Summary Report of a Public Workshop: Case Studies of Multi-Regional Clinical Trial Incorporating Concept of the ICH E17 Guideline.

To further our understanding of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) E17 guideline and promote effective implementation, a public workshop was held in Japan by regulatory agency and industry representatives. In this workshop, important concepts explained in the ICH E17 guideline, such as intrinsic/extrinsic ethnic factors that influence treatment effects ("effect modifiers") and the holistic evaluation of consistency of treatment effect were actively discussed through case studies. The importance of holistic evaluation of consistency was recognized, and it was concluded that the evaluation and relevant discussion should be shared with regulatory authorities, sponsors, and broader stakeholders.

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. The power is obtained noninvasively using magnetoencephalography and is summarized by spectral parameters such as the median frequency (MF), individual alpha frequency (IAF), spectral edge frequency 95 (SEF95), and Shannon's spectral entropy (SSE). As these parameters are less sensitive to practice effects, they are suitable for longitudinal studies. However, their reliability remains unestablished, hindering their proactive use in clinical practice. Therefore, we aimed to quantify the within-participant reliability of these parameters using repeated measurements of healthy participants to facilitate their clinical use and to evaluate the observed changes/differences in these parameters reported in previous studies. Methodology Resting-state brain activity with eyes closed was recorded using magnetoencephalography for five minutes from 15 healthy individuals (29.3 ± 4.6 years old: ranging from 23 to 28 years old). The following four spectral parameters were calculated: MF, IAF, SEF95, and SSE. To quantify reliability, the minimal detectable change (MDC) and intraclass correlation coefficient (ICC) were computed for each parameter. In addition, we used MDCs to evaluate the changes and differences in the spectral parameters reported in previous longitudinal and cross-sectional studies. Results The MDC at 95% confidence interval (MDC95) of MF, IAF, SEF95, and SSE were 0.61 Hz, 0.44 Hz, 2.91 Hz, and 0.028, respectively. The ICCs of these parameters were 0.96, 0.92, 0.94, and 0.83, respectively. The MDC95 of these parameters was smaller than the mean difference in the parameters between cognitively healthy individuals and patients with dementia, as reported in previous studies. Conclusions The spectral parameter changes/differences observed in prior studies were not attributed to measurement errors but rather reflected genuine effects. Furthermore, all spectral parameters exhibited high ICCs (>0.8), underscoring their robust within-participant reliability. Our results support the clinical use of these parameters, especially in the longitudinal monitoring and evaluation of the outcomes of interventions.

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. Walking ability, disease duration, possibility of air stacking, Unified MSA Rating Scale (UMSARS), and Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III were also assessed. Data were separately analyzed for ambulatory and non-ambulatory groups categorized by Functional Ambulation Categories. PCF, respiratory function, respiratory muscle strength, and MPT were significantly lower in the non-ambulatory group than in the ambulatory group. On the other hand, no correlation between PCF and disease duration was observed. A significant number of patients in the non-ambulatory group were unable to hold their breath. The UMSARS and MDS-UPDRS Part III in the non-ambulatory group were significantly higher than in the ambulatory group. It was concluded that ambulatory dysfunction is associated with the decline of cough function and respiratory-related function in patients with MSA.

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. They were categorized into air stacking and non-air stacking groups. First, we investigated how the inspiration volume changes by applying maximum insufflation capacity (MIC). Second, peak cough flow (PCF) was measured by different cough augmentation methods: 1) spontaneous coughing (SpC); 2) SpC with MIC (SpC + MIC); 3) SpC with manually assisted cough (MAC) (SpC + MAC); and 4) SpC with MIC and MAC (SpC + MIC + MAC). Among these four conditions, PCF values were compared to determine the most effective approach for cough augmentation. Receiver operating characteristic analysis was performed on percent forced vital capacity (%FVC) to determine an index for discriminating PCF below160 L/min, which indicates a high risk of suffocation, involving SpC and SpC + MIC. Results: Inspiration volume increased significantly with MIC in both groups (P < 0.05), and PCF increased significantly with MIC in the air stacking group (P < 0.01). PCF could not be maintained at 160 L/min when %FVC fell below 59%, even when MIC was applied. Conclusions: PCF increases with MIC in patients with MSA. It may be meaningful to consider the timing of gastrostomy introduction based on the severity of cough and respiratory dysfunction.

