Japanese Phase Research Articles

The effect of transportation modality to dialysis facilities on health-related quality of life among hemodialysis patients: results from the Japanese Dialysis Outcomes and Practice Pattern Study.

BackgroundFor hemodialysis (HD) patients, travel to the dialysis facility is an issue that can affect their quality of life (QOL), both physically and mentally. However, evidence on this association of transportation modality with health-related QOL (HRQOL) is scarce.Methods We conducted a cohort study among maintenance HD patients participating in the Japanese Dialysis Outcomes and Practice Pattern Study Phase 5. The study included patients who were functionally independent and able to walk. The primary exposure was the means of transportation to the dialysis facility, categorized into three groups, namely transportation by other drivers (Group 1), transportation via self-driving (Group 2) and transportation by bicycle or walking with or without public transportation (Group 3). The primary outcomes were physical and mental health composite scores (PCS and MCS) in the 12-item Short Form at 1 year after study initiation.ResultsAmong 1225 eligible patients (Group 1, 34.4%; Group 2, 45.0%; Group 3, 20.7%), 835 were analyzed for the primary outcomes. Linear regression analyses revealed that patients in Groups 2 and 3 had significantly higher PCS and MCS at 1 year than those in Group 1 {adjusted mean differences of PCS 1.42 [95% confidence interval (CI) 0.17–2.68] and 1.94 [95% CI 0.65–3.23], respectively, and adjusted mean differences of MCS 2.53 [95% CI 0.92–4.14] and 2.20 [95% CI 0.45–3.95], respectively}.ConclusionsTransportation modality was a significant prognostic factor for both PCS and MCS after 1 year in maintenance HD patients.

Epidermal growth factor receptor (EGFR) amplification rates observed in screening patients for randomized trials in glioblastoma

Epidermal growth factor receptor (EGFR) amplification has been reported to occur in ~ 50% of glioblastomas (GBMs). We are conducting several global studies that require central testing for EGFR amplification during screening, representing an opportunity to confirm the frequency of amplification in GBM in a large cohort and to evaluate whether EGFR amplification differs by region of the world. EGFR amplification was measured by fluorescence in situ hybridization during screening for therapeutic trials of an EGFR antibody-drug conjugate: two Phase 2/3 global trials (INTELLANCE-1, INTELLANCE-2), and a Japanese Phase 1/2 trial (INTELLANCE-J). We evaluated the proportion of tumor tissue samples harboring EGFR amplification among those tested and differences in amplification frequency by geography. EGFR was amplified in 54% of 3150 informative cases screened for INTELLANCE-1 and -2, consistent with historic controls, but was significantly lower in patients from Asia versus the rest of the world (35% vs. 56%, P < 0.0030). The independent INTELLANCE-J trial validated this finding (33% amplified of 153 informative cases). EGFR amplification occurs less frequently in patients from Asia than elsewhere. Further study is required to understand biological differences to optimize treatment in glioblastoma.

Neutropenia management with palbociclib in Japanese patients with advanced breast cancer

BackgroundThe cyclin-dependent kinase 4/6 (CDK4/6) inhibitor palbociclib, in combination with endocrine therapy (ET), significantly prolonged progression-free survival in women with hormone receptor–positive, human epidermal growth factor receptor 2–negative advanced breast cancer (HR+/HER2− ABC) in PALOMA-2 and PALOMA-3. Neutropenia and palbociclib dose reductions/interruptions occurred more frequently in the Japanese versus overall populations. We evaluated neutropenia patterns, palbociclib dose management, and clinical responses after dose reduction in Japanese patients in PALOMA-2 and PALOMA-3 and a single-arm Japanese phase 2 study.MethodsPALOMA-2 and the Japanese phase 2 study enrolled postmenopausal women with estrogen receptor–positive, HER2− ABC who had not received prior systemic therapy for advanced disease; PALOMA-3 enrolled women with HR+/HER2− ABC, regardless of menopausal status, whose disease had progressed after prior ET. Palbociclib (125 mg/day) was administered 3 weeks on/1 week off. Dose reduction/interruption, cycle delay, tumor response, and laboratory-assessed neutropenia were analyzed in Japanese patients who received palbociclib.ResultsA total of 101 Japanese patients received palbociclib + ET. Among Japanese patients in the 3 studies, the frequency of all-grade/grade 3/grade 4 neutropenia was 94%/53%/34%, 100%/69%/21%, and 100%/67%/26%, respectively. Twenty (63%), 28 (67%), and 15 (56%) patients required palbociclib dose reduction. Dose interruption or reduction did not affect palbociclib treatment duration, and durable tumor response was observed despite dose reduction.ConclusionNeutropenia was manageable with dose modifications, without affecting palbociclib treatment duration or efficacy.Trial registrationPfizer (NCT01740427, NCT01684215, NCT01942135).

