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Summary Background Trifluridine/tipiracil showed activity and was well tolerated in a phase 2 study of pretreated patients with advanced gastric cancer done in Japan. We investigated whether the treatment was efficacious compared with placebo in a global population. Methods TAGS was a randomised, double-blind, placebo-controlled, phase 3 trial done in 110 academic hospitals in 17 countries. Patients aged 18 years or older with histologically confirmed, non-resectable, metastatic gastric adenocarcinoma (including adenocarcinoma of the gastroesophageal junction) as defined by the American Joint Committee on Cancer staging classification (7th edition) who had received at least two previous chemotherapy regimens and had experienced radiological disease progression were eligible for inclusion. Patients were randomly assigned (2:1) via dynamic randomisation from a centralised interactive voice-response system to receive either oral trifluridine/tipiracil (35 mg/m2 twice daily on days 1–5 and days 8–12 every 28 days) plus best supportive care or placebo plus best supportive care. Participants were allocated to groups by study-site personnel. Randomisation was stratified by region (Japan vs rest of world), ECOG performance status (0 vs 1), and previous treatment with ramucirumab (yes vs no). Both patients and investigators were masked to treatment allocation. The primary endpoint was overall survival. Efficacy was assessed in the intention-to-treat population and safety in all patients who received at least one dose of treatment. This trial is registered with ClinicalTrials.gov , number NCT02500043 . The trial, including follow-up of all participants, has been completed. Findings Between Feb 24, 2016, and Jan 5, 2018, 507 patients were enrolled and randomly assigned, 337 to the trifluridine/tipiracil group and 170 to the placebo group. Median overall survival was 5·7 months (95% CI 4·8–6·2) in the trifluridine/tipiracil group and 3·6 months (3·1–4·1) in the placebo group (hazard ratio 0·69 [95% CI 0·56–0·85]; one-sided p=0·00029, two-sided p=0·00058). Grade 3 or worse adverse events of any cause occurred in 267 (80%) patients in the trifluridine/tipiracil group and 97 (58%) in the placebo group. The most frequent grade 3 or worse adverse events of any cause were neutropenia (n=114 [34%]) and anaemia (n=64 [19%]) in the trifluridine/tipiracil group and abdominal pain (n=15 [9%]) and general deterioration of physical health (n=15 [9%]) in the placebo group. Serious adverse events of any cause were reported in 143 (43%) patients in the trifluridine/tipiracil group and 70 (42%) in the placebo group. One treatment-related death was reported in each group (because of cardiopulmonary arrest in the trifluridine/tipiracil group and because of toxic hepatitis in the placebo group). Interpretation Trifluridine/tipiracil significantly improved overall survival compared with placebo and was well tolerated in this heavily pretreated population of patients with advanced gastric cancer. Trifluridine/tipiracil could be a new treatment option in this population who represent a high unmet medical need. Funding Taiho Oncology and Taiho Pharmaceutical.

IMPORTANCE: Trifluridine/tipiracil (FTD/TPI) treatment has shown clinical benefit in patients with pretreated metastatic gastric cancer or gastroesophageal junction cancer (mGC/GEJC). Patients who have undergone gastrectomy constitute a significant proportion of patients with mGC/GEJC. OBJECTIVE: To assess the efficacy and safety of FTD/TPI among patients with previously treated mGC/GEJC who had or had not undergone gastrectomy. DESIGN, SETTING, AND PARTICIPANTS: This preplanned subgroup analysis of TAGS (TAS-102 Gastric Study), a phase 3, randomized, placebo-controlled, clinical trial included patients with mGC/GEJC who had received at least 2 previous chemotherapy regimens, and was conducted at 110 academic hospitals in 17 countries in Europe, Asia, and North America, with enrollment between February 24, 2016, and January 5, 2018; the data cutoff was March 31, 2018. INTERVENTIONS: Patients were randomized 2:1 to receive oral FTD/TPI 35 mg/m2 twice daily or placebo twice daily with best supportive care on days 1 through 5 and days 8 through 12 of each 28-day treatment cycle. MAIN OUTCOMES AND MEASURES: The primary end point was overall survival. This