Profile In Japanese Patients Research Articles

Effect of switching from conventional continuous subcutaneous insulin infusion to sensor augmented pump therapy on glycemic profile in Japanese patients with type 1 diabetes.

Evidence suggests that sensor augmented pump (SAP) therapy is superior to conventional continuous subcutaneous insulin infusion (CSII) for achieving glycemic control in patients with type 1 diabetes. However, the clinical benefit of SAP therapy in East Asians has not yet been demonstrated. The effect of switching from conventional CSII to SAP therapy on glycemic profile was examined in 18 Japanese patients with type 1 diabetes. The glycemic profile of the patients was determined by retrospective continuous glucose monitoring (CGM) within 1month before the treatment switch, whereas that at 6 and 12months after the switch was evaluated with the CGM function of the SAP device. Hemoglobin A1c levels were also measured before and after the switch to SAP therapy. The duration of hypoglycemia was significantly decreased at both 6 and 12months after the change in treatment (6.6±4.5, 3.2±4.1, and 3.0±2.8min/h for before and 6 and 12months, respectively), as was the HbA1c level at 12months (7.8±1.0 and 7.4±0.9%, respectively). The duration of hyperglycemia did not differ between before and after the treatment switch. The decline in HbA1c level at 12months after the switch to SAP was negatively correlated with age. Switching from conventional CSII to SAP therapy was associated with a decrease in both the duration of hypoglycemia and the level of HbA1c in Japanese patients with type 1 diabetes.

Effects of linagliptin monotherapy compared with voglibose on postprandial lipid profiles in Japanese patients with type 2 diabetes: linagliptin study of effects on postprandial blood glucose (L-STEP) sub-study 1.

Recently, we reported that linagliptin had equivalent efficacy to voglibose in reducing postprandial blood glucose levels in drug-naïve patients with type 2 diabetes (L-STEP Study). As a sub-study of the L-STEP Study we examined the effect of linagliptin on postprandial lipids profile. Between October 2012 and April 2014, the study enrolled patients with type 2 diabetes mellitus who had inadequate glycemic control. Patients were randomly assigned to either the linagliptin group (5 mg once daily, n = 85) or the voglibose group (0.2 mg/meal thrice daily, n = 71). Meal tolerance tests were performed at baseline (week 0) and endpoint (week 12). The increments in 4-h postprandial triglyceride, remnant lipoprotein cholesterol (RLP-C), and apolipoprotein B48 (ApoB48) from baseline to endpoint in the linagliptin group were lower (p < 0.001, p = 0.025 and p < 0.001). 4-h postprandial ApoB48 at endpoint was lower in the linagliptin group (p = 0.007), and positive correlation was detected between change of ApoB48 and changes in both triglyceride (r = 0.67, p < 0.001) and RLP-C (r = 0.73, p < 0.001) at 4 h. This study revealed that in drug-naïve Japanese patients with relatively mild type 2 diabetes mellitus, linagliptin improves not only postprandial blood glucose level but also levels of lipids such as TG and RLP-C by reducing the ApoB48 level compared with voglibose.

Effects of switching to low-dose rosuvastatin (5mg/day) on glucose metabolism and lipid profiles in Japanese patients with type 2 diabetes and dyslipidemia: a single-arm, prospective, interventional trial.

We investigated the effects of switching from other statins, such as pravastatin (5 or 10mg/day), rosuvastatin (2.5mg/day), or pitavastatin (1 or 2mg/day), to low-dose rosuvastatin (5mg/day) on glucose metabolism and lipid profiles in Japanese patients with type 2 diabetes and dyslipidemia. This was a prospective, two-center, open-label, single-arm, interventional trial. Several clinical parameters were analyzed at baseline and 24weeks after switching from other statins to rosuvastatin at 5mg/day. The primary endpoints were changes in hemoglobin (Hb) A1c level and lipid profile. Forty-five patients were enrolled in the trial. The mean HbA1c level increased significantly from 7.1±0.7 to 7.5±0.9% (P<0.001), whereas the mean low-density lipoprotein cholesterol (LDL-C) level decreased significantly from 108.9±16.5 to 91.6±24.5mg/dL (P<0.001). Multiple linear regression analysis showed that changes in HbA1c levels were significantly and positively correlated with fasting plasma glucose (FPG) levels at baseline. Receiver operating characteristic (ROC) curve analysis examining the relationship between HbA1c and FPG showed that FPG was a significant predictor of changes in HbA1c levels (area under the curve, 0.72). The cutoff FPG value of 168mg/dL had a sensitivity of 47% and a specificity of 93%. Switching to a low dose of rosuvastatin impaired glucose metabolism in Japanese patients with type 2 diabetes and dyslipidemia. Patients with high FPG levels were particularly prone to an exacerbation of glucose metabolism.