A systematic review of observational studies of trifluridine/tipiracil (TAS-102) for metastatic colorectal cancer

Background: The treatment options for patients with therapy refractory metastatic colorectal cancer (mCRC) are sparse. TAS-102 (FTD/TPI) is a new oral anti-tumour agent composed of a nucleoside analogue, trifluridine, and a thymidine phosphorylase inhibitor, tipiracil, indicated for patients with mCRC who are refractory to standard therapies. This study summarizes published and unpublished experience with FTD/TPI in clinical practice settings.Patients and methods: The Medline/PubMed, Embase and Cochrane Library databases were searched to identify observational studies on FTD/TPI monotherapy for mCRC. Papers describing use of FTD/TPI monotherapy outside clinical trials in series of patients evaluable for effectiveness were eligible. The outcomes of interest were median progression free survival (mPFS), median overall survival (mOS) as well as mean PFS time restricted to six months (PFS6m) and mean OS time restricted to one year (OS1y). Results of the pooled analyses of observational studies were compared to the results of the Japanese phase II trial and the two phase III trials, RECOURSE and TERRA.Results: Seven published and two unpublished studies with 1008 patients from 64 centres were included for analysis. The pooled mPFS was 2.2 months (95% CI 2.1 to 2.3 months), and the pooled mOS was 6.6 months (95% CI 6.1 to 7.1 months). PFS6m was 2.9 months (95% CI 2.6 to 3.1 months) and OS1y was 6.8 (95% CI 6.0 to 7.5) months. While these results all reflect RECOURSE, the pooled mOS is lower than in the phase II trial and the OS1y is inferior to both the phase II trial and TERRA.Conclusion: This systematic review and a meta-analysis indicates that in real life settings, the survival benefit of FTD/TPI monotherapy in patients with therapy refractory mCRC reflects the outcomes in RECOURSE but is inferior to outcomes in the two Asian efficacy trials.What is already knownTAS 102 (Lonsurf) is an oral fixed dose combination of trifluridine (FTD) and tipiracil (TPI) indicated as salvage-line treatment in patients with therapy refractory metastatic colorectal cancer (mCRC). A Japanese phase II trial and two phase III trials, RECOURSE and TERRA, demonstrated that FTD/TPI prolonged overall survival.What this study addsThis systematic review and meta-analysis of real life data from 64 sites indicates that the effectiveness in daily clinical practice settings of FTD/TPI monotherapy in late stage mCRC reflects the outcomes in RECOURCE but is inferior to the outcomes in the Japanese phase II trial and TERRA.

