Publications by authors named "Shunsuke Kondo"

116 Publications

Merestinib monotherapy or in combination for japanese patients with advanced and/or metastatic cancer: A phase 1 study.

Cancer Med 2021 Sep 9. Epub 2021 Sep 9.

Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan.

This phase 1, multi-center, nonrandomized, open-label, dose-escalation study consisted of Part A wherein merestinib 80 or 120 mg (40-mg tablets) was administered orally QD during a 28-day cycle to patients diagnosed with solid tumors and Part B wherein merestinib 80 mg (40-mg tablets) was administered orally QD, and cisplatin 25 mg/m  + gemcitabine 1000 mg/m administered IV on Day 1 and Day 8 of a 21-day cycle (for a maximum of eight cycles) to patients diagnosed with biliary tract carcinoma (BTC). Nineteen patients were screened and 18 patients were (Part A, n = 10; Part B, n = 8) enrolled in the trial and received treatment. All patients in Parts A and B were from Japan and were within an age range of 43-73 years, with an ECOG PS of 0.1. No dose-limiting toxicity or deaths were experienced in the study. Dose-limiting toxicity equivalent toxicity of Grade 4 platelet count decreased (n = 1) and was observed in Part B. In Part A, treatment-related Grade ≥3 TEAEs were reported in one patient (PT: ALT increased and AST increased), while in Part B, five patients reported treatment-related Grade ≥3 TEAEs with four of the five patients reporting an event of neutrophil count decreased. No complete response was reported in either Part. One patient in Part B reported partial response while four patients in each part reported stable disease. Merestinib monotherapy was concluded to be tolerable in Japanese patients, and its combination with cisplatin and gemcitabine is a tolerable regimen for Japanese patients with BTC. Trial registration: NCT03027284 (ClinicalTrials.gov) registered on 23 January 2017.
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http://dx.doi.org/10.1002/cam4.4110DOI Listing
September 2021

A phase II study of FOLFIRINOX with primary prophylactic pegfilgrastim for chemotherapy-naïve Japanese patients with metastatic pancreatic cancer.

Int J Clin Oncol 2021 Aug 8. Epub 2021 Aug 8.

Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan.

Background: Although FOLFIRINOX is currently one of the standard therapies for chemotherapy-naïve patients with metastatic pancreatic cancer (MPC), the high rate of febrile neutropenia (FN) presents a clinical problem. This study aimed to evaluate the safety and efficacy of primary prophylactic pegfilgrastim with FOLFIRINOX in Japanese MPC patients.

Methods: FOLFIRINOX (intravenous oxaliplatin 85 mg/m, irinotecan 180 mg/m, levofolinate 200 mg/m, 5-fluorouracil (5-FU) bolus 400 mg/m and 5-FU 46 h infusion 2400 mg/m) and pegfilgrastim 3.6 mg on day 4 or 5, every 2 weeks was administered to previously untreated MPC patients. The primary endpoint was the incidence of FN during the first 3 cycles. The planned sample size was 35 patients, but the trial was predefined to discontinue enrollment for safety if 4 patients developed FN.

Results: At the enrollment of 22 patients, 4 patients developed FN in the first cycle, resulting in an incidence of FN of 18% {95% confidence interval [CI], 0.5-40.3%}, and enrollment was discontinued early. The incidence of grade 3 or higher neutropenia was 36.4%. Median relative dose intensities during the initial 3 cycles of oxaliplatin, irinotecan, bolus 5-FU, infusional 5-FU, and levofolinate maintained high (100%, 89.0%, 100%, 66.0%, and 100%, respectively). Response rate and median overall survival were 54.5% (95% CI 32.7-74.9) and 15.7 months (95% CI 7.9-18.8), respectively.

Conclusions: This phase II study could not demonstrate any reduction in the incidence of FN, nevertheless some patients experience benefits for efficacy by maintaining dose intensity using prophylactic pegfilgrastim.

Trial Registration: http://www.umin.ac.jp/ctr/index-j.htm , UMIN000017538. Date of registration: May/13/2015.
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http://dx.doi.org/10.1007/s10147-021-02001-yDOI Listing
August 2021

Safety, pharmacokinetics, and efficacy of budigalimab with rovalpituzumab tesirine in patients with small cell lung cancer.

Cancer Treat Res Commun 2021 25;28:100405. Epub 2021 May 25.

Cancer Care Center, Blacktown Hospital, Sydney, NSW, Australia. Electronic address:

Background: Agents targeting programmed cell death protein 1 (PD-1) have been approved as monotherapy for patients with small cell lung cancer (SCLC). In preclinical models, the combined targeting of PD-1 and delta-like protein 3 resulted in enhanced antitumor activity. Herein, we report results from the expansion arm of study NCT03000257 evaluating the combination of the anti-PD-1 antibody budigalimab and the targeted antibody-drug conjugate rovalpituzumab tesirine (Rova-T) in patients with previously treated SCLC.

Materials And Methods: This expansion arm of a multicenter, open-label, multi-arm, first-in-human phase 1 clinical trial enrolled adult patients with progressive SCLC. The primary objective was to assess safety and tolerability. Patients received budigalimab 375 mg via intravenous infusion every 3 weeks, and Rova-T was administered as a dose of 0.3 mg/kg intravenously, on day 1 of the first and third 3-week cycle.

Results: As of October 2019, 31 patients with SCLC were enrolled and treated with budigalimab plus Rova-T. The combination was tolerated, with the most common treatment-emergent adverse events (in >30%) being pleural effusion, fatigue, and cough. The overall response rate was 24.1%, with one confirmed complete response and six confirmed partial responses. The overall response rate in patients with high delta-like protein 3 expression was similar (21.1%). The median progression-free survival was 3.48 months.

Conclusion: Combination therapy with budigalimab and Rova-T had promising efficacy and appeared to be tolerated in patients with SCLC. Although Rova-T development has been discontinued, development of budigalimab combined with other anticancer agents is ongoing.

Clinical Trial Registration Number: NCT03000257 Statement on originality of the work The manuscript represents original work and has not been submitted for publication elsewhere nor previously published. Statement of prior presentation Data from this study were previously presented at the European Society for Medical Oncology (ESMO) Congress 2019.
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http://dx.doi.org/10.1016/j.ctarc.2021.100405DOI Listing
May 2021

Bintrafusp Alfa, a Bifunctional Fusion Protein Targeting TGFβ and PD-L1, in Patients with Esophageal Squamous Cell Carcinoma: Results from a Phase 1 Cohort in Asia.

Target Oncol 2021 07 11;16(4):447-459. Epub 2021 Apr 11.

National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.

Background: Patients with esophageal squamous cell carcinoma (SCC) have limited treatment options. Blocking transforming growth factor-β (TGFβ), which can be overexpressed in these tumors, may enhance responses to programmed cell death protein 1/programmed death-ligand 1 [PD-(L)1] inhibitors. Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGFβ receptor II (TGFβRII) (a TGFβ "trap") fused to a human IgG1 monoclonal antibody blocking PD-L1.

Objective: The objective of this study was to investigate the safety and efficacy of bintrafusp alfa in Asian patients with pretreated, PD-L1-unselected esophageal SCC.