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. The risk of bias was assessed using the Risk of Bias 2 tool. We followed the Grading of Recommendations, Assessment, Development, and Evaluation approach to summarize the evidence. RESULTS: Four studies (558 participants) identified via search strategies were included. Two studies involved individualized exercise and lifestyle interventions. In three out of the four studies, individual interventions were applied. Overall, when compared with a control group, the intervention group was more likely to positively affect increasing life-space mobility (standardized mean difference 0.47, 95% confidence interval [0.020 to 0.92]). The heterogeneity statistic indicated considerable heterogeneity (I2 = 84%). The evidence was downgraded one step owing to imprecision. CONCLUSIONS: Interventions on increasing life-space mobility for community-dwelling older adults have a positive effect. Combination interventions may be more effective than single interventions, and individual interventions may be more effective than group interventions. However, owing to the limited number of studies, conducting further research to enhance the generalizability of results is crucial. Additionally, subgroup analysis should be conducted to clarify differences in intervention methods and effects. Geriatr Gerontol Int 2023; 23: 842-848.

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. The hazard ratio for progression-free survival of ALK-TKIs increased in patients with ALK fusion-positive non-small cell lung cancer with FGFR1- and FGF2-high mRNA expression at baseline. The combination of FGFR and targeted TKIs enhanced cell growth inhibition and apoptosis induction in basal FGFR1- and FGF2-high protein expressing cells with ALK-rearranged and epidermal growth factor receptor (EGFR)-mutated NSCLC, human epidermal growth factor receptor 2 (HER2)-amplified breast cancer, or v-raf murine sarcoma viral oncogene homolog B1 (BRAF)-mutated melanoma by preventing compensatory extracellular signal-regulated kinase (ERK) reactivation. These results suggest that a targeted TKI-induced DTP state results from an oncogenic switch from activated oncogenic driver signaling to the FGFR1 pathway in basal FGFR1- and FGF2-high expressing cancers and initial dual blockade of FGFR and driver oncogenes based on FGFR1 and FGF2 expression levels at baseline is a potent treatment strategy to prevent acquired drug resistance to targeted TKIs through DTP cells regardless of types of driver oncogenes.

Pertuzumab Plus Trastuzumab for Treatment-Refractory HER2-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 (HER2)-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 HER2-amplified treatment-refractory mCRC receiving routine clinical care. This study used a deidentified US-based clinico-genomic database (CGDB). For patients in the CGDB who met study eligibility criteria at multiple index dates (treatment initiation dates in the treatment-refractory setting), all eligible index dates were used for the analysis. Standardized mortality ratio weighting on the basis of propensity score derived a pseudopopulation (postweighting population) balancing key prognostic variables between arms. Multivariate Cox proportional hazards models were used for estimation of the hazard ratio (HR) in the primary OS analysis. A series of sensitivity analyses were conducted to investigate the robustness and consistency of the primary analysis. RESULTS: The PER-HER arm comprised 57 patients enrolled in the MyPathway study by August 1, 2017 (data cutoff); the external control arm comprised 18 patients (27 index dates) with HER2-amplified mCRC who met the major MyPathway eligibility criteria in CGDB collected between 2011 and 2019. The estimated HR for OS from the multivariate Cox proportional hazards model in the postweighting population was 0.729 (95% CI, 0.184 to 3.900). The results of sensitivity analyses were consistent with the primary analysis in terms of the point estimate of HR. CONCLUSION: Despite a small sample size, these findings suggest that PER-HER could have a potential OS benefit for this population.

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. The study met the primary endpoint with a confirmed objective response rate of 30% in 27 tissue-positive patients and 28% in 25 ctDNA-positive patients, as compared to an objective response rate of 0% in a matched real-world reference population treated with standard-of-care salvage therapy. Post hoc exploratory analyses revealed that baseline ctDNA genotyping of HER2 copy number and concurrent oncogenic alterations adjusted for tumor fraction stratified patients according to efficacy with similar accuracy to tissue genotyping. Decreased ctDNA fraction 3 weeks after treatment initiation associated with therapeutic response. Pertuzumab plus trastuzumab showed similar efficacy in patients with mCRC with HER2 amplification in tissue or ctDNA, showing that ctDNA genotyping can identify patients who benefit from dual-HER2 blockade as well as monitor treatment response. These findings warrant further use of ctDNA genotyping in clinical trials for HER2-amplified mCRC, which might especially benefit patients in first-line treatment.