Efficacy of duloxetine for multi-site pain in patients with knee pain due to osteoarthritis: an exploratory post hoc analysis of a Japanese phase 3 randomized study

Efficacy of duloxetine for multi-site pain in patients with knee pain due to osteoarthritis: an exploratory post hoc analysis of a Japanese phase 3 randomized study

Real-world outcomes of the Xarelto Post-Authorization Safety & Effectiveness Study in Japanese Patients with Atrial Fibrillation (XAPASS)

BackgroundAlthough the efficacy and safety of the factor Xa inhibitor rivaroxaban for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF) were shown in global and Japanese phase III clinical trials, safety and effectiveness data from unselected patients in everyday clinical practice are limited. The objective of the XAPASS (Xarelto Post-Authorization Safety & Effectiveness Study in Japanese Patients with Atrial Fibrillation) is to investigate the safety and effectiveness of rivaroxaban in Japanese real-world clinical practice. MethodsThe XAPASS is a prospective, single-arm, real-world observational study mandated by the Japanese authority as post-marketing surveillance. In total, 11,308 patients with NVAF who began treatment with rivaroxaban were enrolled from April 2012 to June 2014, and 9578 patients were analyzed to examine the one-year outcomes. ResultsThe mean treatment duration was 300±119 days. The patients’ age was 73.2±9.8 years, and their CHADS2 score was 2.2±1.3. Any bleeding and major bleeding occurred in 602 patients (7.6 events per 100 patient-years) and 143 patients (1.8 events per 100 patient-years), respectively. Stroke/non-central nervous system systemic embolism/myocardial infarction was observed in 144 patients (1.8 events per 100 patient-years). ConclusionsReal-world outcomes of the XAPASS showed incidence rates of major bleeding and thromboembolic events, suggesting that rivaroxaban is safe and effective in Japanese daily clinical practice (Clinicaltrials.gov: NCT01582737).

Efficacy and safety of trifluridine/tipiracil (FTD/TPI) in patients (pts) with metastatic gastric cancer (mGC) with or without prior gastrectomy: Results from a phase III study (TAGS).

3 Background: The phase 3 study TAGS demonstrated that the novel oral therapy FTD/TPI (TAS-102) represents an effective treatment option with a manageable safety profile for pts with heavily pretreated mGC. In an earlier single-arm Japanese phase 2 trial in mGC, no differences were found in the pharmacokinetics of either FTD or TPI in pts with or without prior gastrectomy. We evaluated the efficacy and safety of FTD/TPI in pts with or without prior gastrectomy within the TAGS study. Methods: In this global phase 3 study of adult pts with mGC who had received ≥ 2 prior regimens of chemotherapy, pts were randomized 2:1 to receive FTD/TPI (35 mg/m2 BID on days 1–5 and 8–12 of each 28-day cycle) or placebo, plus best supportive care. We performed a preplanned analysis of efficacy and safety endpoints in pt subgroups with or without prior gastrectomy. Results: Of 507 randomized pts, 221 (44%) had a prior gastrectomy (FTD/TPI, 147/337; placebo, 74/170). Baseline pt characteristics were balanced across pt subgroups. FTD/TPI prolonged survival versus placebo regardless of gastrectomy (table). The frequency of neutropenia/leukopenia appeared to be higher among FTD/TPI-treated pts with vs without gastrectomy, but this did not result in more treatment discontinuations (table). Conclusions: In the TAGS study, subgroup analysis demonstrated that FTD/TPI is an effective treatment option with a manageable safety profile for pts with heavily pretreated mGC, regardless of prior gastrectomy. Clinical trial information: NCT02500043. [Table: see text]

Analyses of natural courses of Japanese patients with Alzheimer's disease using placebo data from placebo-controlled, randomized clinical trials: Japanese Study on the Estimation of Clinical course of Alzheimer's disease

IntroductionSymptomatic anti-Alzheimer's disease (AD) drugs have been commonly used for the treatment of AD. Knowing the natural courses of patients with AD on placebo is highly relevant for clinicians to understand their efficacy and for investigators to design clinical studies. MethodsThe data on rating scales for dementia such as Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and Severe Impairment Battery were extracted from eight previous Japanese Phase II and III studies. Natural courses of Japanese AD patients in placebo groups were evaluated and statistically analyzed in a pooled and retrospective fashion. ResultsDecreases in ADAS-cog and Severe Impairment Battery was larger at week 22 or 24 than at week 12. Scores of ADAS-cog appeared to deteriorate faster in moderate AD than in mild AD. DiscussionThe present data will provide clinicians following up patients with AD with helpful information on how to manage AD patients and investigators with instruction for clinical study design.

