Search

Purpose: The aim of the study was to evaluate the safety/tolerability and pharmacokinetics of simlukafusp alfa (FAP-IL2v), an immunocytokine containing an anti-fibroblast activation protein-α (FAP) antibody and an IL2 variant, administered alone or with the PDL1 inhibitor atezolizumab, in Japanese patients with advanced solid tumors., Patients and Methods: In this phase 1, open-label, dose-escalation study, patients received i.v. FAP-IL2v at 10 or 15/20 mg alone or 10 mg when combined with i.v. atezolizumab. The primary objectives were identification of dose-limiting toxicities (DLT), recommended dose, and maximum tolerated dose, and evaluation of the safety/tolerability and pharmacokinetics of FAP-IL2v alone and combined with atezolizumab., Results: All 11 patients experienced adverse events (AE) during FAP-IL2v treatment. Although most AEs were of mild severity, four treatment-related AEs led to study treatment discontinuation in two patients: one with infusion-related reaction, hypotension, and capillary leak syndrome, and the other with increased aspartate aminotransferase. No AE-related deaths occurred. One DLT (grade 3 hypotension) occurred in a patient receiving FAP-IL2v 15/20 mg alone. The recommended dose and maximum tolerated dose could not be determined. The pharmacokinetics of FAP-IL2v remained similar with or without atezolizumab. The study was terminated early as FAP-IL2v development was discontinued because of portfolio prioritization (not for efficacy/safety reasons)., Conclusions: This study describes the safety/tolerability of FAP-IL2v 10 mg alone and in combination with atezolizumab in Japanese patients with advanced solid tumors; one DLT (hypotension) occurred with FAP-IL2v 15/20 mg. However, dose escalation of FAP-IL2v was not conducted because of early study termination., Significance: This phase I study assessed the safety/tolerability and PK of simlukafusp alfa alone or combined with atezolizumab in Japanese patients with advanced solid tumors. No notable differences in PK were noted with the combination versus simlukafusp alfa alone; however, high-dose simlukafusp alfa treatment was associated with recombinant IL2-related toxicity, despite the drug's FAP targeting and IL2Rβγ-biased IL2 variant design., (©2024 The Authors; Published by the American Association for Cancer Research.)

Purpose: Tiragolumab is a monoclonal antibody that binds to the inhibitory immune checkpoint TIGIT (T-cell immunoreceptor with Ig and ITIM domains). In early phase clinical trials, tiragolumab in combination with the programmed death-ligand 1-inhibitor atezolizumab was well tolerated and has demonstrated preliminary anti-tumor activity in patients with advanced/metastatic solid tumors. We report the results of a phase I study of tiragolumab plus atezolizumab in Japanese patients (jRCT2080224926)., Methods: Japanese patients ≥ 20 years old received tiragolumab (600 mg) and atezolizumab (1200 mg) intravenously every 21 days until unacceptable toxicity or disease progression. Primary endpoints were safety and pharmacokinetic (PK) parameters of tiragolumab plus atezolizumab. Secondary endpoints were anti-tumor activity., Results: Three patients were enrolled with diagnoses of non-small cell lung cancer, pancreatic cancer, and cholangiocarcinoma. No dose-limiting toxicities were observed. Two patients experienced treatment-related adverse events (AEs) of any grade. There were no grade ≥ 3 AEs, serious AEs, AEs leading to discontinuation, modification or withdrawal of any study drug, or AEs leading to death. At cycle 1, mean PK parameters of tiragolumab were as follows: C max 217 μg/mL; C min 54.9 μg/mL; area under the concentration-time curve from 0 to the last measurable concentration, 2000 μg·day/mL; t 1/2 , 17.6 days. Best overall response was stable disease in two patients., Conclusion: Tiragolumab plus atezolizumab was well tolerated in Japanese patients with advanced/metastatic solid tumors, and no differences in tiragolumab PK characteristics were noted between Japanese patients enrolled in this study, and non-Japanese patients enrolled in a global phase Ia/Ib study. These results may support the inclusion of Japanese patients in ongoing global phase III clinical trials., Trial Registration Number: jRCT2080224926., (© 2024. The Author(s).)

Established treatment options for rare cancers are limited by the small number of patients. The current comprehensive genomic profiling (CGP) testing might not fully exploit opportunities for precision oncology in patients with rare cancers. Therefore, we aimed to explore the factors associated with CGP testing utility in rare cancers and identify barriers to implementing precision oncology. Patients who underwent CGP testing at our institution between September 2019 and June 2021 were enrolled in this retrospective study. Based on their results, the patients received molecularly targeted drugs or immune checkpoint inhibitors. Univariate and multivariate analyses evaluated the association between patient characteristics and the proportion of patients receiving molecularly targeted drugs. Overall, 790 patients underwent CGP testing. Among them, 333 patients with rare cancers were identified, of whom 278 (83.5%) had actionable genomic alterations, 127 (38.1%) had druggable genomic alterations, and 25 (7.5%) received genomically matched therapy. The proportion of patients receiving molecularly targeted drugs was significantly higher among those with treatment options with evidence levels A-D (8.7%) than those without treatment options with evidence levels A-D (2.9%). A potential barrier to CGP testing utility in rare cancers is the limited number of molecularly targeted drugs with clinical evidence. We propose that CGP testing be performed in patients with rare cancers who have treatment options with evidence levels A-D to maximize CGP testing utility in real-world practice., (© 2024 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Purpose: TAS-117 is a highly potent and selective, oral, allosteric pan-AKT inhibitor under development for advanced/metastatic solid tumors. The safety, clinical pharmacology, pharmacogenomics and efficacy were investigated., Methods: This phase I, open-label, non-randomized, dose-escalating, first-in-human study enrolled patients with advanced/metastatic solid tumors and comprised three phases (dose escalation phase [DEP], regimen modification phase [RMP], and safety assessment phase [SAP]). The SAP dose and regimen were determined in the DEP and RMP. Once-daily and intermittent dosing (4 days on/3 days off, 21-day cycles) were investigated. The primary endpoints were dose-limiting toxicities (DLTs) in Cycle 1 of the DEP and RMP and incidences of adverse events (AEs) and adverse drug reactions (ADRs) in the SAP. Secondary endpoints included pharmacokinetics, pharmacodynamics, pharmacogenomics, and antitumor activity., Results: Of 66 enrolled patients, 65 received TAS-117 (DEP, n = 12; RMP, n = 10; SAP, n = 43). No DLTs were reported with 24-mg/day intermittent dosing, which was selected as a recommended dose in SAP. In the SAP, 98.5% of patients experienced both AEs and ADRs (grade ≥ 3, 67.7% and 60.0%, respectively). In the dose range tested (8 to 32 mg/day), TAS-117 pharmacokinetics were dose proportional, and pharmacodynamic analysis showed a reduction of phosphorylated PRAS40, a direct substrate of AKT. Four patients in the SAP had confirmed partial response., Conclusion: Oral doses of TAS-117 once daily up to 16 mg/day and intermittent dosing of 24 mg/day were well tolerated. TAS-117 pharmacokinetics were dose proportional at the doses evaluated. Antitumor activity may occur through AKT inhibition., Trial Registration: jRCT2080222728 (January 29, 2015)., (© 2024. The Author(s).)

Background: Retifanlimab is a humanized monoclonal antibody targeting programmed death protein-1, and INCB001158 is an oral arginase inhibitor. This phase Ib study investigated retifanlimab, INCB001158, and their combination in Japanese patients with advanced solid tumors., Methods: Patients received retifanlimab (500 mg every 4 weeks [Q4W] i.v.) or escalating doses of INCB001158 (75 or 100 mg twice daily [BID]) monotherapy in Part 1 and combination of retifanlimab (500 mg Q4W) and INCB001158 (100 mg BID) in Part 2. Primary endpoints were safety, tolerability, dose-limiting toxicities (DLTs), and determination of recommended phase II doses in Japanese patients., Results: Eighteen patients (retifanlimab or INCB001158 monotherapy and combination; n = 6 each) were enrolled at 2 sites in Japan. There were no DLTs, fatal adverse events (AEs), or discontinuations due to AEs. Rash (all grade 1) was the most common treatment-emergent AE with retifanlimab (n = 6). Treatment-related AEs were reported with retifanlimab (n = 4) or INCB001158 (n = 2) monotherapy and with combination (n = 4); an immune-related AE (thyroid disorder, grade 2) was reported with combination. Two responses were observed with retifanlimab monotherapy (1 complete, 1 partial) and 1 stable disease (SD), for an overall response rate of 33.3% (95% confidence interval [CI], 4.3-77.7) and disease control rate (DCR) of 50% (95% CI, 11.8-88.2). Three patients had SD with INCB001158 monotherapy (DCR 50%; 95% CI, 11.8-88.2). No responses or SD were observed with combination therapy., Conclusion: Retifanlimab, INCB001158, and their combination had acceptable safety profiles. Promising retifanlimab antitumor activity warrants further investigation in Japanese patients., (© 2024 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Patients with cancer, particularly those undergoing chemotherapy, are at risk from the low immunogenicity of Coronavirus Disease 19 (COVID-19) vaccines., Methods: This prospective study assessed the seroconversion rate of COVID-19 vaccines among patients with cancer and hospital staff. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein-specific IgG (S-IgG) concentrations were evaluated before the first vaccination, and 1-3 and 4-6 months after the second vaccination. The primary endpoint was the seroconversion rate measured 1-3 months after the second vaccine., Results: In total, 590 patients and 183 healthy hospital staff were analyzed. At 1-3 months after the second vaccination, the S-IgG antibody concentration exceeded the cut-off value (20 BAU/mL) in 96.1% (567/590) of the patients with cancer and 100% (183/183) of the healthy controls (p = 0.0024). At 4-6 months after the second vaccination, the S-IgG antibody concentration exceeded the cut-off value (20 BAU/ml for S-IgG) in 93.1% (461/495) of the patients with cancer and 100% (170/170) of the healthy controls (p < 0.0001). Old age, being male, and low lymphocyte count were related to low SARS-CoV-2 S-IgG levels 1-3 months after the second vaccination among patients, while body mass index, smoking history, and serum albumin level were not. Patients undergoing platinum combination therapy and alkylating agent among cytotoxic drugs, and PARP inhibitor, mTOR inhibitor, and BCR-ABL inhibitor exhibited a low S-IgG antibody concentration compared to the no treatment group., Conclusions: COVID-19 vaccine immunogenicity was reduced among patients with cancer, especially under several treatment regimens., (© 2024. The Author(s).)