Abstract 380: Systematic identification of novel functional tumor-specific mutations in receptor tyrosine kinases based on their pan-cancer mutational profiles in Japanese patients with cancer

Abstract Background: Recent accumulation of large amounts of cancer genome information has revealed the presence of tumor-specific mutations with unknown functions; characterization of these mutations should facilitate the identification of novel therapeutic targets. Some tumor-specific mutations in receptor tyrosine kinases (RTKs) act as oncogenic drivers in multiple cancer types. Here, we aimed to identify novel, functional, tumor-specific, single nucleotide variants (SNVs) in cancer-related RTKs based on pan-cancer mutational profiles in Japanese patients with cancer. Methods: Surgically resected tissue and corresponding peripheral blood samples of 1,685 patients enrolled in Project HOPE (High-tech Omics-based Patient Evaluation), an ongoing prospective molecular profiling study at the Shizuoka Cancer Center, collected between January 2014 and December 2015, were subjected to whole-exome sequencing with an ion torrent proton platform. Newly detected tumor-specific SNVs that could represent functional mutations between the transmembrane and kinase domains of 35 cancer-related RTKs were subjected to serum response element (SRE)-reporter assay to assess effects on extracellular signal-regulated kinase (ERK) signaling relevant to cancer cell survival. Results: We identified 201,422 nonsynonymous tumor-specific SNVs in 1,685 patients. Of these SNVs, 1,049 were observed in our focused 35 cancer-related RTKs. Approximately 45% of patients with lung squamous cell carcinoma, which was the most frequent cancer type, followed by lung adenocarcinoma (39%), harbored tumor-specific SNVs in RTKs. The relative frequencies of tumor-specific SNVs in RTKs in other tumor types were 32%, 31%, 29%, 28%, and 19% in liver cancer, colorectal cancer, gastric cancer, head and neck cancer, and breast cancer, respectively. After filtering out of SNVs registered in multiple cancer-related databases, such as COSMIC, dbSNP, and DoCM, to select putative novel tumor-specific SNVs, 22 SNVs were selected as novel tumor-specific SNVs with high potential as functional mutations through an additional selection process based on amino acid substitution patterns and multiple alignment of amino acid residues coupled with information regarding functional mutations. Among these SNVs, 13 had already been assessed using an SRE reporter assay. We identified two SNVs in NTRK1 and IGF1R that were involved in activation of the ERK pathway, indicating that these SNVs may be activating mutations. Moreover, inactivating mutations were also identified. Nine SNVs in FLT3, NTRK1, EPHA5, ERBB4, FGFR3, and KDR significantly reduced ERK activity. Conclusions: A systematic evaluation of functionally unknown tumor-specific SNVs detected in cancer genome sequencing is necessary to expand the range of molecularly targeted cancer therapeutics. Citation Format: Masakuni Serizawa, Takeshi Nagashima, Yuji Shimoda, Shumpei Ohnami, Sumiko Ohnami, Keiichi Ohshima, Tohru Mochizuki, Takashi Nakajima, Kenichi Urakami, Masatoshi Kusuhara, Ken Yamaguchi. Systematic identification of novel functional tumor-specific mutations in receptor tyrosine kinases based on their pan-cancer mutational profiles in Japanese patients with cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 380. doi:10.1158/1538-7445.AM2017-380

Phase 1 study of new formulation of patritumab (U3-1287) Process 2, a fully human anti-HER3 monoclonal antibody in combination with erlotinib in Japanese patients with advanced non-small cell lung cancer

BackgroundThis phase 1 study evaluated the safety, tolerability, pharmacokinetics and efficacy of patritumab (U3-1287) Process 2, a new formulation of fully human anti-HER3 monoclonal antibody in combination with erlotinib, an epidermal growth factor receptortyrosine kinase inhibitor (EGFR-TKI) in prior chemotherapy treated Japanese patients with advanced non-small cell lung cancer (NSCLC).MethodsPatients received intravenous patritumab Process 2 formulation at 9 mg/kg every 3 weeks after initiation of 18 mg/kg loading dose combined with continuous daily dose of erlotinib (150 mg QD) until any of the withdrawal criteria are met. Adverse events (AEs) were assessed using CTCAE v4.0 and tumor response was assessed using RECIST v1.1. Full pharmacokinetic sampling and serum biomarker analyses were mainly performed during cycle 1 and 2.ResultsTotal of six EGFR-mutant NSCLC patients including one EGFR-TKI naïve patient received patritumab Process 2 formulation combined with erlotinib. No dose-limiting toxicities were observed. The most frequent AEs were gastrointestinal or skin toxicities, which were generally mild and manageable. One patient discontinued from study due to reversible grade 3 interstitial lung disease. The mean area under the curve (AUC) value was 2640 μg/day/mL; the Cmax value was 434 μg/mL, respectively. The median progression-free survival (95% confidence interval) was 220.0 (100.0–363.0) days. HER3 ligand heregulin was detected in serum from only a patient that maintained most durable stable disease.ConclusionsPatritumab Process 2 formulation in combination with erlotinib was well tolerated compatible with favorable PK profile in Japanese patients with advanced NSCLC.