Vibegron: First Global Approval

Vibegron is a selective beta 3 adrenergic receptor (β3AR) agonist that is being developed in Japan jointly by Kyorin Pharmaceutical Co., Ltd and Kissei Pharmaceutical Co., Ltd and in other regions worldwide (except in several other Asian countries) by Urovant Sciences for the treatment of overactive bladder (OAB). Based on results from Japanese phase III trials, vibegron received approval in Japan in September 2018 for this indication. This article summarizes the milestones in the development of vibegron leading to this first global approval for the treatment of OAB.

Response to duloxetine in patients with knee pain due to osteoarthritis: an exploratory post hoc analysis of a Japanese Phase III randomized study.

PurposeTo assess whether patients with knee osteoarthritis pain who have early pain reduction or treatment-related adverse events of special interest (TR-AESIs; constipation, decreased appetite, malaise, nausea, somnolence, thirst) with duloxetine treatment are more likely to have later improvements in pain and quality of life (QOL) relative to placebo than patients without these early indicators.Patients and methodsThis was a post hoc analysis of 14-week randomized trial of Japanese patients with knee osteoarthritis pain (Brief Pain Inventory [BPI]-Severity average pain score ≥4) receiving duloxetine 60 mg/day (n=177 analyzed) or placebo (n=176). Primary trial outcome was change from baseline in BPI-Severity average pain at Week 14. Subgroups included early pain reduction (≥30%, 10%–30%, or <10% decrease in BPI-Severity average pain at Week 4) and early TR-AESIs (with/without TR-AESIs by Week 2). Measures included changes from baseline in BPI-Severity average pain, QOL (BPI-Interference, Western Ontario and McMaster Universities Osteoarthritis Index), Patient Global Impression of Improvement (PGI-I), and response rate (proportion achieving ≥30% or ≥50% pain reduction at Week 14).ResultsThe ≥30% early pain reduction subgroup (n=93) had significantly greater improvements in pain, QOL, and PGI-I and higher ≥30% and ≥50% response rates than placebo; the 10%–30% (n=45) and the <10% (n=33) pain reduction subgroups did not show the same (except 10%–30% group: PGI-I at Week 10 and some QOL at Weeks 10 and/or 14). Both TR-AESI subgroups (with, n=52; without, n=125) had significantly greater improvements in pain, PGI-I, and most QOL measures and higher response rates than placebo.ConclusionEarly efficacy responses to duloxetine treatment, but not early TR-AESIs, may predict later pain reduction and QOL improvements in Japanese patients with knee osteoarthritis pain.ClinicalTrials.govNCT02248480.

685P - Relation of overall survival, progression free survival, post progression survival and response rate in four randomized Japanese phase III trials comparing various combinations of S-1 therapy for first-line treatment of advanced gastric cancer

685P - Relation of overall survival, progression free survival, post progression survival and response rate in four randomized Japanese phase III trials comparing various combinations of S-1 therapy for first-line treatment of advanced gastric cancer

Docetaxel Plus RAmucirumab With Primary Prophylactic Pegylated Granulocyte-ColONy Stimulating Factor Support for Elderly Patients With Advanced Non–small-cell Lung Cancer: A Multicenter Prospective Single Arm Phase II Trial: DRAGON Study (WJOG9416L)