Background: Comprehensive genome profiling (CGP) serves as a guide for suitable genomically matched therapies for patients with cancer. However, little is known about the impact of the timing and types of cancer on the therapeutic benefit of CGP., Materials and Methods: A single hospital-based pan-cancer prospective study (TOP-GEAR; UMIN000011141) was conducted to examine the benefit of CGP with respect to the timing and types of cancer. Patients with advanced solid tumors (>30 types) who either progressed with or without standard treatments were genotyped using a single CGP test. The subjects were followed up for a median duration of 590 days to examine therapeutic response, using progression-free survival (PFS), PFS ratio, and factors associated with therapeutic response., Results: Among the 507 patients, 62 (12.2%) received matched therapies with an overall response rate (ORR) of 32.3%. The PFS ratios (≥1.3) were observed in 46.3% (19/41) of the evaluated patients. The proportion of subjects receiving such therapies in the rare cancer cohort was lower than that in the non-rare cancer cohort (9.6% and 17.4%, respectively; P = 0.010). However, ORR of the rare cancer patients was higher than that in the non-rare cancer cohort (43.8% and 20.0%, respectively; P = 0.046). Moreover, ORR of matched therapies in the first or second line after receiving the CGP test was higher than that in the third or later lines (62.5% and 21.7%, respectively; P = 0.003). Rare cancer and early-line treatment were significantly and independently associated with ORR of matched therapies in multivariable analysis (P = 0.017 and 0.004, respectively)., Conclusion: Patients with rare cancer preferentially benefited from tumor mutation profiling by increasing the chances of therapeutic response to matched therapies. Early-line treatments after profiling increase the therapeutic benefit, irrespective of tumor types., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: We aimed to assess the safety, pharmacokinetic profile, and antitumor activity of adavosertib monotherapy in Japanese patients with advanced solid tumors., Materials and Methods: This was a single-center, open-label, phase I study with two consecutive cohorts (250 mg and 200 mg cohorts). Patients received adavosertib at 250 mg or 200 mg, orally once daily for 5 days on and 2 days off for Weeks 1 and 2 of a 21-day cycle., Results: Dose-limiting toxicities (Grade 3 febrile neutropenia) occurred in 2/6 patients in the 250 mg cohort. None of the three patients in the 200 mg cohort developed dose-limiting toxicities. The most frequent treatment-emergent adverse event was nausea (250 mg: 83.3 %; 200 mg: 100.0 %). Median time to peak drug concentration was 4.03 and 2.08 h after the first dose and 2.82 and 1.90 h after multiple dosing in the 250 and 200 mg cohorts, respectively; respective mean terminal elimination half-lives were 7.36 and 7.30 h (first dose) and 10.55 and 8.88 h (multiple dosing). Systemic exposure increased in a slightly more than dose-proportional manner. No RECIST v1.1 response was observed. Disease control rate was 0 % and 33.3 % in the 250 and 200 mg cohorts, respectively. One patient (33.3 %) in the 200 mg cohort showed a best overall response of stable disease at ≥ 8 weeks; the rest showed progressive disease., Conclusions: Adavosertib 200 mg once daily was well tolerated in this patient population and no safety concerns were raised. Exposure increased in a slightly more than dose-proportional manner and limited antitumor activity was shown., Trial Registration: ClinicalTrials.gov, NCT04462952., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: S Kondo has received research funding from AstraZeneca, Chugai, Astellas, AbbVie, Eisai, and Incyte. Y Katsuya has no conflicts of interest to disclose. K Yonemori has received honoraria from Pfizer, Eisai, AstraZeneca, Eli Lilly, Takeda, Chugai, Fuji Film Pharma, PDR Pharma, MSD, Boehringer Ingelheim, Ono, Daiichi-Sankyo, Bayer, Jansen, and Sanofi; and research funding from MSD, Daiichi-Sankyo, AstraZeneca, Taiho, Pfizer, Novartis, Takeda, Chugai, Ono, Sanofi, Seattle genetics, Eisai, Eli Lilly, Genmab, Boehringer Ingelheim, Kyowa Hakko Kirin, Nihon Kayaku, and Haihe. N Yamamoto has a leadership/advisory role in Healios; has received honoraria from Chugai; and has received research funding from Astellas, Chugai, Eisai, Taiho, BMS, Pfizer, Novartis, Eli Lilly, AbbVie, Daiichi-Sankyo, Bayer, Boehringer Ingelheim, Kyowa Kirin, Takeda, Ono, Janssen Pharma, MSD, MERCK, GSK, Sumitomo Pharma, Chiome Bioscience, Otsuka, Carna Biosciences, Genmab, Shionogi, TORAY, KAKEN, AstraZeneca, Cmic, InventisBio, and Rakuten Medical. K Komuro, M Sugeno, T Kawata, D Ghiorghiu, and D Meulendijks are employees of AstraZeneca and may own stock in AstraZeneca., (Copyright © 2024. Published by Elsevier Ltd.)

The bevacizumab (bev)/olaparib (ola) maintenance regimen was approved for BRCA1/2-mutated (BRCAmut) and Homologous Recombination Deficient (HRD) high-grade Advanced Ovarian Cancer (AOC) first line setting, based on a significantly improved progression-free survival (PFS) compared to bev alone in the PAOLA-1/ENGOT-ov25 trial (NCT02477644), where HRD was detected by MyChoice CDx PLUS test. The academic shallowHRDv2 test was developed based on shallow whole-genome sequencing as an alternative to MyChoice. Analytical and clinical validities of shallowHRDv2 as compared to MyChoice on 449 PAOLA-1 tumor samples are presented. The overall agreement between shallowHRDv2 and MyChoice was 94% (369/394). Less non-contributive tests were observed with shallowHRDv2 (15/449; 3%) than with MyChoice (51/449; 11%). Patients with HRD tumors according to shallowHRDv2 (including BRCAmut) showed a significantly prolonged PFS with bev+ola versus bev (median PFS: 65.7 versus 20.3 months, hazard ratio (HR): 0.36 [95% CI: 0.24-0.53]). This benefit was significant also for BRCA1/2 wild-type tumors (40.8 versus 19.5 months, HR: 0.45 [95% CI: 0.26-0.76]). ShallowHRDv2 is a performant, clinically validated, and cost-effective test for HRD detection., (© 2023. The Author(s).)

Importance: Genotype-matched trials, which are becoming increasingly important in the precision oncology era, require referrals from institutions providing comprehensive genomic profiling (CGP) testing to those conducting these trials, and the travel burden for trial participation is significant. However, it remains unknown whether travel time or distance are associated with genotype-matched trial participation., Objective: To assess whether travel time or distance are associated with disparities in genotype-matched trial participation following CGP testing., Design, Setting, and Participants: This retrospective cohort study from June 2020 to June 2022 included patients with advanced or metastatic solid tumors referred to the National Cancer Center Hospital for participation in genotype-matched trials following CGP testing and discussion by molecular tumor boards. Data were analyzed from June to October 2022., Exposures: Travel time and distance., Main Outcomes and Measures: The primary and secondary outcomes were enrollment in genotype-matched trials and all-cancer clinical trials, respectively., Results: Of 1127 patients (mean [range] age, 62 [16-85] years; 584 women [52%]; all residents of Japan), 127 (11%) and 241 (21%) were enrolled in genotype-matched trials and all-cancer clinical trials, respectively. The overall median (IQR) travel distance and time were 38 (21-107) km and 55 (35-110) minutes, respectively. On multivariable regression with 23 covariates, travel distance (≥100 km vs <100 km) was not associated with the likelihood of genotype-matched trial participation (26 of 310 patients [8%] vs 101 of 807 patients [12%]; odds ratio [OR], 0.64; 95% CI, 0.40-1.02), whereas in patients with travel time of 120 minutes or more, the likelihood of genotype-matched trial participation was significantly lower than those with travel time less than 120 minutes (19 of 276 patients [7%] vs 108 of 851 patients [13%]; OR, 0.51; 95% CI, 0.29-0.84). The likelihood of genotype-matched trial participation decreased as travel time increased from less than 40 (38 of 283 patients [13%]) to 40 to 120 (70 of 568 patients [12%]) and 120 or more (19 of 276 patients [7%]) minutes (OR, 0.74; 95% CI, 0.48-1.17; OR, 0.41; 95% CI, 0.22-0.74, respectively). Neither travel time nor distance were associated with the likelihood of all-cancer clinical trial participation., Conclusions and Relevance: In this cohort study of patients undergoing CGP testing, an increased travel time was associated with a decreased likelihood of genotype-matched trial participation. This warrants further research on interventions, such as decentralization of clinical trials to mitigate travel burden.