subgroup analysis was conducted to examine potential trends and was not powered for statistical significance. Efficacy and safety end points were evaluated in the subgroups. RESULTS: Of 507 randomized patients (369 [72.8%] male; mean [SD] age, 62.5 [10.5] years), 221 (43.6%) had undergone gastrectomy (147 randomized to FTD/TPI and 74 to placebo) and 286 (56.4%) had not undergone gastrectomy (190 randomized to FTD/TPI and 96 to placebo). In the gastrectomy subgroup, the overall survival hazard ratio (HR) in the FTD/TPI group vs placebo group was 0.57 (95% CI, 0.41-0.79), and the progression-free survival HR was 0.48 (95% CI, 0.35-0.65). In the no gastrectomy subgroup, the overall survival HR in the FTD/TPI group vs placebo group was 0.80 (95% CI, 0.60-1.06), and the progression-free survival HR was 0.65 (95% CI, 0.49-0.85). Among FTD/TPI-treated patients, grade 3 or higher adverse events of any cause occurred in 122 of 145 patients (84.1%) in the gastrectomy subgroup and 145 of 190 (76.3%) in the no gastrectomy subgroup: 64 (44.1%) in the gastrectomy subgroup and 50 (26.3%) in the no gastrectomy subgroup had grade 3 or higher neutropenia, 31 (21.4%) in the gastrectomy subgroup and 33 (17.4%) in the no gastrectomy subgroup had grade 3 or higher anemia, and 21 (14.5%) in the gastrectomy subgroup and 10 (5.3%) in the no gastrectomy subgroup hD grade 3 or higher leukopenia. In the gastrectomy subgroup, 94 (64.8%) had dosing modifications because of adverse events vs 101 (53.2%) in the no gastrectomy subgroup; 15 (10.3%) in the gastrectomy group and 28 (14.7%) in the no gastrectomy group discontinued treatment because of adverse events. Treatment exposure was similar between groups. CONCLUSIONS AND RELEVANCE: The FTD/TPI treatment was tolerable and provided efficacy benefits among patients with pretreated mGC/GEJC regardless of previous gastrectomy. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02500043. ispartof: JAMA ONCOLOGY vol:6 issue:1 ispartof: location:United States status: published

This subgroup analysis of a randomized clinical trial compares trifluridine/tipiracil treatment with placebo for progression-free and overall survival among patients with previously treated metastatic gastric or gastroesophageal junction cancer who had or had not undergone gastrectomy. Is trifluridine/tipiracil treatment safe and effective for the subpopulation of patients with previously treated metastatic gastric or gastroesophageal junction cancer who have undergone gastrectomy? In this subgroup analysis of a randomized clinical trial, trifluridine/tipiracil treatment improved overall survival and progression-free survival compared with placebo among patients with previously treated metastatic gastric or gastroesophageal junction cancer and who had or had not undergone gastrectomy. No new safety concerns were reported, and hematologic toxic effects were more frequent among the subgroup who had undergone gastrectomy but were treated using dosing modifications. Trifluridine/tipiracil is a safe and effective treatment option for patients with pretreated metastatic gastric or gastroesophageal junction cancer regardless of previous gastrectomy. Trifluridine/tipiracil (FTD/TPI) treatment has shown clinical benefit in patients with pretreated metastatic gastric cancer or gastroesophageal junction cancer (mGC/GEJC). Patients who have undergone gastrectomy constitute a significant proportion of patients with mGC/GEJC. To assess the efficacy and safety of FTD/TPI among patients with previously treated mGC/GEJC who had or had not undergone gastrectomy. This preplanned subgroup analysis of TAGS (TAS-102 Gastric Study), a phase 3, randomized, placebo-controlled, clinical trial included patients with mGC/GEJC who had received at least 2 previous chemotherapy regimens, and was conducted at 110 academic hospitals in 17 countries in Europe, Asia, and North America, with enrollment between February 24, 2016, and January 5, 2018; the data cutoff was March 31, 2018. Patients were randomized 2:1 to receive oral FTD/TPI 35 mg/m 2 twice daily or placebo twice daily with best supportive care on days 1 through 5 and days 8 through 12 of each 28-day treatment cycle. The primary end point was overall survival. This subgroup analysis was conducted to examine potential trends and was not powered for statistical significance. Efficacy and safety end