Publications by authors named "Toshiyuki Tamai"

15 Publications

  • Page 1 of 1

Pharmacodynamic Biomarkers Predictive of Survival Benefit with Lenvatinib in Unresectable Hepatocellular Carcinoma: From the Phase III REFLECT Study.

Clin Cancer Res 2021 Jun 9. Epub 2021 Jun 9.

Beatson West of Scotland Cancer Centre, University of Glasgow, Glasgow, UK.

Purpose: In REFLECT, lenvatinib demonstrated an effect on overall survival (OS) by confirmation of noninferiority to sorafenib in unresectable hepatocellular carcinoma. This analysis assessed correlations between serum or tissue biomarkers and efficacy outcomes from REFLECT.

Experimental Design: Serum biomarkers (VEGF, ANG2, FGF19, FGF21, and FGF23) were measured by ELISA. Gene expression in tumor tissues was measured by the nCounter PanCancer Pathways Panel. Pharmacodynamic changes in serum biomarker levels from baseline, and associations of clinical outcomes with baseline biomarker levels, were evaluated.

Results: Four hundred and seven patients were included in the serum analysis set (lenvatinib = 279, sorafenib = 128); 58 patients were included in the gene-expression analysis set (lenvatinib = 34, sorafenib = 24). Both treatments were associated with increases in VEGF; only lenvatinib was associated with increases in FGF19 and FGF23 at all time points. Lenvatinib-treated responders had greater increases in FGF19 and FGF23 versus nonresponders at cycle 4, day 1 (FGF19: 55.2% vs. 18.3%, = 0.014; FGF23: 48.4% vs. 16.4%, = 0.0022, respectively). Higher baseline VEGF, ANG2, and FGF21 correlated with shorter OS in both treatment groups. OS was longer for lenvatinib than sorafenib [median, 10.9 vs. 6.8 months, respectively; HR, 0.53; 95% confidence interval (CI), 0.33-0.85; interaction = 0.0397] with higher baseline FGF21. In tumor tissue biomarker analysis, VEGF/FGF-enriched groups showed improved OS with lenvatinib versus the intermediate VEGF/FGF group (HR, 0.39; 95% CI, 0.16-0.91; = 0.0253).

Conclusions: Higher baseline levels of VEGF, FGF21, and ANG2 may be prognostic for shorter OS. Higher baseline FGF21 may be predictive for longer OS with lenvatinib compared with sorafenib, but this needs confirmation.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4219DOI Listing
June 2021

Lenvatinib versus sorafenib for first-line treatment of unresectable hepatocellular carcinoma: patient-reported outcomes from a randomised, open-label, non-inferiority, phase 3 trial.

Lancet Gastroenterol Hepatol 2021 Aug 2;6(8):649-658. Epub 2021 Jun 2.

FSBSI N N Blokhin Russian Cancer Research Center, Moscow, Russia.

Background: Hepatocellular carcinoma is the third-leading cause of cancer-related death worldwide. Preservation of health-related quality of life (HRQOL) during treatment is an important therapeutic goal. The aim of this study was to evaluate the effect of treatment with lenvatinib versus sorafenib on HRQOL.

Methods: REFLECT was a previously published multicentre, randomised, open-label, non-inferiority phase 3 study comparing the efficacy and safety of lenvatinib versus sorafenib as a first-line systemic treatment for unresectable hepatocellular carcinoma. Eligible patients were aged 18 years or older with unresectable hepatocellular carcinoma and one or more measurable target lesion per modified Response Evaluation Criteria in Solid Tumors criteria, Barcelona Clinic Liver Cancer stage B or C categorisation, Child-Pugh class A, Eastern Cooperative Oncology Group (ECOG) performance status of 1 or lower, and adequate organ function. Patients were randomly assigned (1:1) via an interactive voice-web response system; stratification factors for treatment allocation included region; macroscopic portal vein invasion, extrahepatic spread, or both; ECOG performance status; and bodyweight. Patient-reported outcomes (PROs), collected at baseline, on day 1 of each subsequent cycle, and at the end of treatment, were evaluated in post-hoc analyses of secondary and exploratory endpoints in the analysis population, which was the subpopulation of patients with a PRO assessment at baseline. A linear mixed-effects model evaluated change from baseline in PROs, including European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) and hepatocellular carcinoma-specific QLQ-HCC18 scales (both secondary endpoints of the REFLECT trial). Time-to-definitive-deterioration analyses were done based on established thresholds for minimum differences for worsening in PROs. Responder analyses explored associations between HRQOL and clinical response. This study is registered with ClinicalTrials.gov, NCT01761266.