Purpose: To determine a recommended dose of liposomal eribulin (E7389-LF) in combination with nivolumab in patients with advanced solid tumors, and to evaluate the safety, efficacy, pharmacokinetics, and biomarker impact of this regimen., Experimental Design: Japanese patients with advanced, nonresectable, or recurrent solid tumors and no existing alternative standard/effective therapy (except nivolumab monotherapy) were assigned to either E7389-LF 1.7 mg/m 2 plus nivolumab 360 mg every 3 weeks, E7389-LF 2.1 mg/m 2 plus nivolumab 360 mg every 3 weeks, E7389-LF 1.1 mg/m 2 plus nivolumab 240 mg every 2 weeks, or E7389-LF 1.4 mg/m 2 plus nivolumab 240 mg every 2 weeks. Primary objectives were to evaluate the safety/tolerability of each dose cohort and to determine the recommended phase II dose (RP2D). Secondary/exploratory objectives, including safety [dose-limiting toxicities (DLT) and adverse events (AE)], pharmacokinetics, efficacy [including objective response rate (ORR)], and biomarker results were used in determining the RP2D., Results: Twenty-five patients were enrolled to treatment [E7389-LF 1.7 mg/mg 2 every 3 weeks ( n = 6), E7389-LF 2.1 mg/m 2 every 3 weeks ( n = 6), E7389-LF 1.1 mg/m 2 every 2 weeks ( n = 7), E7389-LF 1.4 mg/m 2 every 2 weeks ( n = 6)]. Twenty-four patients were evaluated for DLTs, of whom 3 had DLTs (1 at E7389-LF 1.7 mg/m 2 every 3 weeks, 1 at 1.1 mg/m 2 every 2 weeks, and 1 at 1.4 mg/m 2 every 2 weeks). All patients had ≥1 treatment-related treatment-emergent AE (TEAE); 68.0% had ≥1 grade 3-4 treatment-related TEAE. Changes in vasculature and IFN-related biomarkers were seen in each cohort. The overall ORR was 16%., Conclusions: E7389-LF plus nivolumab was tolerable overall; the recommended dose for future study was 2.1 mg/m 2 plus nivolumab 360 mg every 3 weeks., Significance: This phase Ib part of a phase Ib/II study assessed the tolerability and activity of a liposomal formulation of eribulin (E7389-LF) plus nivolumab in 25 patients with advanced solid tumors. The combination was tolerable overall; 4 patients had a partial response. Vasculature and immune-related biomarker levels increased, suggesting vascular remodeling., (© 2023 The Authors; Published by the American Association for Cancer Research.)

This report summarizes the presentations and discussions in the first Asian Clinical Trials Network for Cancers (ATLAS) international symposium that was held on 24 April 2022, in Bangkok, Thailand, and hosted by the National Cancer Center Hospital (NCCH), co-hosted by the Pharmaceuticals and Medical Devices Agency (PMDA), Clinical Research Malaysia (CRM) and the Thai Society of Clinical Oncology (TSCO), and supported by Embassy of Japan in Thailand. Since 2020, the NCCH has conducted the ATLAS project to enhance research environments and infrastructures to facilitate international clinical research and cancer genomic medicine in the Asian region. The purpose of the symposium was to discuss what we can achieve under the ATLAS project, to share the latest topics and common issues in cancer research and to facilitate mutual understanding. Invitees included stakeholders from academic institutions, mainly at ATLAS collaborative sites, as well as Asian regulatory authorities. The invited speakers discussed ongoing collaborative research, regulatory perspectives to improve new drug access in Asia, the status of phase I trials in Asia, the introduction of research activities at the National Cancer Center (NCC) and the implementation of genomic medicine. As the next steps after this symposium, the ATLAS project will foster increased cooperation between investigators, regulatory authorities and other stakeholders relevant to cancer research, and establish a sustainable pan-Asian cancer research group to increase the number of clinical trials and deliver novel drugs to patients with cancer in Asia., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Tissue specimen quality assurance is a major issue of precision medicine for rare cancers. However, the laboratory standards and quality of pathological specimens prepared in Asian hospitals remain unknown. To understand the methods in Southeast Asian oncology hospitals and to clarify how pre-analytics affect the quality of formalin-fixed paraffin-embedded (FFPE) specimens, a questionnaire surveying pre-analytical procedures (Part I) was administered, quality assessment of immunohistochemistry (IHC) staining and DNA/RNA extracted from the representative FFPE specimens from each hospital (Part II) was conducted, and the quality of DNA/RNA extracted from FFPE of rare-cancer patients for genomic sequencing (Part III) was examined. Quality measurements for DNA/RNA included ΔΔCt, DV200, and cDNA yield. Six major cancer hospitals from Malaysia, Philippines, and Vietnam participated. One hospital showed unacceptable quality for the DNA/RNA assessment, but improved by revising laboratory procedures. Only 57% (n = 73) of the 128 rare-cancer patients' specimens met both DNA and RNA quality criteria for next-generation sequencing. Median DV200 was 80.7% and 64.3% for qualified and failed RNA, respectively. Median ΔΔCt was 1.25 for qualified and 4.89 for failed DNA. Longer storage period was significantly associated with poor DNA (fail to qualify ratio = 1579:321 days, p < 0.001) and RNA (fail to qualify ratio = 1070:280 days, p < 0.001). After improvement of pre-analytical factors, the qualification rate increased for hospitals A and E from 41.5% to 70.5% and 62.5% to 86%, respectively. This is the first report to elucidate the pre-analytical laboratory procedures of main Southeast Asian oncology hospitals. An external quality assessment program may improve factors associated with tumor FFPE specimen quality., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

To determine the maximum tolerated dose (MTD) and recommended dose (RD) of orally-administered bendamustine in Japanese patients with advanced solid tumors. The optimal dosing schedule, safety, pharmacokinetics, and preliminary antitumor effects were also evaluated. A multicenter, open-label trial with a standard 3 + 3 design and dose escalation by dose-limiting toxicity (DLT) was conducted. The treatment schedules were once daily for 7, 14, and 21 days every 3 weeks as one cycle. The total dose per cycle was increased from 175 to 840 mg/m 2 . Eighteen patients were enrolled in this study. DLT occurred in one of six patients at 75 mg/m 2 /day × 7 days, and one of three patients at 37.5 mg/m 2 /day × 14 days and 25 mg/m 2 /day × 21 days. However, the delayed recovery from a decrease in neutrophil or platelet count hampered the start of subsequent treatment cycles, and the trend was more prominent at 37.5 mg/m 2 /day × 14 days and 25 mg/m 2 /day × 21 days than in 75 mg/m 2 /day × 7 days. MTD was determined as 75 mg/m 2 /day × 7 days to allow acceptable hematologic recovery. The pharmacokinetics of orally-administered bendamustine were generally dose-dependent; however, the inter-individual variability is relatively large. The major adverse events were hematologic toxicities; gastrointestinal disorders were generally mild. Adverse drug reactions did not lead to the discontinuation of the drug. A partial response was observed in two of six patients (prostatic small cell carcinoma and thymic carcinoma) at 75 mg/m 2 /day × 7 days. The RD and optimal dosing schedule of orally-administered bendamustine was 75 mg/m 2 once daily for 7 days every 3 weeks for the treatment of advanced solid tumors. (Trial registration number ClinicalTrials.gov NCT03604679. Registration date July 27, 2018)., (© 2022. The Author(s).)

Ocular toxicities arising from anti-cancer drugs occur sporadically and are sometimes underestimated because they are not life-threatening. Reports focusing on ocular toxicities from cancer therapy are limited. We investigated the detailed progress of ocular toxicities of anti-cancer drugs including first-in-class ones. A retrospective review of medical records was conducted for patients who were involved in early phase clinical trials with scheduled ophthalmologic examinations according to their protocols between January 2014 and August 2021. Patients with ocular toxicity suspected to be related to the investigational drugs in the ophthalmic examination were investigated in detail. In total, 37 ocular toxicities related to investigational drugs occurred in 7.6% of patients (33/434). The median age of the 33 patients was 61 years (range, 33-76 years), and 20 were male. Causal drugs with a high incidence of ocular toxicities were HSP90 inhibitors and FGFR inhibitors. Retinopathy was most frequent, while conjunctivitis, dry eye, keratitis, keratopathy, and uveitis were also observed. Dim vision as a subjective finding was a unique adverse event. Most patients developed ocular toxicities even though their dose was below the drug's maximum tolerated dose. Except for one case, all ocular toxicities occurred bilaterally. About 60% (22/37) of ocular toxicity cases needed a temporary hold of the drug. All except for three cases fully recovered. This study reported the risks and timing of the onset of a variety of ocular toxicities of anti-cancer drugs, which were fundamentally controllable. (Trial registration number. Retrospectively registered)., (© 2022. The Author(s).)

