A phase 1/1b, open-label, dose-escalation study of PD-1 inhibitor, cetrelimab alone and in combination with FGFR inhibitor, erdafitinib in Japanese patients with advanced solid tumors.

Immune checkpoint inhibitors are the leading approaches in tumor immunotherapy. The aim of the study was to establish recommended phase 2 doses (RP2Ds) of intravenous cetrelimab, a checkpoint inhibitor, alone and with oral erdafitinib in Japanese patients with advanced solid tumors. This open-label, non-randomized, dose-escalation phase 1/1b study enrolled adults with advanced solid tumors who were ineligible for standard therapy. Study was conducted in two parts: phase 1a assessed cetrelimab at three dosing levels (80 mg every 2 weeks [Q2W], 240 mg Q2W, and 480 mg Q4W); phase 1b assessed cetrelimab+erdafitinib at two dosing levels (240 mg Q2W + 6 mg once daily [QD] and 240 mg Q2W + 8 mg QD). Primary endpoint was frequency and severity of dose-limiting toxicities (DLTs) of cetrelimab ± erdafitinib. In total 22 patients (phase 1a, n = 9; phase 1b, n = 13) were enrolled. Median duration of follow-up was 8.64 months in phase 1a and 2.33 months in phase 1b. In phase 1a, DLTs weren't reported while in phase 1b, 1 patient who received 240 mg cetrelimab + 6 mg erdafitinib reported Stevens-Johnson syndrome (grade 3, immune-related). Overall, 88.9% patients in phase 1a (grade ≥ 3: 44.4%) and 100.0% in phase 1b (grade ≥ 3: 53.8%) experienced ≥ 1 treatment-related adverse events (TEAEs); 33.3% in phase 1a and 38.5% in phase 1b reported serious TEAEs, of which 11.1% patients in phase 1a and 15.4% in phase 1b had TEAEs which led to treatment discontinuation. Cetrelimab alone and in combination with erdafitinib showed manageable safety in Japanese patients with advanced solid tumors. RP2Ds were determined as 480 mg cetrelimab Q4W for monotherapy, and cetrelimab 240 mg Q2W + erdafitinib 8 mg QD for combination therapy.

Phase 3 THOR Japanese subgroup analysis: erdafitinib in advanced or metastatic urothelial cancer and fibroblast growth factor receptor alterations.

BACKGROUND: In the THOR trial (NCT03390504) Cohort 1, erdafitinib demonstrated significantly prolonged overall survival (OS) (median 12.1 versus 7.8 months) and reduced risk of death by 36% (hazard ratio 0.64, P = 0.005) compared with chemotherapy in metastatic urothelial carcinoma (mUC) patients with FGFR alterations who progressed after ≥ 1 prior treatments, including anti-PD-(L)1. There have been no reports of the Japanese subgroup results yet. METHODS: THOR Cohort 1 randomized patients to erdafitinib once daily or docetaxel/vinflunine once every 3 weeks. Primary endpoint was OS. Secondary endpoints included progression-free survival (PFS) and objective response rate (ORR). No specific statistical power was set for this Japanese subgroup analysis. RESULTS: Of 266 patients randomized, 27 (14 erdafitinib; 13 chemotherapy) were Japanese. Baseline characteristics were generally similar between treatments and to the overall population, except for more males, lower body weight, and more upper tract primary tumors among Japanese patients. Compared with chemotherapy, erdafitinib showed improved OS (median 25.4 versus 12.4 months), PFS (median 8.4 versus 2.9 months) and ORR (57.1% versus 15.4%). Any grade treatment-related adverse events (AEs) occurred in all patients from both arms but Grade 3/4 AEs and AEs leading to discontinuation were lower in the erdafitinib arm. No new safety signals were observed in the Japanese subgroup. CONCLUSION: In the Japanese subgroup, erdafitinib showed improved survival and response compared to chemotherapy, with no new safety concerns. These results support erdafitinib as a treatment option for Japanese mUC patients with FGFR alterations, and early FGFR testing after diagnosis of mUC should be considered.

Bias correction based on weighted likelihood for conditional estimation of subgroup effects in randomized clinical trials.

Currently, many confirmatory randomized clinical trials (RCTs) with predictive markers have taken the all-comers approach because of the difficulty in developing predictive markers that are biologically compelling enough to apply the enrichment approach to restrict the patient population to a marker-defined subgroup. However, such a RCT with weak marker credentials can conclude that the new treatment is efficacious only in the subgroup, especially when the primary analysis demonstrates some treatment efficacy in the subgroup, but the overall treatment efficacy is not significant under a control of study-wise alpha rate. In this article, we consider conditional estimation of subgroup treatment effects, given the negative result in testing the overall treatment efficacy in the trial. To address the problem of unstable estimation due to the truncation in the distribution of the test statistic on overall treatment efficacy, we propose a new approach based on a weighted likelihood for the truncated distribution. The weighted likelihood can be derived by invoking a randomized test with a smooth critical function for the overall test. Our approach allows for point and interval estimations of the conditional effects consistently based on the standard maximum likelihood inference. Numerical evaluations, including simulations and application to real clinical trials, and guidelines for implementing our methods with R-codes, are provided.