Findings: Of 954 eligible patients randomly assigned to lenvatinib (n=478) or sorafenib (n=476) between March 14, 2013, and July 30, 2015, 931 patients (n=468 for lenvatinib; n=463 for sorafenib) were included in this analysis. Baseline PRO scores reflected impaired HRQOL and functioning and considerable symptom burden relative to full HRQOL. Differences in overall mean change from baseline estimates in most PRO scales generally favoured the lenvatinib over the sorafenib group, although the differences were not nominally statistically or clinically significant. Patients treated with lenvatinib experienced nominally statistically significant delays in definitive, meaningful deterioration on the QLQ-C30 fatigue (hazard ratio [HR] 0·83, 95% CI 0·69-0·99), pain (0·80, 0·66-0·96), and diarrhoea (0·52, 0·42-0·65) domains versus patients treated with sorafenib. Significant differences in time to definitive deterioration were not observed for other QLQ-C30 domains, and there was no difference in time to definitive deterioration on the global health status/QOL score (0·89, 0·73-1·09). For most PRO scales, differences in overall mean change from baseline estimates favoured responders versus non-responders. Across all scales, HRs for time to definitive deterioration were in favour of responders; median time to definitive deterioration for responders exceeded those for non-responders by a range of 4·8 to 14·6 months.

Interpretation: HRQOL for patients undergoing treatment for unresectable hepatocellular carcinoma is an important therapeutic consideration. The evidence of HRQOL benefits in clinically relevant domains support the use of lenvatinib compared with sorafenib to delay functional deterioration in advanced hepatocellular carcinoma.

Funding: Eisai and Merck Sharp & Dohme.
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http://dx.doi.org/10.1016/S2468-1253(21)00110-2DOI Listing
August 2021

Safety and efficacy of lenvatinib by starting dose based on body weight in patients with unresectable hepatocellular carcinoma in REFLECT.

J Gastroenterol 2021 Jun 4;56(6):570-580. Epub 2021 May 4.

Toranomon Hospital, Tokyo, Japan.

Background: REFLECT was an open-label, phase 3 study comparing the efficacy and safety of lenvatinib versus sorafenib in patients with unresectable hepatocellular carcinoma (uHCC). Based on phase 2 study (Study 202) results, body weight-based dosing for lenvatinib was used in REFLECT to minimize dose disruptions and modifications needed to address dose-related adverse events. This post hoc analysis of REFLECT data assessed lenvatinib efficacy and safety by body weight group.

Methods: The study randomly administered lenvatinib (n = 476) or sorafenib (n = 475) to patients with untreated (no prior systemic therapy) uHCC. Lenvatinib starting-dose data were stratified by body weight: patients weighing < 60 kg received 8 mg/day; patients weighing ≥ 60 kg received 12 mg/day. Overall survival (OS), progression-free survival (PFS), objective response rate, and safety were assessed.

Results: Survival outcomes and safety profiles appeared similar between the two body-weight-based lenvatinib starting-dose groups. Median OS for patients in the < 60 kg body weight group (n = 153) was 13.4 months [95% confidence interval (CI) 10.5-15.7] compared to 13.7 months (95% CI 12.0-15.6) in the ≥ 60 kg body weight group (n = 325). In both lenvatinib groups, PFS was 7.4 months (< 60 kg group: 95% CI 5.4-9.2; ≥ 60 kg group: 95% CI 6.9-9.0). Treatment-emergent adverse events (TEAEs) required dose modifications in 43.0% in the < 60 kg body weight group and 57.5% in the ≥ 60 kg body weight group.

Conclusions: This exploratory analysis of data from REFLECT indicated that body weight-based lenvatinib dosing in patients with uHCC was successful in maintaining efficacy, with comparable rates of TEAEs and dose modifications in the two body weight groups.

Clinincal Trial: Trial registration ID: ClinicalTrials.gov # NCT01761266.
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http://dx.doi.org/10.1007/s00535-021-01785-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8137475PMC
June 2021

Comparison of efficacy outcomes of anticancer drugs between Japanese patients and the overall population.

