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Recurrent gene fusions, such as ROS1 fusions, are oncogenic drivers of various cancers, including non-small-cell lung cancer (NSCLC). Up to 36% of patients with ROS1 fusion-positive NSCLC have brain metastases at the diagnosis of advanced disease. Entrectinib is a ROS1 inhibitor that has been designed to effectively penetrate and remain in the CNS. We explored the use of entrectinib in patients with locally advanced or metastatic ROS1 fusion-positive NSCLC. We did an integrated analysis of three ongoing phase 1 or 2 trials of entrectinib (ALKA-372-001, STARTRK-1, and STARTRK-2). The efficacy-evaluable population included adult patients (aged ≥18 years) with locally advanced or metastatic ROS1 fusion-positive NSCLC who received entrectinib at a dose of at least 600 mg orally once per day, with at least 12 months' follow-up. All patients had an Eastern Cooperative Oncology Group performance status of 0–2, and previous cancer treatment (except for ROS1 inhibitors) was allowed. The primary endpoints were the proportion of patients with an objective response (complete or partial response according to Response Evaluation Criteria in Solid Tumors version 1.1) and duration of response, and were evaluated by blinded independent central review. The safety-evaluable population for the safety analysis included all patients with ROS1 fusion-positive NSCLC in the three trials who received at least one dose of entrectinib (irrespective of dose or duration of follow-up). These ongoing studies are registered with ClinicalTrials.gov, NCT02097810 (STARTRK-1) and NCT02568267 (STARTRK-2), and EudraCT, 2012–000148–88 (ALKA-372-001). Patients were enrolled in ALKA-372-001 from Oct 26, 2012, to March 27, 2018; in STARTRK-1 from Aug 7, 2014, to May 10, 2018; and in STARTRK-2 from Nov 19, 2015 (enrolment is ongoing). At the data cutoff date for this analysis (May 31, 2018), 41 (77%; 95% CI 64–88) of 53 patients in the efficacy-evaluable population had an objective response. Median follow-up was 15·5 monhts (IQR 13·4–20·2). Median duration of response was 24·6 months (95% CI 11·4–34·8). In the safety-evaluable population, 79 (59%) of 134 patients had grade 1 or 2 treatment-related adverse events. 46 (34%) of 134 patients had grade 3 or 4 treatment-related adverse events, with the most common being weight increase (ten [8%]) and neutropenia (five [4%]). 15 (11%) patients had serious treatment-related adverse events, the most common of which were nervous system disorders (four [3%]) and cardiac disorders (three [2%]). No treatment-related deaths occurred. Entrectinib is active with durable disease control in patients with ROS1 fusion-positive NSCLC, and is well tolerated with a manageable safety profile, making it amenable to long-term dosing in these patients. These data highlight the need to routinely test for ROS1 fusions to broaden therapeutic options for patients with ROS1 fusion-positive NSCLC. Ignyta/F Hoffmann-La Roche.

Nivolumab is a fully human monoclonal antibody that inhibits programmed death‐1 activation. The clinical pharmacology profile of nivolumab was analyzed by a population pharmacokinetics model that assessed covariate effects on nivolumab concentrations in 1,895 patients who received 0.3–10.0 mg/kg nivolumab in 11 clinical trials. Nivolumab pharmacokinetics is linear with a time‐varying clearance. A full covariate model was developed to assess covariate effects on pharmacokinetic parameters. Nivolumab clearance and volume of distribution increase with body weight. The final model included the effects of baseline performance status (PS), baseline body weight, and baseline estimated glomerular filtration rate (eGFR), sex, and race on clearance, and effects of baseline body weight and sex on volume of distribution in the central compartment. Sex, PS, baseline eGFR, age, race, baseline lactate dehydrogenase, mild hepatic impairment, tumor type, tumor burden, and programmed death ligand‐1 expression had a significant but not clinically relevant (<20%) effect on nivolumab clearance.