points were evaluated in the subgroups. Of 507 randomized patients (369 [72.8%] male; mean [SD] age, 62.5 [10.5] years), 221 (43.6%) had undergone gastrectomy (147 randomized to FTD/TPI and 74 to placebo) and 286 (56.4%) had not undergone gastrectomy (190 randomized to FTD/TPI and 96 to placebo). In the gastrectomy subgroup, the overall survival hazard ratio (HR) in the FTD/TPI group vs placebo group was 0.57 (95% CI, 0.41-0.79), and the progression-free survival HR was 0.48 (95% CI, 0.35-0.65). In the no gastrectomy subgroup, the overall survival HR in the FTD/TPI group vs placebo group was 0.80 (95% CI, 0.60-1.06), and the progression-free survival HR was 0.65 (95% CI, 0.49-0.85). Among FTD/TPI-treated patients, grade 3 or higher adverse events of any cause occurred in 122 of 145 patients (84.1%) in the gastrectomy subgroup and 145 of 190 (76.3%) in the no gastrectomy subgroup: 64 (44.1%) in the gastrectomy subgroup and 50 (26.3%) in the no gastrectomy subgroup had grade 3 or higher neutropenia, 31 (21.4%) in the gastrectomy subgroup and 33 (17.4%) in the no gastrectomy subgroup had grade 3 or higher anemia, and 21 (14.5%) in the gastrectomy subgroup and 10 (5.3%) in the no gastrectomy subgroup hD grade 3 or higher leukopenia. In the gastrectomy subgroup, 94 (64.8%) had dosing modifications because of adverse events vs 101 (53.2%) in the no gastrectomy subgroup; 15 (10.3%) in the gastrectomy group and 28 (14.7%) in the no gastrectomy group discontinued treatment because of adverse events. Treatment exposure was similar between groups. The FTD/TPI treatment was tolerable and provided efficacy benefits among patients with pretreated mGC/GEJC regardless of previous gastrectomy. ClinicalTrials.gov identifier

Background Studies in patients with rheumatoid arthritis have shown that the rituximab biosimilar CT-P10 (Celltrion, Incheon, South Korea) has equivalent efficacy and pharmacokinetics to rituximab. In this phase 3 study, we aimed to assess the non-inferior efficacy and pharmacokinetic equivalence of CT-P10 compared with rituximab, when used in combination with cyclophosphamide, vincristine, and prednisone (CVP) in patients with newly diagnosed advancedstage follicular lymphoma. Methods In this ongoing, randomised, double-blind, parallel-group, active-controlled study, patients aged 18 years or older with Ann Arbor stage III-IV follicular lymphoma were assigned 1: 1 to CVP plus intravenous infusions of 375 mg/m(2) CT-P10 or rituximab on day 1 of eight 21-day cycles. Randomisation was done by the investigators using an interactive web or voice response system and a computer-generated randomisation schedule, prepared by a clinical research organisation. Randomisation was balanced using permuted blocks and was stratified by country, gender, and Follicular Lymphoma International Prognostic Index score (0-2 vs 3-5). Study teams from the sponsor and clinical research organisation, investigators, and patients were masked to treatment assignment. The study was divided into two parts: part 1 assessing equivalence of pharmacokinetics (in the pharmacokinetics subset), and part 2 assessing efficacy in all randomised patients (patients from the pharmacokinetics subset plus additional patients enrolled in part 2). Equivalence of pharmacokinetics was shown if the 90% CIs for the geometric mean ratio of CT-P10 to rituximab in AUC tau and C-maxSS were within the bounds of the equivalence margin of 80% and 125%. Non-inferiority of response was shown if the one-sided 97 center dot 5% CI lay on the positive side of the -7% margin, using a one-sided test done at the 2 center dot 5% significance level. The primary efficacy endpoint was the proportion of patients who had an overall response over eight cycles and was assessed in the efficacy population (all randomised patients). The primary pharmacokinetic endpoints were area under the serum concentration-time curve at steady state (AUCt) and maximum serum concentration at steady state (C-maxSS) at cycle 4, assessed in the pharmokinetic population. This trial is registered with ClinicalTrials. gov, number NCT02162771. Findings Between July 28, 2014, and Dec 29, 2015, 140 patients were enrolled. Here we report data for the eight-cycle induction period, up to week 24. The proportion of patients with an overall response in the efficacy population was 64 (97 . 0%) of 66 patients in the CT-P10 treatment group and 63 (92 . 