid biopsy. The inter- and intra-tumoral heterogeneity of HCC are illustrated, and these collective data provide solid evidence in the decision-making process of treatment regimens. This article reviews the current understanding of HCC detection methods and aims to update the development of HCC surveillance using liquid biopsy. Recent critical findings on the molecular basis, epigenetic profiles, circulating tumor cells, circulating DNAs, and omics studies are elaborated for HCC diagnosis. Besides, biomarkers related to the choice of therapeutic options are discussed. Some notable recent clinical trials working on targeted therapies are also highlighted. Insights are provided to translate the knowledge into potential biomarkers for detection and diagnosis, prognosis, treatment response, and drug resistance indicators in clinical practice.

Artificial Intelligence (AI) has made significant strides due to advancements in processing algorithms and data availability. Recent years have shown a resurgence in AI, driven by breakthroughs in deep machine learning. AI has attracted particular interest in the medical sector, especially in the field of personalized medicine, which for example uses large-scale genomic and molecular data to predict individual patient treatment responses. The applications of AI in disease diagnosis, monitoring, and treatment are expanding rapidly, leading to a growing number of registered trials. Therefore, this study aimed to identify and evaluate clinical trials registered between January 1st 2016, and September 30th 2023 that connect AI and cancer. Our findings show that the number of clinical trials linking AI with cancer research has grown significantly compared to other diseases, with colorectal and breast tumour types showing the highest number of registered trials. The most frequent intervention was disease diagnosis and monitoring. Regarding countries, China and the United States hold the highest numbers of registered trials. In conclusion, oncology is a field with a great interest in AI, where the developed countries are leading the studies in this field. Unfortunately, developing countries are still crawling in this aspect and government policies should be made to improve that area.