Background News stories represent an important source of information. We aimed to evaluate the impact of “spin” (i.e., misrepresentation of study results) in health news stories reporting studies of pharmacologic treatments on patients’/caregivers’ interpretation of treatment benefit. Methods We conducted three two-arm, parallel-group, Internet-based randomized trials (RCTs) comparing the interpretation of news stories reported with or without spin. Each RCT considered news stories reporting a different type of study: (1) pre-clinical study, (2) phase I/II non-RCT, and (3) phase III/IV RCT. For each type of study, we identified news stories reported with spin that had earned mention in the press. Two versions of the news stories were used: the version with spin and a version rewritten without spin. Participants were patients/caregivers involved in Inspire, a large online community of more than one million patients/caregivers. The primary outcome was participants’ interpretation assessed by one specific question “What do you think is the probability that ‘treatment X’ would be beneficial to patients?” (scale, 0 [very unlikely] to 10 [very likely]). Results For each RCT, 300 participants were randomly assigned to assess a news story with spin ( n  = 150) or without spin ( n  = 150), and 900 participants assessed a news story. Participants were more likely to consider that the treatment would be beneficial to patients when the news story was reported with spin. The mean (SD) score for the primary outcome for abstracts reported with and without spin for pre-clinical studies was 7.5 (2.2) versus 5.8 (2.8) (mean difference [95% CI] 1.7 [1.0–2.3], p  < 0.001); for phase I/II non-randomized trials, 7.6 (2.2) versus 5.8 (2.7) (mean difference 1.8 [1.0–2.5], p  < 0.001); and for phase III/IV RCTs, 7.2 (2.3) versus 4.9 (2.8) (mean difference 2.3 [1.4–3.2], p  < 0.001). Conclusions Spin in health news stories reporting studies of pharmacologic treatments affects patients’/caregivers’ interpretation. Trial registration ClinicalTrials.gov, NCT03094078 , NCT03094104 , NCT03095586

Background Combination therapies involving novel agents, such as immunotherapies and targeted therapies, offer significant antitumor benefits by increasing dose intensity, targeting multiple pathways, and benefiting a broader patient population. To further explore these advantages, the National Cancer Institute (NCI) has initiated Combination Therapy Platform Trial with Molecular Analysis for Therapy Choice (ComboMATCH) to evaluate the effectiveness of new drug combinations in treating both adults and children. However, designing dose optimization trials for these combination therapies presents substantial challenges due to the complex interactions and unique mechanisms of action. Methods To address these challenges, we propose COMPACT, a Bayesian phase I-II randomized design for combination cancer therapies that uses progression-free survival (PFS) as the primary efficacy endpoint to identify the optimal dose combination (ODC) based on restricted mean survival time (RMST). The COMPACT design jointly evaluates both toxicity and PFS, with continuous toxicity monitoring throughout the trial. Toxicity probabilities are modeled using a partial ordering assumption without relying on complex parametric models, while PFS is modeled through a Bayesian Pareto proportional hazards model with gamma-shared frailty. The trial consists of two seamlessly connected stages. In the first stage, the dose space is explored primarily based on toxicity, while PFS data are concurrently collected. In the second stage, patients are adaptively randomized to safe and potentially promising dose combinations based on PFS, and the dose combination with the highest RMST among those deemed safe is selected as the ODC. Results Simulation studies demonstrate that COMPACT has desirable operating characteristics and outperforms conventional designs in identifying the ODC, allocating more patients to ODC, while maintaining patient safety. Sensitivity analysis is performed to examine the robustness of the proposed design. A trial example is provided to facilitate the practical implementation of the proposed COMPACT design. Conclusions The proposed COMPACT design offers a novel and robust framework for combination cancer therapies with progression-free survival end point.

Near-infrared spectroscopy-derived regional tissue oxygen saturation of haemoglobin (rSt O 2 ) reflects venous oxygen saturation. If cerebral metabolism is stable, rSt O 2 can be used as an estimate of cerebral oxygen delivery. The SafeBoosC phase II randomised clinical trial hypothesises that the burden of hypo- and hyperoxia can be reduced by the combined use of close monitoring of the cerebral rSt O 2 and a treatment guideline to correct deviations in rSt O 2 outside a predefined target range. Aims: To describe the rationale for and content of this treatment guideline. Methods: Review of the literature and assessment of the quality of evidence and the grade of recommendation for each of the interventions. Results and Conclusions: A clinical intervention algorithm based on the main determinants of cerebral perfusion-oxygenation changes during the first hours after birth was generated. The treatment guideline is presented to assist neonatologists in making decisions in relation to cerebral oximetry readings in preterm infants within the SafeBoosC phase II randomised clinical trial. The evidence grades were relatively low and the guideline cannot be recommended outside a research setting.