Previous clinical trials indicate that 10%-25% of patients received genomically matched therapy after comprehensive genomic profiling (CGP) tests. However, the clinical utility of CGP tests has not been assessed in clinical practice. We assessed the clinical utility of CGP tests for advanced or metastatic solid tumor and determined the proportion of patients receiving genomically matched therapy among those with common and non-common cancers. From August 2019 to July 2020, a total of 418 patients had undergone CGP tests, and the results were discussed through the molecular tumor board at our site. The median age of patients was 57 (range: 3-86) years. Colorectal cancer was the most common, with 47 (11%) patients. Actionable genomic alterations (median 3, range: 1-17) were identified in 368 (88.0%) of 418 patients. Druggable genomic alterations were determined in 196 (46.9%) of 418 patients through the molecular tumor board. Genomically matched therapy was administered as the subsequent line of therapy in 51 (12.2%) patients, which is comparable to the proportion we previously reported in a clinical trial (13.4%) (p = 0.6919). The proportion of patients receiving genomically matched therapy was significantly higher among those with common cancers (16.2%) than non-common cancers (9.4%) (p = 0.0365). Genomically matched therapy after the CGP tests was administered to 12.2% of patients, which is similar to the proportion reported in the previous clinical trials. The clinical utility of CGP tests in patients with common cancers greatly exceeded that in patients with non-common cancers., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Purpose: We conducted a first-in-human, dose-escalation study, to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and activity of TAK-931, a cell division cycle 7 inhibitor, in Japanese patients with advanced solid tumors., Experimental Design: Patients ages ≥20 years received oral TAK-931: once daily for 14 days in 21-day cycles (schedule A; from 30 mg); once daily or twice daily for 7 days on, 7 days off in 28-day cycles (schedule B; from 60 mg); continuous once daily (schedule D; from 20 mg); or once daily for 2 days on, 5 days off (schedule E; from 100 mg) in 21-day cycles., Results: Of the 80 patients enrolled, all had prior systemic treatment and 86% had stage IV disease. In schedule A, 2 patients experienced dose-limiting toxicities (DLTs) of grade 4 neutropenia and the maximum tolerated dose (MTD) was 50 mg. In schedule B, 4 patients experienced DLTs of grade 3 febrile neutropenia ( n = 3) or grade 4 neutropenia ( n = 1); the MTD was 100 mg. Schedules D and E were discontinued before MTD determination. The most common adverse events were nausea (60%) and neutropenia (56%). Time to maximum plasma concentration of TAK-931 was approximately 1-4 hours postdose; systemic exposure was approximately dose proportional. Posttreatment pharmacodynamic effects correlating to drug exposure were observed. Overall, 5 patients achieved a partial response., Conclusions: TAK-931 was tolerable with a manageable safety profile. TAK-931 50 mg once daily days 1-14 in 21-day cycles was selected as a recommended phase II dose and achieved proof of mechanism., Trial Registration Id: NCT02699749., Significance: This was the first-in-human study of the CDC7 inhibitor, TAK-931, in patients with solid tumors. TAK-931 was generally tolerable with a manageable safety profile. The recommend phase II dose was determined to be TAK-931 50 mg administered once daily on days 1-14 of each 21-day cycle. A phase II study is ongoing to confirm the safety, tolerability, and antitumor activity of TAK-931 in patients with metastatic solid tumors., Competing Interests: Y. Kuboki reports grants and personal fees from Takeda during the conduct of the study; grants and personal fees from Taiho, Lilly, Boehringer Ingelheim, Bristol-Myers-Squibb; grants from Astelas, Daiichi-Sankyo, AstraZeneca, Chugai, Genmab, GlaxoSmithkline, Incyte, Abbie; grants, personal fees, and non-financial support from Amgen outside the submitted work. T. Shimizu reports grants and personal fees from Takeda during the conduct of the study; grants from AbbVie, Eli Lilly, LOXO Oncology, Novartis, Daiichi-Sankyo, Bristol-Myers Squibb, Pfizer, Eisai, AstraZeneca, Astellas, Incyte, Chordia Therapeutics, 3D-Medicine, Symbio Pharmaceuticals, PharmaMar; personal fees from Chugai, MSD, Eli Lilly, and Chordia Therapeutics outside the submitted work. K. Yonemori reports personal fees from Pfizer, Eisai, Takeda, AstraZeneca, Eli Lilly, Daiichi Sankyo, Chugai, Fuji Film, MSD, Ono, Bayel, Boeringer Ingelheim, OncoXerna, Genmab; grants from MSD, Takeda, Sanofi, Chugai, Daiichi Sankyo, AstraZeneca, Taiho, Pfizer, Novartis, Ono, Seagen, genmab, Eli Lilly, Haihe, Boeringer Ingelheim, Nihon Kayaku, and Bayel outside the submitted work. T. Kojima reports personal fees from Merck Biopharma Co., Ltd, Oncolys BioPharma Inc, Astellas Pharma Inc, Bristol Myers Squibb, Bristol Myers Squibb, Ono Pharmaceutical Co., Ltd, Covidien Japan, Inc, MSD K.K, Taiho Pharmaceutical Co., Ltd., Oncolys BioPharma Inc; grants from Ono Pharmaceutical Co., Ltd., Bristol Myers Squibb, BeiGene Ltd., EPS Corporation, MSD K.K, Amgen Inc, Shionogi & Co., Ltd, Chugai Pharmaceutical Co., Ltd, Taiho Pharmaceutical Co., Ltd., Parexel International, and Merck Biopharma Co., Ltd. outside the submitted work. S. Koganemaru reports other from Eisai Inc. outside the submitted work. S. Iwasa reports grants from Takeda during the conduct of the study; grants and personal fees from Daiichi Sankyo, Taiho, BMS, Ono; personal fees from Lilly, Chugai, Agilent; grants from Pfizer, Zymeworks, Segen, Bayer, and Amgen outside the submitted work. K. Harano reports personal fees from AstraZeneca, Takeda, Chugai, and Nihon Kayaku; grants and personal fees from MSD; grants from Diichi-Sankyo during the conduct of the study; personal fees from AstraZeneca, Takeda, Chugai, and Nihon Kayaku; grants and personal fees from MSD; grants from Daiichi-Sankyo outside the submitted work. T. Koyama reports personal fees from Sysmex; grants from Chugai, Lilly, Takeda, Daiichi Sankyo, and Novartis outside the submitted work. X. Zhou reports other from Takeda Development Center Americas outside the submitted work. T. Yanai reports personal fees from Takeda Pharmaceutical company outside the submitted work; and is an employee of Takeda Pharmaceutical Company. I. Garcia-Ribas reports personal fees from Takeda during the conduct of the study. T. Doi reports grants from Lilly, MSD, Novartis, Merck Biopharma, Janssen Pharma, Boehringer Ingelheim, Pfizer, Eisai, IQVIA; grants and personal fees from Daiichi Sankyo, Sumitomo Dainippon, Taiho, BMS, Abbvie, Chugai Pharma; personal fees from Takeda, Bayer, Rakuten Medical, Otsuka Pharma, Kaken Pharma, Kyowa Kirin, Shionogi, PRA Health Science, Ono Pharma, and AstraZeneca outside the submitted work. N. Yamamoto reports grants from Chugai, Taiho, Eisai, Eli Lilly, Astellas, BMS, Novartis, Daiichi-Sankyo, Pfizer, Boehringer Ingelheim, Kyowa-Hakko Kirin, Bayer, Ono Pharmaceutical Co., Ltd, Takeda, Janssen Pharma, MSD, Merck, GSK, Sumitomo Dainippon, Chiome Bioscience Inc., Otsuka, Carna Biosciences, Genmab, Shionogi, TORAY; personal fees from Ono Pharmaceutical Co., Ltd, Chugai, BMS, Sysmex, Eisai, Eisai, Otsuka, Takeda, Boehringer Ingelheim, and Cimic outside the submitted work. No disclosures were reported by the other authors., (© 2022 The Authors; Published by the American Association for Cancer Research.)

Envafolimab is the first and only globally approved subcutaneously injectable PD-L1 antibody. This open-label, multicenter Phase 1 trial assessed the safety, tolerability, pharmacokinetic (PK) profile, and efficacy of envafolimab as a single agent in Japanese patients with advanced solid tumors. In the dose-escalation phase, 10 patients received subcutaneous (SC) envafolimab QW at 1.0 mg/kg, 2.5 mg/kg and 5.0 mg/kg. In the dose-expansion phase, 16 patients were treated at 2.5 or 5.0 mg/kg Q2W in part-1 and 9 patients received SC envafolimab 300 mg Q4W in part-2. No dose-limiting toxicities (DLTs) were reported. Envafolimab was well tolerated and no new safety signals were identified compared with other marketed products of the same class. Three patients reported Grade ≥ 3 envafolimab-related treatment-emergent adverse events (TEAE), including adrenal insufficiency, cerebral infarction, and immune-mediated enterocolitis. Envafolimab demonstrated dose-proportional increases in area under the time-concentration curve (AUC) and maximum serum concentration (C max ). The overall response rate (ORR) was 11.4% (n = 4) and disease control rate (DCR) was 34.3% (n = 12). Consistent with that observed in other envafolimab Phase 1 trials and approved PD-1/PD-L1 inhibitors, the safety profile of SC envafolimab in Japanese patients with advanced solid tumors was well tolerated with efficacy comparable to IV administered treatments. Pharmacokinetics data and preliminary anti-tumor response support dose regimens with longer dosing intervals (Q2W or Q4W). As such, envafolimab offers patients a more convenient treatment option than currently available intravenously administered PD-1/PD-L1 inhibitors. CLINICALTRIALS.GOV IDENTIFIER: NCT03248843(August 14, 2017)., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Aberrant fibroblast growth factor receptor (FGFR) signaling can substantially influence oncogenicity. Despite that FGFR gene abnormality is often detected by cancer genome profiling tests, there is no tumor-agnostic approval yet for these aberrations. E7090 (tasurgratinib) is an orally available selective tyrosine kinase inhibitor of FGFR1-3. Specific FGFR alterations were previously reported to be highly sensitive to E7090 based on a high-throughput functional evaluation method, called mixed-all-nominated-mutants-in-one (MANO) method, narrowing down the most promising targets. This trial was focused on the alterations identified by the MANO method and was performed under the nationwide large registry network for rare cancers in Japan (MASTER KEY Project)., Methods/design: This single-arm Phase 2 trial was designed to evaluate the safety and efficacy of E7090 in patients with advanced or recurrent solid tumors harboring FGFR alterations. Three cohorts were set based on the type of FGFR alterations and the results of MANO method. A maximum of 45 patients will be enrolled from 5 institutions over 2.5 years. E7090 will be administered once daily as an oral single agent in 28-day cycles. The primary endpoint is the objective overall response rate; whereas, the secondary endpoints include progression-free survival, overall survival, disease control rate, safety, duration of response, and time to response. Ethics approval was granted by the National Cancer Center Hospital Certified Review Board. Patient enrollment began in June 2021., Discussion: A unique investigator-initiated multicenter Phase 2 trial was designed based on the results of preclinical investigation aiming to acquire the approval of E7090 for solid tumors harboring FGFR gene alterations. The findings may serve as a novel model for the development of tumor-agnostic molecular targeted therapies against rare genetic abnormalities., Trial Registration: Japan Registry of Clinical Trial: jRCT2031210043 (registered April 20, 2021) ClinicalTrials.gov: NCT04962867 (registered July 15, 2021)., (© 2022. The Author(s).)

In first-in-human (FIH) trials, sequential tumor biopsies, i.e., two consecutive tumor biopsies, the first performed at baseline (pretreatment) and the second during the early treatment period (on-treatment), provide proof of concept in investigational new drugs. We evaluated the success of sequential tumor biopsies in FIH trials, and explored approaches for improved success rates. We retrospectively reviewed the sequential tumor biopsies required in 17 of 52 FIH trials conducted from 2015 to 2020. One hundred and thirty-eight patients were identified. Success of either pretreatment or on-treatment biopsy alone, and of sequential tumor biopsies, was defined as the acquisition of viable tumor cells and as obtaining tumor cells from both biopsy specimens, respectively. The success rates of pretreatment and on-treatment biopsy were 98.6% and 94.2%, respectively, and of sequential tumor biopsies was 70.3%. Adverse events associated with the pretreatment biopsies (33.3% positive; 72.0% negative) and timing of the first imaging assessment (before on-treatment biopsy = 40.0%; after on-treatment biopsy = 82.7%) correlated with successful sequential tumor biopsies. The reasons for unsuccessful sequential tumor biopsies could be categorized into two groups: 1) patient refusal of the on-treatment biopsy (most frequently due to early disease progression); and 2) absence of tumor cells in the pretreatment or on-treatment biopsy specimen. We propose an approach to achieving greater success in sequential tumor biopsies in FIH trials; the first imaging assessment during the study should be scheduled after on-treatment biopsy. (Registration number UMIN000042487, Date of registration November 18, 2020)., (© 2022. The Author(s).)

