Japanese Phase Research Articles

Risk of Death From Other Diseases in Lung Cancer Patients After Sublobar Resection Versus Lobectomy.

A recent Japanese phase three clinical trial for lung cancer suggested a possible advantage of segmentectomy over lobectomy in terms of death from other diseases. This study aimed to compare the risk of death from other diseases based on surgical procedures in lung cancer patients without recurrence. We retrospectively reviewed 2121 patients without disease recurrence after curative resection for lung cancer at our institution. Patient characteristics and overall survival were compared between sublobar resection and lobectomy. The sublobar group (n = 595) had a significantly higher proportion of women, non-smokers, patients without comorbidities, patients with a history of other cancers, and patients with earlier-staged disease when compared with the lobectomy group (n = 1526). The overall survival was significantly longer in the sublobar group than in the lobectomy group (p = 0.0034). After adjusting for background characteristics in an analysis of 488 patients, the overall survival had a trend to be longer in the sublobar group than in the lobectomy group (p = 0.071). Our results suggested that the risk of death from other diseases was potentially higher after lobectomy than after sublobar resection. Although several clinical factors could influence the results, these results may support the benefit of sublobar resection, assuming that the curability of both procedures is similar.

Descriptive analysis of safety and immunogenicity profiles of a 15-valent pneumococcal conjugate vaccine between subcutaneous and intramuscular administration in a phase 1 study of healthy Japanese infants (V114-028)

IntroductionSubcutaneous (SC) administration is typically used for pediatric inactivated vaccines in Japan, whereas intramuscular (IM) administration is used outside Japan. We previously reported the safety and immunogenicity of V114, a 15-valent pneumococcal conjugate vaccine (PCV), administered subcutaneously and intramuscularly in a Japanese phase 1 study (V114-028). Here, we report secondary descriptive analyses on V114 groups of the study to further assess the safety and immunogenicity profiles of V114 between the administration routes. MethodsA total of 133 healthy Japanese infants were randomized to receive V114-SC (n = 44), V114-IM (n = 45), or PCV13-SC (n = 44) at approximately 3, 4, 5, and 12–15 months of age. Adverse events (AEs) from Days 1–14 post-vaccination and vaccine-related serious AEs from Day 1 to 1-month post-dose 4 were reported. Serotype-specific immunoglobulin G (IgG) responses were measured across the vaccination series. ResultsProportions of participants with solicited systemic AEs (irritability, somnolence, decreased appetite, and urticaria) and pyrexia were generally comparable between the groups. Compared with V114-SC, patients receiving V114-IM had a lower incidence of irritability and somnolence, and higher incidence of decreased appetite. Proportion of participants with solicited injection-site erythema was lower with V114-IM (82.2%) than V114-SC (100.0%). Those with other solicited injection-site AEs (induration, swelling, and pain) were generally comparable between the groups, with lower observed proportions with V114-IM. Serotype-specific IgG responses were also generally comparable between the groups, including at pre-toddler dose. ConclusionsThese results suggest the utility of IM administration as an option for V114 vaccination in Japanese infants.

Tapinarof cream for the treatment of atopic dermatitis: Efficacy and safety results from two Japanese phase 3 trials.

Tapinarof is a nonsteroidal, topical, aryl hydrocarbon receptor agonist. We evaluated the efficacy and safety of tapinarof cream 1% in Japanese patients aged ≥12 years with atopic dermatitis (AD) in two phase 3 trials, ZBB4-1 and ZBB4-2. ZBB4-1 (N = 216) consisted of an 8-week, double-blind, vehicle-controlled treatment period (period 1) and a 16-week extension treatment period (period 2). Patients were randomized 2:1 to tapinarof or vehicle in period 1; subsequently, all patients who enrolled in period 2 received tapinarof. ZBB4-2 (N = 291) was a 52-week, open-label, uncontrolled trial in which all patients received tapinarof. In period 1 of ZBB4-1, the proportion of patients who achieved an Investigator's Global Assessment (IGA) score of 0 (clear) or 1 (almost clear) with ≥2-grade improvement from baseline at week 8 (IGA treatment success, the primary end point) was 20.24% in the tapinarof group and 2.24% in the vehicle group (p = 0.0007). The proportion of patients with ≥75% improvement from baseline in Eczema Area and Severity Index (EASI) score at week 8 (EASI-75 response, the key secondary end point) was 40.3% in the tapinarof group and 4.3% in the vehicle group (p < 0.0001). In ZBB4-2, IGA treatment success rate was 28.1% at week 16, 32.3% at week 24, and 41.3% at week 52, and EASI-75 response rate was 53.3% at week 16, 63.7% at week 24, and 76.6% at week 52, indicating that efficacy responses improved over time and were maintained over 52 weeks. Across the two trials, most adverse events (AEs) were mild or moderate; common AEs included folliculitis, acne, and headache. In summary, tapinarof cream 1% was effective and generally safe for up to 52 weeks of treatment in Japanese patients with AD.