A randomized, double-blind, phase II study of ramucirumab plus docetaxel vs placebo plus docetaxel in Japanese patients with stage IV non-small cell lung cancer after disease progression on platinum-based therapy

ObjectivesRamucirumab plus docetaxel prolongs survival in patients with non-small cell lung cancer (NSCLC) with disease progression after platinum-based therapy. This phase II, double-blind, randomized, placebo-controlled study assessed efficacy and safety of second-line ramucirumab-docetaxel in Japanese patients with NSCLC. Materials and methodsPatients with NSCLC with progression after platinum-based therapy (28 Japanese sites; 19 December, 2012 to 22 May, 2015) were randomized (computer-generated sequence) to ramucirumab 10mg/kg or placebo, followed by docetaxel 60mg/m2 (Day 1, 21-day cycle). Prior epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) monotherapy was prohibited in the primary population, but EGFR mutation-positive NSCLC patients who were treated with EGFR-TKI were enrolled as a separate exploratory population. Primary endpoint was progression-free survival (PFS); secondary outcomes included overall survival, tumor response rates, and safety. Investigator tumor assessments were used for the efficacy endpoints. ResultsIn the primary population (N=160 randomized, n=157 treated), median (95% CI) PFS was longer with ramucirumab-docetaxel (5.22 [3.52–6.97] months; n=76) than with placebo-docetaxel (4.21 [2.83–5.62] months; n=81); hazard ratio 0.83 (95% CI 0.59–1.16). Median (95% CI) overall survival was 15.15 (12.45–26.55) months with ramucirumab-docetaxel and 14.65 (11.93–24.44) months with placebo-docetaxel (hazard ratio [95% CI] 0.86 [0.56–1.32]). Objective response rate (28.9% vs 18.5%) and disease control rate (78.9% vs 70.4%) were numerically greater with ramucirumab-docetaxel than with placebo-docetaxel. Incidence and severity of most adverse events were similar, but febrile neutropenia was more common with ramucirumab-docetaxel (34.2%) than with placebo-docetaxel (19.8%). ConclusionSecond-line ramucirumab-docetaxel improved PFS similar to that seen in the REVEL trial with a manageable safety profile in Japanese patients with NSCLC.

Ethnic sensitivity assessment of the antibody-drug conjugate trastuzumab emtansine (T-DM1) in patients with HER2-positive locally advanced or metastatic breast cancer.

Trastuzumab emtansine (T-DM1) is indicated for previously treated HER2-positive metastatic breast cancer. Ethnic sensitivity assessment of T-DM1 was conducted using data from eight clinical studies to ensure that the clinically recommended dose is appropriate across ethnicities. Four approaches were used: (1) non-compartmental analysis (NCA) comparing pharmacokinetic parameters of T-DM1 and relevant analytes across ethnic groups, (2) population pharmacokinetic (popPK) analysis assessing the impact of ethnicity on pharmacokinetics, (3) comparison of T-DM1 pharmacokinetics in Japanese patients versus the global population, and (4) exposure-response analyses assessing the impact of ethnicity on safety and efficacy. NCA pharmacokinetic parameters (T-DM1, total trastuzumab, DM1) were comparable across ethnic groups; mean cycle 1 T-DM1 AUCinf was 475, 442, and 518dayµg/mL for white (n=461), Asian (n=68), and others (n=57), respectively. PopPK analysis showed that ethnicity (white, Asian, and others) was not a significant covariate for T-DM1 pharmacokinetics (n=671). Additionally, visual predictive check plots indicated that observed pharmacokinetic profiles in Japanese patients (n=42) were within the prediction interval generated from the final PopPK model. Exposure-response analyses showed that ethnicity was not a significant covariate impacting efficacy or hepatotoxicity risk, but there was a trend of greater thrombocytopenia risk among Asians versus non-Asians, which could not be explained by similar exposure between the ethnic groups. Most Asians with thrombocytopenia were able to continue T-DM1 using dose-adjustment rules recommended for the global population. These results suggest that T-DM1 pharmacokinetics are comparable across ethnic groups and that use of the current dosing regimen is appropriate across ethnicities.

Abstract B31: A Phase I study of single-agent ribociclib in Japanese patients with advanced solid tumors