Purpose: Investigate the frequency and prognostic factors of severe drug-induced interstitial lung disease (DILD) caused by antineoplastic drugs regardless of cancer types or type of drugs., Methods: From 2014 to 2018, we reviewed patients with a history of antineoplastic agents administration in the real-world database of our hospital's electronic medical record and extracted patients who experienced "severe" DILD, requiring hospitalization with treatment or developed during hospitalization and required treatment. We collected patients' backgrounds, clinical and radiological features, laboratory data, treatment, and survival outcomes., Results: 19,132 cancer patients received antineoplastic drug therapy during the study period, and 120 (0.62%) experienced severe DILD. The incidence of severe DILD in patients with thoracic cancer was highest among the patients included in this analysis (2.52% vs. 0.34% other cancers). Diffuse alveolar damage (DAD) pattern on CT was associated with higher mortality in patients with severe DILD compared with non-DAD pattern (hazard ratio [HR], 11.24; 95% CI, 4.82-26.2). Multivariate analysis revealed that the DAD pattern at diagnosis as severe DILD (HR, 3.59; 95% CI, 1.17-11.03), concurrent/previous interstitial lung disease (HR, 3.20; 95% CI, 1.27-8.10), and ECOG performance status of 2-4 (HR, 3.81; 95% CI, 1.10-13.17) were independent risk factors for mortality in patients with severe DILD., Conclusions: The frequency of severe DILD was highest in patients with thoracic cancer. The DAD pattern was associated with a poor outcome. From the perspective of DILD, special attention should be paid when administering antineoplastic agents to patients with thoracic cancer., (© 2022. The Author(s).)

Purpose: We report the dose-escalation part of a phase I study of liposomal eribulin (E7389-LF) in Japanese patients with advanced solid tumors and no alternative standard therapy., Patients and Methods: Patients ≥20 years old were enrolled. E7389-LF doses of 1.0 to 1.5 mg/m2 once every two weeks (Q2W) or 1.0 to 2.5 mg/m2 once every three weeks (Q3W) were planned. The primary objective was to determine the MTD by evaluating dose-limiting toxicities (DLT). Secondary objectives included safety/tolerability assessments, objective response rate (ORR), and progression-free survival; serum biomarker assessment was an exploratory objective., Results: Twenty-one patients were enrolled and treated; 12 in the Q3W group (1.0 mg/m2, n = 3; 1.5 mg/m2, n = 3; 2.0 mg/m2, n = 6) and 9 in the Q2W group (1.0 mg/m2, n=3; 1.5 mg/m2, n = 6). The Q3W and Q2W MTDs were 2.0 mg/m2 and 1.5 mg/m2, respectively. One patient receiving 2.0 mg/m2 Q3W had a DLT of grade 3 febrile neutropenia. The most common grade 3 treatment-emergent adverse events were neutropenia (66.7% in Q3W and Q2W) and leukopenia (Q3W, 58.3%; Q2W, 33.3%). One patient in the Q3W group (2.0 mg/m2) and 3 in the Q2W group (1.0 mg/m2, n = 1; 1.5 mg/m2, n = 2) achieved a partial response [overall ORR, 19.0%; 95% confidence interval (CI), 5.4-41.9]. Endothelial [TEK receptor tyrosine kinase (TEK), intercellular adhesion molecule 1 (ICAM1), vascular endothelial growth factor receptor 3 (VEGFR3), platelet/endothelial cell adhesion molecule 1 (PECAM1)], vasculature (collagen IV), and immune-related [interferon gamma (IFNγ), C-X-C motif chemokine ligand 11 (CXCL11), C-X-C motif chemokine ligand 10 (CXCL10)] biomarker levels were increased., Conclusions: E7389-LF was well tolerated at 2.0 mg/m2 Q3W and 1.5 mg/m2 Q2W. Considering the toxicity profile of both regimens, the recommended dose was 2.0 mg/m2 Q3W. Expansion cohorts are ongoing., (©2022 The Authors; Published by the American Association for Cancer Research.)

Background: Sapanisertib is an oral, highly selective inhibitor of mammalian target of rapamycin complexes 1 and 2., Objective: The aim of this study was to assess the safety, tolerability, pharmacokinetics, preliminary efficacy, and to establish the recommended phase 2 dose (RP2D) of sapanisertib., Patients and Methods: In this dose-escalation and expansion study, East Asian patients with nonhematologic malignancies received increasing sapanisertib doses once-daily (QD; starting at 2 mg) or once-weekly (QW; starting at 20 mg) in 28-day cycles., Results: Among 28 patients (QD dosing, n = 22; QW dosing, n = 6), three dose-limiting toxicities were reported (stomatitis [n = 2], gastrointestinal inflammation, gingivitis, and acute myocardial infarction [all n = 1]), all in the 4 mg QD cohort. The RP2D of sapanisertib was 3 mg QD. The most common adverse events were stomatitis (64%), nausea (50%), and decreased appetite (50%) in the QD arm, and nausea (100%), blood alkaline phosphatase increased (67%), and hyperglycemia (67%) in the QW arm. The T max of sapanisertib was ~ 0.5-2.6 h and the T 1/2 was ~ 5.9-7.6 h. Three patients achieved stable disease for ≥ 6 months (1 each in 3 mg QD, 4 mg QD and 20 mg QW cohorts, respectively); the clinical benefit rate was 45% and 67% in the QD and QW arms, respectively., Conclusions: The RP2D of sapanisertib in East Asian patients (3 mg QD) was lower than in Western patients (4 mg QD), but the pharmacokinetics and safety profiles were similar. Sapanisertib was well tolerated and showed moderate anti-tumor effects in heavily pretreated patients with nonhematologic malignancies., Nct Number: NCT03370302; Registered December 7, 2017., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

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 2 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 2 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 2 weekly dosing occurred in 1/5 patients; five patients had grade ≥ 2 abnormal LFT changes at 40- and 56-mg/m 2 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 2 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., (© 2021. The Author(s).)

Purpose: We assessed the intratumor pharmacokinetics of [fam-] trastuzumab deruxtecan, T-DXd (known as DS-8201a), a novel HER2-targeted antibody-drug conjugate, using phosphor-integrated dots (PID)-imaging analysis to elucidate its pharmacologic mechanism., Experimental Design: We used two mouse xenograft models administered T-DXd at the concentration of 4 mg/kg: (i) a heterogeneous model in which HER2-positive and HER2-negative cell lines were mixed, and (ii) a homogeneous model in which both cell types were transplanted separately into the same mouse. PID imaging involved immunostaining using novel high-intensity fluorescent nanoparticles. The distribution of T-DXd was assessed by PID imaging targeting the parent antibody, trastuzumab, and the payload, DXd, in serial frozen sections, respectively., Results: After T-DXd administration in the heterogeneous model, HER2 expression tended to decrease in a time-dependent manner. The distribution of trastuzumab and DXd was observed by PID imaging along the HER2-positive area throughout the observation period. A detailed comparison of the PID distribution between trastuzumab and DXd showed that trastuzumab matched almost perfectly with the HER2-positive area. In contrast, DXd exhibited widespread distribution in the surrounding HER2-negative area as well. In the HER2-negative tumor of the homogeneous model, the PID distribution of trastuzumab and DXd remained extremely low throughout the observation period., Conclusions: Our results suggest that T-DXd is distributed to tumor tissues via trastuzumab in a HER2-dependent manner and then to adjacent HER2-negative areas. We successfully visualized the intratumor distribution of T-DXd and its mechanism of action, the so-called "bystander effect.", (©2021 American Association for Cancer Research.)

Purpose: MORAb-202, an antibody-drug conjugate containing farletuzumab and eribulin with a cathepsin-B cleavable linker, targets folate receptor α (FRα)-expressing tumor cells. The primary objective of this first-in-human study was to evaluate the safety and tolerability of MORAb-202 in patients with solid tumors., Patients and Methods: Patients ≥20 years with adequate organ function and FRα-positive solid tumors who failed to respond to standard therapy were eligible. Patients received MORAb-202 intravenously at doses of 0.3 to 1.2 mg/kg once every three weeks. Endpoints included dose-limiting toxicities, safety, tumor responses, pharmacokinetics, and pharmacodynamics., Trial Registration Number: NCT03386942 (ClinicalTrials.gov)., Results: Between November 28, 2017 and June 4, 2019, 22 patients (median age, 58.0 years) with advanced solid tumors were enrolled. Treatment-emergent adverse events occurred in 21 (95%) patients, with leukopenia and neutropenia in 10 (45%) patients each. One patient (0.9 mg/kg cohort) experienced two grade 3 dose-limiting toxicities: serum alanine aminotransferase and γ-glutamyl transferase increases. Following review by an independent adjudication committee, grade 1/2 interstitial lung disease thought to be related to MORAb-202 was identified in five (23%) patients. Complete response, partial response, and stable disease were observed in one, nine, and eight patients, respectively. The normalized predose serum FRα tended to be positively correlated with the maximum tumor shrinkage ( R 2 = 0.2379; P = 0.0291)., Conclusions: The MTD of MORAb-202 was not reached. MORAb-202 demonstrated promising antitumor activity in FRα-positive solid tumors and was generally well-tolerated at the tested doses. Further investigations are required to establish appropriate dosage and clinical utility of MORAb-202., (©2021 American Association for Cancer Research.)