Real-world safety of nivolumab in patients with malignant pleural mesothelioma in Japan: post-marketing surveillance study.

This post-marketing surveillance (PMS) was conducted to evaluate the incidence of adverse events with nivolumab in patients with unresectable, advanced or recurrent malignant pleural mesothelioma (MPM) that had progressed after first-line chemotherapy and to identify factors that potentially affected its safety in real-world clinical practice. Patients who had not received nivolumab previously were registered between November 2018 and February 2021. Nivolumab was given intravenously 240mg every 2weeks or 480mg every 4weeks. Patients were followed up for 6months after treatment initiation. Information on patient characteristics, treatment status, and adverse events was collected. This PMS enrolled 124 patients, involving 48 sites across Japan. At 6months, nivolumab therapy was ongoing in 35.5% of patients (44/124) and had been discontinued in 64.5% (80/124). The overall incidence of treatment-related adverse events (TRAEs) was 40.3%; the incidence of Grade 3 or higher TRAEs was 12.9%. The pattern of TRAEs based on System Organ Class categories was generally consistent with those seen in the Japanese phase II MERIT study. The most common Grade 3 or higher TRAEs were interstitial lung disease (2.4%), lung disorder, and diarrhea (each 1.6%). The incidence of TRAEs was significantly higher in inpatients or patients who had good PS, high bodyweight, high body mass index, or autoimmune diseases than in those without these characteristics. The post-marketing incidence of TRAEs with nivolumab in patients with MPM has been evaluated, and no new safety signals were identified compared to the phase II clinical trial in Japan.

Tapinarof cream for the treatment of plaque psoriasis: Efficacy and safety results from 2 Japanese phase 3 trials.

Tapinarof is a non-steroidal, topical, aryl hydrocarbon receptor agonist. We evaluated the efficacy and safety of tapinarof cream (1%) in Japanese patients aged ≥18 years with plaque psoriasis in two phase 3 trials, ZBA4-1 and ZBA4-2. ZBA4-1 (N = 158) consisted of a 12-week, double-blind, vehicle-controlled treatment period (period 1) and a 12-week extension treatment period (period 2). Patients were randomized 2:1 to tapinarof or vehicle in period 1; subsequently, all patients who were enrolled in period 2 received tapinarof. ZBA4-2 (N = 305) was a 52-week, open-label, uncontrolled trial in which all patients received tapinarof. In period 1 of ZBA4-1, the proportion of patients who achieved a Physician Global Assessment (PGA) score of 0 (clear) or 1 (almost clear) with ≥2-grade improvement from baseline at week 12 (PGA treatment success, the primary endpoint) was 20.06% in the tapinarof group and 2.50% in the vehicle group (p = 0.0035). The proportion of patients with ≥75% improvement from baseline in the Psoriasis Area and Severity Index (PASI) score at week 12 (PASI75 response, a key secondary endpoint) was 37.7% in the tapinarof group and 3.8% in the vehicle group (p < 0.0001). In ZBA4-2, PGA treatment success rate was 30.0% at week 12, 51.3% at week 24, and 56.3% at week 52, and PASI75 response rate was 50.4% at week 12, 77.5% at week 24, and 79.9% at week 52, indicating that efficacy responses improved over time and were maintained over 52 weeks. Across the two trials, most adverse events (AEs) were mild or moderate; common AEs included folliculitis and contact dermatitis. In summary, tapinarof cream (1%) was efficacious and generally safe for up to 52 weeks of treatment in Japanese patients with plaque psoriasis.

A lower initial dose of bosutinib for patients with chronic myeloid leukemia patients resistant and/or intolerant to prior therapy: a single-arm, multicenter, phase 2 trial (BOGI trial)

Although bosutinib is generally safe and effective, drug-related toxicities (DRTs) such as diarrhea or increased transaminase levels often lead to treatment discontinuation. To clarify whether a lower initial dose of bosutinib (i.e., starting at 200 mg) would reduce rates of discontinuation due to DRTs, we conducted a phase 2 study of BOsutinib Gradual Increase (BOGI trial, UMIN 000032282) as a second/third-line treatment for chronic myeloid leukemia (CML). Between February 4, 2019 and May 24, 2022, 35 patients were enrolled. The rate of bosutinib discontinuation at 12 months was 25.7% vs. 35.9% in a historical control study (Japanese phase 1/2 study) (p = 0.102). The rate of bosutinib discontinuation due to DRTs was significantly lower, at 11.4% vs. 28.2% (p = 0.015). The incidence of grade 3/4 transaminase elevation was 20% vs. 29% (p = 0.427), while the incidence of diarrhea was 3% vs. 25% (p = 0.009). The median dose intensity of bosutinib was higher (391.7 mg/day vs. 353.9 mg/day). Pharmacokinetic analysis of bosutinib showed that patients who achieved a major molecular response tended to have high trough concentrations. Thus, a low initial dose of bosutinib followed by dose escalation reduced discontinuation due to severe DRTs while maintaining high dose intensity and efficacy.