6%) of 68 patients in the rituximab treatment group (4 . 3%; one-sided 97 . 5% CI -4 . 25), which lay on the positive side of the predefined non-inferiority margin. The ratio of geometric least squares means (CT-P10/rituximab) was 102 . 25% (90% CI 94 . 05-111 . 17) for AUCt and 100 u 67% (93 . 84-108 . 00) for C-maxSS, with all CIs within the bioequivalence margin of 80-125%. Treatment-emergent adverse events were reported for 58 (83%) of 70 patients in the CT-P10 treatment group and 56 (80%) of 70 in the rituximab treatment group. The most common grade 3 or 4 treatment-emergent adverse event in each treatment group was neutropenia (grade 3, 15 [21%] of 70 patients in the CT-P10 group and seven [10%] of 70 patients in the rituximab group). The proportion of patients who experienced at least one treatment-emergent serious adverse event was 16 (23%) of 70 patients in the CT-P10 group and nine (13%) of 70 patients in the rituximab group. Interpretation In this study, we show that CT-P10 exhibits non-inferior efficacy and pharmacokinetic equivalence to rituximab. The safety profile of CT-P10 was comparable to that of rituximab. CT-P10 might represent a new therapeutic option for advanced-stage follicular lymphoma.

Introduction : CT-P10 is an approved biosimilar to the innovator rituximab by both US FDA and EMA based on a review of comprehensive data package inclusive of foundational and extensive analytical characterization, nonclinical and clinical data. In patients with newly diagnosed advanced stage follicular lymphoma (AFL), equivalence of pharmacokinetics and noninferiority of efficacy was demonstrated in the primary analysis (Kim WS et al. Lancet Hematol. 2017), and progression-free survival (PFS) and overall survival (OS) at a median follow-up of 22.6 months showed the therapeutic similarity between the CT-P10 and Rituxan (RTX) (Kim WS et al. Blood 2018;132:1616). Here, we report the updated data at a median follow-up of 40 months regarding time-to-event endpoints and safety in this CT-P10 3.3 study. Methods: This phase III, randomized, and double-blind study in patients with previously untreated AFL (NCT02162771) was completed within the planned study period. Patients received R-CVP induction therapy (every 3 weeks for 8 cycles) in the Core Study Period and rituximab monotherapy (every 2 months for 12 cycles) in the Maintenance Study Period. Computerized Tomography scans were performed at baseline, month 3 and 6 during the Core Study Period, and then every 6 months for 2 years during the Maintenance Study Period. After 2 years, patients were followed every 6 months for tumor evaluation up to 3 years from the last patient's first infusion date. Kaplan-Meier (KM) method was used to estimate the time-to-event endpoints. Results: In total, 140 patients with AFL were enrolled (CT-P10-CVP; N=70, R-CVP; N=70) with a median age of 58 years and 55.0% of female. The majority of patients completed the induction therapy (62 patients [88.6%] in each group, respectively). Among them, 122 patients (62 [88.6%] patients in CT-P10 and 60 [85.7%] patients in RTX) entered the Maintenance Period and 84 patients (46 [65.7%] patients in CT-P10 and 38 [54.3%] patients in RTX) completed the maintenance therapy. To date, investigator assessed PFS, time-to-progression (TTP) and OS, medians had not been reached in either group due to insufficient number of events. The median follow-up durations of each group were 40 months (25th-75th percentile, 37 to 44) in CT-P10 and 39 months (25th-75th percentile, 36 to 43) in RTX. A total of 42 patients (21 [30.0%] patients in each group, respectively) experienced disease progression and 12 patients reported death during the study. Of these 12 patients, 5 patients (3 [4.3%] patients in CT-P10 and 2 [2.9%] patients in RTX) died due to lymphoma and the other 7 patients (5 [7.1%] patients in CT-P10 and 2 [2.9%] patients in RTX) died due to adverse events or other reasons. There were no significant differences between the 2 groups in PFS (Cox proportional Hazard Ratio [HR]: 1.33; 95% Confidence Interval [CI]: 0.67-2.63; 4-year PFS: CT-P10 60.9% [95% CI: 46.5%-72.5%], RTX 54.7% [95% CI: 36.1%-70.0%]; Figure 1). The TTP revealed the trends similar to PFS. The KM curves showed no significant differences between the 2 groups in TTP (Cox proportional HR: 1.17; 95% CI: 0.58-2.37; 4-year