Int J Clin Oncol 2021 Feb 14;26(2):296-304. Epub 2020 Oct 14.

School of Pharmacy, Kitasato University, 5-9-1, Shirogane, Minato-ku, Tokyo, 108-8641, Japan.

Background: It is important to recognize regional and racial differences in drug efficacy and safety when performing multi-regional clinical trials (MRCTs). To understand regional differences, we compared the efficacy results in Japanese patients and the overall population in the MRCTs of anticancer drugs.

Methods: All new approvals of oncology drugs in Japan from January 2009 to December 2018 were searched using the Pharmaceuticals and Medical Devices Agency web site to find phase 3 MRCTs for the analysis. As the supporting data source, a literature search was performed in PubMed and Google Scholar. Linear regression analysis was performed and Pearson correlation coefficients (r) were calculated to compare the overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) between Japanese patients and the overall population.

Results: Seventy MRCTs were identified. The correlation of hazard ratios (HRs) for OS between Japanese patients and the overall population was moderate (r = 0.45), and OS was 1.31 times longer in Japanese patients than in the overall population, although the correlation of median OS was strong (r = 0.91). The HRs for PFS were moderately correlated (r = 0.70) and the correlation of median PFS was strong (r = 0.90). The correlation of ORR was very strong (r = 0.96).

Conclusion: The PFS and ORR were consistent between Japanese patients and the overall population. A longer median OS was observed in Japanese patients. Our results would be a useful reference when planning and conducting MRCTs that include Japan for global simultaneous drug development.
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http://dx.doi.org/10.1007/s10147-020-01804-9DOI Listing
February 2021

Crystal structure of 7,7'-[(pyridin-2-yl)methyl-ene]bis-(5-chloro-quinolin-8-ol).

Acta Crystallogr E Crystallogr Commun 2020 Aug 14;76(Pt 8):1271-1274. Epub 2020 Jul 14.

Osaka Research Institute of Industrial Science and Technology, Joto-ku, Osaka, 536-8553, Japan.

In the title compound, CHClNO, one quinoline ring system is essentially planar and the other is slightly bent. An intra-molecular O-H⋯N hydrogen bond involving the hy-droxy group and a pyridine N atom forms an (5) ring motif. In the crystal, two mol-ecules are associated into an inversion dimer with two (7) ring motifs through inter-molecular O-H⋯N and O-H⋯O hydrogen bonds. The dimers are further linked by an inter-molecular C-H⋯O hydrogen bond and four C-H⋯π inter-actions, forming a two-dimensional network parallel to (001).
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http://dx.doi.org/10.1107/S2056989020009317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405569PMC
August 2020

REFLECT-a phase 3 trial comparing efficacy and safety of lenvatinib to sorafenib for the treatment of unresectable hepatocellular carcinoma: an analysis of Japanese subset.

J Gastroenterol 2020 Jan 12;55(1):113-122. Epub 2019 Nov 12.

Department of Hepatology, Toranomon Hospital, Tokyo, Japan.

Background: A phase 3, multinational, randomized, non-inferiority trial (REFLECT) compared the efficacy and safety of lenvatinib (LEN) and sorafenib (SOR) in patients with unresectable hepatocellular carcinoma (uHCC). LEN had an effect on overall survival (OS) compared to SOR, statistically confirmed by non-inferiority [OS: median = 13.6 months vs. 12.3 months; hazard ratio (HR) 0.92, 95% confidence interval (CI) 0.79-1.06], and demonstrated statistically significant improvements in progression-free survival (PFS) and the objective response rate (ORR) in the overall population. The results of a subset analysis that evaluated the efficacy and safety of LEN and SOR in the Japanese population are reported.

Methods: The intent-to-treat population enrolled in Japan was analyzed.

Results: Of 954 patients in the overall population, 168 Japanese patients were assigned to the LEN arm (N = 81) or the SOR arm (N = 87). Median OS was 17.6 months for LEN vs. 17.8 months for SOR (HR 0.90; 95% CI 0.62-1.29). LEN showed statistically significant improvements over SOR in PFS (7.2 months vs. 4.6 months) and ORR (29.6% vs. 6.9%). The relative dose intensity of LEN and SOR in the Japanese population was lower than in the overall population. Frequently observed, related adverse events included palmar-plantar erythrodysaesthesia syndrome (PPES), hypertension, decreased appetite, and proteinuria in the LEN arm, and PPES, hypertension, diarrhea, and alopecia in the SOR arm.