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of a Muscarinic M3 Receptor-Positive Allosteric Modulator ASP8302 Following Single and Multiple Ascending Oral Doses in Healthy Volunteers.

ASP8302 is an orally administered positive allosteric modulator of the muscarinic M3 receptor. Two Phase 1 studies were conducted, a first-in-human study in Europe and a Japanese phase 1 study. Both were randomized, participant- and investigator-blinded, placebo-controlled, single and multiple ascending oral doses, parallel group, clinical studies in healthy volunteers. Both studies evaluated safety and pharmacokinetics and also included salivary secretion and pupil diameter as pharmacodynamic assessments. There were no deaths, serious adverse events, or treatment-emergent adverse events reported leading to study discontinuation. There were no clinically relevant findings in any of the laboratory, vital signs, electrocardiogram assessments, or photosensitivity testing following multiple administration of up to 150 mg or up to 140 mg once daily for 14 days in the European first-in-human and Japanese Phase 1 study, respectively. The pharmacokinetics of ASP8302 were approximately linear over the dose range studied. There was no evidence of drug accumulation upon repeated dosing. In both studies, ASP8302 showed a dose-dependent pharmacodynamic effect on saliva production at doses from 100 mg onward, which was maintained during repeated dosing. No effect was observed on pupil diameter. These data supported progression of ASP8302 into Phase 2 clinical trials for further clinical development.

Efficacy and safety of sarilumab in patients with rheumatoid arthritis stratified by age (

This study aimed to assess the efficacy and safety of sarilumab in older patients with active rheumatoid arthritis (RA). This is a post-hoc analysis of KAKEHASI (NCT02293902) and HARUKA (NCT02373202) trials with stratification by age (<65 and ≥65 years). Patients with moderately-to-severely active RA were treated with sarilumab in combination with methotrexate (MTX) or with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) or as monotherapy. The primary endpoints in KAKEHASI and HARUKA trials were the American College of Rheumatology 20% improvement criteria (ACR20) responses at Week 24 and safety, respectively. Secondary endpoints were other RA disease activity measures, including Clinical Disease Activity Index (CDAI). Approximately 20% of patients were aged ≥65 years in treatment arms across both trials, except the sarilumab+csDMARDs arm (40%, 12/30). ACR20 response rates were similar between age groups across sarilumab treatment arms and similar results were obtained for CDAI scores. Safety profiles were similar between age groups except for a higher incidence of serious adverse events in patients aged ≥65 years in the sarilumab+MTX arm. In Japanese patients with RA enrolled in phase 3 studies for sarilumab, no clear difference in efficacy or safety was observed between patients aged <65 and ≥65 years.

Safety and efficacy of acalabrutinib and obinutuzumab in treatment-naive chronic lymphocytic leukemia: a Japanese phase 1 study

This report focuses on part 3 of a multicenter, open-label, phase 1 study (NCT03198650) assessing the safety, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of acalabrutinib plus obinutuzumab in Japanese patients with treatment-naive (TN) chronic lymphocytic leukemia (CLL). Ten patients were included; median age was 68 years. With a median treatment duration of 27.2 months, treatment-emergent adverse events (AEs) occurred in all patients (grade ≥3, 70%), and the most common AEs were anemia and headache (40% each). One patient had a grade 4 AE of neutropenia (the only dose-limiting toxicity). PK results suggested no marked effects of concomitant obinutuzumab treatment on the exposure of acalabrutinib. PD assessment indicated that combination therapy provided >98% Bruton tyrosine kinase (BTK) occupancy. Overall response rate (ORR) was 100% with median duration of response (DoR) and median progression-free survival (PFS) not reached. Treatment with acalabrutinib plus obinutuzumab was generally safe and efficacious in adult Japanese patients with TN CLL.