We exhibit our ongoing multicenter, prospective, single-arm, phase II trial of docetaxel plus ramucirumab with primary prophylactic pegylated-granulocyte-colony stimulating factor (PEG-G-CSF) support for chemotherapy-naive elderly patients with advanced non–small-cell lung cancer (NSCLC) (University Hospital Medical Information Network database: UMIN000030598). Docetaxel monotherapy is the Japanese standard of care for chemotherapy-naive elderly patients with advanced NSCLC. Docetaxel plus ramucirumab showed superior survival benefit over docetaxel monotherapy in the second-line setting for NSCLC. A Japanese phase II study comparing docetaxel plus ramucirumab and docetaxel monotherapy in the second-line setting showed febrile neutropenia (FN) incidence of approximately one-third in the docetaxel plus ramucirumab arm. Docetaxel plus ramucirumab could be a promising candidate for elderly patients with NSCLC, but such high FN incidence is a clinically critical concern. To overcome this problem, we adopt a routine primary prophylactic PEG-G-CSF with docetaxel plus ramucirumab therapy. We hypothesize that primary prophylactic PEG-G-CSF reduces FN and maximizes the efficacy of docetaxel plus ramucirumab in Japanese elderly patients with NSCLC. Intravenous docetaxel (60 mg/m2, day 1) plus ramucirumab (10 mg/kg, day 1) with subcutaneous PEG-G-CSF (3.6 mg, day 2) every 3 weeks is administered until progression. The primary endpoint is overall response rate (ORR). We decided the threshold ORR to be 20%, and the expected ORR 35%. Taking statistical points (α/β errors: 0.05/0.80) and ineligible patients into account, the sample size was set at 65. When the study results are promising, we will conduct a phase III trial to compare docetaxel plus ramucirumab with PEG-G-CSF support versus docetaxel monotherapy for chemotherapy-naive elderly patients with NSCLC.

Semaglutide: Review and Place in Therapy for Adults With Type 2 Diabetes.

Guidelines increasingly highlight the importance of multifactorial management in type 2 diabetes, in contrast to the more traditional focus on glycemic control. Semaglutide, a recently approved glucagon-like peptide-1 receptor agonist, is indicated in Canada for adults with type 2 diabetes to improve glycemic control as monotherapy with diet and exercise when metformin is inappropriate or as an add-on to either metformin alone or metformin plus a sulfonylurea or basal insulin. The Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes (SUSTAIN) clinical trial program for semaglutide comprises 6 pivotal global phase 3a trials (SUSTAIN 1 through 6) and 2 Japanese phase 3a trials. Phase 3b trials include SUSTAIN 7, and SUSTAIN 8 and 9 (both ongoing). Results from the completed trials support the superiority of semaglutide for reduction of glycated hemoglobin levels and weight loss vs. placebo as well as active comparators, including sitagliptin, exenatide extended-release, dulaglutide and insulin glargine. SUSTAIN 6 trial data confirmed cardiovascular safety and demonstrated significant reductions in major cardiovascular events with semaglutide vs. placebo, an outcome that confirmed the noninferiority of semaglutide. The robust and sustained effects of semaglutide on glycated hemoglobin levels and weight loss vs. comparators, as well as its safety and possible cardiovascular benefit, address an unmet need in the treatment of type 2 diabetes. This article overviews data from across the semaglutide clinical trial program, including efficacy and safety results and findings from post hoc analyses. The potential place of semaglutide in clinical practice is discussed.

Nationwide Multicenter Observational Study of FOLFIRINOX Chemotherapy in 399 Patients With Unresectable or Recurrent Pancreatic Cancer in Japan.

FOLFIRINOX (oxaliplatin, irinotecan, 5-fluorouracil, and leucovorin) is the standard therapy worldwide for unresectable pancreatic cancer; however, clinical data for Japanese patients are limited. Therefore, the observational study of FOLFIRINOX for patients with pancreatic cancer was conducted. The study included 399 patients with unresectable or recurrent pancreatic cancer, from 27 institutions in Japan, treated with FOLFIRINOX and surveyed until December 2015. The median age was 63 years; in most patients, the Eastern Cooperative Oncology Group performance status was 1 or lower. The initial dose was reduced in 270 patients (68%). The main grade 3/4 toxicities were neutropenia (64%), anorexia (14%), and febrile neutropenia (13%). Fatal adverse events occurred in 5 patients, 4 of whom did not satisfy the main inclusion criteria of a previous Japanese phase II FOLFIRINOX study. The median overall survival and progression-free survival times were 10.8, and 4.5 months, respectively. The objective response rate was 21%, and the disease control rate was 61%. The median overall survival times were 11.1, 18.5, and 4.9 months in chemotherapy-naïve patients with metastatic, locally advanced, and recurrent disease, respectively. When carefully managed, FOLFIRINOX is acceptably safe and efficacious in Japanese patients with unresectable pancreatic cancer.