Patients And Methods: In a phase 1 study, Asian patients with pretreated esophageal SCC received bintrafusp alfa 1200 mg every 2 weeks until disease progression, unacceptable toxicity, or withdrawal. The primary endpoint was safety/tolerability with a goal of exploring clinical activity.

Results: By the database cutoff of August 24, 2018, 30 patients (76.7% had two or more prior anticancer regimens) received bintrafusp alfa for a median of 6.1 weeks; two remained on treatment. Nineteen patients (63.3%) had treatment-related adverse events, seven (23.3%) with grade 3/4 events, and there were no treatment-related deaths. The confirmed objective response rate (ORR) per independent review was 10.0% (95% confidence interval [CI] 2.1-26.5); responses lasted 2.8-8.3 + months. All responses occurred in immune-excluded tumors. Investigator-assessed confirmed ORR was 20.0% (95% CI 7.7-38.6). Median overall survival was 11.9 months (95% CI 5.7-not reached).

Conclusions: Bintrafusp alfa demonstrated a manageable safety profile and efficacy in Asian patients with pretreated esophageal SCC.

Clinical Trials Registration: NCT02699515.
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http://dx.doi.org/10.1007/s11523-021-00810-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266718PMC
July 2021

Coordinated Expression of HPV-6 Genes with Predominant E4 and E5 Expression in Laryngeal Papilloma.

Microorganisms 2021 Mar 3;9(3). Epub 2021 Mar 3.

Department of Otorhinolaryngology, Head and Neck Surgery, Graduate School of Medicine, University of the Ryukyus, Okinawa 903-0215, Japan.

Laryngeal papilloma (LP) associated with human papillomavirus (HPV)-6 or -11 infection shows aggressive growth. However, the detailed molecular mechanism of virus-driven tumorigenesis has not been uncovered fully. HPV-6 viral gene expression and dynamic alterations were investigated with in situ localization of viral DNA and RNA in 13 patients with HPV-6-infected laryngeal papilloma. The average viral load was 4.80 × 10 ± 1.86 × 10 copies/ng DNA. , , and mRNAs accounted for 96% of the expression of 9 mRNAs. The alteration of viral DNA load during recurrence paralleled the mRNA expression levels, and the expression of all mRNAs showed a similar curve. , , and were expressed in the middle to upper part of the epithelium and were co-expressed in the same cells. E4 immunohistochemistry demonstrated an extensively positive reaction in the upper cell layer in accordance with mRNA expression. These results suggest that individual viral genes are coordinately expressed for viral replication, virus release, and immunosurveillance avoidance. The newly developed E4-specific monoclonal antibody can be applied to further functional studies and clinical applications such as targeted molecular therapies.
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http://dx.doi.org/10.3390/microorganisms9030520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998961PMC
March 2021

The safety, tolerability and pharmacokinetics of niraparib in Japanese patients with solid tumours: results of a phase I dose-escalation study.

Jpn J Clin Oncol 2021 Apr;51(5):693-699

Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan.

Background: Niraparib is the only poly (adenosine diphosphate-ribose)-polymerase (PARP) inhibitor available as oral monotherapy for maintenance, regardless of BRCA mutational status.

Methods: This phase I, open-label, non-randomized, dose-escalation study was conducted in Japan using a 3 + 3 design. Adults (≥20 years) with metastatic or locally advanced solid tumours were enrolled. Niraparib 200 mg (cohort 1) or 300 mg (cohort 2) was administered once daily in 21-day cycles (no drug holiday between cycles) until progressive disease (PD) or unacceptable toxicity. The primary objective was to evaluate the safety and tolerability of niraparib in Japanese patients with advanced solid tumours. The number of patients with dose-limiting toxicities in cycle 1 and number with treatment-emergent adverse events were primary endpoints. Secondary endpoints were pharmacokinetics and tumour response.

Results: There were three patients in cohort 1 and six patients in cohort 2. Only one patient, in cohort 2, developed a dose-limiting toxicity (grade 4 platelet count decreased). All patients in both cohorts developed treatment-emergent adverse events. The most common treatment-related treatment-emergent adverse events were decreased appetite (n = 2) in cohort 1, and platelet count decreased as well as aspartate aminotransferase increased (both n = 5) in cohort 2. Mean Cmax and AUC0-24 of niraparib increased dose-proportionally after multiple doses (accumulation ratio of between 1.64 and 3.65); median tmax was 3-4 h. Two patients, both in cohort 2, had a partial response to treatment.

Conclusions: Niraparib (200 or 300 mg/day) was tolerable and had a favourable pharmacokinetic profile in Japanese patients with advanced solid tumours.
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http://dx.doi.org/10.1093/jjco/hyab013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086052PMC
April 2021

First-in-human study of the cancer peptide vaccine TAS0313 in patients with advanced solid tumors.

Cancer Sci 2021 Apr 25;112(4):1514-1523. Epub 2021 Feb 25.

Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan.

TAS0313, a novel cancer vaccine cocktail, was developed to overcome the disadvantages of previously developed short and long peptide vaccines; it comprises several long peptides targeting multiple cancer antigens. We evaluated TAS0313 monotherapy in Japanese patients with advanced solid tumors for which no other therapies were available. In the dose-finding cohort, patients received TAS0313 (9 or 27 mg) on days 1, 8, and 15 of cycles 1 and 2, and then on day 1 of each subsequent 21-day cycle. The primary objective was the evaluation of safety and tolerability. Secondary objectives were evaluation of efficacy, tumor responses, and immune activation (CTL, IgG, and tumor-infiltrating lymphocyte [TIL] levels). The full analysis set contained 10 patients in the 9-mg group and seven in the 27-mg group. No dose-limiting toxicities were reported in cycle 1. All adverse drug reactions (ADRs) were grade 1 or 2; the most common ADRs were injection site-related events. The best response was stable disease in four of 17 patients. The median progression-free survival (PFS) duration was 2.2 (95% confidence interval, 1.0-2.3) months overall; patients with baseline low lymphocyte counts (≤750/μL) had shorter PFS. Compared with baseline, TILs were increased in five patients. Although CTLs, IgG, and TILs were induced, no correlative pattern with clinical outcomes was observed. The safety, tolerability, and induction of immune responses in patients with advanced solid tumors receiving TAS0313 were confirmed. Further evaluation of TAS0313's efficacy as monotherapy or in combination with pembrolizumab is underway. The study is registered at www.clinicaltrials.jp (JapicCTI-183824).
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http://dx.doi.org/10.1111/cas.14765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019195PMC
April 2021

A first-in-human, phase 1 study of the NEDD8 activating enzyme E1 inhibitor TAS4464 in patients with advanced solid tumors.

Invest New Drugs 2021 Aug 9;39(4):1036-1046. Epub 2021 Feb 9.

Department of Medical Oncology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan.