Abstract PO1-05-05: Overall survival (OS) and subsequent therapy patterns in Japanese patients with HR+/HER2− advanced breast cancer (ABC) treated with palbociclib (PAL) plus letrozole (LET) in first-line setting (1L)

Abstract Background: PAL is a first-in-class cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) for the treatment of HR+/HER2− ABC. In PALOMA-2 study, PAL plus LET demonstrated a numerically, not statistically significant, prolonged OS versus placebo plus LET (53.9 vs 51.2 months; HR, 0.956; 95% CI, 0.777–1.177) in patients with HR+/HER2− ABC in 1L. Subgroup analyses showed a similar trend in Asia/Pacific region (73.4 vs 55.1 months; HR, 0.744), however, data specific to Japanese subgroup have not been reported. An open-label, single-arm, multicenter Japanese phase 2 study (J-Ph2) investigated the efficacy and safety of PAL plus LET in postmenopausal Japanese women with HR+/HER2− ABC in 1L and showed a median progression-free survival (PFS) of 35.7 months (95% CI, 21.7–46.7) in the final analysis of PFS. However, OS data were immature at the data cutoff. Here, we report the findings from a follow-up study of J-Ph2 (NCT04735367) evaluating OS and subsequent therapy in these Japanese patients. Methods: Patients (N=42) who participated in J-Ph2 were enrolled in this follow-up study. The primary endpoint was OS, defined as the time from the first dose of PAL plus LET in J-Ph2 to date of death due to any cause. Secondary endpoints included chemotherapy-free survival (CFS) and type and duration of subsequent therapy. Median OS, CFS, duration of subsequent therapy and associated 95% CIs were estimated using the Kaplan–Meier method. Outcomes were also assessed for baseline demographic and disease characteristic subgroups including visceral or nonvisceral metastatic disease, disease-free interval (DFI; ≤12 months, &amp;gt;12 months, de novo metastatic), and duration of 1L PAL use (≤24 months or &amp;gt;24 months). Results: Patients had a median age of 62.5 years; 48% had visceral metastases; 33% had de novo disease; 48% had a TFI &amp;gt;12 months; 93% had an ECOG performance status (PS) of 0. At a median follow up of 89.7 months, the median OS was 85.4 months (95% CI, 64.3–not estimable [NE]). Median OS was longer in patients with nonvisceral versus visceral metastases (not reached [NR] vs 67.3 months), with TFI &amp;gt;12 months versus ≤12 months (85.4 vs 45.4 months), or with duration of 1L PAL use &amp;gt;24 months versus ≤24 months (NR vs 47.5 months). Median CFS was 69.1 months (95% CI, 24.2–85.4), and that was longer in patients with nonvisceral versus visceral metastases (77.5 vs 37.5 months). At the data cutoff, 3 patients (7.1%) were still receiving PAL plus LET (90.9–93.2 months). Subsequent therapy after disease progression was administered to 34 of 42 patients (81%). Of these patients, 28 (82%) received endocrine-based therapy, while 3 (9%) patients each received chemotherapy and other therapy, respectively. The median duration of the first subsequent therapy was 8.3 months (95% CI, 3.9–12.2), and that was similar among patients with nonvisceral versus visceral metastases (7.8 vs 8.3 months). Conclusion: This interim analysis showed a median OS of &amp;gt;7 years with 1L PAL plus LET. Patient demographics (geographic, racial factors), disease characteristics (ECOG PS, visceral metastases), and subsequent therapy decisions may have contributed to the extended median OS observed in this study. Further, this report provides insight into real-world subsequent treatment patterns following PAL plus ET. Table Citation Format: Masato Takahashi, Tomofumi Osako, Hiroyuki Yasojima, Kenichi Inoue, Masahiro Kawashima, Hideki Maeda, Mitsuya Ito, Yasuaki Sagara, Kan Yonemori, Masaya Hattori, Naohito Yamamoto, Eriko Tokunaga, Shozo Ohsumi, Yutaka Yamamoto, Akemi Ichikawa, Yasuaki Muramatsu, Norikazu Masuda. Overall survival (OS) and subsequent therapy patterns in Japanese patients with HR+/HER2− advanced breast cancer (ABC) treated with palbociclib (PAL) plus letrozole (LET) in first-line setting (1L) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-05-05.

A Japanese multi-institutional phase II study of moderate hypofractionated intensity-modulated radiotherapy with image-guided technique for prostate cancer.