Conclusions: The efficacy and safety of LEN in the Japanese population were similar to those in the overall population of REFLECT. With manageable adverse events, LEN is a new treatment option for Japanese patients with uHCC.

Trial Registration Id: ClinicalTrials.gov. No. NCT01761266.
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http://dx.doi.org/10.1007/s00535-019-01642-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6942573PMC
January 2020

Crystal structure of -poly[[[bis-(3-oxo-1,3-di-phenyl-prop-1-enolato-κ ,')zinc(II)]-μ-tris-[4-(pyridin-3-yl)phen-yl]amine-κ :'] tetra-hydro-furan monosolvate].

Acta Crystallogr E Crystallogr Commun 2019 Oct 10;75(Pt 10):1432-1435. Epub 2019 Sep 10.

Osaka Research Institute of Industrial Science and Technology, 1-6-50 Morinomiya, Joto-ku, Osaka 536-8553, Japan.

The reaction of bis-(3-oxo-1,3-di-phenyl-prop-1-enolato-κ ,')zinc(II), [Zn(dbm)], with tris-[4-(pyridin-3-yl)phen-yl]amine (T3PyA) in tetra-hydro-furan (THF) afforded the title crystalline coordination polymer, {[Zn(CHO)(CHN)]·CHO} . The asymmetric unit contains two independent halves of Zn(dbm), one T3PyA and one THF. Each Zn atom is located on an inversion centre and adopts an elongated octa-hedral coordination geometry, ligated by four O atoms of two dbm ligands in equatorial positions and by two N atoms of pyridine moieties from two different bridging T3PyA ligands in axial positions. The crystal packing shows a one-dimensional polymer chain in which the two pyridyl groups of the T3PyA ligand bridge two independent Zn atoms of Zn(dbm). In the crystal, the coordination polymer chains are linked C-H⋯π inter-actions into a sheet structure parallel to (010). The sheets are cross-linked further C-H⋯π inter-actions into a three-dimensional network. The solvate THF mol-ecule shows disorder over two sets of atomic sites having occupancies of 0.631 (7) and 0.369 (7).
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http://dx.doi.org/10.1107/S2056989019012350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6775726PMC
October 2019

Crystallite Size Increase of Silver Nanoparticles by Ligand Exchange and Subsequent Washing Process with Antisolvent.

J Nanosci Nanotechnol 2019 Aug;19(8):4565-4570

Department of Applied Chemistry, Faculty of Systems Engineering, Wakayama University, 930 Sakae-dani, Wakayama 640-8510, Japan.

Desorption performance of ligands from silver nanoparticles extremely affects a sintering process of nanoinks for their writing fine pattern. In this study, we investigated desorption behaviors of ligands on the surface of silver nanoparticle through ligand exchange and subsequent washing process with antisolvent. Ligand exchange reactions from oleic acid to tri-n-octylphosphine oxide (TOPO), octanoic acid (OA), and 1-dodecanethiol (DDT) were carried out on the surface of silver nanoparticle. After the washing process with methanol as an antisolvent, their crystallite sizes and the amounts of ligands existing on the particle surface were evaluated by powder X-ray diffraction and thermogravimetric analysis, respectively. In the case of ligand exchange with TOPO, the crystallite size dramatically increased and the amount of ligands existing on the particle surface significantly decreased. This result shows that TOPO is easy to desorb from the silver surface in the washing process with methanol, which resulted in the efficient coalescence of silver. In contrast, the coalescence of silver nanoparticles capped with OA and DDT was less efficient. Moreover, the effect of the antisolvent in the washing process on the coalescence of silver was demonstrated in detail.
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http://dx.doi.org/10.1166/jnn.2019.16361DOI Listing
August 2019

Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial.

Lancet 2018 03;391(10126):1163-1173

National Taiwan University Hospital, Taipei, Taiwan.