TTP: CT-P10 64.2% [95% CI: 49.4%-75.7%], RTX 55.8% [95% CI: 36.8%-71.1%]; Figure 2). Even with a limited number of events, OS was comparable between the 2 groups (Log rank p-value: 0.287; 4-year OS: CT-P10 88.0% [95% CI: 77.5%-93.8%], RTX 93.3% [95% CI: 83.2%-97.4%]). Overall safety profiles of CT-P10 were consistent with those of RTX (Table 1). No new safety signals were identified during the study and a similar number of patients in each group experienced at least 1 treatment-emergent adverse event, infusion-related reaction, or infection considered to be related to the study drug. One patient from each group reported hepatitis B virus activation related to the study drug. The proportion of patients with positive anti-drug antibody was also similar in both groups (4.3% [3/70] vs 5.7% [4/70] in CT-P10 and RTX) and 2 patients (2.9%) in each group showed the positive neutralizing antibody results. Conclusion: Long-term efficacy results in patients with AFL showed comparable PFS, TTP and OS between the 2 groups, indicating therapeutic similarity of CT-P10 to originator RTX. In addition, CT-P10 was consistently well tolerated and showed comparable safety profiles, including immunogenicity, over the entire study period without any unexpected toxicities compared to RTX. Disclosures Buske: Amgen: Research Funding; Hexal: Honoraria, Speakers Bureau; Bayer: Research Funding; Roche: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria; Celltrion: Honoraria, Speakers Bureau. Kwak:Pepromene Bio: Consultancy, Equity Ownership, Research Funding; InnoLifes: Consultancy, Equity Ownership; Xeme BioPharma, Inc: Consultancy, Equity Ownership; Enzychem LifeSciences: Consultancy; Celltrion Healthcare: Consultancy; Celltrion, Inc.: Consultancy. Jurczak:Celtrion: Research Funding; Sandoz: Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca/Acerta: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Research Funding; Loxo: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Research Funding; Takeda: Research Funding; Servier: Research Funding; Roche: Research Funding; Novo Nordisk: Research Funding; Incyte: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Morphosys: Research Funding; Celgene: Research Funding; Bayer: Research Funding. Sancho:ROCHE: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GILEAD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; JANSSEN: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; CELGENE: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria; SANOFI: Honoraria; SERVIER: Honoraria; CELLTRION: Consultancy; Kern-Pharma: Honoraria; Sandoz: Consultancy. Kim:Novartis: Research Funding; Donga: Research Funding; Celltrion: Research Funding; J&J: Research Funding; Kyowa-Kirin: Research Funding; Mundipharma: Research Funding; Roche: Research Funding. Ogura:Celltrion: Honoraria; Celgene: Honoraria; MeijiSeika Pharma: Honoraria; Mundi Pharma: Honoraria; Teva Takeda: Honoraria; Verastem: Honoraria. Lee:Celltrion: Employment. Kim:Celltrion: Employment. Ahn:Celltrion: Employment.

Treatment of metastatic colorectal cancer (mCRC) is one of the most challenging and important problems in oncology at present moment. This article presents the interim results of treatment of patients with colorectal cancer, who were enrolled from 2016 till 2019 (n=60) with the use of maintenance metronomic chemotherapy. Metronomic regimen consisted of oral capecitabine 500 mg 3 times a day and oral cyclophosphane 50 mg daily. The control arm consisted of mCRC patients who received the same induction chemotherapy without maintenance from 2011 till 2015 (n=70). Median follow-up time was 18.5 months. Median progression-free survival (PFS) was 9.0 and 7.4 months in the maintenance and control arms respectively. Median overall survival (OS), counted from the beginning of induction chemotherapy, is currently 22.9 months in the maintenance arm, and 14.7 months in control. High expression levels of genes, encoding enzymes TS (thymidylate synthetase), DPD (dihydropyrimidine dehydrogenase) and receptor VEGFR1, low expression level of gene TP (thymidylate phosphorylase), as well as low levels of tumor markers CEA and СА 19-9 are the prognostic factors of sensitivity to metronomic chemotherapy given to colorectal cancer patients. Based on these data, we identified a group of patients who are recommended to use this method of treatment.