The aim of this multi-institutional phase II study was to confirm the safety and the potential efficacy of moderately hypofractionated intensity-modulated radiotherapy (IMRT) with prostate-based image-guidance for Japanese patients. Patients with low- or intermediate-risk localized prostate cancer were eligible. Patients with a part of high risk (having only one of the following factors, cT3a, 20 < PSA ≤ 30, or GS = 8 or 9) were also included. Hypofractionated IMRT using daily image-guided technique with prostate matching was performed with a total dose of 70Gy in 28 fractions. Neoadjuvant hormonal therapy for 4-8months was mandatory for patients with intermediate or high-risk prostate cancer. From 20 institutions, 134 patients enrolled. The median follow-up was 5.16years (range, 1.43-6.47years). The number of patients with low, intermediate, and high-risk prostate cancer was 20, 80, and 34, respectively. The 5-year overall, biochemical failure-free, and clinical failure-free survival was 94.5%, 96.0%, and 99.2%, respectively. The 5-year biochemical failure-free survival for patients with low-, intermediate-, and high-risk disease was 94.1%, 97.4%, and 93.9%, respectively. The incidences of grade 2 gastrointestinal (GI) and genitourinary (GU) late toxicities at 5years were 5.3% and 5.3%, respectively. There are no acute or late toxicities ≥ grade 3. Of 124 patients who were followed for up to 5years, the grade 2 late GU or GI toxicities were 10.5% (90% confidence intervals, 6.3-16.2%, p = 0.0958). The safety and efficacy of moderately hypofractionated IMRT with prostate-based image-guidance was confirmed among Japanese patients with prostate cancer.

Factors affecting responsiveness of vadadustat in patients with anemia associated with chronic kidney disease: a post-hoc subgroup analysis of Japanese phase 3 randomized studies

BackgroundVadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor developed for treating anemia in chronic kidney disease (CKD). The purpose of this post-hoc analysis was to investigate the factors affecting the responsiveness to vadadustat in anemia patients with nondialysis-dependent (NDD) or hemodialysis-dependent (HDD) CKD in two Japanese phase 3 studies.MethodsOf 151 and 162 patients enrolled in NDD-CKD and HDD-CKD studies, 136 and 140 patients, respectively, were included and divided into subgroups for the analysis. To assess vadadustat responsiveness, the resistance index was defined as the mean body weight-adjusted dose of vadadustat (mg/kg) at weeks 20–24 divided by the mean hemoglobin (g/dL) at weeks 20–24. Multivariate analysis was performed to identify the variables affecting the resistance index.ResultsIndependent factors identified as determinants for better response to vadadustat were as follows: high baseline hemoglobin, low baseline eGFR, high week-20–24 ferritin, and CKD not caused by autoimmune disease/glomerulonephritis/vasculitis in NDD-CKD; and male sex, high baseline C-reactive protein, and low baseline erythropoiesis-stimulating agent resistance index (ERI) in HDD-CKD.ConclusionsIn this post-hoc analysis, several factors were identified as affecting the response to vadadustat. These results may provide useful information leading to an appropriate dose modification for vadadustat.Clinical trial registrationNCT03329196 (MT-6548-J01) and NCT03439137 (MT-6548-J03).

Autologous HSCT with novel agent-based induction and consolidation followed by lenalidomide maintenance for untreated multiple myeloma.

Triplet regimen comprising proteasome inhibitors, immunomodulatory drugs, and dexamethasone (DEX) is a recommended induction/consolidation therapy for multiple myeloma (MM) patients eligible for transplant. In this Japanese phase II study conducted from 2017 to 2019, newly diagnosed MM patients aged 20-65 received four induction cycles with bortezomib (Bor), lenalidomide (Len), and DEX (VRD), followed by Bor and high-dose melphalan with autologous stem cell rescue. Subsequently, they underwent four consolidation cycles with carfilzomib, Len, and DEX (KRD), followed by Len maintenance until disease progression. A total of 141 patients were analyzed. In an intent-to-treat population, the complete or better response post induction was 19.9%, rising to 39.7%, 58.9%, and 62.4% after transplant, consolidation, and 1-year maintenance, respectively. With a median follow-up of 38 months, the 3-year progression-free survival (PFS) rate was 83.5% and the 3-year overall survival rate was 92.5%. Severe adverse events (≥grade 3) occurred in ~30% of patients; however, there was no treatment-related mortality. These findings clearly showed the tolerability and effectiveness of this protocol. Nevertheless, patients with high-risk cytogenetics showed a trend toward lower 3-year PFS than those without (77.8% vs. 89.4%, p = 0.051), and ultra-high-risk cytogenetics (≥2 high-risk cytogenetics) had an even worse prognosis, with 61.2% 3-year PFS. To overcome this situation, a more potent treatment strategy incorporating novel agents such as the CD38-antibody should be assessed in future studies.