Purpose: Anaplastic lymphoma kinase ( ALK ) rearrangement is a well-known driver oncogene in non-small-cell lung cancer and has also been identified in other types of tumors. However, there is limited evidence on the clinical response to ALK tyrosine kinase inhibitors (TKIs), such as alectinib and crizotinib, in rare tumors with ALK fusion. We evaluated the therapeutic effect of ALK-TKIs in rare ALK -rearranged tumors., Patients and Methods: Between April 2012 and April 2019, clinical outcomes and characteristics of patients with ALK -rearranged nonlung solid tumors who received ALK-TKIs (alectinib and/or crizotinib) outside of clinical trials were reviewed. Expression and/or rearrangement of ALK was evaluated by immunohistochemistry, fluorescence in situ hybridization, and next-generation sequencing. The tumor response was assessed according to RECIST (version 1.1). Progression-free survival was estimated from initial ALK-TKI initiation until progression., Results: We identified seven patients (inflammatory myofibroblastic tumors, n = 3; ALK-positive histiocytosis, n = 1; histiocytic sarcoma, n = 1; osteosarcoma, n = 1; and parotid adenocarcinoma, n = 1), with a median age of 17 years. Two rare ALK fusions, namely, CTNNA1-AL K and ITSN2-ALK , were identified. As initial ALK-TKI therapy, five patients received alectinib and two received crizotinib. The objective response rate for the initial ALK-TKI therapy was 85.7% (95% CI, 44 to 97), including two patients who received alectinib and achieved complete response. The median progression-free survival was 8.1 months (range, 1.7 to not estimable). There were no treatment interruptions or dose reductions because of adverse events caused by alectinib., Conclusion: This study highlights the potential benefit of ALK-TKIs, especially alectinib, in patients with ALK -rearranged nonlung solid tumors., Competing Interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). Tadaaki Nishikawa Honoraria: AstraZeneca, Eisai Consulting or Advisory Role: Eisai Speakers' Bureau: AstraZeneca, EisaiKazuki Sudo Honoraria: AstraZeneca, PfizerEmi Noguchi Honoraria: Nippon Kayaku Speakers' Bureau: Sysmex, AstraZeneca, Pfizer, Eisai, Lilly Japan, Taiho Pharmaceutical, Chugai PharmaAyumu Arakawa Research Funding: Chugai Pharma Travel, Accommodations, Expenses: AmgenKuniko Sunami Honoraria: Sysmex, Chugai Pharma, AstraZeneca, Novartis, Eisai, Riken Genesis, LillyTakashi Kubo Consulting or Advisory Role: SysmexTakashi Kohno Consulting or Advisory Role: LOXO Oncology, Lilly Japan Research Funding: Daiichi Sankyo, SysmexNoboru Yamamoto Honoraria: AstraZeneca, Pfizer, Chugai Pharma, Bristol Myers Squibb Japan, Ono Pharmaceutical, Lilly Japan, Sysmex Consulting or Advisory Role: Eisai, Takeda, Otsuka, Boehringer Ingelheimm, CMIC, Chugai Pharma Research Funding: Chugai Pharma, Taiho Pharmaceutical, Eisai, Astellas Pharma, Novartis, Daiichi Sankyo, Lilly Japan, Boehringer Ingelheim, Takeda, Kyowa Hakko Kirin, Bayer, Pfizer, Ono Pharmaceutical, Janssen, IQVIA, Merck Sharp & Dohme, Abbvie, Bristol Myers Squibb, Merck Serono, GlaxoSmithKline, Sumitomo Dainippon, Chiome Bioscience, OtsukaKan Yonemori Honoraria: Eisai, Pfizer, AstraZeneca, Novartis, Taiho Pharmaceutical Consulting or Advisory Role: Chugai Pharma, Ono Pharmaceutical, Novartis, Eisai Research Funding: Ono Pharmaceutical No other potential conflicts of interest were reported.Tadaaki Nishikawa Honoraria: AstraZeneca, Eisai Consulting or Advisory Role: Eisai Speakers' Bureau: AstraZeneca, Eisai Kazuki Sudo Honoraria: AstraZeneca, Pfizer Emi Noguchi Honoraria: Nippon Kayaku Speakers' Bureau: Sysmex, AstraZeneca, Pfizer, Eisai, Lilly Japan, Taiho Pharmaceutical, Chugai Pharma Ayumu Arakawa Research Funding: Chugai Pharma Travel, Accommodations, Expenses: Amgen Kuniko Sunami Honoraria: Sysmex, Chugai Pharma, AstraZeneca, Novartis, Eisai, Riken Genesis, Lilly Takashi Kubo Consulting or Advisory Role: Sysmex Takashi Kohno Consulting or Advisory Role: LOXO Oncology, Lilly Japan Research Funding: Daiichi Sankyo, Sysmex Noboru Yamamoto Honoraria: AstraZeneca, Pfizer, Chugai Pharma, Bristol Myers Squibb Japan, Ono Pharmaceutical, Lilly Japan, Sysmex Consulting or Advisory Role: Eisai, Takeda, Otsuka, Boehringer Ingelheimm, CMIC, Chugai Pharma Research Funding: Chugai Pharma, Taiho Pharmaceutical, Eisai, Astellas Pharma, Novartis, Daiichi Sankyo, Lilly Japan, Boehringer Ingelheim, Takeda, Kyowa Hakko Kirin, Bayer, Pfizer, Ono Pharmaceutical, Janssen, IQVIA, Merck Sharp & Dohme, Abbvie, Bristol Myers Squibb, Merck Serono, GlaxoSmithKline, Sumitomo Dainippon, Chiome Bioscience, Otsuka Kan Yonemori Honoraria: Eisai, Pfizer, AstraZeneca, Novartis, Taiho Pharmaceutical Consulting or Advisory Role: Chugai Pharma, Ono Pharmaceutical, Novartis, Eisai Research Funding: Ono Pharmaceutical No other potential conflicts of interest were reported.Tadaaki Nishikawa Honoraria: AstraZeneca, Eisai Consulting or Advisory Role: Eisai Speakers' Bureau: AstraZeneca, Eisai Kazuki Sudo Honoraria: AstraZeneca, Pfizer Emi Noguchi Honoraria: Nippon Kayaku Speakers' Bureau: Sysmex, AstraZeneca, Pfizer, Eisai, Lilly Japan, Taiho Pharmaceutical, Chugai Pharma Ayumu Arakawa Research Funding: Chugai Pharma Travel, Accommodations, Expenses: Amgen Kuniko Sunami Honoraria: Sysmex, Chugai Pharma, AstraZeneca, Novartis, Eisai, Riken Genesis, Lilly Takashi Kubo Consulting or Advisory Role: Sysmex Takashi Kohno Consulting or Advisory Role: LOXO Oncology, Lilly Japan Research Funding: Daiichi Sankyo, Sysmex Noboru Yamamoto Honoraria: AstraZeneca, Pfizer, Chugai Pharma, Bristol Myers Squibb Japan, Ono Pharmaceutical, Lilly Japan, Sysmex Consulting or Advisory Role: Eisai, Takeda, Otsuka, Boehringer Ingelheimm, CMIC, Chugai Pharma Research Funding: Chugai Pharma, Taiho Pharmaceutical, Eisai, Astellas Pharma, Novartis, Daiichi Sankyo, Lilly Japan, Boehringer Ingelheim, Takeda, Kyowa Hakko Kirin, Bayer, Pfizer, Ono Pharmaceutical, Janssen, IQVIA, Merck Sharp & Dohme, Abbvie, Bristol Myers Squibb, Merck Serono, GlaxoSmithKline, Sumitomo Dainippon, Chiome Bioscience, Otsuka Kan Yonemori Honoraria: Eisai, Pfizer, AstraZeneca, Novartis, Taiho Pharmaceutical Consulting or Advisory Role: Chugai Pharma, Ono Pharmaceutical, Novartis, Eisai Research Funding: Ono Pharmaceutical No other potential conflicts of interest were reported., (© 2021 by American Society of Clinical Oncology.)

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., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Telisotuzumab vedotin (formerly ABBV-399) is an antibody-drug conjugate targeting c-Met-overexpressing tumor cells, irrespective of MET gene amplification status. Safety, pharmacokinetics, and preliminary efficacy of telisotuzumab vedotin were evaluated outside of Japan. This phase 1 open-label study evaluated the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of telisotuzumab vedotin in Japanese patients with advanced solid tumors. Telisotuzumab vedotin was administered intravenously at either 2.4 mg/kg (n = 3) or 2.7 mg/kg (n = 6) every 3 weeks, following a 3 + 3 design. Maximum tolerated dose was not reached on the basis of the study design; no dose-limiting toxicity events were observed. The most common treatment-emergent adverse events related to telisotuzumab vedotin were peripheral sensory neuropathy (44%), and nausea, decreased appetite, and decreased white blood cell count (33% each). Most frequent grade ≥3 treatment-emergent adverse events, irrespective of relationship to telisotuzumab vedotin, were decreased neutrophil count and hypoalbuminemia, reported in two patients (22%) each. Systemic exposure of telisotuzumab vedotin at both dose levels was approximately dose proportional. Pharmacokinetic profile in Japanese patients was similar to that previously reported in non-Japanese patients. Two (22%) patients achieved a partial response, six (67%) had stable disease, one (11%) had progressive disease. Overall disease control rate was 89% (eight of nine patients; 95% confidence interval: 51.8%-99.7%]). Median progression-free survival was 7.1 months (95% confidence interval: 1.2-10.4). In conclusion, telisotuzumab vedotin demonstrated a manageable safety profile, with antitumor activity in Japanese patients with advanced solid tumors; the recommended phase 2 dose was confirmed as 2.7 mg/kg every 3 weeks. ClinicalTrials.gov registration number: NCT03311477., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

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)., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Purpose: In Japan, for pharmaceutical products to be covered by public medical insurance, their efficacy and safety must first be confirmed in clinical trials. To our knowledge, this study is the first investigation into the off-label use of pharmaceutical products at a high-volume cancer treatment center in Japan. The objective of this study is to explore the framework necessary for future pharmaceutical development and regulatory approval in the field of oncology by surveying the frequency of and indications for off-label use of pharmaceutical products at the National Cancer Center Hospital in Tokyo, Japan., Materials and Methods: The pharmaceutical products used off-label in daily practice from 2003 to 2015 at the National Cancer Center Hospital were retrospectively examined based on applications that had been submitted to an internal review committee requesting off-label use., Results: A total of 1,390 applications were submitted during the study period. The most frequently used supporting documents were the results of phase II trials, followed by case series and phase III trials. The cancer most frequently treated with off-label drugs was sarcoma (15.1%), followed by urologic cancer (9.2%) and GI cancer (7.6%)., Conclusion: As reported in previous studies, pharmaceutical products were generally used off-label for the treatment of rare cancers, for which large-scale clinical trials are difficult to conduct. Continued discussion of the types of frameworks that are needed to guide pharmaceutical development is necessary., Competing Interests: Conflicts of Interest Statement:The authors have declared that no competing interests exist.