Retrospective comparison of modified FOLFIRINOX with full-dose FOLFIRINOX for advanced pancreatic cancer: A Japanese cancer center experience.

469 Background: Various modified FOLFIRINOX (mFFX) regimens have been reported and widely used in clinical practice. Although there are retrospective studies and single-arm phase 2 studies comparing modified regimens to the full-dose regimen of the historical control group, head-to-head comparisons in the same population are limited. This study aimed to compare mFFX with full-dose FOLFIRINOX (fFFX) in patients with advanced pancreatic cancer (APC). Methods: We reviewed 85 patients with APC who received mFFX (no bolus fluorouracil and irinotecan 150 mg per square) or fFFX as first-line chemotherapy between January 2014 and December 2016. mFFX has been used since January 2016 on the basis of results of a Japanese phase 2 study. The efficacy, safety, and dose reduction pattern were evaluated. Results: A total of 56 eligible patients (26 treated with mFFX and 30 with fFFX) were selected. Baseline characteristics of each group were well-balanced. The median relative dose intensities of oxaliplatin, irinotecan, bolus fluorouracil, and continuous infusion fluorouracil were 68.6%, 78.5%, 0%, and 88.5% in the mFFX group, and 80.5%, 76.5%, 25.6%, and 83.6% in the fFFX group, respectively. Second cycle dose reduction occurred in 38% of the patients in the mFFX group and in 62% of those in the fFFX group. The median overall survival (OS) was 19.0 months in the mFFX group, compared to 13.2 months in the fFFX group (HR 0.60, 95% CI 0.25–1.47, P = 0.27). In a multivariate analysis to adjust for prognostic factors for OS, the hazard ratio for death with mFFX was significant (adjusted HR 0.36, 95% CI 0.14–0.93, P = 0.04). The median progression-free survival was 8.3 months in the mFFX group and 5.9 months in the fFFX group (HR 0.83, 95% CI 0.44–1.54, P = 0.55). The response rate was 35% in the mFFX group versus 30% (P = 0.78) in the fFFX group, respectively. Grade 3 or 4 leucopenia (15% versus 40%), neutropenia (42% versus 70%), febrile neutropenia (8% versus 17%), and nausea (4% versus 13%) were decreased in the mFFX group, but the differences were not statistically significant. Conclusions: mFFX had equivalent or higher efficacy and improved safety compared to fFFX in the same population.

Response to duloxetine in chronic low back pain: exploratory post hoc analysis of a Japanese Phase III randomized study.

PurposeDuloxetine is efficacious for chronic low back pain (CLBP). This post hoc analysis of a Japanese randomized, placebo-controlled trial (ClinicalTrials.gov, NCT01855919) assessed whether patients with CLBP with early pain reduction or treatment-related adverse events of special interest (TR-AESIs; nausea, somnolence, constipation) have enhanced responses to duloxetine.Patients and methodsPatients (N = 456) with CLBP for ≥6 months and Brief Pain Inventory (BPI) average pain severity score of ≥4 were randomized (1:1) to duloxetine 60 mg/day or placebo for 14 weeks. Primary outcome was change from baseline in BPI average pain severity score (pain reduction). Subgroup analyses included early pain reduction (≥30%, 10%–30%, or <10% at Week 4) and early TR-AESIs (with or without TR-AESIs by Week 2). Measures included changes from baseline in BPI average pain severity score and BPI Interference scores (quality of life; QOL), and response rate (≥30% or ≥50% pain reduction at Week 14).ResultsPatients with ≥30% early pain reduction (n = 108) or early TR-AESIs (n = 50) had significantly greater improvements in pain and QOL than placebo-treated patients (n = 226), whereas patients with 10%–30% (n = 63) or <10% (n = 48) pain reduction did not; patients without early TR-AESIs (n = 180) had significant improvements in pain at Week 14. Response rates (≥30%/≥50% pain reduction) were 94.4%/82.4%, 66.7%/49.2%, and 25.0%/18.8% for patients with ≥30%, 10%–30%, and <10% early pain reduction, respectively, 74.0%/64.0% for patients with early TR-AESIs, 67.2%/54.4% for patients without early TR-AESIs, and 52.2%/39.4% for placebo.ConclusionEarly pain reduction or TR-AESIs may predict which CLBP patients are most likely to respond to duloxetine with improvements in pain and QOL.