Safety, reactogenicity, and immunogenicity of Ad26.COV2.S: Results of a phase 1, randomized, double-blind, placebo-controlled COVID-19 vaccine trial in Japan.

BACKGROUND: This study evaluated safety, reactogenicity, and immunogenicity of a 2-month homologous booster regimen of Ad26.COV2.S in Japanese adults. METHODS: In this multicenter, placebo-controlled, Phase 1 trial, adults (Cohort 1, aged 20-55 years, N = 125; Cohort 2, aged ≥ 65 years, N = 125) were randomized 2:2:1 to receive Ad26.COV2.S 5 × 1010 viral particles (vp), Ad26.COV2.S 1 × 1011 vp, or placebo, followed by a homologous booster 56 days later. Safety, reactogenicity, and immunogenicity were assessed. RESULTS: Two hundred participants received Ad26.COV2.S and 50 received placebo. The most frequent solicited local adverse event (AE) was vaccination-site pain, and the most frequent solicited systemic AEs were fatigue, myalgia, and headache. After primary vaccination, neutralizing and binding antibody levels increased through Day 57 (post-prime) in both cohorts. Fourteen days after boosting (Day 71), neutralizing antibody geometric mean titers (GMTs) had almost reached their peak value in Cohort 1 (5 × 1010 vp: GMT = 1049; 1 × 1011 vp: GMT = 1470) and peaked in Cohort 2 (504; 651); at Day 85, GMTs had declined minimally in Cohort 2. For both cohorts, binding antibody levels peaked at Day 71 with minimal decline at Day 85. CONCLUSION: A single dose and homologous Ad26.COV2.S booster increased antibody responses with an acceptable safety profile in Japanese adults (ClinicalTrials.gov Identifier: NCT04509947).

Decentralized clinical trials and rare diseases: a Drug Information Association Innovative Design Scientific Working Group (DIA-IDSWG) perspective.

BACKGROUND: Traditional clinical trials require tests and procedures that are administered in centralized clinical research sites, which are beyond the standard of care that patients receive for their rare and chronic diseases. The limited number of rare disease patients scattered around the world makes it particularly challenging to recruit participants and conduct these traditional clinical trials. MAIN BODY: Participating in clinical research can be burdensome, especially for children, the elderly, physically and cognitively impaired individuals who require transportation and caregiver assistance, or patients who live in remote locations or cannot afford transportation. In recent years, there is an increasing need to consider Decentralized Clinical Trials (DCT) as a participant-centric approach that uses new technologies and innovative procedures for interaction with participants in the comfort of their home. CONCLUSION: This paper discusses the planning and conduct of DCTs, which can increase the quality of trials with a specific focus on rare diseases.

Structured patient interview to assess clinical outcomes in complicated urinary tract infections in the APEKS-cUTI study: pilot investigation.

BACKGROUND: The APEKS-cUTI study demonstrated the non-inferiority of cefiderocol to imipenem-cilastatin in the primary endpoint of the composite of clinical and microbiological outcome in patients with complicated urinary tract infections (cUTIs). We piloted a structured patient interview (SPI) to evaluate clinical outcomes based on patient-reported symptoms while conducting this pivotal randomized, double-blind, phase-2 study. The objectives were to assess the value of the SPI, using its performance relative to physician assessment, and also to strengthen the value of patient-reported measures in conducting clinical trials for cUTI treatment. METHODS: In addition to the protocol-defined clinical and microbiological outcomes, patients randomized in the APEKS-cUTI study were interviewed by the investigator or qualified study personnel at screening/baseline, early assessment (EA), end of treatment (EOT), test of cure (TOC), and follow-up (FUP). The 14-element questionnaire graded cUTI symptoms as absent or present, and if present, as mild, moderate, or severe. Changes in post-baseline symptoms based on patients' responses were rated by the interviewer. The overall clinical outcome was evaluated based on the responses provided by patients at each time point. RESULTS: Among the 371 patients in the modified intention-to-treat population, the rate of SPI completion in each treatment arm exceeded 90% at each time point. SPI-assessed clinical cure rates were 89.7% in the cefiderocol arm and 84.9% in the imipenem-cilastatin arm. There was substantial agreement between SPI evaluation and investigator global assessment of clinical outcome at TOC and FUP, with lower agreement at EA and EOT. CONCLUSION: This analysis suggests that patient-reported symptoms can be effectively captured in hospitalized patients with cUTI in a clinical trial setting. Development of a validated patient-reported outcome for use in such a setting is warranted. REGISTRATION: NCT02321800 (registered on 22 December 2014).