4043 Background: The phase 3, randomized, double-blind, placebo-controlled study (TAGS) evaluated the efficacy and safety of FTD/TPI (35 mg/m² given orally twice a day on days 1–5 and 8–12 of a 28-day cycle) in mGC patients who had previously received≥2 prior regimens for advanced disease and demonstrated a clinically relevant and statistically significant benefit in OS and PFS with a predictable and manageable safety profile. HRQoL data and association between QoL and time to ECOG status deterioration (2 or more) are reported here. Methods: HRQoL was evaluated using EORTC QLQ-C30 and the gastric-specific module (QLQ-STO22) questionnaires at baseline and at every 4 weeks thereafter until treatment discontinuation. Prespecified key HRQoL were changes from baseline and time to deterioration. Changes ≥10 points were deemed clinically relevant. A time-dependent Cox-regression analysis was performed to evaluate the association of 10-point Global Health Status deterioration with worsening ECOG status. Results: Of 507 patients randomized, 332/337 (98.5%) of FTD/TPI and 164/170 (96.5%) of placebo had baseline QoL data. Overall compliance was 84% for both questionnaires. Demographic and disease were generally balanced between the two groups; QoL scores were also similar between groups. HRQoL was largely maintained during treatment in both arms for most items; mean changes from baseline remained under the 10-point threshold. Clinically relevant changes from baseline were observed only for pain relief at cycle 2 (favouring FTD/TPI); and improved role functioning at cycle 3 (favouring placebo). In a sensitivity analysis including death or progression as an event, FTD/TPI was associated with a positive trend suggesting a reduced risk of QoL deterioration across all scales compared to placebo (HRs ranged from 0.57 to 0.74. A 10-point Global Health Status deterioration was associated with a worsening ECOG status (HR, 95% CI, 1.5, 1.2 to 1.86). Conclusions: During the treatment period, HRQoL remained stable for most functional and symptom scales in both arms, suggesting that HRQoL is largely maintained with FTD/TPI. Treatment with FTD/TPI was associated with a positive trend toward a lower risk of QoL deterioration than placebo across all scales. Changes in QoL were informative for patients ‘expected ECOG status. Clinical trial information: NCT02500043.

We introduce an approach which allows one to introduce the concept of cell plasticity into models for tissue regeneration. In contrast to most of the recent models for tissue regeneration, cell differentiation is considered a gradual process, which evolves in time and which is regulated by an arbitrary number of parameters. In the current approach, cell differentiation is modelled by means of a differentiation state variable. Cells are assumed to differentiate into an arbitrary number of cell types. The differentiation path is considered as reversible, unless differentiation has fully completed. Cell differentiation is incorporated into the partial differential equations (PDEs), which model the tissue regeneration process, by means of an advection term in the differentiation state space. This allows one to consider the differentiation path of cells, which is not possible if a reaction-like term is used for differentiation. The boundary conditions, which should be specified for the general PDEs, are derived from the flux of the fully non-differentiated cells and from the irreversibility of the fully completed differentiation process. An application of the proposed model for peri-implant osseointegration is considered. Numerical results are compared with experimental data. Potential lines of further development of the present approach are proposed.