251P - Efficacy and safety of olaparib combined with eribulin in patients with advanced or metastatic triple negative breast cancer (TNBC) previously treated with anthracyclines and taxanes: The final analysis of a Japanese phase I/II trial

251P - Efficacy and safety of olaparib combined with eribulin in patients with advanced or metastatic triple negative breast cancer (TNBC) previously treated with anthracyclines and taxanes: The final analysis of a Japanese phase I/II trial

A phase I, open-label, nonrandomized, pharmacokinetic study of trifluridine/tipiracil (TAS-102) in Chinese patients with solid tumors.

e14079 Background: Trifluridine/tipiracil (TAS-102) is an oral combination of an antineoplastic thymidine-based nucleoside analog, trifluridine (FTD), and the thymidine phosphorylase inhibitor, tipiracil (TPI). Trifluridine/tipiracil is demonstrated as a valid treatment choice for Asian and Western patients (pts) with metastatic colorectal cancer refractory or intolerant to standard chemotherapies in earlier studies. Its pharmacokinetic (PK) profile was also investigated in American and Japanese phase 1 studies, but never in Chinese pts. This study was conducted to investigate the PK profile of Trifluridine/tipiracil in a Chinese population with solid tumors. Methods: Pts who has responded poorly to existing standard treatment received Trifluridine/tipiracil (35 mg/m2/dose), orally BID, on days 1-5 and days 8-12 every 4 weeks until one of discontinuation criteria was met. Blood samples for PK analysis of FTD (the active compound), fluorothymine (FTY, inactive metabolite) and TPI were collected after single and multiple doses of Trifluridine/tipiracil on days 1 and 12 of cycle 1. The safety, tolerability, and antitumor activity of Trifluridine/tipiracil were also assessed as secondary endpoints. Results: A total of 15 pts were administered Trifluridine/tipiracil and analyzed for PKs. The PKs of FTD, FTY, and TPI in Chinese pts were comparable to those in Japanese pts. Compared with American pts, although the AUC0-t of TPI on day 12 was significantly lower in Chinese pts, the Cmax and AUC0-t of FTD were not significantly different. Thirteen (86.7%) pts reported treatment-emergent adverse events (TEAEs), and eight (53.3%) pts experienced grade 3 TEAEs, of which anemia and fatigue were most frequently (≥10% of patients) reported. Grade 4 or 5 TEAEs were not observed. Conclusions: The PKs of Trifluridine/tipiracil in Chinese pts were comparable to those in Japanese pts. The exposure of FTD was showed without significant difference between Chinese, Japanese and American pts. Trifluridine/tipiracil was well-tolerated in Chinese pts and had the similar safety profile in comparison with previous studies. Clinical trial information: NCT02261532.