Background Personalized and effective treatments for pancreatic ductal adenocarcinoma (PDAC) continue to remain elusive. Novel clinical trial designs that enable continual and rapid evaluation of novel therapeutics are needed. Here, we describe a platform clinical trial to address this unmet need. Methods This is a phase II study using a Bayesian platform design to evaluate multiple experimental arms against a control arm in patients with PDAC. We first separate patients into three clinical stage groups of localized PDAC (resectable, borderline resectable, and locally advanced disease), and further divide each stage group based on treatment history (treatment naïve or previously treated). The clinical stage and treatment history therefore define 6 different cohorts, and each cohort has one control arm but may have one or more experimental arms running simultaneously. Within each cohort, adaptive randomization rules are applied and patients will be randomized to either an experimental arm or the control arm accordingly. The experimental arm(s) of each cohort are only compared to the applicable cohort specific control arm. Experimental arms may be added independently to one or more cohorts during the study. Multiple correlative studies for tissue, blood, and imaging are also incorporated. Discussion To date, PDAC has been treated as a single disease, despite knowledge that there is substantial heterogeneity in disease presentation and biology. It is recognized that the current approach of single arm phase II trials and traditional phase III randomized studies are not well-suited for more personalized treatment strategies in PDAC. The PIONEER Panc platform clinical trial is designed to overcome these challenges and help advance our treatment strategies for this deadly disease. Trial registration This study is approved by the Institutional Review Board (IRB) of MD Anderson Cancer Center, IRB-approved protocol 2020-0075. The PIONEER trial is registered at the US National Institutes of Health (ClinicalTrials.gov) NCT04481204 .

Background Patients with moderate-to-severe atopic dermatitis (AD) have increased infection risk, including skin infections and systemic infections. Immunomodulators (e.g., anti-tumor necrosis factors, anti-interleukin [anti-IL]-23, anti-IL-17, Janus kinase inhibitors) increase risk of infections. Dupilumab (a monoclonal antibody blocking the shared receptor component for IL-4 and IL-13) is approved for inadequately controlled moderate-to-severe AD and for moderate-to-severe eosinophilic or oral corticosteroid-dependent asthma. Objective The aim was to determine the impact of dupilumab on infection rates in patients with moderate-to-severe AD. Methods This analysis pooled data from seven randomized, placebo-controlled dupilumab trials in adults with moderate-to-severe AD. Exposure-adjusted analyses assessed infection rates. Results Of 2932 patients, 1091 received placebo, 1095 dupilumab 300 mg weekly, and 746 dupilumab 300 mg every 2 weeks. Treatment groups had similar infection rates overall per 100 patient-years (placebo, 155; dupilumab weekly, 150; dupilumab every 2 weeks, 156; dupilumab combined, 152), and similar non-skin infection rates. Serious/severe infections were reduced with dupilumab (risk ratio 0.43; p  < 0.05), as were bacterial and other non-herpetic skin infections (risk ratio 0.44; p  < 0.001). Although herpesviral infection rates overall were slightly higher with dupilumab than placebo, clinically important herpesviral infections (eczema herpeticum, herpes zoster) were less common with dupilumab (risk ratio 0.31; p  < 0.01). Systemic anti-infective medication use was lower with dupilumab. Conclusions Dupilumab is associated with reduced risk of serious/severe infections and non-herpetic skin infections and does not increase overall infection rates versus placebo in patients with moderate-to-severe AD. ClinicalTrials.gov Identifiers NCT01548404, NCT02210780, NCT01859988, NCT02277743, NCT02277769, NCT02260986, and NCT02755649.

The current recommendation for treating Lassa fever with ribavirin is supported only by weak evidence. Given the persistent effects in areas with endemic transmission and epidemic potential, there is an urgent need to reassess ribavirin and investigate other potential therapeutic candidates; however, a robust clinical trial method adapted to Lassa fever epidemiology has not yet been established. We propose an adaptive phase II/III multicenter randomized controlled platform trial that uses a superiority framework with an equal allocation ratio and accounts for challenges selecting the primary end point and estimating the target sample size by using an interim analysis.