Purpose: Part A of the open-label, phase I KEYNOTE-434 study evaluated the safety and tolerability of epacadostat, an indoleamine 2,3-dioxygenase-1 inhibitor, alone and in combination with pembrolizumab in Japanese patients with advanced solid tumors., Methods: Japanese patients with refractory/recurrent metastatic or locally advanced tumors were enrolled. Cohort 1 received oral epacadostat 25 mg or 100 mg twice daily (BID) and subsequently received epacadostat in combination with intravenous pembrolizumab 200 mg every 3 weeks. Cohort 2 received epacadostat 25 mg or 100 mg BID with pembrolizumab 200 mg every 3 weeks. The primary objective was evaluation of safety and tolerability using a modified toxicity probability interval method. Secondary objectives were pharmacokinetic (PK) and pharmacodynamic profiles of epacadostat alone and in combination with pembrolizumab., Results: Six patients were enrolled in cohort 1 (epacadostat 25 mg, n = 3; epacadostat 100 mg, n = 3); none experienced dose-limiting toxicities (DLTs). Nine patients were enrolled in cohort 2 (epacadostat 25 mg and pembrolizumab, n = 3; epacadostat 100 mg and pembrolizumab, n = 6); one patient receiving epacadostat 100 mg and pembrolizumab experienced grade 4 rhabdomyolysis-a DLT. Grade 3 or 4 treatment-related adverse events occurred in two patients (13.3%). There were no treatment-related deaths. Pembrolizumab had no impact on epacadostat PK and vice versa. The PK profile of pembrolizumab in the current study was comparable with historical pembrolizumab PK data., Conclusion: Epacadostat in combination with pembrolizumab was generally safe and well tolerated among Japanese patients with advanced solid tumors. Clinical trial registration NCT02862457.

Penetration of nanoparticles into viable tumor regions is essential for an effective response. Mass spectrometry imaging (MSI) is a novel method for evaluating the intratumoral pharmacokinetics (PK) of a drug in terms of spatial distribution. The application of MSI for analysis of nanomedicine PK remains in its infancy. In this study, we evaluated the applicability of MALDI-MSI for nanoparticle-formulated drug visualization in tumors and biopsies, with an aim toward future application in clinical nanomedicine research. We established an analytic method for the free drug (AZD2811) and then applied it to visualize nanoparticle-formulated AZD2811. MSI analysis demonstrated heterogeneous intratumoral drug distribution in three xenograft tumors. The intensity of MSI signals correlated well with total drug concentration in tumors, indicating that drug distribution can be monitored quantitatively. Analysis of tumor biopsies indicated that MSI is applicable for analyzing the distribution of nanoparticle-formulated drugs in tumor biopsies, suggesting clinical applicability.

For rare cancers, challenges in establishing standard therapies are greater than those for major cancers, and effective methods are needed. MASTER KEY Project is a multicenter study based in Japan, with two main parts: prospective registry study and multiple clinical trials. Advanced rare cancers, cancers of unknown primary origin, and those with rare tissue subtypes of common cancers are targeted. The registry study accumulates highly reliable consecutive data that can be used for future drug development. The multiple trials are conducted simultaneously, targeting either a specific biomarker or a rare tumor type of interest. The first interim data set from the registry part presented here shows the prevalence of genetic abnormalities, response rates, survival rates, and clinical trial enrollment rates. From May 2017 to April 2019, 560 patients (mean age = 53) were enrolled in the project. Frequent cancer types included soft tissue sarcomas, neuroendocrine tumors, and central nervous system tumors. Among the 528 patients with assessable data, 69% (364/528) had next-generation sequencing tests, with 48% (176/364) harboring an "actionable" alteration. Seventy-one (13%) patients have been enrolled in one of the clinical trials, with an accrual rate of 3.94 patients/month. A descriptive analysis of biomarker-directed or non-biomarker-directed treatment survival was performed. This project is expected to accelerate development of treatments for rare cancers and show that comprehensive platform trials are an advantageous strategy., (© 2020 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

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.

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) 2 -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., (© 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

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.

Little is known about the toxicity of various therapeutics for cancer over time because randomized controlled clinical trials that compare several treatments are limited. In this study, we focused on the toxicities most frequently discussed, which are investigations (lab abnormalities), gastrointestinal disorders, skin and subcutaneous tissue disorders, and cardiac disorders, and compared their longitudinal toxicity data among four types of cancer therapeutics. In total, 28,235 patients who were enrolled into 772 early-phase trials to evaluate the monotherapies of cytotoxic drugs, molecularly targeted agents, immunomodulatory drugs, or cancer vaccines were evaluated. For each toxicity, we compared their grade prevalence, mean grade at each cycle, and time to toxicity occurrence and identified the potential underlying similarities and differences of longitudinal toxicities among the four cancer treatment types. Our results will further help in understanding the profile of cancer therapeutic toxicities and their impact on oncology treatment in practice., (© 2019 The Authors Clinical Pharmacology & Therapeutics © 2019 American Society for Clinical Pharmacology and Therapeutics.)

Objective Few reports have analyzed the diagnostic process of carcinoma of unknown primary site (CUP) or have focused on the frequency of nonmalignant lesions among patients with suspected malignant diseases. The aim of this study was to investigate the incidence and characteristics of nonmalignant diseases that tend to be mistaken for malignant diseases. Patients We retrospectively analyzed the medical records of patients with suspected CUP who were referred to the National Cancer Center Hospital (Tokyo, Japan) between April 2007 and December 2014. All patients underwent a thorough history and physical examination as well as radiological and ultrasonography imaging tests for the CUP diagnostic work up. Results Among 830 patients with suspected CUP, 46 were diagnosed with nonmalignant diseases, and 780 were diagnosed with a malignant neoplasm (409 neoplasms with detected primary site and 371 CUP neoplasms). Four patients discontinued the diagnostic workup because they refused further examinations or had a poor general status. The final diagnosis of the 46 patients with nonmalignant disease comprised 10 benign tumors, 10 benign diseases, and 26 with no evidence of disease. The nonmalignant tumors comprised three hemangiomas, two schwannomas, two uterine myomas, two pseudomyxoma peritonei, one lymphangioma, one meningioma, and one poroma. Conclusion The incidence of nonmalignant diseases among patients with suspected CUP was 46 out of 830 patients in our institution. It is important to perform a thorough pathological examination in the CUP diagnostic workup. To confirm a diagnosis, some patients may need to visit specialized institutions, especially those with liver and bone lesions.

Next-generation sequencing (NGS) of tumor tissue (ie, clinical sequencing) can guide clinical management by providing information about actionable gene aberrations that have diagnostic and therapeutic significance. Here, we undertook a hospital-based prospective study (TOP-GEAR project, 2nd stage) to investigate the feasibility and utility of NGS-based analysis of 114 cancer-associated genes (the NCC Oncopanel test). We examined 230 cases (comprising more than 30 tumor types) of advanced solid tumors, all of which were matched with nontumor samples. Gene profiling data were obtained for 187 cases (81.3%), 111 (59.4%) of which harbored actionable gene aberrations according to the Clinical Practice Guidelines for Next Generation Sequencing in Cancer Diagnosis and Treatment (Edition 1.0) issued by 3 major Japanese cancer-related societies. Twenty-five (13.3%) cases have since received molecular-targeted therapy according to their gene aberrations. These results indicate the utility of tumor-profiling multiplex gene panel testing in a clinical setting in Japan. This study is registered with UMIN Clinical Trials Registry (UMIN 000011141)., (© 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Taselisib is a potent and selective phosphatidylinositide 3-kinase (PI3K) inhibitor. The present article reports the first study of taselisib administration in Japanese patients. The aim of this 2-stage, phase I, multicenter, open-label, dose-escalation study was to evaluate the safety, pharmacokinetics, and preliminary efficacy of taselisib as monotherapy in Japanese patients with advanced solid tumors (stage 1), and as part of combination therapy in Japanese patients with hormone receptor (HR)-positive locally advanced or recurrent breast cancer (stage 2). In stage 1, oral taselisib tablets 2, 4, and 6 mg/d were given in 28-day cycles. In stage 2, successive cohorts of patients received oral taselisib tablets (2 or 4 mg/d) with i.m. fulvestrant 500 mg. Nine and 6 patients were enrolled in stage 1 and stage 2, respectively. Taselisib was well tolerated. No dose-limiting toxicities were experienced in any cohort of patients and no deaths were observed. The most common treatment-related adverse events in stage 1 and stage 2, respectively, were rash (55.6%, 66.7%), diarrhea (44.4%, 66.7%), and stomatitis (44.4%, 66.7%). Taselisib was rapidly absorbed after dosage; its half-life was 12.9-32.0 hours in stage 1 and 16.1-26.5 hours in stage 2. Two patients achieved partial response (PR), 5 patients had stable disease (SD) and 2 patients had progressive disease (PD) in stage 1, and 1 patient had PR and 3 patients had SD in stage 2. All patients with PR were positive for PIK3CA gene mutations. These preliminary data suggest that taselisib may be effective in patients with PIK3CA-mutated solid tumors or HR-positive advanced breast cancer., (© 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Phase 1 trials of molecularly targeted agents (MTA) often do not use toxicity data beyond the first cycle of treatment to determine a recommended phase 2 dose (RP2D). We investigated the potential utility of longitudinal relative dose intensity (RDI) that may be a better new way of determining a more accurate RP2D as a lower dose that is presumably more tolerable over the long term without compromising efficacy. All consecutive patients who were initially treated using a single MTA at the conventional RP2D or at one level lower dose (OLLD) of that RP2D in 9 phase 1 trials sponsored by the National Cancer Institute were included. The associations between longitudinal RDI, time to first progression, and response rate were analyzed. The RDI of the conventional RP2D group were maintained a rate of ≥70% throughout 10 cycles, and were higher than those of the OLLD group, although in both groups the RDI gradually decreased with additional treatment cycles. The RP2D group was similar to the OLLD group with respect to time to first progression and response rate. In both groups, however, the decreasing RDI over time was significantly associated with shorter time to first disease progression; therefore, the longitudinal RDI, which takes into account lower grade toxicity occurrences, may be useful in determining a more desirable dose to use in phase 2 and 3 studies., (© 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