Background: In a phase 2 trial, lenvatinib, an inhibitor of VEGF receptors 1-3, FGF receptors 1-4, PDGF receptor α, RET, and KIT, showed activity in hepatocellular carcinoma. We aimed to compare overall survival in patients treated with lenvatinib versus sorafenib as a first-line treatment for unresectable hepatocellular carcinoma.

Methods: This was an open-label, phase 3, multicentre, non-inferiority trial that recruited patients with unresectable hepatocellular carcinoma, who had not received treatment for advanced disease, at 154 sites in 20 countries throughout the Asia-Pacific, European, and North American regions. Patients were randomly assigned (1:1) via an interactive voice-web response system-with region; macroscopic portal vein invasion, extrahepatic spread, or both; Eastern Cooperative Oncology Group performance status; and bodyweight as stratification factors-to receive oral lenvatinib (12 mg/day for bodyweight ≥60 kg or 8 mg/day for bodyweight <60 kg) or sorafenib 400 mg twice-daily in 28-day cycles. The primary endpoint was overall survival, measured from the date of randomisation until the date of death from any cause. The efficacy analysis followed the intention-to-treat principle, and only patients who received treatment were included in the safety analysis. The non-inferiority margin was set at 1·08. The trial is registered with ClinicalTrials.gov, number NCT01761266.

Findings: Between March 1, 2013 and July 30, 2015, 1492 patients were recruited. 954 eligible patients were randomly assigned to lenvatinib (n=478) or sorafenib (n=476). Median survival time for lenvatinib of 13·6 months (95% CI 12·1-14·9) was non-inferior to sorafenib (12·3 months, 10·4-13·9; hazard ratio 0·92, 95% CI 0·79-1·06), meeting criteria for non-inferiority. The most common any-grade adverse events were hypertension (201 [42%]), diarrhoea (184 [39%]), decreased appetite (162 [34%]), and decreased weight (147 [31%]) for lenvatinib, and palmar-plantar erythrodysaesthesia (249 [52%]), diarrhoea (220 [46%]), hypertension (144 [30%]), and decreased appetite (127 [27%]) for sorafenib.

Interpretation: Lenvatinib was non-inferior to sorafenib in overall survival in untreated advanced hepatocellular carcinoma. The safety and tolerability profiles of lenvatinib were consistent with those previously observed.

Funding: Eisai Inc.
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http://dx.doi.org/10.1016/S0140-6736(18)30207-1DOI Listing
March 2018

Dose Finding of Lenvatinib in Subjects With Advanced Hepatocellular Carcinoma Based on Population Pharmacokinetic and Exposure-Response Analyses.

J Clin Pharmacol 2017 09 31;57(9):1138-1147. Epub 2017 May 31.

Department of Hepatology, Toranomon Hospital, Tokyo, Japan.

Hepatocellular carcinoma (HCC) accounts for up to 90% of primary liver cancer occurrences worldwide. Lenvatinib, a multikinase inhibitor, was approved in radioiodine-refractory differentiated thyroid cancer. In this phase 2 study (study 202), we aimed to identify the lenvatinib optimal dose for subjects with advanced HCC Child-Pugh class A. Pooled data from phase 1 studies in healthy adults and in subjects with mixed tumor types, and from study 202 in subjects with HCC, were analyzed using a population pharmacokinetic approach. The relationship between treatment-emergent adverse events leading to withdrawal or dose reduction during cycle 1 and lenvatinib exposure was explored by logistic regression analysis. A receiver operating characteristics analysis was used to investigate the best cutoff values of lenvatinib exposure and body weight to identify a high-risk group for early dose modification. The final pharmacokinetic model included body-weight effects on apparent clearance and volume. The relationship between the lenvatinib area under the plasma concentration-time curve (AUC) at steady state and body weight demonstrated an increase in AUC as body weight decreased in subjects with HCC. An exposure-response relationship was observed, with higher lenvatinib AUC and lower body weight resulting in earlier drug withdrawal or dose reduction. The best cutoff values for body weight and lenvatinib AUC were 57.8 kg and 2430 ng·h/mL, respectively, to predict the group at high risk for early drug withdrawal or dose reduction. We therefore recommend 12-mg and 8-mg starting doses for subjects ≥60 kg and <60 kg, respectively, in subjects with HCC Child-Pugh class A.
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http://dx.doi.org/10.1002/jcph.917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5575539PMC
September 2017

Phase 2 study of lenvatinib in patients with advanced hepatocellular carcinoma.