P541 Long-term follow-up results of darvadstrocel for complex perianal fistulas in patients with Crohn's disease: 3-year outcomes from a Japanese phase 3 study

Abstract Background Darvadstrocel (DVS), a suspension of expanded human allogeneic mesenchymal stem cells extracted from adipose tissue, is for the treatment of complex perianal fistulas in patients with Crohn's disease (CD). In Japan, DVS was approved in 2021 based on the Japanese phase 3 study Week 52 data combined with the pivotal study ADMIRE-CD data. Patients who participated in the Japanese study were monitored for 3 years, and we report the results at Week (W) 156. Methods This was an open-label, uncontrolled, phase 3 study (converted to a post-marketing clinical study after approval) conducted from March 2019 to February 2023 in Japan. Subjects had complex Crohn’s perianal fistulas (CPF) refractory to conventional treatments with a maximum of 2 internal openings (IO) and 3 external openings (EO). The fistula tract was curetted approximately 2-3 weeks before DVS administration, and a drainage seton was placed. On the day of administration, seton was removed, fistula tracts were curetted again, and IO was sutured. A total of 24 mL of DVS (including 120x106 cells) was administered around the IO and into the wall of fistula tracts. During the 2-year follow-up period after W52, medical and surgical treatment for CD and CPF was given as needed, and subjects were assessed every 6 months. Results 22 Japanese patients were enrolled from 9 sites. The mean (SD) age was 36.4 (10.4) years, 63.6% were male, and the mean (SD) duration of CD was 11.3 (6.6) years. By W156, most frequently reported adverse events (AE) were anal fistula (7/22), proctalgia (7/22), and nasopharyngitis (6/22). New serious AE occurred after W52 were found in 9 subjects: COVID-19 (4), CD (2), perianal fistula, small bowel obstruction, premature labour (1 each). None of these were considered DVS-related. At W156, the combined remission rate (clinical and MRI assessment) was 15/22 (68.2%, 95% CI [48.7%, 87.6%]), clinical remission rate (clinical assessment) was 15/22 (68.2%, 95% CI [48.7%, 87.6%]), response rate (no drainage from ≥50% of treated EOs) was 20/22 (90.9%, 95% CI [78.9%, 100.0%]), and relapse rate (at least 1 relapse by W156 after achieving remission at W52) was 3/15 (20.0%, 95% CI [0.0%, 40.2%]). Mean Perianal Disease Activity Index (PDAI) total score (SD) was 4.8 (2.2) at baseline, which was decreased to 2.1 (2.1) at W52, and 1.7 (2.0) at W156. Mean Crohn's Disease Activity Index (CDAI) total score (SD) was 94.3 (60.1) on the day of administration, which was decreased to 73.7 (73.6) at W52, and 71.4 (51.2) at W156. Conclusion This is the first prospectively observed clinical outcomes in CPF for 3 years after DVS administration. There were no new safety findings, and fistula remission observed at W52 was maintained until W156.

Correlation of multiple endpoints in the first-line chemotherapy of advanced gastric cancer: Pooled analysis of individual patient data from Japanese Phase III trials.

Individual-level surrogates are important for management in patients treated for advanced gastric cancer (AGC). This study aimed to comprehensively investigate the correlation of multiple clinical endpoints in the first-line chemotherapy of AGC. Individual patient data (IPD) were collected from four Japanese Phase III trials comparing S-1-based first-line chemotherapies (SPIRITS, START, GC0301/TOP-002, and G-SOX trials). Patients without Response Evaluation Criteria in Solid Tumors (RECIST)-based radiological assessments were excluded. Spearman's rank correlation coefficient was tested for correlation among overall survival (OS), progression-free survival (PFS), and postprogression survival (PPS). OS, PFS, and PPS were compared between responders (best response: complete response or partial response) and nonresponders (best response: stable disease or progressive disease). The study included a total of 1492 patients. Eighty percent of the patients (n = 1190) received subsequent chemotherapies after the failure of each trial's treatment protocol. PFS moderately correlated with OS (Spearman correlation coefficient = 0.66, p < 0.005), whereas the correlation between PPS and OS was strong (Spearman correlation coefficient = 0.87, p < 0.005). Responders had significantly longer OS (median, 17.7 vs. 9.1 months, p < 0.005), PFS (median, 6.9 vs. 2.8 months, p < 0.005), and PPS (median, 10.5 vs. 6.0 months, p < 0.005) than nonresponders. Our results reacknowledged the mild surrogacy of PFS and importance of postprogression treatments in patients with AGC receiving first-line chemotherapy. Consistent longer survival outcomes in better RECIST categories suggested that tumor response might be a useful individual-level surrogate.

An Overview of the Use of Anti-Angiogenic Agents in the Treatment of Thymic Epithelial Tumors

Angiogenesis significantly influences the carcinogenesis of thymic epithelial tumors (TET). Both thymomas and thymic carcinoma (TC) overexpress VEGF-A and VEGFR-1 and -2. This review aims to provide an appraisal of the use of anti-angiogenics in the treatment of TET. The literature research identified 16 studies that were deemed eligible for further analysis. Seven studies assessed the clinical efficacy of sunitinib and five studies the use of apatinib and/or anlotinib. The multicenter Japanese phase II REMORA trial investigated the efficacy of lenvatinib, which is a multi-targeted inhibitor of VEGFR, FGFR, RET, c-Kit, and other kinases. The objective response rate was 38% (25.6–52%), which is the highest documented in TET that progressed after first-line chemotherapy. Anti-angiogenic agents may be useful in the treatment of TET, which are not amenable to curative treatment. Their toxicity profile seems to be acceptable. However, angiogenesis inhibitors do not appear to have a major influence on either thymomas or TC, although multikinase inhibitors may have some effect on TC. The current evidence suggests that the most active agent is lenvatinib, whereas sunitinib could be proposed as an acceptable second-line therapy for TC. Further research concerning the combination of immune checkpoint inhibitors with anti-angiogenic drugs is warranted.