Background This open-label, phase 1 study investigated TAS4464, a potent NEDD8-activating enzyme inhibitor, in patients with advanced/metastatic solid tumors (JapicCTI-173,488; registered 13/01/2017). The primary objective was dose-limiting toxicities (DLTs). Maximum-tolerated dose (MTD) was investigated using an accelerated titration design. Methods The starting 10-mg/m dose was followed by an initial accelerated stage (weekly dosing; n = 11). Based on liver function test (LFT) results, a 14-day, 20-mg/m dose lead-in period was implemented (weekly dosing with lead-in; n = 6). Results Abnormal LFT changes and gastrointestinal effects were the most common treatment-related adverse events (AEs). DLTs with 56-mg/m weekly dosing occurred in 1/5 patients; five patients had grade ≥ 2 abnormal LFT changes at 40- and 56-mg/m weekly doses. Further dose escalation ceased because of the possibility of severe abnormal LFT changes occurring. DLTs with weekly dosing with lead-in occurred in 1/5 patients at a 56-mg/m dose; MTD could not be determined because discontinuation criteria for additional enrollment at that particular dose level were met. As no further enrollment at lower doses occurred, dose escalation assessment was discontinued. Serious treatment-related AEs, AEs leading to treatment discontinuation, and DLTs were all related to abnormal LFT changes, suggesting that TAS4464 administration could affect liver function. This effect was dose-dependent but considered reversible. Complete or partial responses to TAS4464 were not observed; one patient achieved prolonged stable disease. Conclusions MTD could not be determined due to TAS4464 effects on liver function. Further evaluation of the mechanism of NEDD8-activating enzyme inhibitor-induced abnormal liver function is required. Trial registration number JapicCTI-173,488 (registered with Japan Pharmaceutical Information Center). Registration date 13 January 2017.
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http://dx.doi.org/10.1007/s10637-020-01055-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279981PMC
August 2021

Phase I studies of peptide vaccine cocktails derived from GPC3, WDRPUH and NEIL3 for advanced hepatocellular carcinoma.

Immunotherapy 2021 Apr 2;13(5):371-385. Epub 2021 Feb 2.

Department of Medical Oncology, Kyorin University Faculty of Medicine, Tokyo, Japan.

Two peptide cocktail vaccines using glypican-3, WD-repeat-containing protein up-regulated in hepatocellular carcinoma (HCC) and nei endonuclease VIII-like three epitopes were evaluated in advanced HCC in two Phase I studies. Study 1 evaluated dose-limiting toxicities (DLTs) of peptides 1-3 (HLA-A24-restricted) and study 2 evaluated DLTs of peptides 1-6 (HLA-A24 or A02-restricted). Overall, 18 and 14 patients were enrolled in studies 1 and 2, respectively. No DLTs were observed up to 7.1 mg of the vaccine cocktail. No complete response/partial response was observed. Stable disease was reported in nine and five patients with a disease control rate of 52.9% and 35.7% in studies 1 and 2, respectively. Both vaccines showed good tolerability and potential usefulness against HCC. Clinical trial registration: JapicCTI-121933; JapicCTI-142477.
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http://dx.doi.org/10.2217/imt-2020-0278DOI Listing
April 2021

Raptor and rictor expression in patients with human papillomavirus-related oropharyngeal squamous cell carcinoma.

BMC Cancer 2021 Jan 22;21(1):87. Epub 2021 Jan 22.

Department of Otorhinolaryngology, Head and Neck Surgery, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara-cho, Okinawa, 903-0215, Japan.

Background: Despite reports of a link between human papillomavirus (HPV) infection and mechanistic target of rapamycin (mTOR) signaling activation, the role of the mTOR pathway, especially raptor and rictor, in HPV-related head and neck cancer is still unclear. The aim of the present study was to elucidate the role of the mTOR pathway in HPV-related oropharyngeal squamous cell carcinoma (OPSCC).

Methods: The present study involved two strategies. The first was to investigate the activity of mTOR and mTOR-related complexes in high-risk HPV-positive (UM-SCC47 and CaSki) and HPV-negative (SCC-4 and SAS) cancer cell lines. The second was to elucidate mTOR complex expression in 80 oropharyngeal cancer tissues and to examine the relationship between mTOR complex expression and survival in patients with OPSCC.

Results: The UM-SCC47 and CaSki cell lines showed high gene and protein expression of raptor. They also exhibited G1/S and G2/M phase cell cycle arrest following 24 h incubation with 6 μM temsirolimus, a rapamycin analog, and temsirolimus administration inhibited their growth. HPV-related OPSCC samples showed high gene and protein expression of raptor and rictor compared with HPV-unrelated OPSCC. In addition, HPV-related OPSCC patients with high raptor and rictor expression tended to have a worse prognosis than those with low or medium expression.

Conclusions: These results suggest that raptor and rictor have important roles in HPV-related OPSCC and that temsirolimus is a potential therapeutic agent for patients with HPV-related OPSCC. This is the first report to reveal the overexpression of raptor and rictor in HPV-related OPSCC.
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http://dx.doi.org/10.1186/s12885-021-07794-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821513PMC
January 2021

Cabozantinib in Japanese patients with advanced hepatocellular carcinoma: a phase 2 multicenter study.

J Gastroenterol 2021 02 3;56(2):181-190. Epub 2021 Jan 3.

Oncology Clinical Research Department, Oncology Therapeutic Area Unit for Japan and Asia, Takeda Pharmaceutical Company Limited, Osaka, Japan.

Background: To evaluate the efficacy and safety of cabozantinib in Japanese patients with advanced hepatocellular carcinoma (HCC) who had progressed following one or two lines of systemic therapy including sorafenib. An exploratory evaluation in sorafenib-naïve patients was performed.

Methods: In this open-label, single-arm, phase 2 trial, patients received oral cabozantinib 60 mg once daily. The primary endpoint was progression-free survival (PFS) rate at Week 24. Secondary endpoints included PFS, overall survival (OS), objective response rate (ORR, best response of complete/partial response), disease control rate (DCR, objective response or stable disease) and safety.

Results: Thirty-four patients received cabozantinib across 17 centers (prior sorafenib cohort, n = 20; sorafenib-naïve cohort, n = 14). PFS rate at 24 weeks was 59.8% [90% confidence interval (CI) 36.1-77.2%] in the prior sorafenib cohort, 16.7% (90% CI 4.0-36.8%) in the sorafenib-naïve cohort and 40.1% (90% CI 24.8-55.0%) overall. Median PFS was 7.4 months for the prior sorafenib cohort, 3.6 months for the sorafenib-naïve cohort, and 5.6 months overall. OS rate at 6 months was 100.0%, 78.6% and 91.1%, respectively; DCR was 85.0%, 64.3% and 76.5%, respectively. The ORR was 0.0% for both cohorts. All patients required dose modifications due to adverse events, the most common of these were palmar-plantar erythrodysesthesia syndrome and diarrhea. Three patients (8.8%) discontinued due to adverse events other than disease progression.

Conclusions: Cabozantinib 60 mg/day has a favorable benefit/risk profile for Japanese patients with advanced HCC who have previously received one or two lines of systemic anticancer therapy including sorafenib. (Clinical trial registration: NCT03586973).
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http://dx.doi.org/10.1007/s00535-020-01753-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862203PMC
February 2021

Dose exploration results from Phase 1 study of cemiplimab, a human monoclonal programmed death (PD)-1 antibody, in Japanese patients with advanced malignancies.