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. METHODS: Randomized clinical trials comparing two interventions against a solid tumor were simulated under conditions where progressive disease (PD)-dominant PFS or a non-negligible number of deaths (death-competitive PFS) contributed to PFS events, which are conditions that resemble clinical trials of first-line therapy and later-line therapy, respectively. We assessed the impact of tumor assessment frequency on the statistical power. RESULTS: Under the PD-dominant PFS condition, even in extreme scenarios, statistical power loss was only approximately 3%. Under the death-competitive PFS condition, tumor assessment frequency affected the statistical power of PFS if the effect of the treatment on overall survival was lower than that on time to progression. In this case, loss of statistical power was often more than 10% in some realistic scenarios. CONCLUSION: In trials investigating first-line treatments (PD-dominant PFS), tumor assessment frequency has a negligible impact on statistical power, whereas in trials investigating late-line therapies (death-competitive PFS), the potential impact of tumor assessment frequency on statistical power should be carefully evaluated at the design stage.

The efficacy and safety of pertuzumab plus trastuzumab and docetaxel as a first-line therapy in Japanese patients with inoperable or recurrent HER2-positive breast cancer: the COMACHI study.

PURPOSE: In the CLEOPATRA study of patients with human epidermal growth factor receptor 2 (HER2)-positive recurrent or metastatic breast cancer, the Japanese patient subgroup did not demonstrate the improved progression-free survival (PFS) of pertuzumab plus trastuzumab and docetaxel vs. placebo that was seen in the overall population. Therefore, COMACHI was conducted to confirm the efficacy and safety of this treatment regimen in this patient subgroup. METHODS: This was a phase IV study of pertuzumab plus trastuzumab and docetaxel in Japanese patients with histologically/cytologically confirmed inoperable or recurrent HER2-positive breast cancer. All patients received pertuzumab, trastuzumab, and docetaxel intravenously every 3 weeks until disease progression/unacceptable toxicity. The primary endpoint was investigator-assessed PFS. Secondary endpoints were overall survival (OS), investigator-assessed objective response rate, and duration of response (DoR). Safety was also assessed. RESULTS: At final analysis, median investigator-assessed PFS was 22.8 months (95% CI 16.9-37.5). From first dose, OS rate at 1 year was 97.7%; and at 2 and 3 years were 88.5% and 79.1%, respectively. Of the 118 patients with measurable disease at baseline, response rate was 83.9% (95% CI 77.3-90.5) and median investigator-assessed DoR was 26.3 months (95% CI 17.1-not evaluable). Treatment was well tolerated, with no new safety signals detected. CONCLUSIONS: Our results suggest similar efficacy and safety for pertuzumab plus trastuzumab and docetaxel in Japanese patients compared with the overall population of CLEOPATRA, providing further support for this combination therapy as standard of care for Japanese patients with inoperable or recurrent HER2-positive breast cancer.

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, 99.7 % confidence interval [CI]: 0.17-0.71, P < 0.0001). We report final PFS data and the second pre-planned interim analysis of overall survival (OS) and safety (data cutoff: June 30, 2018). METHODS: Patients aged ≥20 years who were ALK inhibitor-naïve and chemotherapy-naïve, or had received one prior chemotherapy regimen, were randomized to receive alectinib 300 mg (n = 103) or crizotinib 250 mg (n = 104) twice daily. The primary end point was IRF-assessed PFS. Secondary end points included OS and safety. All patients entered survival follow-up in July 2018. RESULTS: Median follow-up was 42.4 months for alectinib and 42.2 months for crizotinib. Sustained improvement in IRF-assessed PFS with alectinib was shown (HR 0.37, 95 % CI: 0.26-0.52; median PFS 34.1 months vs 10.2 months crizotinib). At the second interim OS analysis, superiority of alectinib to crizotinib could not be concluded (stratified HR 0.80, 99.8799 % CI: 0.35-1.82, stratified log-rank P = 0.3860; median OS not reached alectinib vs 43.7 months crizotinib). Fewer alectinib-treated patients experienced grade ≥3 adverse events (36.9 % vs 60.6 % crizotinib). CONCLUSIONS: At the final PFS analysis, alectinib continued to demonstrate superiority in IRF-assessed PFS versus crizotinib in ALK-inhibitor-naïve ALK-positive NSCLC, with a favorable safety profile. OS follow-up continues.