Abstract Background: Ribociclib (LEE011), an orally bioavailable, highly specific cyclin-dependent kinase (CDK) 4/6 inhibitor, causes cell cycle arrest and tumor growth inhibition in multiple preclinical models with intact retinoblastoma protein (pRb+). During a Phase I dose escalation study in the US and Europe, preliminary signs of clinical activity were observed when patients with pRb+ advanced solid tumors and lymphomas were treated with single-agent ribociclib (NCT01237236). Here we report on a Phase I dose escalation study in Japanese patients with advanced solid tumors (NCT01898845). Methods: Patients with pRb+ advanced solid tumors were treated with escalating doses of ribociclib on a 21-of-28-day schedule. Dose escalation decisions were based on the synthesis of relevant data, guided by a Bayesian Logistic Regression Model and escalation with overdose control principle. The primary objective was to establish the maximum tolerated dose and/or recommended dose for expansion (RDE) of ribociclib. Secondary objectives included assessment of the safety, pharmacokinetics, and preliminary antitumor activity of ribociclib. Results: As of January 28, 2015, 17 patients (median age 57 years [range 33-73]) were treated with 400 mg (n = 4) and 600 mg (n = 13) ribociclib. Primary sites of cancer were breast (n = 4), esophagus (n = 9), peritoneum (n = 3), and soft tissue (n = 1). Patients were heavily pretreated: 71% (n = 12) received ≥3 prior antineoplastic regimens. Median durations of treatment were 54.5 days (400 mg) and 59.0 days (600 mg). The mean relative dose intensities were 100% (400 mg) and 98% (600 mg). Six dose-limiting toxicities were reported: one at 400 mg (Grade [G]3 febrile neutropenia) and five at 600 mg (G3 febrile neutropenia [n = 1]; G4 neutropenia [n = 1]; G4 thrombocytopenia [n = 1]; G3 QTc prolongation [n = 2]). The RDE was declared as 600 mg/day on a 21-of-28-day schedule. Ribociclib was absorbed rapidly (the median Tmax on Cycle 1 Day 1 was 3.12 h [range 1.97-6.00] at 400 mg and 2.97 h [range 1.92-5.87] at 600 mg), and dose-dependent increases in exposure (AUC) were observed. The geometric mean effective half-life on Cycle 1 Day 21 was 63.6 h at 400 mg, and 53.6 h at 600 mg. The most frequent study drug-related adverse events (all-grade, &amp;gt;35% of patients) were (all-grade; G3/4): leukopenia (100%; 82%), neutropenia (94%; 77%), lymphopenia (82%; 53%), thrombocytopenia (71%; 24%), QTc prolongation (41%; 12%), increased creatinine (41%; 0%), nausea (41%; 0%), vomiting (41%; 0%), and anemia (35%; 6%). Four patients had stable disease as best overall response. Conclusions: Single-agent ribociclib demonstrated an acceptable safety and tolerability profile in Japanese patients with advanced solid tumors. The RDE was declared as 600 mg/day on a 21-of-28-day schedule. Ribociclib was absorbed rapidly and showed a dose-dependent plasma exposure. Ribociclib is currently being studied at lower doses in combination with other agents in Japanese patients, including in patients with breast cancer. Citation Format: Yasuhide Yamada, Norifumi Ishikawa, Tomoyuki Kakizume, Takeshi Tajima, Becker Hewes, Toshihiko Doi. A Phase I study of single-agent ribociclib in Japanese patients with advanced solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B31.

Regorafenib for advanced gastrointestinal stromal tumors following imatinib and sunitinib treatment: a subgroup analysis evaluating Japanese patients in the phase III GRID trial

The randomized, double-blind, placebo-controlled GRID trial tested the oral multikinase inhibitor regorafenib in 199 patients with advanced gastrointestinal stromal tumors (GIST) following failure of at least imatinib and sunitinib, and showed a significant improvement in progression-free survival (PFS) versus placebo [hazard ratio (HR) 0.27; 95 % confidence interval (CI) 0.19-0.39; p < 0.0001]. A subgroup analysis of Japanese patients in the GRID study was performed to compare the efficacy and safety of oral regorafenib 160 mg once daily with matching placebo, in combination with best supportive care. The primary study endpoint was progression-free survival (PFS); safety was evaluated through the incidence of adverse events (AEs). Seventeen Japanese patients were randomized to regorafenib (n = 12) or placebo (n = 5). Patient demographics were consistent with those of the overall study population. PFS was significantly longer with regorafenib than placebo (HR 0.08; 95 % CI 0.02-0.45; p = 0.000164). Centrally assessed disease control rates were 58 % and 20 % in the regorafenib and placebo groups, respectively (p = 0.080796). Treatment-related adverse events (AEs) were reported in all regorafenib-treated patients and 60 % of placebo recipients; the most frequent AE was hand-foot skin reaction (HFSR) (92 % versus 20 %, respectively). Regorafenib showed efficacy and a manageable safety profile in Japanese patients with advanced GIST, consistent with the overall GRID study population. AEs, such as HFSR and maculopapular rash, were observed more frequently in Japanese patients. Although dose modification was frequently reported, only one patient with hepatic failure discontinued regorafenib because of AEs.

Evaluation of Safety, Tolerability, Pharmacokinetics and Efficacy of Dabrafenib, a Braf Inhibitor, in Japanese Patients with Braf V600 Mutation-Positive Advanced Solid Tumors: a Phase I Study