Cancer Chemother Pharmacol 2021 01 4;87(1):53-64. Epub 2020 Nov 4.

Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA.

Purpose: Part 1 of this two-part, open-label, Phase 1 study (NCT03233139) assessed the safety, tolerability, pharmacokinetics, immunogenicity, and clinical activity of cemiplimab in Japanese patients with advanced malignancies.

Methods: Patients received cemiplimab 250 mg (n = 6) or 350 mg (n = 7) every 3 weeks intravenously for up to 108 weeks in Part 1. Tumor responses were assessed by investigators every 9 weeks using the Response Evaluation Criteria in Solid Tumors version 1.1.

Results: Of 13 patients enrolled, median age was 62 years (range 33-75) and eight patients were female. Median duration of cemiplimab exposure was 13.1 weeks (range 3.0‒113.6). At the time of data cut-off, 11 patients (84.6%) had discontinued treatment (majority due to disease progression: n = 8, 61.5%). The most common treatment-emergent adverse events (TEAEs) of any grade were contact dermatitis, rash, and viral upper respiratory tract infection (each n = 3, 23.1%). Five grade ≥ 3 TEAEs were reported in four patients: autoimmune colitis, dehydration, hyponatremia, hypophosphatemia, and muscular weakness. No dose-limiting toxicities were reported and no TEAEs led to death. Cemiplimab concentrations in serum were consistent with previously reported pharmacokinetic characteristics of cemiplimab. No anti-drug antibodies were detected in serum. Objective response rate [ORR; complete response + partial response (PR)] was 30.8% (four PR) and disease control rate [ORR + stable disease (SD)] was 46.2% (6/13; two SD).

Conclusion: Cemiplimab exhibited antitumor activity in Japanese patients with advanced malignancies. The safety profile was comparable to those previously reported for cemiplimab and other PD-1 inhibitors.

Trial Registration: NCT03233139 at ClinicalTrials.gov.
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http://dx.doi.org/10.1007/s00280-020-04161-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801352PMC
January 2021

Correction to: Phase 1 dose-escalation study of a novel oral PI3K/mTOR dual inhibitor, LY3023414, in patients with cancer.

Invest New Drugs 2020 Dec;38(6):1846

Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Chiba, Japan.

The article Phase 1 dose-escalation study of a novel oral PI3K/mTOR dual inhibitor, LY3023414, in patients with cancer, written by Shunsuke Kondo, Masaomi Tajimi, Tomohiko Funai, Koichi Inoue, Hiroya Asou, Vinay Kumar Ranka, Volker Wacheck, Toshihiko Doi, was originally published electronically on the publisher's internet portal on 23 June 2020 without open access.
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http://dx.doi.org/10.1007/s10637-020-00981-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7852856PMC
December 2020

Model Informed Dosing Regimen and Phase I Results of the Anti-PD-1 Antibody Budigalimab (ABBV-181).

Clin Transl Sci 2021 01 26;14(1):277-287. Epub 2020 Dec 26.

Next Oncology, San Antonio, Texas, USA.

Budigalimab is a humanized, recombinant, Fc mutated IgG1 monoclonal antibody targeting programmed cell death 1 (PD-1) receptor, currently in phase I clinical trials. The safety, efficacy, pharmacokinetics (PKs), pharmacodynamics (PDs), and budigalimab dose selection from monotherapy dose escalation and multihistology expansion cohorts were evaluated in patients with previously treated advanced solid tumors who received budigalimab at 1, 3, or 10 mg/kg intravenously every 2 weeks (Q2W) in dose escalation, including Japanese patients that received 3 and 10 mg/kg Q2W. PK modeling and PK/PD assessments informed the dosing regimen in expansion phase using data from body-weight-based dosing in the escalation phase, based on which patients in the multihistology expansion cohort received flat doses of 250 mg Q2W or 500 mg every four weeks (Q4W). Immune-related adverse events (AEs) were reported in 11 of 59 patients (18.6%), of which 1 of 59 (1.7%) was considered grade ≥ 3 and the safety profile of budigalimab was consistent with other PD-1 targeting agents. No treatment-related grade 5 AEs were reported. Four responses per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 were reported in the dose escalation cohort and none in the multihistology expansion cohort. PK of budigalimab was approximately dose proportional and sustained > 99% peripheral PD-1 receptor saturation was observed by 2 hours postdosing, across doses. PK/PD and safety profiles were comparable between Japanese and Western patients, and exposure-safety analyses did not indicate any trends. Observed PK and PD-1 receptor saturation were consistent with model predictions for flat doses and less frequent regimens, validating the early application of PK modeling and PK/PD assessments to inform the recommended dose and regimen, following dose escalation.
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http://dx.doi.org/10.1111/cts.12855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877859PMC
January 2021

Measurement of stapes footplate thickness in otosclerosis by ultra-high-resolution computed tomography.

Acta Otolaryngol 2020 Nov 23;140(11):899-903. Epub 2020 Jul 23.

Department of Radiology, Graduate School of Medicine, University of the Ryukyus, Nishihara-cho, Japan.

Background: Ultra-high-resolution computed tomography (U-HRCT) utilizes a 1024 × 1024 matrix with 0.25-mm section thickness, offering better spatial resolution than conventional multi-detector row CT to detect anatomic data for otologic surgery.

Aims: We examined stapes footplate thickness using U-HRCT in relation to stapedotomy to predict the difficulty of the surgical procedure.

Materials And Methods: Subjects were 12 otosclerosis patients and 25 controls who underwent diagnostic U-HRCT. A profile curve (Hounsfield units) was used to measure stapes footplate thickness along a perpendicular line across the stapes footplate in a plane parallel to the lateral semicircular canal.

Results: Footplate thickness was smaller at the midpoint than just before the anterior crus and just after the posterior crus. Interobserver variability was lowest at the midpoint, where foot plate thickness was significantly greater in the affected ear in otosclerosis patients compared with controls (0.60 ± 0.09 mm vs 0.46 ± 0.04 mm;  < .001). Otosclerosis patients were detected using U-HRCT with a high area under the curve. Difficulty in the stapes opening procedure correlated with stapes footplate thickness.

Conclusions: Footplate thickness on U-HRCT correlated with temporal bone anatomy and corresponded to surgical difficulty. U-HRCT-derived anatomic data is useful for evaluating the stapes.
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http://dx.doi.org/10.1080/00016489.2020.1788225DOI Listing
November 2020

Phase 1 dose-escalation study of a novel oral PI3K/mTOR dual inhibitor, LY3023414, in patients with cancer.

Invest New Drugs 2020 12 23;38(6):1836-1845. Epub 2020 Jun 23.

Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Chiba, Japan.