Pertuzumab plus trastuzumab and chemotherapy for Japanese patients with HER2-positive metastatic gastric or gastroesophageal junction cancer: a subgroup analysis of the JACOB trial.

BACKGROUND: The phase III JACOB trial (NCT01774786) compared the efficacy and safety of pertuzumab and trastuzumab plus chemotherapy with placebo and trastuzumab plus chemotherapy in patients with previously untreated human epidermal growth factor receptor 2 (HER2)-positive metastatic gastric or gastroesophageal junction cancer. We conducted a subgroup analysis in Japanese patients. METHODS: Patients were randomized 1:1 to pertuzumab 840 mg or placebo, plus trastuzumab (loading dose, 8 mg/kg; maintenance dose, 6 mg/kg) and chemotherapy (cisplatin 80 mg/m2, and capecitabine 1000 mg/m2 twice daily for 28 doses or 5-fluorouracil 800 mg/m2 every 24 h for 120 h), every 3 weeks. Continuation of chemotherapy after 6 cycles was at the discretion of the patient and the treating physician. RESULTS: A total of 40 Japanese patients were included in each arm. Median overall survival was 22.0 months (95% confidence interval [CI] 13.8-not evaluable) and 15.6 months (95% CI 9.7-19.2) in the pertuzumab and placebo arms, respectively (hazard ratio [HR] 0.64 [95% CI 0.37-1.10]). Median progression-free survival was 12.4 months (95% CI 6.1-14.1) in the pertuzumab arm and 6.3 months (95% CI 4.3-8.1) in the placebo arm (HR 0.50 [95% CI 0.30-0.82]). Grade ≥ 3 adverse events and serious adverse events were more frequent in the pertuzumab arm than the placebo arm. CONCLUSIONS: Results from this subgroup analysis of the JACOB trial suggest similar efficacy of pertuzumab in Japanese patients and patients in the overall population, encouraging continued investigation of new agents for gastric cancer in Japanese patients.

Effectiveness of Home-Based Exercises Without Supervision by Physical Therapists for Patients With Early-Stage Amyotrophic Lateral Sclerosis: A Pilot Study.

OBJECTIVE: To verify the effects of structured home-based exercises without supervision by a physical therapist in patients with early-stage amyotrophic lateral sclerosis (ALS). DESIGN: A historical controlled study that is part of a multicenter collaborative study. SETTING: Rehabilitation departments at general hospitals and outpatient clinics with a neurology department. PARTICIPANTS: Patients (N=21) with ALS were enrolled and designated as the home-based exercise (Home-EX) group, and they performed unsupervised home-based exercises. As a control group, 84 patients with ALS who underwent supervised exercise with a physical therapist for 6 months were extracted from a database of patients with ALS and matched with the Home-EX group in terms of their basic attributes and clinical features. INTERVENTION: The Home-EX group was instructed to perform structured home-based exercises without supervision by a physical therapist that consisted of muscle stretching, muscle training, and functional training for 6 months. MAIN OUTCOME MEASURES: The primary outcome was the score on the ALS Functional Rating Scale-Revised (ALSFRS-R), which is composed of 3 domains: bulbar function, limb function, and respiratory function. The score ranges from 0 to 48 points, with a higher score indicating better function. RESULTS: In the Home-EX group, 15 patients completed the home-based exercises for 6 months, and 6 patients dropped out because of medical reasons or disease progression. No adverse events were reported. The Home-EX group was found to have a significantly higher respiratory function subscore and total score on the ALSFRS-R than the control group at follow-up (P<.001 and P<.05, respectively). CONCLUSIONS: Structured home-based exercises without supervision by a physical therapist could be used to alleviate functional deterioration in patients with early-stage ALS.

