Planning and Implementing Master Protocol Trials in Japan: Key Considerations of the Japanese Guideline.

The importance of master protocol trials, which encompass basket, umbrella, and platform trials, has been increasingly recognized worldwide for their efficiency in evaluating multiple drugs or diseases within a single trial. While the US Food and Drug Administration and European regulatory bodies have issued guidelines to facilitate such trials, Japan only recently introduced its own set of guidelines to address the unique challenges and opportunities within its regulatory and healthcare landscape. Our study elaborates on these newly issued Japanese guidelines, which were developed through a collaborative effort involving biostatisticians, physicians, clinical trialists, regulatory authorities, and industry representatives.

Magnetoencephalographic brain activity evoked by the optic-flow task is correlated with β-amyloid burden and parahippocampal atrophy.

Visuospatial perception is often impaired in people with Alzheimer's disease (AD). Because visuospatial information is thought to be processed in the visual dorsal stream, it is believed that brain activities in the dorsal stream will be altered in AD patients. In this study, we investigated whether regional brain activity related to visuospatial perception were associated with AD progression markers.

Effects of an arm ergometer for a patient with knee osteoarthritis and central sensitization: A case report.

Aerobic exercise may be an effective treatment for knee osteoarthritis and central sensitization, but no interventional studies have examined its effects. In this study, the patient showed improvement in central sensitization, pain, and autonomic nervous system activity after aerobic exercise using an arm ergometer.

Impact of Bevacizumab Being Skipped due to Adverse Events of Special Interest for Bevacizumab in Patients with Unresectable Hepatocellular Carcinoma Treated with Atezolizumab plus Bevacizumab: An Exploratory Analysis of the Phase III IMbrave150 Study.

Introduction: The phase III IMbrave150 study established atezolizumab + bevacizumab as the global standard of care in patients with unresectable hepatocellular carcinoma (HCC). This exploratory analysis examined the impact of bevacizumab interruption due to bevacizumab adverse events of special interest (AESIs).

Methods: Patients in IMbrave150 who were randomized to atezolizumab + bevacizumab and received treatment for ≥6 months (to reduce immortal time bias) were included in group A-1 if bevacizumab had ever been skipped due to bevacizumab AESIs or to group A-2 otherwise.

Reliability of Spectral Features of Resting-State Brain Activity: A Magnetoencephalography Study.

Background Cognition is a vital sign and its deterioration is a major concern in clinical medicine. It is usually evaluated using neuropsychological assessments, which have innate limitations such as the practice effect. To compensate for these assessments, the oscillatory power of resting-state brain activity has recently become available.

FGFR blockade inhibits targeted therapy-tolerant persister in basal FGFR1- and FGF2-high cancers with driver oncogenes.

Cancer cell resistance arises when tyrosine kinase inhibitor (TKI)-targeted therapies induce a drug-tolerant persister (DTP) state with growth via genetic aberrations, making DTP cells potential therapeutic targets. We screened an anti-cancer compound library and identified fibroblast growth factor receptor 1 (FGFR1) promoting alectinib-induced anaplastic lymphoma kinase (ALK) fusion-positive DTP cell's survival. FGFR1 signaling promoted DTP cell survival generated from basal FGFR1- and fibroblast growth factor 2 (FGF2)-high protein expressing cells, following alectinib treatment, which is blocked by FGFR inhibition.

Deterioration of Cough, Respiratory, and Vocal Cord Functions in Patients with Multiple System Atrophy.

The purpose of this study was to clarify changes in cough function in patients with multiple system atrophy (MSA). Seventeen probable patients with MSA were studied. Peak cough flow (PCF), respiratory function (percentage of vital capacity, percentage of forced vital capacity, and percentage of predicted forced expiratory volume in one second), respiratory muscle strength (percentage of maximal inspiratory mouth pressure and percentage of maximal expiratory mouth pressure), and maximum phonation time (MPT) were assessed.

Effects of interventions on life-space mobility for community-dwelling older adults: A systematic review and meta-analysis.