LY3023414 is an oral, selective adenosine triphosphate-competitive inhibitor of class I phosphatidylinositol 3-kinase isoforms, mammalian target of rapamycin, and DNA-protein kinase in clinical development. We report results of a 3 + 3 dose-escalation Phase 1 study for twice-daily (BID) dosing of LY3023414 monotherapy in Japanese patients with advanced malignancies. The primary objective was to evaluate tolerability and safety of LY3023414. Secondary objectives were to evaluate pharmacokinetics and to explore antitumor activity. A total of 12 patients were enrolled and received 150 mg (n = 3) or 200 mg (n = 9) LY3023414 BID. Dose-limiting toxicities were only reported at 200 mg LY3023414 for 2 patients with Grade 3 stomatitis. Common treatment-related adverse events (AEs) across both the dose levels included stomatitis (75.0%), nausea (66.7%), decreased appetite (58.3%), diarrhea, and decreased platelet count (41.7%), and they were mostly mild or moderate in severity. Related AEs Grade ≥ 3 reported for ≥1 patient included anemia, stomatitis, hypophosphatemia, and hyperglycemia (n = 2, 16.7%). Two patients discontinued due to AEs (interstitial lung disease and stomatitis). No fatal events were reported. The pharmacokinetic profile of LY3023414 was characterized by rapid absorption and elimination. Five patients had a best overall response of stable disease (150 mg, n = 3; 200 mg, n = 2) for a 55.6% disease control rate. LY3023414 up to 200 mg BID is tolerable and safe in Japanese patients with advanced malignancies.
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http://dx.doi.org/10.1007/s10637-020-00968-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575488PMC
December 2020

Induction Chemotherapy in Hypopharyngeal Cancer: Influence of DNA Repair Gene Polymorphisms.

Anticancer Res 2020 Jun;40(6):3277-3285

Department of Otorhinolaryngology, Head and Neck Surgery, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.

Background/aim: The aim was to clarify whether DNA repair gene polymorphisms can be used to predict response to cisplatin, 5-fluorouracil, and docetaxel (TPF) as induction chemotherapy (ICT) in Japanese patients with hypopharyngeal cancer (HPC).

Materials And Methods: DNA repair gene polymorphisms (rs3212986, rs1799793, rs13181, and rs25487) were analyzed in 117 HPC patients and 125 control subjects by PCR-restriction fragment length polymorphism. Forty-one HPC patients who received TPF-based ICT, followed by surgery or chemoradiotherapy/radiotherapy were analyzed for ICT response, laryngeal preservation, and survival outcome.

Results: ICT responders (29 cases) had significantly better overall survival than ICT non-responders (12 cases; 86.0% vs. 37.0%, respectively, p<0.01 by log-rank test) and better laryngeal preservation rates. The DNA repair gene polymorphisms were not related to ICT response.

Conclusion: ICT is beneficial for chemoselection of HPC patients, but a role for DNA repair gene polymorphisms in ICT response was not confirmed.
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http://dx.doi.org/10.21873/anticanres.14310DOI Listing
June 2020

Phase I study of bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in patients with pretreated biliary tract cancer.

J Immunother Cancer 2020 05;8(1)

Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan

Background: Patients with biliary tract cancer (BTC) have poor prognosis with few treatment options. Bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of the transforming growth factor (TGF)-βRII receptor (a TGF-β 'trap') fused to a human IgG1 antibody blocking programmed death ligand 1 (PD-L1), has shown clinical efficacy in multiple solid tumors.

Methods: In this phase I, open-label trial expansion cohort, Asian patients with BTC whose disease progressed after first-line chemotherapy received bintrafusp alfa 1200 mg every 2 weeks until disease progression, unacceptable toxicity, or withdrawal. The primary endpoint is safety/tolerability, while the secondary endpoints include best overall response per Response Evaluation Criteria in Solid Tumors version 1.1.

Results: As of August 24, 2018, 30 patients have received bintrafusp alfa for a median of 8.9 (IQR 5.7-32.1) weeks; 3 patients remained on treatment for >59.7 weeks. Nineteen (63%) patients experienced treatment-related adverse events (TRAEs), most commonly rash (17%), maculopapular rash and fever (13% each), and increased lipase (10%). Eleven (37%) patients had grade ≥3 TRAEs; three patients had grade 5 events (septic shock due to bacteremia, n=1; interstitial lung disease (reported term: interstitial pneumonitis), n=2). The objective response rate was 20% (95% CI 8 to 39) per independent review committee (IRC), with five of six responses ongoing (12.5+ to 14.5+ months) at data cut-off. Two additional patients with durable stable disease had a partial response per investigator. Median progression-free survival assessed by IRC and overall survival were 2.5 months (95% CI 1.3 to 5.6) and 12.7 months (95% CI 6.7 to 15.7), respectively. Clinical activity was observed irrespective of PD-L1 expression and microsatellite instability-high status.

Conclusions: Bintrafusp alfa had clinical activity in Asian patients with pretreated BTC, with durable responses. Based on these results, bintrafusp alfa is under further investigation in patients with BTC (NCT03833661 and NCT04066491).

Trial Registration Number: NCT02699515.
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http://dx.doi.org/10.1136/jitc-2020-000564DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7254161PMC
May 2020

Safety and Tolerability of Bintrafusp Alfa, a Bifunctional Fusion Protein Targeting TGFβ and PD-L1, in Asian Patients with Pretreated Recurrent or Refractory Gastric Cancer.

Clin Cancer Res 2020 07 16;26(13):3202-3210. Epub 2020 Apr 16.

National Cancer Center Hospital East, Chiba, Japan.

Purpose: Patients with advanced gastric/gastroesophageal junction cancer (GC/GEJC) have limited treatment options after first-line therapy. Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGFβRII receptor (a TGFβ "trap") fused to a human IgG1 antibody against programmed death ligand 1 (PD-L1), potentially offering a new treatment approach for these patients. We report results for bintrafusp alfa in GC/GEJC.

Patients And Methods: Asian patients with recurrent GC/GEJC for whom standard therapy does not exist or for whom standard therapy has failed enrolled in this expansion cohort of an ongoing phase I trial and received bintrafusp alfa 1,200 mg once every 2 weeks until disease progression, unacceptable toxicity, or withdrawal. The primary objective was to assess safety/tolerability.

Results: By July 23, 2018, 31 heavily pretreated patients received bintrafusp alfa for a median of 10.1 weeks; 3 patients remained on treatment. Six patients (19%) experienced grade 3 treatment-related adverse events (AE); no grade 4 events occurred. One on-treatment death occurred (sudden death); rupture of a preexisting thoracic aortic aneurysm was the suspected cause. Ten patients (32%) had immune-related AEs. The confirmed objective response rate per independent review committee was 16%; disease control rate was 26%. Median duration of response was 8.7 months (range, 2.4-12.4+). Responses occurred irrespective of PD-L1 expression or microsatellite instability status and appeared to correlate with high tumor levels.

Conclusions: In this first evaluation in Asian patients with heavily pretreated advanced GC/GEJC, bintrafusp alfa demonstrated a manageable safety profile and clinical activity.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3806DOI Listing
July 2020

Novel endoscopic technique for trisegment drainage in patients with unresectable hilar malignant biliary strictures (with video).

Gastrointest Endosc 2020 Sep 10;92(3):763-769. Epub 2020 Mar 10.

Department of Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan.

Background And Aims: Three or more stents may be needed in patients with extensive stricturing in Bismuth type IIIa/IV hilar malignant strictures. Partial stent-in-stent (PSIS) deployment has been the primary intervention for hilar malignant biliary stricture (MBS). However, simultaneous side-by-side (SBS) stent placement has become feasible with the development of the <6F diameter stent delivery system. Our aim was to assess the efficacy and safety of a new hybrid method combining PSIS and SBS stent placement for trisegment biliary drainage.