ABSTRACT Aim: Dabrafenib, a potent and selective BRAF inhibitor, has demonstrated clinical significance for BRAF V600 mutation-positive metastatic melanoma and has been approved in the US and EU. However, there is less clinical experience of treatment with dabrafenib in the Japanese population. Therefore, this study has been designed and conducted to evaluate safety, tolerability, pharmacokinetics (PK) and efficacy of dabrafenib in Japanese patients with BRAF V600 mutation-positive advanced solid tumors as the first clinical trial. Methods: Patients with BRAF V600 mutation-positive advanced solid tumors refractory to standard therapies were enrolled. Dose escalation was performed according to a standard 3 + 3 design. Dabrafenib was given twice a day (BID), which started 7 days after a single dose administration for a single-dose PK analysis. Antitumor activity was evaluated based on RECIST version 1.1. This study was registered at www.clinicaltrials.gov as NCT01582997. Results: Twelve patients (11 melanoma and 1 papillary thyroid cancer) with BRAF V600E mutation received dabrafenib at doses of 75 mg (n = 3), 100 mg (n = 3), or 150 mg (n = 6). The median duration of treatment was approximately 39 weeks. No dose-limiting toxicities were observed in these three dose cohorts. The most common adverse events (AEs) included alopecia, leucopenia, pyrexia and arthralgia. Most AEs were reported as grade 1 or 2. Squamous-cell carcinoma or keratoacanthoma, which is a well-documented BRAF inhibitor class toxicity, was not observed in this study. Preliminary PK results showed no obvious ethnic difference. Partial responses were confirmed in 7 patients (58.3%), 6 melanoma patients and 1 papillary thyroid cancer patient. The data also suggested dabrafenib had an antitumor activity in Japanese patients with BRAF V600 mutation-positive melanoma as well as papillary thyroid cancer. Conclusions: Compared with the data published for the caucasian population, dabrafenib exhibited comparable tolerability, safety and PK profiles in Japanese patients at the dose of 150 mg BID. This dose also gave a suggestive outcome for the potential efficacy to the Japanese population. Disclosure: A. Suzuki: A. Suzuki is an employee of GlaxoSmithKline K.K; A. Mukaiyama: A. Mukaiyama is an employee of GlaxoSmithKline K.K. All other authors have declared no conflicts of interest.

The glycemic/metabolic responses to meal tolerance tests at breakfast, lunch and dinner, and effects of the mitiglinide/voglibose fixed-dose combination on postprandial profiles in Japanese patients with type 2 diabetes mellitus

Background: Meal tolerance tests (MTTs) are usually conducted at breakfast after overnight fasting in type 2 diabetes mellitus (T2DM) patients, but differences in postprandial glycemic responses between meals have been reported.Objective: We conducted MTTs at breakfast, lunch, and dinner to examine the effects of a fixed combination of 10 mg mitiglinide/0.2 mg voglibose (the combination) on glycemic/metabolic responses to meals during the day in T2DM patients. MTTs with unified meals were conducted in 11 T2DM patients before and after 4 weeks of treatment with the combination administered thrice daily before meals. Glycemic/metabolic profiles measured before and at 30, 60, and 120 min after each meal were compared between each meal and between the baseline and treatment periods.Results and conclusion: The combination significantly reduced postprandial hyperglycemia after each meal. Postprandial AUC0 – 120 min for insulin significantly decreased after lunch and dinner compared with after breakfast, while insulin levels significantly increased at only 30 min after breakfast and dinner. The combination also significantly increased postprandial C-peptide and active glucagon-like peptide-1 levels, and reduced free fatty acid and triglyceride levels, but did not significantly affect glucagon levels compared with baseline, confirming that treatment with the combination improves postprandial responses in Japanese T2DM patients.

Abstract C68: Phase I study of administration of LY2523355, an Eg5 inhibitor, for 3 consecutive days every 3 weeks in Japanese patients with refractory solid tumors.

Abstract Background: Eg5, a mitotic motor kinesin, plays an essential role in bipolar spindle formation. Clinical studies on LY2523355 (Litronesib), an allosteric Eg5 inhibitor, were ongoing in several countries. This Phase I study evaluated the tolerability, safety and pharmacokinetics of LY2523355 in Japanese patients with refractory solid tumors to determine the recommended dose for further studies. Methods: This was an open-label, dose-escalation study. LY2523355 was intravenously administered over 60 min on days 1, 2, and 3 every 3 weeks at 1 of 3 dose levels: 2, 4, and 5 mg/m2/day. Doses were escalated in a classic 3 + 3 design. Toxicity was assessed with NCI-CTCAE. Tumor responses were assessed according to the RECIST. Dose-limiting toxicity (DLT) was defined as grade 4 neutropenia for &amp;gt;7 days, grade 4 thrombocytopenia or grade 3 thrombocytopenia requiring platelet transfusion, a neutrophil count of &amp;lt;500/μL with a fever of &amp;gt;38.5°C that lasted for &amp;gt;2 days, or grade ≥3 non-hematologic toxicity. G-CSF was used to treat grade 4 neutropenia or grade 3 febrile neutropenia. Results: Twelve patients were treated at doses of 2 (n = 3), 4 (n = 3), and 5 (n = 6) mg/m2/day. The male-to-female ratio was 7:5 and the median age was 61.5 years. The tumor types were non-small cell lung cancer (n = 2), colorectal cancer (n = 3), small cell lung cancer (n = 2), angiosarcoma (n = 1), breast cancer (n = 1), esophageal cancer (n = 1), gastric cancer (n = 1), and ovarian cancer (n = 1). The main toxicities were neutropenia and leukopenia (100%). Grade 4 neutropenia was observed in 83% of patients; neutrophil levels recovered to &amp;gt;500/μL within 7 days with G-CSF support in all patients. Grade 3 febrile neutropenia was observed in 2 (66%) patients at 4 mg/m2/day and in 6 (100%) patients at 5 mg/m2/day, but these were manageable with appropriate antibiotics administration. DLT was not noted up to 5 mg/m2/day, the dose used in parallel overseas Phase II studies. In pharmacokinetic analysis, exposure of LY2523355 increased dose-proportionally across these doses. None of the predictive factors, including gender, were associated with pharmacokinetic parameters or toxicity. The pharmacokinetic parameters were similar to those observed in Western populations. No objective tumor responses were observed. Conclusions: The recommended dose of LY2523355 with therapeutic G-CSF use for further studies was determined to be 5 mg/m2/day on days 1, 2, and 3 with a manageable safety profile in Japanese patients with refractory solid tumors. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C68. Citation Format: Yutaka Fujiwara, Hiroshi Nokihara, Noboru Yamamoto, Yasuhide Yamada, Hiroshi Wakui, Shinji Nakamichi, Hidenori Mizugaki, Satoru Kitazono, Hironori Kanda, Kohei Suzuki, Shiro Akinaga, Tomohide Tamura. Phase I study of administration of LY2523355, an Eg5 inhibitor, for 3 consecutive days every 3 weeks in Japanese patients with refractory solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C68.