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. Patients were randomly assigned (1:1) via an interactive web response system using a permuted-block method stratified by Eastern Cooperative Oncology Group performance status, treatment line, and disease stage to receive oral alectinib 300 mg twice daily or crizotinib 250 mg twice daily until progressive disease, unacceptable toxicity, death, or withdrawal. The primary endpoint was progression-free survival assessed by an independent review facility. The efficacy analysis was done in the intention-to-treat population, and safety analyses were done in all patients who received at least one dose of the study drug. The study is ongoing and patient recruitment is closed. This study is registered with the Japan Pharmaceutical Information Center (number JapicCTI-132316). FINDINGS: Between Nov 18, 2013, and Aug 4, 2015, 207 patients were recruited and assigned to the alectinib (n=103) or crizotinib (n=104) groups. At data cutoff for the second interim analysis, 24 patients in the alectinib group had discontinued treatment compared with 61 in the crizotinib group, mostly due to lack of efficacy or adverse events. At the second interim analysis (data cutoff date Dec 3, 2015), an independent data monitoring committee determined that the primary endpoint of the study had been met (hazard ratio 0·34 [99·7% CI 0·17-0·71], stratified log-rank p<0·0001) and recommended an immediate release of the data. Median progression-free survival had not yet been reached with alectinib (95% CI 20·3-not estimated) and was 10·2 months (8·2-12·0) with crizotinib. Grade 3 or 4 adverse events occurred at a greater frequency with crizotinib (54 [52%] of 104) than alectinib (27 [26%] of 103). Dose interruptions due to adverse events were also more prevalent with crizotinib (77 [74%] of 104) than with alectinib (30 [29%] of 103), and more patients receiving crizotinib (21 [20%]) than alectinib (nine [9%]) discontinued the study drug because of an adverse event. No adverse events with a fatal outcome occurred in either treatment group. INTERPRETATION: These results provide the first head-to-head comparison of alectinib and crizotinib and have the potential to change the standard of care for the first-line treatment of ALK-positive non-small-cell lung cancer. The dose of alectinib (300 mg twice daily) used in this study is lower than the approved dose in countries other than Japan; however, this limitation is being addressed in the ongoing ALEX study. FUNDING: Chugai Pharmaceutical Co, Ltd.

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 (0.3-4 Hz and 4-8 Hz) using standardized low-resolution brain electromagnetic tomography (sLORETA) modified for a quantifiable method (sLORETA-qm). ROIs were automatically applied to the anterior cerebral artery (ACA), anterior middle cerebral artery (MCAa), posterior middle cerebral artery (MCAp), and posterior cerebral artery (PCA) using statistical parametric mapping (SPM). Positron emission tomography with 15O-gas inhalation (15O-PET) was also performed to evaluate cerebral blood flow (CBF) and oxygen extraction fraction (OEF). Statistical analyses were performed using laterality index of MEG and 15O-PET in each ROI with respect to distribution and intensity. RESULTS: MEG revealed statistically significant laterality in affected MCA regions, including 4-8 Hz waves in MCAa, and 0.3-4 Hz and 4-8 Hz waves in MCAp (95% confidence interval: 0.020-0.190, 0.030-0.207, and 0.034-0.213), respectively. We found that 0.3-4 Hz waves in MCAp were highly correlated with CBF in MCAa and MCAp (r = 0.74, r = 0.68, respectively), whereas 4-8 Hz waves were moderately correlated with CBF in both the MCAa and MCAp (r = 0.60, r = 0.63, respectively). We also found that 4-8 Hz waves in MCAp were statistically significant for misery perfusion identified on 15O-PET (p<0.05). CONCLUSIONS: Quantitatively imaged spontaneous neuromagnetic fields using the automated ROI setting enabled clear depiction of cerebral ischemic areas. Frequency analysis may reveal unique neural activity that is distributed in the impaired vascular metabolic territory, in which the cerebral infarction has not yet been completed.