Methods: This study included 17 consecutive patients with Bismuth IIIa or IV malignant strictures who underwent endoscopic drainage using the hybrid method. Diameters of the delivery stents were 5.4F (n = 10) and 5.7F (n = 7).

Results: The technical success rate was 82% (14/17), and the median length of procedures was 54 minutes. Two patients required predilatation for deployment of the third self-expandable metallic stent through the mesh of the first deployed stent. Two patients (12%) developed cholecystitis as early adverse events, and 1 patient (6%) developed liver abscess as a late adverse event. The time to recurrent biliary obstruction among those with successful initial trisegmental drainage was 189 days (95% confidence interval, 124-254).

Conclusions: The hybrid method for unresectable hilar MBS is an effective endoscopic drainage method, and the ease of these procedures is partly attributed to the thinner stent delivery system.
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http://dx.doi.org/10.1016/j.gie.2020.03.003DOI Listing
September 2020

Highly Sensitive Circulating MicroRNA Panel for Accurate Detection of Hepatocellular Carcinoma in Patients With Liver Disease.

Hepatol Commun 2020 Feb 19;4(2):284-297. Epub 2019 Dec 19.

Division of Molecular and Cellular Medicine National Cancer Center Research Institute Tokyo Japan.

Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer deaths worldwide. The high mortality rate in HCC is largely due to the difficulty of early detection. In this study, to improve patient outcomes, serum samples from 345 patients with HCC, 46 patients with chronic hepatitis (CH), 93 patients with liver cirrhosis (LC), and 1,033 healthy individuals were analyzed with microRNA (miRNA) microarrays. We investigated the diagnostic potential of circulating miRNAs in serum and developed a detection model of HCC, including early stage. A diagnostic model was constructed based on the expression levels of a combination of miRNAs in a discovery set. We selected 52 miRNAs that had altered expressions according to disease progression status, established the diagnostic model with a combination of eight miRNAs in the discovery set, and tested the model in a validation set. The diagnostic values for discriminating cancer from HCC at-risk control samples were as follows: area under the curve, 0.99; sensitivity, 97.7%; specificity, 94.7%. With this model, 98% of stage I HCC cases were detected; these results were much better than those observed from conventional methods. Circulating miRNAs could serve as biomarkers for the accurate detection of HCC. Because the diagnostic accuracy was maintained even in stage I, this may represent an accurate detection method even for early stage HCC.
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http://dx.doi.org/10.1002/hep4.1451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996324PMC
February 2020

First-in-human phase I study of E7090, a novel selective fibroblast growth factor receptor inhibitor, in patients with advanced solid tumors.

Cancer Sci 2020 Feb;111(2):571-579

Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan.

Fibroblast growth factor receptors (FGFR) are a family of transmembrane receptor tyrosine kinases involved in regulating cellular processes. FGFR mutations are implicated in oncogenesis, representing therapeutic potential in the form of FGFR inhibitors. This phase I, first-in-human study in Japan evaluated safety and tolerability of E7090, a potent selective FGFR1-3 inhibitor, in patients with advanced solid tumors. Dose escalation (daily oral dose of 1-180 mg) was carried out to assess dose-limiting toxicity (DLT), maximum tolerated dose, and pharmacokinetics. Pharmacodynamic markers (serum phosphate, fibroblast growth factor 23, and 1,25-(OH) -vitamin D) were also evaluated. A total of 24 patients refractory to standard therapy or for whom no appropriate treatment was available were enrolled. No DLT were observed up to the 140-mg dose; one patient in the 180-mg cohort experienced a DLT (increased aspartate aminotransferase/alanine aminotransferase, grade 3). The maximum tolerated dose was not reached. Dose-dependent increases in the maximum concentration and area under the curve from time 0 to the last measurable concentration were observed up to 180 mg. Dose-dependent increases were observed in all pharmacodynamic markers and plateaued at 100-140 mg, indicating sufficient FGFR pathway inhibition at doses ≥100 mg. In conclusion, E7090 showed a manageable safety profile with no DLT at doses ≤140 mg. Maximum tolerated dose was not determined. The recommended dose for the follow-up expansion part, restricted to patients with tumors harboring FGFR alterations, was determined as 140 mg, once daily.
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http://dx.doi.org/10.1111/cas.14265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004556PMC
February 2020

ERCC1 C8092A polymorphism predicts fair survival outcome in Japanese patients with pharyngo-laryngeal squamous cell carcinoma.

Eur Arch Otorhinolaryngol 2020 Feb 20;277(2):601-610. Epub 2019 Nov 20.

Department of Otorhinolaryngology, Head and Neck Surgery, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara-cho, Okinawa, 903-0215, Japan.

Purpose: To evaluate the prognostic significance of DNA excision repair gene polymorphisms, excision repair cross-complementation group 1 (ERCC1) and X-ray repair complementing defective repair in Chinese hamster cells 1 (XRCC1) polymorphisms were investigated in Japanese patients with head and neck squamous cell carcinoma (HNSCC).

Methods: A total of 225 consecutive patients with HNSCC who underwent surgery or chemoradiotherapy/radiotherapy (CRT/RT) with curative intent as primary treatment from 2006 to 2017 were recruited. ERCC1 C8092A and XRCC1 Arg399Gln polymorphisms in DNA extracted from individual blood samples were determined by the polymerase chain reaction-restriction fragment length polymorphism method. Cumulative survival was estimated by Kaplan-Meier analysis with a log-rank test and Cox proportional hazards model stratified by treatment arm, adjusting for clinical prognostic factors.

Results: Multivariate analysis showed that carriers with the ERCC1 8092 (C/A+A/A) genotype (hazard ratio, 3.56; 95% confidence interval, 1.22-7.39; p = 0.02) had significantly worse survival than those with ERCC1 8092 C/C who received CRT/RT. Conversely, the XRCC1 Arg399Gln polymorphism did not influence survival in patients who received CRT/RT as well as surgery.

Conclusion: The ERCC1 C8092A polymorphism might be an independent predictor of response to CRT and survival outcome in patients with HNSCC. This is the first report to investigate the role of DNA excision repair gene polymorphisms in patients with head and neck cancer in a Japanese population.
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http://dx.doi.org/10.1007/s00405-019-05731-yDOI Listing
February 2020

Improved survival among patients enrolled in oncology phase 1 trials in recent decades.

Cancer Chemother Pharmacol 2020 02 19;85(2):449-459. Epub 2019 Nov 19.

Department of Experimental Therapeutics, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.

Purpose: This study aimed to compare the survival of patients enrolled in phase 1 trials in recent decades.

Methods: The medical records of consecutive patients with advanced cancer who participated in single-agent oncology phase 1 trials from 1995 to 2015 at a single institution were retrospectively investigated.