The effects of abaloparatide on hip geometry and biomechanical properties in Japanese osteoporotic patients assessed using DXA-based hip structural analysis: results of the Japanese phase 3 ACTIVE-J trial

SummaryDaily subcutaneous injection of 80 μg abaloparatide increased bone mineral density in Japanese patients with osteoporosis at high fracture risk in the ACTIVE-J trial. Dual-energy X-ray absorptiometry–based hip structural analysis from ACTIVE-J data showed improved hip geometry and biomechanical properties with abaloparatide compared with placebo.PurposeAbaloparatide (ABL) increased bone mineral density (BMD) in Japanese patients with osteoporosis at high fracture risk in the ACTIVE-J trial. To evaluate the effect of ABL on hip geometry and biomechanical properties, hip structural analysis (HSA) was performed using ACTIVE-J trial data.MethodsHip dual-energy X-ray absorptiometry scans from postmenopausal women and men (ABL, n = 128; placebo, n = 65) at baseline and up to week 78 were analyzed to extract bone geometric parameters at the narrow neck (NN), intertrochanteric region (IT), and proximal femoral shaft (FS). Computed tomography (CT)-based BMD and HSA indices were compared between baseline and week 78.ResultsABL treatment showed increased mean percent change from baseline to week 78 in cortical thickness at the NN (5.3%), IT (5.3%), and FS (2.9%); cross-sectional area at the NN (5.0%), IT (5.0%), and FS (2.6%); cross-sectional moment of inertia at the NN (7.6%), IT (5.1%), and FS (2.5%); section modulus at the NN (7.4%), IT (5.4%), and FS (2.4%); and decreased mean percent change in buckling ratio (BR) at the IT (− 5.0%). ABL treatment showed increased mean percent change in total volumetric BMD (vBMD; 2.7%) and trabecular vBMD (3.2%) at the total hip and decreased mean percent change in BR at femoral neck (− 4.1%) at week 78 vs baseline. All the changes noted here were significant vs placebo (P < 0.050 using t-test).ConclusionA 78-week treatment with ABL showed improvement in HSA parameters associated with hip geometry and biomechanical properties vs placebo.Trial registrationJAPIC CTI-173575

Lower-Initiating Dose of Bosutinib for Resistant or Intolerant to Prior Therapy Chronic Myeloid Leukemia Patients (BOGI trial): A Single-Arm, Multicenter, Phase II Trial