J Gastroenterol 2017 Apr 4;52(4):512-519. Epub 2016 Oct 4.

Department of Hepatology, Toranomon Hospital, Toranomon 2-2-2, Minato-ku, Tokyo, 105-8470, Japan.

Background: Lenvatinib is an oral inhibitor of vascular endothelial growth factor receptor 1-3, fibroblast growth factor receptor 1-4, platelet-derived growth factor receptor alpha, RET, and KIT. This phase 2, single-arm, open-label multicenter study evaluated lenvatinib in advanced hepatocellular carcinoma (HCC).

Methods: Patients with histologically/clinically confirmed advanced HCC who did not qualify for surgical resection or local therapies received lenvatinib at a dosage of 12 mg once daily (QD) in 28-day cycles. The primary efficacy endpoint was time to progression (TTP) per modified Response Evaluation Criteria in Solid Tumors v1.1; secondary efficacy endpoints included objective response rate (ORR), disease control rate (DCR), and overall survival (OS).

Results: Between July 2010 and June 2011, 46 patients received lenvatinib at sites across Japan and Korea. The median TTP, as determined by independent radiological review, was 7.4 months [95 % confidence interval (CI): 5.5-9.4]. Seventeen patients (37 %) had partial response and 19 patients (41 %) had stable disease (ORR: 37 %; DCR: 78 %). Median OS was 18.7 months (95 % CI: 12.7-25.1). The most common any-grade adverse events (AEs) were hypertension (76 %), palmar-plantar erythrodysesthesia syndrome (65 %), decreased appetite (61 %), and proteinuria (61 %). Dose reductions and discontinuations due to AEs occurred in 34 (74 %) and 10 patients (22 %), respectively. Median body weight was lower in patients with an early (<30 days) dose withdrawal or reduction than in those without.

Conclusions: Lenvatinib 12-mg QD showed clinical activity and acceptable toxicity profiles in patients with advanced HCC, but early dose modification was necessary in patients with lower body weight. Further development of lenvatinib in HCC should consider dose modification by body weight. TRIAL REGISTRATION ID: www.ClinicalTrials.gov NCT00946153.
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http://dx.doi.org/10.1007/s00535-016-1263-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5357473PMC
April 2017

Safety and Pharmacokinetics of Lenvatinib in Patients with Advanced Hepatocellular Carcinoma.

Clin Cancer Res 2016 Mar 23;22(6):1385-94. Epub 2015 Oct 23.

Toranomon Hospital, Tokyo, Japan.

Purpose: To determine the maximum tolerable dose (MTD), safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of lenvatinib in patients with advanced hepatocellular carcinoma (HCC).

Experimental Design: This multicenter, open-label, phase I, dose-escalation study included patients aged 20 to 80 years, refractory to standard therapy, and stratified by hepatic function measured using Child-Pugh (CP) scores: CP-A (score, 5-6) and CP-B (score, 7-8). Lenvatinib was administered continually once daily for 4-week cycles. MTD was defined as the maximum dose associated with ≤ 1 dose-limiting toxicity (DLT) occurring in cycle 1 among 6 patients.

Results: In total, 20 patients (9 in CP-A and 11 in CP-B) were enrolled. The MTD was 12 and 8 mg once daily in CP-A and CP-B, respectively; DLTs included proteinuria, hepatic encephalopathy, and hyperbilirubinemia. The most common grade 3 toxicities included hypertension in CP-A and hyperbilirubinemia in CP-B. Lenvatinib plasma concentration at 24 hours after administration (C24 h) for 12 mg once daily was higher in patients with HCC than in patients with other solid tumors shown in a previous phase I study, but C24 h for 25 mg once daily lenvatinib was comparable. After lenvatinib treatment, the number of circulating endothelial and c-Kit(+) cells decreased and the levels of interleukin (IL)-6, IL10, granulocyte-colony stimulating factor, and vascular endothelial growth factor increased (P < 0.05). Partial responses were observed in 3 patients and tumor shrinkage occurred in 14 patients.