Results: A total of 267 (34.1%) patients participated in 1995-2004 and 516 (65.9%) participated in 2005-2015. The median follow-up period was 25.4 months (range 1.3-166.9). The response rate did not differ significantly between the two periods (3.9% vs. 6.2%, p = 0.17). The median survival times were 9.5 (95% confidence interval 8.4-11.2) months in 1995-2004 and 11.8 (95% confidence interval 10.9-13.3) months in 2005-2015 (p = 0.0009). The enrolment period was an independent prognostic factor of overall survival according to multivariate analysis (hazard ratio: 0.85, 95% confidence interval 0.72-0.99, p = 0.042).

Conclusions: In our single-centre, retrospective analysis, the trends in patients characteristic were consistent with those of Western countries, and the overall survival of cancer patients enrolled in oncology phase 1 trials tended to improve in recent decades, suggesting that patient selection, the population that benefits from investigational agents and treatment after phase 1 trials have improved.
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http://dx.doi.org/10.1007/s00280-019-03992-2DOI Listing
February 2020

Germline mutations in cancer-predisposition genes in patients with biliary tract cancer.

Oncotarget 2019 Oct 15;10(57):5949-5957. Epub 2019 Oct 15.

Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan.

The prevalence of germline mutations in patients with biliary tract carcinoma (BTC) remains unclear. Here, we investigated the prevalence and types of germline mutations in patients with BTC. We reviewed 269 patients with pathologically proven BTC and collected clinical characteristics, including medical and family histories. Additionally, we evaluated germline variants in 21 genes associated with hereditary predisposition for cancer by targeted sequencing in patients meeting ≥1 of the following criteria: 1) hereditary breast and/or ovarian cancer (HBOC) testing criteria modified for BTC, 2) Revised Bethesda Guidelines (RBGs) modified for BTC (modified RBG), 3) familial BTC criteria, or 4) young BTC criteria. Among the 269 patients, 80 met at least one criterion. Three pathogenic mutations in three patients were identified: two in and one in . Among the 16 patients meeting modified HBOC testing criteria, 2 harbored germline mutations, and 1 harbored a germline mutation. However, no mutation in mismatch-repair genes were detected, despite 63 patients meeting modified RBG screening criteria and 18 qualifying as young BTC patients. We detected high prevalence of pathogenic germline mutations in and none in mismatch-repair genes in BTC patients following enrichment according to family or medical history in this study.
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http://dx.doi.org/10.18632/oncotarget.27224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6800267PMC
October 2019

Improvement of driver active interventions during automated driving by displaying trajectory pointers-A driving simulator study.

Traffic Inj Prev 2019 ;20(sup1):S152-S156

c Graduate School of Information Science and Technology, The University of Tokyo , Bunkyo-ku , Japan.

The handover of vehicle control from automated to manual operation is a critical aspect of interaction between drivers and automated driving systems (ADS). In some cases, it is possible that the ADS may fail to detect an object. In this event, the driver must be aware of the situation and resume control of the vehicle without assistance from the system. Consequently, the driver must fulfill the following 2 main roles while driving: (1) monitor the vehicle trajectory and surrounding traffic environment and (2) actively take over vehicle control if the driver identifies a potential issue along the trajectory. An effective human-machine interface (HMI) is required that enables the driver to fulfill these roles. This article proposes an HMI that constantly indicates the future position of the vehicle. This research used the Toyota Dynamic Driving Simulator to evaluate the effect of the proposed HMI and compares the proposed HMI with an HMI that notifies the driver when the vehicle trajectory changes. A total of 48 test subjects were divided into 2 groups of 24: One group used the HMI that constantly indicated the future position of the vehicle and the other group used the HMI that provided information when the vehicle trajectory changed. The following instructions were given to the test subjects: (1) to not hold the steering wheel and to allow the vehicle to drive itself, (2) to constantly monitor the surrounding traffic environment because the functions of the ADS are limited, and (3) to take over driving if necessary. The driving simulator experiments were composed of an initial 10-min acclimatization period and a 10-min evaluation period. Approximately 10 min after the start of the evaluation period, a scenario occurred in which the ADS failed to detect an object on the vehicle trajectory, potentially resulting in a collision if the driver did not actively take over control and manually avoid the object. The collision avoidance rate of the HMI that constantly indicated the future position of the vehicle was higher than that of the HMI that notified the driver of trajectory changes, χ = 6.38, < .05. The steering wheel hands-on and steering override timings were also faster with the proposed HMI ( test; < .05). This research confirmed that constantly indicating the position of the vehicle several seconds in the future facilitates active driver intervention when an ADS is in operation.
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http://dx.doi.org/10.1080/15389588.2019.1610170DOI Listing
February 2020

Impact of the Duration of Diabetes Mellitus on the Outcome of Metastatic Pancreatic Cancer Treated with Gemcitabine: A Retrospective Study.

Intern Med 2019 Sep 7;58(17):2435-2441. Epub 2019 Jun 7.

Department of General Internal Medicine, National Cancer Center Hospital, Japan.

Objective To assess the impact of the duration of diabetes mellitus (DM) on the outcomes of pancreatic cancer patients undergoing chemotherapy. Methods We reviewed the medical records of patients with metastatic pancreatic cancer who received gemcitabine monotherapy as the standard therapy before the introduction of combination regimens. The treatment outcomes of gemcitabine were compared among three groups classified according to the duration of DM: no DM, short DM (<4 years), and long DM (≥4 years). Results Among 350 patients, 218, 87, and 45 patients were classified into the no DM, short DM, and long DM groups, respectively. In comparison to the no DM group, the univariate hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS) were 1.44 [95% confidence interval (CI), 1.02-2.02; p=0.027] and 1.33 (95% CI, 0.93-1.89; p=0.081), respectively, in the long DM group, and 1.12 (95% CI, 0.85-1.46; p=0.426) and 1.06 (95% CI, 0.81-1.40; p=0.678), respectively, in the short DM group; the multivariate-adjusted HRs were 1.33 (95% CI, 0.94-1.89; p=0.103) and 1.37 (95% CI, 0.95-1.98; p=0.095) in the long DM group and 1.12 (95% CI, 0.85-1.47; p=0.410) and 1.10 (95% CI, 0.82-1.46; p=0.533) in the short DM group. The survival outcomes of the long DM group tended to remain poorer in analyses using different cutoffs of DM duration as, well as in hospital-specific analyses. Conclusion Long-standing DM may be associated with shorter PFS and OS in patients with metastatic pancreatic cancer.
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http://dx.doi.org/10.2169/internalmedicine.2539-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6761348PMC
September 2019

Hypopharyngeal cancer risk in Japanese: Genetic polymorphisms related to the metabolism of alcohol- and tobacco-associated carcinogens.

J Cancer Res Ther 2019 Jul-Sep;15(3):556-563

Department of Otorhinolaryngology, Head and Neck Surgery, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.

Background: Several studies have investigated hypopharyngeal cancer (HC) risk in combination with xenobiotic metabolism-related genetic polymorphisms and the burden of alcohol consumption and smoking in European countries but not in East Asian countries.