Introduction: The introduction of ABL1 tyrosine kinase inhibitors (TKIs) has markedly improved the survival outcomes in patients with chronic phase chronic myeloid leukemia (CML-CP). Second-generation TKIs are highly active for patients with newly diagnosed and resistant/intolerant CML-CP. Although bosutinib is generally safe, drug-related toxicities (DRTs) such as diarrhea or increased transaminase leading to treatment discontinuation, are often observed. The standard initial daily dosage of bosutinib is 400 mg for newly diagnosed or 500 mg for resistant/intolerant patients with CML-CP, whereas some experts suggest lower dose (200-300 mg) initiation is recommended to reduce adverse events (AEs). However, the safety and efficacy of lower dose initiation of bosutinib are unknown. Hence, we conducted a phase 2 study of BOsutinib Gradual Increase as a second/third-line treatment for CML-CP (BOGI trial, UMIN 000032282) to clarify whether a lower initiating dose of bosutinib (200 mg daily) would reduce discontinuation or interruption of treatment due to DRTs. Patients and methods We included CML patients who developed at least one line of treatment failure (resistant or intolerant), aged &amp;gt;18 years with an ECOG performance status of 0-2 and adequate organ function. After enrollment, the patients initiated 200 mg of bosutinib daily; subsequently, dose escalation was performed by 100 mg daily (up to 500 mg daily) every 2 weeks if no grade 3 or higher AEs occurred. BCR::ABL1 mRNA levels were measured by the standardized international scale at a central laboratory at 3, 6, 9, and 12 month since treatment initiation. The primary endpoint was the treatment discontinuation rate due to DRTs at 12 months. Secondary endpoints included the treatment interruption rate, mean bosutinib dosage, dosing days and relative dose intensity until 12 months, achievement of cytogenetic response (CCyR), cumulative rates of major molecular response (MMR) or deep molecular response (DMR). Sample size calculation was performed by research and biostatistics SWOG statistical tools (at null proportion = 0.32, alternative proportion = 0.14, one-sided α error = 5% and β error = 20%, power 80%) with the discontinuation rate of the previous Japanese phase 1/2 study of bosutinib as a reference (Nakaseko C, et al. Int J Hematol. 2015). Considering protocol deviations, sample size was 35 participants. Results Between Feb 4, 2019, and May 24, 2022, 35 patients enrolled from four Japanese hospitals. The median age was 61 years (range, 26 - 81 years); 19 patients were male and 16 were female and 16, 12, and 7 patients had low,intermediate, and high Sokal scores, respectively. Ten patients had hypertension, five had diabetes millitus, three had chronic heart disease, two had solid tumor, and one had cerebrovascular disease, respectively. Numbers of patients with previous TKIs were one for 19 (54%), two for 12 (34%) and three for 4 (11%), respectively and prior TKIs are imatinib (8, 23%), dasatinib (27, 77%), nilotinib (16, 46%) and bosutinib (1, 3%), respectively. In the intention to treat population, the bosutinib discontinuation rate at 12 months was 25.7% (95% CI, 15.6-39.3%) which is significantly lower than that of the previous report (v.s. 43.0%, p=0.019). Similarly, bosutinib discontinuation rate due to DRTs was 11.4% (95% CI, 5.2 - 23.2%), which is also significantly lower (v.s. 32%, p = 0.005). These results suggest lower initiating dose of bosutinib reduced bosutinib discontinuation rate due to DRTs, thus the primary endpoint was met. A total of 22 patients (62.9%) interrupted bosutinib at least once. Median bosutinib dosage, bosutinib dosing days and relative dose intensity until 12 months were 391.7 (204.9-477.3) mg/day, 351.0 (20-365) days and 78% (41-95), respectively. 28 patients (80.0%) achieved cytogenetic response (CCyR) at 6 months; cumulative incidence of MMR and DMR at 12 months were 23 (65.7%; 95%CI, 49.2-79.2%) and 15 (42.9%; 95%CI, 28.0-59.1%), indicating these secondary endpoints were comparable with the previous report. Grade 3 to 4 transaminase elevation was 20% which is comparable with the previous report (v.s. 29%, p=0.427), while a lower rate of diarrhea (3%; v.s. 25%, p=0.009) was notable. Conclusion The lower initiating dose followed by a gradual dose increase of bosutinib reduced the drug discontinuation rate due to severe DRTs, especially diarrhea, while efficacy was assured.

58P Safety and pharmacokinetics (PK) of vepdegestrant in Japanese patients with estrogen receptor (ER)+/human epidermal growth factor receptor 2 (HER2)- advanced breast cancer: Results from a Japanese phase I study

58P Safety and pharmacokinetics (PK) of vepdegestrant in Japanese patients with estrogen receptor (ER)+/human epidermal growth factor receptor 2 (HER2)- advanced breast cancer: Results from a Japanese phase I study

Association between matrix metalloprotease-3 levels andradiographic progression inpatients with rheumatoid arthritis: A post hoc analysis from a Japanese Phase 3 clinical trial ofpeficitinib (RAJ4).

The current study assesses the utility of matrix metalloprotease-3 (MMP-3) as a biomarker for joint damage in patients with rheumatoid arthritis receiving peficitinib. Rheumatoid arthritis patients with inadequate response to methotrexate were randomised to peficitinib 100 mg, peficitinib 150 mg, or placebo, combined with methotrexate, for 52 weeks; patients receiving placebo switched to peficitinib 100/150 mg at Week (W)12/28. This post hoc analysis investigated association between MMP-3 above/below upper limit of normal (ULN) at W12/28 and radiographic progression [modified total Sharp score (mTSS), joint space narrowing score, or erosion score >0.5] at W52 or swollen joint count 66 at W28, stratified by baseline glucocorticoid use and renal function. MMP-3 levels decreased in both peficitinib-treated groups but more slowly in patients with baseline glucocorticoids and those with radiographic progression at W52. There was no clear correlation between MMP-3 change from baseline (CFB) at W12, CFB in mTSS, joint space narrowing score, or erosion score at W52, or CFB in swollen joint count 66 at W28. More patients with MMP-3 ≤ULN versus >ULN at W12 had radiographic non-progression at W52. MMP-3 normalisation at W12 was significantly associated with mTSS non-progression at W52. Normalisation of MMP-3 at W12 may be a predictor for subsequent non-progression of joint damage at W52.