Efficacy and safety of cefiderocol or best available therapy for the treatment of serious infections caused by carbapenem-resistant Gram-negative bacteria (CREDIBLE-CR): a randomised, open-label, multicentre, pathogen-focused, descriptive, phase 3 trial.

BACKGROUND: New antibiotics are needed for the treatment of patients with life-threatening carbapenem-resistant Gram-negative infections. We assessed the efficacy and safety of cefiderocol versus best available therapy in adults with serious carbapenem-resistant Gram-negative infections. METHODS: We did a randomised, open-label, multicentre, parallel-group, pathogen-focused, descriptive, phase 3 study in 95 hospitals in 16 countries in North America, South America, Europe, and Asia. We enrolled patients aged 18 years or older admitted to hospital with nosocomial pneumonia, bloodstream infections or sepsis, or complicated urinary tract infections (UTI), and evidence of a carbapenem-resistant Gram-negative pathogen. Participants were randomly assigned (2:1 by interactive web or voice response system) to receive either a 3-h intravenous infusion of cefiderocol 2 g every 8 h or best available therapy (pre-specified by the investigator before randomisation and comprised of a maximum of three drugs) for 7-14 days. For patients with pneumonia or bloodstream infection or sepsis, cefiderocol treatment could be combined with one adjunctive antibiotic (excluding polymyxins, cephalosporins, and carbapenems). The primary endpoint for patients with nosocomial pneumonia or bloodstream infection or sepsis was clinical cure at test of cure (7 days [plus or minus 2] after the end of treatment) in the carbapenem-resistant microbiological intention-to-treat population (ITT; ie, patients with a confirmed carbapenem-resistant Gram-negative pathogen receiving at least one dose of study drug). For patients with complicated UTI, the primary endpoint was microbiological eradication at test of cure in the carbapenem-resistant microbiological ITT population. Safety was evaluated in the safety population, consisting of all patients who received at least one dose of study drug. Mortality was reported through to the end of study visit (28 days [plus or minus 3] after the end of treatment). Summary statistics, including within-arm 95% CIs calculated using the Clopper-Pearson method, were collected for the primary and safety endpoints. This trial is registered with ClinicalTrials.gov (NCT02714595) and EudraCT (2015-004703-23). FINDINGS: Between Sept 7, 2016, and April 22, 2019, we randomly assigned 152 patients to treatment, 101 to cefiderocol, 51 to best available therapy. 150 patients received treatment: 101 cefiderocol (85 [85%] received monotherapy) and 49 best available therapy (30 [61%] received combination therapy). In 118 patients in the carbapenem-resistant microbiological ITT population, the most frequent carbapenem-resistant pathogens were Acinetobacter baumannii (in 54 patients [46%]), Klebsiella pneumoniae (in 39 patients [33%]), and Pseudomonas aeruginosa (in 22 patients [19%]). In the same population, for patients with nosocomial pneumonia, clinical cure was achieved by 20 (50%, 95% CI 33·8-66·2) of 40 patients in the cefiderocol group and ten (53%, 28·9-75·6) of 19 patients in the best available therapy group; for patients with bloodstream infection or sepsis, clinical cure was achieved by ten (43%, 23·2-65·5) of 23 patients in the cefiderocol group and six (43%, 17·7-71·1) of 14 patients in the best available therapy group. For patients with complicated UTIs, microbiological eradication was achieved by nine (53%, 27·8-77·0) of 17 patients in the cefiderocol group and one (20%, 0·5-71·6) of five patients in the best available therapy group. In the safety population, treatment-emergent adverse events were noted for 91% (92 patients of 101) of the cefiderocol group and 96% (47 patients of 49) of the best available therapy group. 34 (34%) of 101 patients receiving cefiderocol and nine (18%) of 49 patients receiving best available therapy died by the end of the study; one of these deaths (in the best available therapy group) was considered to be related to the study drug. INTERPRETATION: Cefiderocol had similar clinical and microbiological efficacy to best available therapy in this heterogeneous patient population with infections caused by carbapenem-resistant Gram-negative bacteria. Numerically more deaths occurred in the cefiderocol group, primarily in the patient subset with Acinetobacter spp infections. Collectively, the findings from this study support cefiderocol as an option for the treatment of carbapenem-resistant infections in patients with limited treatment options. FUNDING: Shionogi.

A roadmap to using historical controls in clinical trials - by Drug Information Association Adaptive Design Scientific Working Group (DIA-ADSWG).