Patients And Methods: This hospital-based case-control study involved 61 male patients with HC and 71 male cancer-free controls. Information on age, body mass index, and alcohol and cigarette consumption was obtained from medical records, a self-completion questionnaire, and a thorough interview by an otolaryngologist. Alcohol dehydrogenase 1B (ADH1B), aldehyde dehydrogenase 2 (ALDH2), cytochrome P450 A1 (CYP1A1) MspI, CYP1A1 Ile462Val, glutathione S-transferase (GST) M1, GSTT1, and GSTP1 gene polymorphisms were determined by polymerase chain reaction-based methods. Univariate and multivariate analyses were performed by adjustment for age by the Mantel-Haenszel method.

Results: The burden of alcohol and cigarette consumption significantly increased the risk of HC and showed a synergistic effect. ADH1B*1/*1 (odds ratio [OR] 7.34) and ALDH2 *1/*2 (OR 13.22) were significant risk factors for HC. Individuals with ADH1B*1/*1 or ALDH2 *1/*2 who consumed alcohol were more susceptible to HC. However, polymorphisms of CYP1A1 gene and GSTs were not significant cancer risk factors in patients with HC.

Conclusions: ADH1B*1/*1 and ALDH2 *1/*2 were significant risk factors for HC, while polymorphism of CYP1A1 gene and GSTs was not a significant risk factor for HC. These polymorphisms determined the effects of alcohol and cigarette smoke in addition to burden of alcohol and cigarettes intake on the risk of HC.
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http://dx.doi.org/10.4103/jcrt.JCRT_980_17DOI Listing
November 2019

Phase I study of the indoleamine 2,3-dioxygenase 1 inhibitor navoximod (GDC-0919) as monotherapy and in combination with the PD-L1 inhibitor atezolizumab in Japanese patients with advanced solid tumours.

Invest New Drugs 2020 04 24;38(2):468-477. Epub 2019 May 24.

Department of Experimental Therapeutics, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 1040045, Japan.

Navoximod (GDC-0919) is a small molecule inhibitor of indoleamine-2,3-dioxygenase 1. This study investigated the safety, tolerability and pharmacokinetics of navoximod alone and in combination with atezolizumab in Japanese patients with advanced solid tumours. This was a phase I, open-label, dose-escalation study. Patients received monotherapy with navoximod 400 mg, 600 mg or 1000 mg orally twice daily (BID) in Stage 1 and navoximod 200 mg, 400 mg, 600 mg or 1000 mg orally BID plus atezolizumab 1200 mg intravenously every 21 days in Stage 2. Objectives included safety, tolerability, efficacy and pharmacokinetic outcomes.Overall, 20 patients were enrolled (Stage 1: n = 10; Stage 2: n = 10). No dose-limiting toxicities were observed. In Stage 1, treatment-related adverse events (TRAEs) of any grade that occurred in ≥20% of patients were chromaturia (50%) and maculopapular rash (20%). Grade ≥ 3 TRAEs were reported in two patients (20%; maculopapular rash and lipase increased). In Stage 2, TRAEs that occurred in ≥30% of patients were chromaturia (60%) and, decreased appetite (40%). Grade ≥ 3 TRAEs were reported in three patients (30%; hyponatraemia, aspartate aminotransferase increased, alanine aminotransferase increased, lymphopaenia and neutropaenia). Stable disease was observed in five patients (50%) in Stage 1 and eight patients (80%) in Stage 2. Navoximod showed linear pharmacokinetics. The recommended dose of navoximod monotherapy was determined as 1000 mg orally BID, and could be considered 1000 mg orally BID in combination with atezolizumab. Navoximod as monotherapy and in combination with atezolizumab was well tolerated in Japanese patients with advanced solid tumours.
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http://dx.doi.org/10.1007/s10637-019-00787-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066107PMC
April 2020

Nivolumab alone or in combination with cisplatin plus gemcitabine in Japanese patients with unresectable or recurrent biliary tract cancer: a non-randomised, multicentre, open-label, phase 1 study.

Lancet Gastroenterol Hepatol 2019 08 17;4(8):611-621. Epub 2019 May 17.

Department of Medical Oncology, Kyorin University Faculty of Medicine, Mitaka, Tokyo, Japan.

Background: This study aimed to assess the safety and tolerability of the immune checkpoint inhibitor nivolumab, as monotherapy or combined with chemotherapy, in Japanese patients with biliary tract cancer.

Methods: This multicentre, open-label, phase 1 trial was done at four cancer centres in Japan. Eligible patients were aged 20-79 years, had biliary tract adenocarcinoma (intrahepatic bile duct cancer, extrahepatic bile duct cancer, gallbladder cancer, or ampullary cancer), Eastern Cooperative Oncology Group performance status 0 or 1, adequate hepatic, renal, and haematological function, and tumour tissue samples for PD-L1 expression analysis. Patients with unresectable or recurrent biliary tract cancer that was refractory or intolerant to gemcitabine-based treatment regimens received nivolumab monotherapy (240 mg every 2 weeks [monotherapy cohort]). Chemotherapy-naive patients with unresectable or recurrent biliary tract cancer received nivolumab (240 mg every 2 weeks) and cisplatin (25 mg/m) plus gemcitabine (1000 mg/m) chemotherapy (combined therapy cohort). The primary objective was to assess tolerability and safety. The primary objective was assessed in the safety population of all patients who had received at least one dose of nivolumab. This study is registered with www.clinicaltrials.jp, number JapicCTI-153098, and follow-up is ongoing.

Findings: 30 patients were enrolled into each cohort between Jan 13, 2016, and April 19, 2017. Data cutoff was Aug 31, 2017. In the monotherapy cohort, the most frequently reported treatment-related adverse events were decreased appetite (five [17%]), malaise (four [13%]), and pruritus (four [13%]). Grade 3-4 treatment-related adverse events were reported by three (10%) patients (rash, maculopapular rash, and amylase increase) and treatment-related serious adverse events were reported by one (3%) patient (pleurisy). In the combined therapy cohort, the most frequently reported treatment-related adverse events were neutrophil count decrease (any grade 25 [83%]; grade 3-4 in 23 [77%] patients) and platelet count decrease (any grade 25 [83%] of 30; grade 3-4 in 15 [50%] patients). Six (20%) patients reported 11 treatment-related serious adverse events (platelet count decrease [three patients], febrile neutropenia [two patients], neutrophil count decrease, anaemia, anaphylactic reaction, decreased appetite, pyrexia, and myocarditis [one patient each]). In the monotherapy cohort, median overall survival was 5·2 months (90% CI 4·5-8·7), median progression-free survival was 1·4 months (90% CI 1·4-1·4), and one of 30 patients had an objective response. In the combined therapy cohort, median overall survival was 15·4 months (90% CI 11·8-not estimable), median progression-free survival was 4·2 months (90% CI 2·8-5·6), and 11 of 30 patients had an objective response.

Interpretation: Nivolumab had a manageable safety profile and signs of clinical activity in patients with unresectable or recurrent biliary tract cancer. This initial assessment of nivolumab for the treatment of advanced biliary tract cancer provides supportive evidence for future larger randomised studies of nivolumab in this difficult to treat cancer.

Funding: Ono Pharmaceutical Co Ltd and Bristol-Myers Squibb Inc.
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http://dx.doi.org/10.1016/S2468-1253(19)30086-XDOI Listing
August 2019
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