In this article, synthetic studies around a pyridylacrylamide-based hit compound (1), utilizing structure-based drug design guided by CDK8 docking models, is discussed. Modification of the pendant 4-fluorophenyl group to various heteroaromatic rings was conducted aiming an interaction with the proximal amino acids, and then replacement of the morpholine ring was targeted for decreasing potential of time-dependent CYP3A4 inhibition. These efforts led to the compound 4k, with enhanced CDK8 inhibitory activity and no apparent potential for time-dependent CYP3A4 inhibition (CDK8 IC 50 : 2.5nM; CYP3A4 TDI: 99% compound remaining). Compound 4k was found to possess a highly selective kinase inhibition profile, and also showed favorable pharmacokinetic profile. Oral administration of 4k (15mg/kg, bid. for 2weeks) suppressed tumor growth (T/C 29%) in an RPMI8226 mouse xenograft model., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Interstitial lung disease is a serious drug-related condition that can cause life threatening organ failure. The incidence and risk factors of drug-induced interstitial lung disease (DILD) are unknown in oncology phase I trials. This study analyzed clinical information from 8906 patients with malignancies who were enrolled in 470 phase I trials sponsored by the Cancer Therapy Evaluation Program, National Cancer Institute, from 1988 to 2014. Logistic and Cox statistical analyses were utilized to determine clinical differences between patients who developed DILD and patients who did not. In this study, the overall incidence rate of patients with pulmonary toxicity was 2.7%. The overall incidence rate for DILD was 0.77%, whereas for grade 3 or 4 DILD it was 0.31%. Median time to occurrence of DILD was 1.4 months. The Cox hazard analysis indicated smaller body surface area and a combination of thoracic radiation with investigational drug regimens were significant risk factors for time to occurrence of interstitial lung disease. Investigators should carefully monitor for DILD in oncology patients enrolled in phase I trials with identified risk factors. A 6-month observation period would be sufficient to detect the onset of most DILD in such patients., (© 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Purpose: This was the first Phase I study to assess the safety and tolerability of the tablet formulation of olaparib (Lynparza™), an oral poly(ADP-ribose) polymerase inhibitor, in Japanese patients with advanced solid tumours. The pharmacokinetic profile and antitumour activity of olaparib tablets were also assessed., Methods: In this open-label, multicentre study (D081BC00001; NCT01813474), a single dose of olaparib (200 or 300 mg, tablets) was administered on day 1, followed 48 h afterwards by multiple dosing (200 or 300 mg twice daily [bid]) for 28-day cycles. Doses were escalated in successive cohorts, with an expansion cohort enrolled at the highest dose that was confirmed to be tolerable during dose escalation., Results: Twenty-eight patients were enrolled and 23 were treated (n = 4, 7 and 12 at 200, 300 and 300 [expansion] mg bid, respectively). No patients experienced a dose-limiting toxicity, so the maximum tolerated dose was not defined. The most frequent adverse events were nausea (43.5 %), decreased appetite (30.4 %), anaemia (26.1 %) and constipation (26.1 %). No patient had dose reductions, two had dose interruptions, and two discontinued treatment because of adverse events. Absorption of olaparib was rapid following single and multiple dosing, and plasma concentrations declined biphasically after single dosing. No patients had a confirmed antitumour response., Conclusions: Olaparib tablet doses of 200 and 300 mg bid were considered tolerable in Japanese patients with advanced solid tumours. Consistent with the global olaparib programme, 300 mg bid was selected as the recommended tablet dose for future studies., Clinical Trial Registration Number: NCT01813474., Competing Interests: Kan Yonemori reports grants from AstraZeneca during the conduct of the study and personal fees from Eisai Co., Ltd, outside the submitted work. Kenji Tamura, Makoto Kodaira, Koshi Fujikawa, and Tamotsu Sagawa report personal fees from AstraZeneca during the conduct of the study. Taito Esaki reports grants from AstraZeneca during the conduct of the study, and outside of the submitted work: grants and personal fees from Boehringer Ingelheim, Eli Lilly, Merck Serono, and Taiho Pharmaceutical Co. Ltd; grants from Astellas, AstraZeneca, Bayer, Daiichi Sankyo, MSD, Novartis Pharma, Ono Pharmaceutical Co. Ltd, Sanofi, and Sumitomo Dainippon; and personal fees from Chugai and Yakult. Tsuyoshi Shirakawa reports personal fees from AstraZeneca during the conduct of the study. Fumihiko Hirai reports grants from AstraZeneca during the conduct of the study, and outside of the submitted work: grants and personal fees from Novartis Pharma; personal fees from Chugai Pharmaceutical Co., Ltd, Eli Lilly, Kyowa Hakko Kirin Co., Ltd, Ono Pharmaceutical Co., Ltd, and Taiho Pharmaceutical Co., Ltd. Yuki Yokoi, Toshio Kawata, Ben Hatano and Yasuo Takahashi report personal fees from AstraZeneca during the conduct of the study.

This phase I study in Japanese patients evaluated the safety, pharmacokinetics, and preliminary efficacy of palbociclib, a highly selective and reversible oral cyclin-dependent kinase 4/6 inhibitor, as monotherapy for solid tumors (part 1) and combined with letrozole as first-line treatment of postmenopausal patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer (part 2). Part 1 evaluated palbociclib 100 and 125 mg once daily (3 weeks on/1 week off; n = 6 each group) to determine the maximum tolerated dose. Part 2 evaluated palbociclib maximum tolerated dose (125 mg) plus letrozole 2.5 mg (n = 6). The most common treatment-related adverse event was neutropenia (all grades/grade 3/4): 100 mg, 83%/67%; 125 mg, 67%/33%; and palbociclib plus letrozole, 100%/83%. Heavier pretreatment with chemotherapy may have resulted in higher neutropenia rates observed with the 100-mg dose. Palbociclib exposure was higher with 125 vs 100 mg (mean area under the plasma concentration-time curve over dosing interval [τ]: 1322 vs 547.5 ng·h/mL [single dose], 2838 vs 1276 ng·h/mL [multiple dose]; mean maximum plasma concentration: 104.1 vs 41.4 ng/mL [single dose], 185.5 vs 77.4 ng/mL [multiple dose]). Half-life was 23-26 h. No drug-drug interactions between palbociclib and letrozole occurred. Four patients had stable disease (≥24 weeks in one patient with rectal cancer [100 mg] and one with esophageal cancer [125 mg]) in part 1; two patients had partial response and two had stable disease (both ≥24 weeks) in part 2. Palbociclib at the 125-mg dose (schedule 3/1) was tolerated and is the recommended dose for monotherapy and letrozole combination therapy in Japanese patients. The trials are registered with www.ClinicalTrials.gov: A5481010 and NCT01684215., (© 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Purpose: Investigate the safety and tolerability of AZD5363 and define a recommended dose for evaluation in Japanese patients with advanced solid malignancies., Methods: AZD5363 was administered orally as a single dose, and then the dose was escalated to twice daily (bid) in separate continuous (every day) and intermittent (4 days on, 3 days off [4/3] or 2 days on, 5 days off [2/5]) dosing schedules to reach recommended doses defined by dose-limiting toxicity (DLT). Doses for continuous, 4/3, and 2/5 intermittent dosing schedules were 80-400, 360-480, and 640 mg, respectively, and were informed by results from an equivalent study in Caucasian patients., Results: Forty-one patients received AZD5363. DLTs were only experienced with continuous dosing. 97.6 % of patients reported at least one adverse event (AE); most common were diarrhea (78.0 %), hyperglycemia (68.3 %), nausea (56.1 %), and maculopapular rash (56.1 %). Grade ≥3 AEs were reported by 63.4 % of patients. Exposure of AZD5363 was generally dose proportional for both single and multiple doses. Single-dose pharmacokinetics of AZD5363 was generally predictive of multiple-dose pharmacokinetics. Confirmed partial responses were reported by two patients, both of whom were Akt1 (E17K) mutation positive. One patient in the 480 mg bid 4/3 dosing cohort maintained partial response for >2 years., Conclusions: Intermittent dosing of AZD5363 was more tolerable than continuous dosing. 480 mg bid intermittent 4/3 dosing for AZD5363 monotherapy was selected for further investigation. Preliminary evidence of antitumor activity was observed. Akt1 (E17K) is a potent driver mutation that may predict clinical response to AZD5363.

Purpose: We conducted phase I and tolerability studies to determine the maximum tolerated dose (MTD) and recommended dose of nab-paclitaxel when administered weekly with solid tumors and to evaluate the tolerability of weekly administration at a dose of 150 mg/m(2) with metastatic breast cancer (MBC) as a first-line therapy in Japanese patients., Methods: In this phase I study, patients with advanced solid tumors received nab-paclitaxel at dose levels of 80-125 mg/m(2) as 30-min infusions once a week for three weekly doses repeated every 4 weeks. In the tolerability study, patients received 150 mg/m(2) nab-paclitaxel. Blood samples at the first dose of nab-paclitaxel were collected for pharmacokinetic analysis., Results: Fifteen patients were treated for a median of five cycles in the phase I study. The MTD was 125 mg/m(2); the dose-limiting toxicity was neutropenia requiring skipping of the second or third weekly administration in the first cycle. In the tolerability study, six patients were treated for a median of six cycles; no intolerable toxicities were observed in the first cycle. Grade 3 sensory and motor neuropathy was observed in four and one patients, respectively. Ocular toxicities were observed in two patients (keratopathy and macular hole). Maximum paclitaxel concentration and area under the curve increased linearly with the dose., Conclusions: Weekly administration of nab-paclitaxel was well tolerated up to 100 mg/m(2) by heavily pretreated patients. For MBC patients, 150 mg/m(2) nab-paclitaxel as a first-line therapy was well tolerated. Dose reduction due to neuropathy allows multiple cycles of treatment.