Aim: The present study aimed to conduct a meta-analysis to evaluate the methods and effects of interventions to increase life-space mobility among community-dwelling older adults.

Methods: Records were identified through nine databases. Eligible study designs for inclusion in the review were randomized controlled trials of interventions on life-space mobility for community-dwelling older adults.

Effects of Rehabilitative Intervention for Augmenting Cough Function in Patients with Multiple System Atrophy.

Objectives: One of the causes of death in patients with multiple system atrophy (MSA) is aspiration pneumonia caused by cough dysfunction. This study aimed to identify an effective approach to improve coughing and to explore the establishment of criteria for the use of gastrostomy based on cough and respiratory dysfunctions.

Methods: Eighteen probable MSA patients participated in the study.

Pertuzumab Plus Trastuzumab for Treatment-Refractory -Amplified Metastatic Colorectal Cancer: Comparison of the MyPathway Trial With a Real-World External Control Arm.

Purpose: We compared overall survival (OS) in patients with human epidermal growth factor receptor 2 ()-amplified, treatment-refractory metastatic colorectal cancer (mCRC) receiving pertuzumab plus trastuzumab (PER-HER) in the phase IIa MyPathway multibasket study (ClinicalTrials.gov identifier: NCT02091141) with OS in those receiving routine clinical care in an electronic health record-derived external control arm.

Methods: A noninterventional study was conducted using patient-level data from MyPathway participants receiving PER-HER and real-world patients with -amplified treatment-refractory mCRC receiving routine clinical care.

Circulating tumor DNA-guided treatment with pertuzumab plus trastuzumab for HER2-amplified metastatic colorectal cancer: a phase 2 trial.

The applicability of circulating tumor DNA (ctDNA) genotyping to inform enrollment of patients with cancer in clinical trials has not been established. We conducted a phase 2 trial to evaluate the efficacy of pertuzumab plus trastuzumab for metastatic colorectal cancer (mCRC), with human epidermal growth factor receptor 2 (HER2) amplification prospectively confirmed by tumor tissue or ctDNA analysis ( UMIN000027887 ). HER2 amplification was confirmed in tissue and/or ctDNA in 30 patients with mCRC.

Impact of Tumor Assessment Frequency on Statistical Power in Randomized Cancer Clinical Trials Evaluating Progression-Free Survival.

Background: Progression-free survival (PFS) is frequently used as a primary endpoint in late-phase clinical trials for anti-metastatic cancer agents. Previous studies have indicated that the frequency of tumor assessment affects the statistical power for PFS because progression dates are inaccurate; however, this finding may be difficult to generalize because of its unrealistic assumptions. Therefore, we re-examined this issue under realistic assumptions and various scenarios that approximate actual clinical trials.

Final progression-free survival results from the J-ALEX study of alectinib versus crizotinib in ALK-positive non-small-cell lung cancer.

Objectives: The J-ALEX study compared the efficacy and safety of alectinib with crizotinib in Japanese patients with advanced ALK-positive non-small-cell lung cancer (NSCLC). Superiority in independent review facility (IRF)-assessed progression-free survival (PFS) was demonstrated for alectinib at the second pre-planned interim PFS analysis (data cutoff: December 3, 2015; hazard ratio [HR] 0.34, 99.

Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an open-label, randomised phase 3 trial.

Background: Alectinib, a potent, highly selective, CNS-active inhibitor of anaplastic lymphoma kinase (ALK), showed promising efficacy and tolerability in the single-arm phase 1/2 AF-001JP trial in Japanese patients with ALK-positive non-small-cell lung cancer. Given those promising results, we did a phase 3 trial to directly compare the efficacy and safety of alectinib and crizotinib.

Methods: J-ALEX was a randomised, open-label, phase 3 trial that recruited ALK inhibitor-naive Japanese patients with ALK-positive non-small-cell lung cancer, who were chemotherapy-naive or had received one previous chemotherapy regimen, from 41 study sites in Japan.

MEG Frequency Analysis Depicts the Impaired Neurophysiological Condition of Ischemic Brain.