Phase I and pharmacokinetic/pharmacodynamic study of RO5126766, a first-in-class dual Raf/MEK inhibitor, in Japanese patients with advanced solid tumors

RO5126766, a highly selective dual Raf and MEK inhibitor, is a first-in-class tandem mitogen-activated protein kinase signaling pathway inhibitor. The objectives of this phase I study were to determine maximum-tolerated dose (MTD) and to evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity of RO5126766 in Japanese patients with advanced solid tumors. Patients received a single oral dose of RO5126766 (0.8, 1.2, 1.8, or 2.25mg) followed by continuous once-daily dosing at the same dosage in 28-day cycles. A 3+3 dose-escalation design was used. PD was evaluated by pMEK and pERK inhibition in peripheral blood mononuclear cells (PBMCs). A total of 12 patients were enrolled in cohorts of 0.8, 1.2, 1.8, and 2.25mg/day. In the dose range tested, no dose-limiting toxicity was observed, and therefore, MTD was not defined. Main adverse events included acneiform dermatitis, creatine phosphokinase elevation, and ocular disorders. The plasma exposure of RO5126766 appeared to increase in a dose-proportional manner with a long plasma half-life (t 1/2) of 45.8-93.7h. Following multiple dose administration, a steady-state condition was reached by Cycle 1Day 8 (240h). The inhibitory effects of RO5126766 on both pERK and pMEK in PBMCs increased in a dose-dependent manner. Five out of 12 patients achieved stable diseases, including a melanoma case with over 20% shrinkage. RO5126766 has a manageable safety profile up to 2.25mg/day once daily with a favorable PK/PD profile in Japanese patients with advanced solid tumors.

A phase I study of EMD 525797, a novel humanized monoclonal antibody to human integrin alpha v, in Japanese patients with solid tumor.

e13510 Background: Integrin alpha v, in association with several integrin beta subunits, plays critical roles in migration, invasion, proliferation, and survival of both tumor and endothelial cells and represents an attractive target for cancer treatment. EMD 525797 is a humanized monoclonal IgG2 antibody specifically targeting integrin alpha v. Methods: The safety, tolerability, pharmacokinetics (PK), and anti-tumor activity of EMD 525797 were assessed in Japanese patients with advanced solid tumors, treated with intravenous infusions of 250, 500, 1000, or 1500 mg of EMD 525797 (given over 1 h), who received 3 doses (weeks 1, 3, and 5) before response assessment during week 6. Thereafter, patients without progressive disease could receive further doses every 2 weeks. Dose-limiting toxicities (DLTs) were assessed over the first 4 weeks and safety was monitored until 31 days after the last administration of EMD 525797. Results: A total of 27 patients were treated. Regarding the primary site of disease, 17 patients had colorectal cancer, 3 pancreatic cancer, 2 gastrointestinal stromal tumors (GIST), 1 esophageal cancer, 1 gastric cancer, 1 rectal carcinoid, 1 cholangiocarcinoma, 1 hepatocellular carcinoma, and 1 leiomyosarcoma. Twenty-five patients (92.6%) experienced treatment-emergent adverse events (TEAEs); nausea (25.9%), headache (22.2%), pyrexia (22.2%), stomatitis (22.2%), and vomiting (22.2%) were the most common. None of these TEAEs was greater than grade 3 by NCI-CTCAE version 4.0 and no DLT was observed. Fourteen (51.9%) of the TEAEs were possibly related to EMD 525797. Two patients, 1 with GIST and 1 with rectal carcinoid, had longer than expected exposure time (&gt;84 days). EMD 525797 showed a non-linear PK profile. Distribution volume and clearance after EMD 525797 administration did not show apparent ethnic difference considering body weight influence. Conclusions: EMD 525797 was well tolerated in Japanese patients. The safety profile in Japanese patients was comparable to the results from Caucasian patients. In some patients EMD 525797 treatment duration was longer than expected. Clinical trial information: NCT01327313.