Risedronate therapy in patients with mild-to-moderate chronic kidney disease with osteoporosis: post-hoc analysis of data from the risedronate phase III clinical trials

BackgroundThe clinical effect of bisphosphonate treatment has not been clearly evaluated by kidney function in Japanese Chronic Kidney Disease (CKD) patients with osteoporosis. This study analyzed the data from three risedronate Japanese phase III trials. The clinical effect of risedronate therapy was evaluated in CKD patients with osteoporosis.MethodsThe Japanese clinical trials involved 852 subjects who received risedronate (2.5 mg once daily or 17.5 mg once weekly) and whose estimated glomerular filtration rate (eGFR) were calculable and at ≥ 30 mL/min. The subjects were divided into subgroups according to the eGFR level: ≥ 90 mL/min/1.73 m2, ≥ 60 to < 90 mL/min/1.73 m2, ≥ 30 to < 60 mL/min/1.73 m2. Lumbar spine bone mineral density (BMD), bone turnover markers (BTMs) and adverse events were evaluated at 48 weeks.ResultsAdverse event incidence was similar among three subgroups. There was also no exacerbation of impaired kidney function associated with risedronate administration in the subjects with eGFR above 30 mL/min/1.73 m2. Risedronate administration induced a significant increase in lumbar spine BMD and significant inhibition of BTMs in three subgroups.ConclusionsThe risedronate therapy showed similar clinical effects in CKD patients with osteoporosis compared to those without CKD.

Abstract ES9-3: ES9-3 (Neo)adjuvant systemic therapy of TNBC: How much is enough?

Abstract The use of neoadjuvant chemotherapy in ER-negative cancers has become quite popular in patients with stage II and III breast cancers, since it gives us important information on long-term prognosis, based on the amount of residual disease burden at the time of definitive surgical resection. Two relatively large phase II randomized neoadjuvant clinical trials have explored the addition of carboplatin to an anthracycline/taxane based chemotherapy regimen for patients with stage II or III triple-negative breast cancers (TNBC): GeparSixto, in Europe, and CALGB40603, in the US. Despite significant differences in chemotherapy backbone, and frequency and duration of carbo administration, both trials showed that the addition of carboplatin significantly increased the rate of pCR from ∼ 40% to 54%. Both trials also reported a significant amount of added toxicity for the carboplatin arms, with a significant amount of patient not being able to complete their planned treatment. However, whereas the GeparSixto trial reported an improvement in 3-year disease-free survival (DFS), the CALGB40603 did not. Since neither of these studies was powered to address disease-free or overall survival benefit from the addition of carboplatin to neoadjuvant systemic chemotherapy, lack of precision from small sample sizes are likely responsible for the difference seen in DFS between these two trials. Additionally, there's not yet a confirmed correlation between increases in frequency of pCR and event-free survival (EFS). A recently pooled analysis by Cortazar et al. could not validate pCR as a surrogate endpoint for improved EFS and overall survival (OS): as some patients who achieve a pCR go on to relapse and many with residual disease never experience a recurrence, small differences in pCR may never translate to improvements in EFS. Long term effects of the added toxicity of carboplatin are also not known. At present, upon completion of neoadjuvant therapy, the standard of care for patients with TNBC (who have no clinical evidence of metastatic disease after surgical excision of the cancer regardless of burden of residual disease) is observation. But recently, preliminary data from a Japanese phase III trial (CREATE-X) that randomized patients with HER2-negative breast cancer with lack of pCR post-neoadjuvant chemotherapy to observation or capecitabine x 8 cycles showed that the addition of capecitabine provided a statistically significantly higher 5-year DFS and OS in the TNBC group. EA1131, an ongoing adjuvant randomized phase III clinical trial seeks to address if patients with basal-like TNBC, with high risk of recurrence due to residual disease post completion of neoadjuvant chemotherapy, have a higher DFS benefit from a platinum agent than from capecitabine. The results of this trial will ultimately help avoid exposing upfront unselected patients, many of whom will never relapse, to toxic therapy in the absence of long-term known benefit. In summary, the addition of a platinum agent routinely in the neoadjuvant setting in TNBC is still an individualized decision and not yet standard of care for all patients. The decision to use capecitabine in patients with residual disease post-neoadjuvant chemo may still be slightly premature, confirmatory results of EA1131 are eagerly awaited. Citation Format: Mayer IA. ES9-3 (Neo)adjuvant systemic therapy of TNBC: How much is enough? [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr ES9-3.