Conclusions: Lenvatinib (12 mg once daily) demonstrated preliminary efficacy with manageable toxicity and is the recommended dose for phase II studies in patients with HCC and CP-A.
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http://dx.doi.org/10.1158/1078-0432.CCR-15-1354DOI Listing
March 2016

A fusion protein N-cadherin-Fc as an artificial extracellular matrix surface for maintenance of stem cell features.

Biomaterials 2010 Jul 15;31(20):5287-96. Epub 2010 Apr 15.

Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, B-57, 4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8501, Japan.

N-cadherin is a cell-cell adhesion molecule and plays important roles in neural development. With conventionally used extracellular matrices (ECMs), maintenance of undifferentiated state of stem cells and regulation of their neural differentiation process is very difficult due to the colony formation through intercellular interactions. To overcome the above-mentioned problems, we developed a new artificial ECM to mimic N-cadherin-mediated cell adhesion. In this study, we constructed a chimeric protein (N-cadherin fused to IgG-Fc, abbreviated as N-cad-Fc), which contains extracellular domain of N-cadherin and Fc domain of IgG. We confirmed that N-cad-Fc can stably adsorb to hydrophobic surface. We checked maintenance of undifferentiated state and neural differentiation ability of stem cells cultured on N-cad-Fc-coated surface. Both P19 and MEB5 cells cultured on N-cad-Fc-coated surface showed scattering morphologies without colony formation and higher proliferating potency than conventional culture systems with maintenance of undifferentiated state. Both of two cell lines cultured on N-cad-Fc-coated surface differentiated into neural cells at a single cell level when induced with proper conditions. Furthermore, the expression of neuron-related gene Neurog1 in two cell lines cultured on N-cad-Fc-coated surface was promoted. Therefore, it will be expected that the constructed N-cad-Fc can be used as an artificial ECM for stem cells.
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http://dx.doi.org/10.1016/j.biomaterials.2010.03.035DOI Listing
July 2010

Formation of metal nanoparticles on the surface of polymer particles incorporating polysilane by UV irradiation.

Langmuir 2008 Dec;24(24):14203-8

Osaka Municipal Technical Research Institute, 1-6-50 Morinomiya, Joto-ku, Osaka 536-8553, Japan.

Polystyrene particles incorporating poly(methylphenylsilane) (PMPS) were synthesized by miniemulsion polymerization. UV irradiation of the emulsion under air in the presence of metal salts such as HAuCl4.4H2O, AgNO3, and Na2PdCl4 led to the formation of metal nanoparticles on the surface of polymer particles; thus, metal nanoparticle/polymer hybrid particles were obtained. The structures of the hybrid particles were confirmed by the surface plasmon resonance band and transmission electron microscopy images. The formation of metal nanoparticles depended on the functional groups and charge on the surface of the polymer particle. The metal nanoparticles were formed due to the reduction of metal ions, accompanied by the oxidation of PMPS. The interaction between the surface of the polymer particle and the metal ions plays an important role in the formation of the metal nanoparticle.
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http://dx.doi.org/10.1021/la801809uDOI Listing
December 2008

Sol-gel reaction in acrylic polymer emulsions: the effect of particle surface charge.

Langmuir 2007 Mar 13;23(6):3062-6. Epub 2007 Feb 13.

Osaka Municipal Technical Research Institute, 1-6-50 Morinomiya, Jyoto-ku, Osaka 536-8553, Japan.

Acrylic polymer-silica hybrid emulsions were synthesized from both anionic and cationic polymer emulsions by simple post-addition of tetraethoxysilane as a silica precursor. Solvent resistance of the films from the hybrid emulsions and the zeta-potential of the hybrid emulsions suggested the different forms of silica components in each hybrid emulsion. Thermal gravimetric analysis, 29Si NMR measurements, and transmission electron microscope observations revealed that the hybrid emulsion from the anionic polymer emulsion was a mixture of anionic polymer particles and homogeneously dissolved silicate oligomer-polymer. On the contrary, the hybrid emulsion from cationic polymer emulsion consisted of polymer core-silica shell particles. The electrostatic interaction between the cationic polymer particle surface and the silicate would be responsible for the accumulation of the silicate onto the particle surface, leading to the silica shell layer formation. The sol-gel condensation reaction of silicate in the acidic emulsion phase was revealed to be controllable by the surface charge of the coexisting particles.
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http://dx.doi.org/10.1021/la062999vDOI Listing
March 2007
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