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. Thirty-five patients were enrolled; median treatment duration was 13.1 months (range 1.1-15.0). Under fasting conditions, exposure of the two formulations was similar; mean AUClast  ± standard deviation 3230 ± 914 h·ng/mL vs 3710 ± 1040 h·ng/mL, respectively, for 150-mg vs 20/40-mg capsules. Food effect with 150 mg alectinib was negligible. Treatment-related adverse events in >20% of patients were constipation (31.4%), dysgeusia (25.7%), and decreased white blood cell and neutrophil count (22.9% each). No treatment-related grade 4/5 events occurred. Median time to response was 1.2 months (95% CI 1.1-2.1). For the full analysis set (n = 35) and crizotinib-failure subpopulations (n = 23), the overall response rate was 70.0% (95% CI 50.6-85.3) and 65.0% (95% CI 40.8-84.6), and median progression-free survival was 13.9 months (95% CI 11.1-not reached) and 12.9 months (95% CI 3.9-not reached), respectively. The 150-mg capsule had a similar exposure profile to 20/40-mg capsules. Alectinib demonstrated promising efficacy and was well tolerated.

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 1.8, 2.4 or 3.6 mg/kg every 3 weeks. The maximum tolerated dose was estimated using the continual reassessment method. RESULTS: This study enrolled 10 patients who were administered trastuzumab emtansine for a median of seven cycles. The dose-limiting toxicity was Grade 3 elevation of aspartate aminotransferase/alanine aminotransferase at the 2.4 mg/kg dose level. The maximum tolerated dose was estimated to be 3.6 mg/kg because at the point when dose-limiting toxicity was evaluable in 10 patients, the probability of dose-limiting toxicity estimated using the continual reassessment method was closest to 25% at a dose of 3.6 mg/kg and this was unchanged by the results for patients enrolled after that. The most frequent adverse events were nausea, arthralgia, fever, fatigue and decreased appetite. Adverse events were generally tolerable. The maximum concentration and area under the concentration-time curve increased linearly with the dose. CONCLUSIONS: Trastuzumab emtansine up to 3.6 mg/kg was well tolerated by Japanese breast cancer patients. Although thrombocytopenia and hepatotoxicity tended to be more severe than was seen in Western patients in previous trastuzumab emtansine trials, those adverse events recovered without special supportive treatment.

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. In this article, we proposed the Bayesian model averaging bivariate continual reassessment method to cope with above risk.

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. In contrast, objective responses are often defined for longer periods because of practical limitations on confirmation and the criteria used to define 'confirmation'. This means that studies have to be carried out for unacceptably long periods of time. Previous studies have not proposed a satisfactory solution to this specific problem. Furthermore, this problem may be a barrier for practitioners who want to implement notable previous dose-finding approaches. To cope with this problem, we propose an approach using unconfirmed early responses as the surrogate efficacy outcome for the confirmed outcome. Because it is reasonable to expect moderate positive correlation between the two outcomes and the method replaces the surrogate outcome with the confirmed outcome once it becomes available, the proposed approach can reduce irrelevant dose selection and accumulation of bias. Moreover, it is also expected that it can significantly shorten study duration. Using simulation studies, we demonstrate the positive utility of the proposed approach and provide three variations of it, all of which can be easily implemented with modified likelihood functions and outcome variable definitions.

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. The primary end point was specificity, i.e., the proportion of patients with radiologically diagnosed invasive lung cancer to patients with pathologically diagnosed invasive lung cancer. The precision-based planned sample size was 450. We expected that the lower limit of the 95% confidence interval (CI) for specificity should be satisfied in ≥97% of patients. RESULTS: We enrolled 811 patients from 31 institutions between December 2002 and May 2004. The primary end point was evaluated in 545 patients. The specificity and sensitivity for the diagnosis of pathologically diagnosed invasive cancer were 96.4% (161/167, 95% CI: 92.3-98.7%) and 30.4% (115/378, 95% CI: 25.8-35.3%), respectively, i.e., a negative result. Nevertheless, the specificity for lung adenocarcinoma ≤2.0 cm with ≤0.25 consolidation to the maximum tumor diameter was 98.7% (95% CI: 93.2-100.0%), and this criterion could be used to radiologically define early adenocarcinoma of the lung. CONCLUSIONS: Although our predetermined criterion for specificity was not statistically confirmed, radiological diagnosis of noninvasive lung cancer with a thin-section computed tomography scan corresponded well with pathological invasiveness. Radiological noninvasive peripheral lung adenocarcinoma could be defined as an adenocarcinoma ≤2.0 cm with ≤0.25 consolidation.