Purpose: Quantitative imaging of neuromagnetic fields based on automated region of interest (ROI) setting was analyzed to determine the characteristics of cerebral neural activity in ischemic areas.

Methods: Magnetoencephalography (MEG) was used to evaluate spontaneous neuromagnetic fields in the ischemic areas of 37 patients with unilateral internal carotid artery (ICA) occlusive disease. Voxel-based time-averaged intensity of slow waves was obtained in two frequency bands (0.

Pharmacologic study (JP28927) of alectinib in Japanese patients with ALK+ non-small-cell lung cancer with or without prior crizotinib therapy.

We report pharmacokinetics, efficacy and safety data for a new 150-mg alectinib capsule in ALK+ non-small-cell lung cancer in a multicenter, open-label pharmacologic study (JP28927). Eligible patients (≥20 years, locally advanced/metastatic ALK+ disease, ALK inhibitor-naïve and -pretreated [including crizotinib refractory]) were randomized 1:1 to receive one of two sequences of alectinib 300 mg twice daily (comprising different schedules of 20/40-mg and 150-mg capsules) until investigator-determined lack of clinical benefit. Co-primary endpoints were: bioequivalence of alectinib 20/40 mg vs 150 mg; food effect with 150 mg; and safety.

Phase I and pharmacokinetic study of trastuzumab emtansine in Japanese patients with HER2-positive metastatic breast cancer.

Objective: Trastuzumab emtansine (T-DM1), an antibody-drug conjugate composed of the cytotoxic agent DM1 conjugated to trastuzumab via a stable thioether linker, has shown clinical activity in human epidermal growth factor receptor 2-positive metastatic breast cancer patients. This study evaluated the maximum tolerated dose, toxicity and pharmacokinetics of trastuzumab emtansine in Japanese breast cancer patients.

Methods: Inoperable advanced or recurrent human epidermal growth factor receptor 2-positive breast cancer patients were administered trastuzumab emtansine intravenously at a dose of 1.

Bayesian model averaging continual reassessment method for bivariate binary efficacy and toxicity outcomes in phase I oncology trials.

Many dose-finding approaches that could evaluate bivariate binary efficacy and toxicity outcomes have been proposed in recent years. In such designs, the operating characteristics with finite sample size can be greatly affected by the assumed dose-toxicity and/or dose-efficacy relationship. However, we do not have much information about a new agent we investigated at the planning stage of Phase I trials and so always face to the risk of misspecifying the true dose-toxicity and/or dose-efficacy relationship by arbitrarily and subjectively choosing skeletons.

A pragmatic dose-finding approach using short-term surrogate efficacy outcomes to evaluate binary efficacy and toxicity outcomes in phase I cancer clinical trials.

There is a growing need for study designs that can evaluate efficacy and toxicity outcomes simultaneously in phase I or phase I/II cancer clinical trials. Many dose-finding approaches have been proposed; however, most of these approaches assume binary efficacy and toxicity outcomes, such as dose-limiting toxicity (DLT), and objective responses. DLTs are often defined for short time periods.

A prospective radiological study of thin-section computed tomography to predict pathological noninvasiveness in peripheral clinical IA lung cancer (Japan Clinical Oncology Group 0201).

Purpose: Pathological noninvasiveness needs to be precisely predicted in preoperative radiological examinations of patients with early lung cancer for the application of limited surgery.

Patients And Methods: Patients with clinical T1N0M0 peripheral lung cancer were recruited. Radiological findings of the main tumor were evaluated as to ground-glass opacity with thin-section computed tomography.

Melphalan-prednisolone and vincristine-doxorubicin-dexamethasone chemotherapy followed by prednisolone/interferon maintenance therapy for multiple myeloma: Japan Clinical Oncology Group Study, JCOG0112.

A multicenter phase III study for untreated multiple myeloma was conducted to investigate a switch-induction chemotherapy with melphalan-prednisolone and vincristine-doxorubicin-dexamethasone followed by randomization on maintenance therapy for patients achieving plateau. Between November 2002 and November 2005, 34 patients were registered. The study was closed early because of poor accrual.