Historical controls (HCs) can be used for model parameter estimation at the study design phase, adaptation within a study, or supplementation or replacement of a control arm. Currently on the latter, there is no practical roadmap from design to analysis of a clinical trial to address selection and inclusion of HCs, while maintaining scientific validity. This paper provides a comprehensive roadmap for planning, conducting, analyzing and reporting of studies using HCs, mainly when a randomized clinical trial is not possible. We review recent applications of HC in clinical trials, in which either predominantly a large treatment effect overcame concerns about bias, or the trial targeted a life-threatening disease with no treatment options. In contrast, we address how the evidentiary standard of a trial can be strengthened with optimized study designs and analysis strategies, emphasizing rare and pediatric indications. We highlight the importance of simulation and sensitivity analyses for estimating the range of uncertainties in the estimation of treatment effect when traditional randomization is not possible. Overall, the paper provides a roadmap for using HCs.

Designing A Pathogen-Focused Study To Address The High Unmet Medical Need Represented By Carbapenem-Resistant Gram-Negative Pathogens - The International, Multicenter, Randomized, Open-Label, Phase 3 CREDIBLE-CR Study.

Carbapenem-resistant (CR) Gram-negative infections, including those caused by Enterobacteriaceae and the non-fermenters, represent the greatest unmet need for new effective treatments. The clinical development of new antibiotics for the treatment of CR infections is challenging and should focus on the individual pathogens irrespective of the infection site. However, the drug approval pathway is generally infection-site specific and rarely includes such drug-resistant pathogens. To overcome this limitation, a streamlined clinical development program may include a pathogen-focused clinical study, such as the CREDIBLE-CR study, to meet the expectations of some health authorities (ie, the European Medicines Agency [EMA]) and the medical community. Cefiderocol is a novel siderophore cephalosporin designed to target CR pathogens, including CR strains of Enterobacteriaceae (CRE), Pseudomonas aeruginosa, Acinetobacter baumannii, and also Stenotrophomonas maltophilia, which is intrinsically CR. The CREDIBLE-CR study was planned to evaluate cefiderocol in patients with CR Gram-negative infections regardless of species or infection-site source. Rapid diagnostic testing and/or selective media were provided to facilitate detection of CR pathogens to rapidly enroll patients with nosocomial pneumonia, bloodstream infection/sepsis, or complicated urinary tract infection. Patients were randomized 2:1 to receive cefiderocol or best available therapy. There were no pre-specified statistical hypotheses for this study, as the sample size was driven by enrollment feasibility and not based on statistical power calculations. The objective of the CREDIBLE-CR study was to provide descriptive evidence of the efficacy and safety of cefiderocol for the target population of patients with CR infections, including the non-fermenters. The CREDIBLE-CR study is currently the largest pathogen-focused, randomized, open-label, prospective, Phase 3 clinical study to investigate a new antibiotic in patients with CR Gram-negative infections. Here we describe the design of this pathogen-focused study and steps taken to aid patient enrollment into the study within an evolving regulatory environment. CLINICALTRIALSGOV REGISTRATION: NCT02714595. EUDRA-CT REGISTRATION: 2015-004703-23.

Effects of green tea gargling on the prevention of influenza infection in high school students: a randomized controlled study.

BACKGROUND: The anti-influenza virus activity of green tea catechins has been demonstrated in experimental studies, but clinical evidence has been inconclusive. School-aged children play an important role in the infection and spread of influenza in the form of school-based outbreaks. Preventing influenza infection among students is essential for reducing the frequency of epidemics and pandemics. As a non-pharmaceutical intervention against infection, gargling is also commonly performed in Asian countries but has not yet been extensively studied. METHODS AND FINDINGS: A randomized, open label, 2-group parallel study of 757 high school students (15 to 17 years of age) was conducted for 90 days during the influenza epidemic season from December 1st, 2011 to February 28th, 2012, in 6 high schools in Shizuoka Prefecture, Japan. The green tea gargling group gargled 3 times a day with bottled green tea, and the water gargling group did the same with tap water. The water group was restricted from gargling with green tea. The primary outcome measure was the incidence of laboratory-confirmed influenza using immunochromatographic assay for antigen detection. 757 participants were enrolled and 747 participants completed the study (384 in the green tea group and 363 in the water group). Multivariate logistic regression indicated no significant difference in the incidence of laboratory-confirmed influenza between the green tea group (19 participants; 4.9%) and the water group (25 participants; 6.9%) (adjusted OR, 0.69; 95%CI, 0.37 to 1.28; P = 0.24). The main limitation of the study is the adherence rate among high school students was lower than expected. CONCLUSIONS: Among high school students, gargling with green tea three times a day was not significantly more efficacious than gargling with water for the prevention of influenza infection. In order to adequately assess the effectiveness of such gargling, additional large-scale randomized studies are needed. TRIAL REGISTRATION: ClinicalTrials.gov NCT01225770.