Safety, tolerability, pharmacokinetics and pharmacodynamics of belimumab in Japanese patients with mild-to-moderate systemic lupus erythematosus

Objectives:Belimumab, an anti-B lymphocyte stimulator (BLyS) human monoclonal antibody, was approved in the United States, Canada and European Union for the treatment of the patients with systemic lupus erythematosus (SLE). However, belimumab had not been evaluated in Japanese patients. The objectives of this study were to evaluate the safety and tolerability of belimumab in Japanese patients with SLE, as well as to investigate the pharmacokinetics (PK) and biological activity of belimumab in this population.Methods:A total of 12 Japanese patients were enrolled in a randomized, single-blind, placebo-controlled, dose-ascending design study. A dosing regimen of a single intravenous infusion over 1 hour of belimumab (1 mg/kg and 10 mg/kg) was employed. Patients were followed for 84 days after dosing to assess adverse events, pharmacokinetics, biomarkers and SLE disease activity.Clinical trial registration number:ClinicalTrials.gov identifier is NCT01381536.Results:Belimumab (1 mg/kg and 10 mg/kg) demonstrated a favorable clinical safety and tolerability profile in Japanese patients with SLE. The incidence of adverse events was similar among the two belimumab groups and placebo group. The PK profile of single-dose belimumab was approximately dose proportional, and the long terminal elimination half-life (12.4–15.7 days), low clearance (3.55–4.65 mL/day/kg), and small volume of distribution (76.2–80.1 mL/kg) were consistent with a fully humanized antibody. Effects of belimumab on B cells suggested biological activity effects expected as an inhibitor of BLyS.Limitation:The small sample size and single dose design of this study prevent definitive conclusions regarding the safety, pharmacokinetics or pharmacodynamics of belimumab in a Japanese population being made.Conclusions:The preliminary safety, PK profile, and observed biological activity of belimumab support further evaluation of its safety and efficacy in Japanese patient with SLE.

Phase 1 study of trebananib (AMG 386), an angiogenesis targeting angiopoietin-1/2 antagonist, in Japanese patients with advanced solid tumors

PurposeTo evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of trebananib (AMG 386)—a first-in-class angiopoietin-1/2 antagonist peptide-Fc fusion protein—in Japanese patients, we conducted a phase 1, dose escalation study.MethodsEligible patients were men or women, aged between 20 and 74 years, who had histologically or cytologically confirmed advanced solid tumors refractory to standard treatment. Trebananib (3, 10, and 30 mg/kg) was administered intravenously over 60 min in weekly cycles.ResultsFrom June 2009 to April 2010, a total of 18 patients (6 for each dose cohort) were enrolled into the study. Trebananib was tolerated at all dose levels. No dose-limiting toxicities were observed. The most common adverse events were peripheral edema, constipation, fatigue, and pyrexia. Exposure to trebananib appeared to increase according to the dose administered. Serum clearance appeared to be similar across the dose range with the mean terminal-phase half-life ranging from 93.9 to 95.9 h. No neutralizing antibodies were detected. Tumor response was assessed in 18 patients. Of these, one patient with colon cancer in the 3-mg/kg cohort and one with bladder cancer in the 30-mg/kg cohort had partial responses as their best responses. These 2 patients were on treatment at the time of data cutoff (January 17, 2012).ConclusionTrebananib was tolerated and showed acceptable safety profile in Japanese patients with advanced solid tumors. The pharmacokinetic profiles were similar to those in the previous studies in the United States. Trebananib also showed evidence of durable antitumor activity in some patients.

O1-073 - Phase I and Pharmacokinetics/Pharmacodynamics (PK/PD) Study of RO5126766, a First-in-Class Dual Raf/Mek Inhibitor, in Japanese Patients with Advanced Solid Tumors

ABSTRACT Backgrounds RO5126766, a highly selective dual Raf and MEK inhibitor, is a first-in-class tandem MAPK signaling pathway inhibitor. The objectives of this phase I study were to determine MTD and to evaluate safety, PK, PD and anti-tumor activity in Japanese patients with advanced solid tumors. Methods 72–144 hours after oral single dose administration of RO5126766 (0.8, 1.2, 1.8 and 2.25 mg/day), patients received oral RO5126766 administered on a continuous once daily dosing (QD) in 28-day cycles. The 3 + 3 dose-escalation design was used. PD was evaluated by pERK and pMEK inhibition in peripheral blood mononuclear cells (PBMCs). Results Twelve patients were enrolled in cohort of 0.8, 1.2, 1.8 and 2.25 mg/day. Considering that 2.25 mg/day had been defined as the MTD on the QD oral dosing regimen in another phase I study conducted in Europe, higher dose than 2.25 mg/day was not administered in this study. In the dose range tested, no DLT was observed and the MTD has not been defined. Main adverse events (AEs) included dermatitis acneiform, creatine phosphokinase (CPK) elevation and eye disorders. The plasma exposures of RO5126766 appeared to increase dose-linearly with long plasma half-life (t1/2) of 45.8–93.7 h. After multiple dose administration, steady-state conditions were reached by cycle 1 day 8 (240 h). The inhibitory effects of RO5126766 on both pERK and pMEK in PBMCs were increased in a dose-dependent manner. Five of 12 patients achieved stable diseases including a case of melanoma with over 20% shrinkage. Conclusions RO5126766 has a manageable safety profile up to 2.25 mg/day once daily with a favorable PK/PD profile in Japanese patients with advanced tumors.

Systemic pharmacokinetics of indacaterol, an inhaled once-daily long-acting ?2-agonist, in different ethnic populations

To assess ethnic sensitivity of indacaterol systemic pharmacokinetics in Japanese vs. non-Japanese patients. Analyses were in three parts: data from a single "all Asian" clinical study; and two on pooled data - one using a linear mixed effects (LME) model and the other a non-linear mixed effects (NLME) model. The NLME model analyzed pharmacokinetic data from nine indacaterol studies; the LME model analyzed peak (C(max)) and trough (C(min)) serum concentration using data from four of these studies. In the all-Asian study, indacaterol serum concentration-time pharmacokinetic profiles in Japanese patients (n = 102) were similar to those in the overall population (n = 229). In the LME model, C(max) (4,392 observations, 1,845 patients) and C(min) (4,664 observations, 1,796 patients) for Japanese patients (n = 94) were on average 25% and 18% higher, respectively, than non-Japanese patients. However, after adjusting for study differences, this apparent ethnicity effect was not significant (p = 0.25 and 0.39, respectively). In the NLME model (25,540 observations, 2,857 patients), there was no statistically significant effect of Japanese (n = 230) ethnicity on indacaterol serum pharmacokinetics. No ethnicity effect was observed on indacaterol systemic pharmacokinetic profile for Japanese patients when compared with the overall Asian patient population or with the Caucasian patient population.

The lipid profiles in Japanese patients with schizophrenia treated with antipsychotic agents

ObjectiveAntipsychotic-treated schizophrenia patients are susceptible to dyslipidemia. However, the results of previous studies of North American and UK populations including various races have been contradictory with regard to which lipid measure was the most affected in patients with schizophrenia taking antipsychotic agents. The aim of this study was to investigate the effect of schizophrenia patients receiving antipsychotic agents on each lipid measure in a Japanese population. MethodsThe samples included 136 control individuals and 157 patients with schizophrenia treated with antipsychotic agents. Age, gender distribution and body mass index (BMI) of the controls were matched with the patients. ResultsThe high-density lipoprotein cholesterol (HDL-cholesterol) levels were significantly lower in patients than in the control subjects (P<.001). However, there were no significant differences in either the low-density lipoprotein cholesterol (LDL-cholesterol) or triglyceride levels between the patient and control groups. We performed a multiple linear regression analysis, and schizophrenia receiving antipsychotics was an independent predictor of decreased HDL-cholesterol. An increased BMI, male gender and cigarette smoking were also major predictors of a decreased HDL-cholesterol level (r2=0.42, P<.001). ConclusionAt least in Japanese with schizophrenia receiving antipsychotic agents, the HDL-cholesterol levels should be closely monitored in all patients, even those who are not obese or do not smoke, to decrease their risk of cardiovascular disease.

Multicenter analysis of fecal microbiota profiles in Japanese patients with Crohn’s disease

We analyzed the fecal microbiota profiles of patients with Crohn's disease (CD) at 4 inflammatory bowel disease (IBD) centers located in different districts in Japan. Terminal restriction fragment length polymorphism (T-RFLP) analysis was performed in 161 fecal samples from CD patients and 121 samples from healthy individuals. The bacterial diversity was evaluated by the Shannon diversity index (SDI). There were no regional differences in the fecal microbiota profiles of the healthy individuals in Japan. A setting of similarity generated three major clusters of T-RFs: one included almost all the healthy individuals (118/121), and the other two clusters were mainly formed by CD patients at different stages of disease activity. The changes in simulated bacterial composition indicated that the class Clostridia, including the genus Faecalibacterium, was significantly decreased in CD patients with active disease and those in remission as compared with findings in the healthy individuals. In contrast, the genus Bacteroides was significantly increased in CD patients during the active phase as compared with findings in the healthy individuals. The genus Bifidobacterium was significantly decreased during the active phase of CD and increased to healthy levels during the remission phase. The bacterial diversity measured by the SDI was significantly reduced in CD patients during the active and remission phases as compared with findings in the healthy individuals. From the clinical data and T-RFLP analysis, we developed a logistic model to predict disease activity based on the fecal microbiota composition. Dysbiosis in CD patients was shown by a multi-IBD center study. The feasibility of using the fecal microbiota profile as a predictive marker for disease activity is proposed.