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]

7532 Background: CT-P10 is a biosimilar candidate to the innovator rituximab (RTX). In patients with rheumatoid arthritis, CT-P10 has demonstrated equivalence in pharmacokinetics (PK) and efficacy (Yoo, ACR 2016). This study aimed to demonstrate non-inferiority of efficacy and PK equivalence between CT-P10 and RTX in patients with newly diagnosed advanced follicular lymphoma (AFL) (NCT02162771). PK equivalence was confirmed (Coiffier, ASH 2016). Methods: A total of 140 patients were randomized in a 1:1 ratio to receive CT-P10 or RTX (375 mg/m2 i.v) plus CVP (cyclophosphamide, vincristine, and prednisone) every 3 weeks over 8 cycles. Overall response rate (ORR) according to the 1999 IWG criteria over 24 weeks was assessed by the independent review committee. Results: Noninferiority of CT-P10 to RTX was shown for the primary efficacy endpoint of ORR. The ORR difference was 4.3% (Table) and the lower bound of the 95% confidence interval was -4.25%. B-cell depleted after the 1st infusion and remained as depleted over 8 cycles in both groups. Overall safety profile of CT-P10 was consistent with that of RTX and the proportion of patients with positive anti-drug antibody was similar in both groups (4.3% and 2.9%) for 24 weeks. Neither progressive multifocal leukoencephalopathy nor Hepatitis B virus reactivation was reported in each group. Conclusions: This study demonstrates noninferiority of efficacy of CT-P10 to RTX combined with CVP in previously untreated AFL. CT-P10 was well-tolerated and the safety profile including immunogenicity of CT-P10 was comparable to that of RTX over 8 cycles of induction period. Clinical trial information: NCT02162771. [Table: see text]

Background: CT-P10 is a biosimilar candidate to the reference rituximab product, EU-approved MabThera® and US-licensed Rituxan®. CT-P10 has an identical amino acid sequence and highly similar physicochemical and in vitro functional properties to its reference drug. In patients with rheumatoid arthritis, CT-P10 has demonstrated compelling similarity in pharmacokinetics (PK), pharmacodynamics (PD), efficacy, safety and immunogenicity (Yoo DH, et al. Arthritis Rheum. 2013;65(10):1736). Objective: The goal of this study was to demonstrate PK similarity of CT-P10 to rituximab, each administered in combination with cyclophosphamide, vincristine, and prednisone (CVP) in patients with newly diagnosed Advanced Follicular Lymphoma (AFL) (NCT02162771) (Kim WS et al. Blood. 2015;126(23): 5111). The results of PK, PD, safety and immunogenicity up to Core Cycle 4 (12 weeks) are presented here from this ongoing study. Methods: Patients with AFL were randomized 1:1 to receive infusion (375mg/m2) of either CT-P10 or rituximab, at a 3-week interval, in combination with CVP. PK analysis was conducted in terms of AUCtau and Cmax at steady state, Core Cycle 4, as primary PK endpoints. PK parameter values considered as outliers determined by robust regression outlier testing were excluded from the pharmacokinetic primary analysis. Results: In total, 121 patients were randomly assigned to receive either CT-P10 (n=59) or rituximab (n=62) in combination with CVP. Result of CT-P10 PK at Core Cycle 4 was similar to that of rituximab. The ratios (90% CI) of geometric least square means (CT-P10 to rituximab treatment group) were 102.3% (94.1%-111.2%) for AUCtau and 100.7% (93.8%-108.0%) for CmaxSS at Core Cycle 4. The 90% CIs of ratio of geometric LS means for both AUCtau and CmaxSS were entirely contained within the equivalence margin of 80% to 125% (Table 1 and Figure 1). Mean serum concentrations of the study drug were highly similar for the 2 treatment groups at each time point (Core Cycle 1 to 4). The B-cell kinetics was similar up to Core Cycle 4 in the 2 treatment groups. Median number of B-cells decreased to below the lower limit of quantification (LLoQ) (20 cells/μL) 1 hour after the end of infusion at Core Cycle 1 and remained below the LLoQ at each subsequent cycle, up to and including Core Cycle 4. The proportion of patients with a positive anti-drug antibody up to Core Cycle 4 at post-treatment visits was similar between the 2 treatment groups; 3/59 (5.1%) patients and 2/62 (3.2%) patients in the CT-P10 and rituximab groups, respectively. In addition, CT-P10 was well tolerated and the safety profile of CT-P10 up to Core Cycle 4 was similar to that of rituximab. The number of patients who experienced at least 1 treatment emergent adverse event (TEAE) was 43 (72.9%) patients and 41 (66.1%) patients in CT-P10 and rituximab treatment groups, respectively. The proportion of patients who experienced at least 1 treatment emergent serious adverse event considered by the investigator to be related to the study treatment was similar between the 2 treatment groups; 2/59 (3.4%) patients and 2/62 (3.2%) patients in the CT-P10 and rituximab groups, respectively. The frequencies of adverse events special interest (AESI) were similar between the 2 treatment groups (Table 2). Conclusion: This study demonstrated similarity of PK in terms of AUCtau and CmaxSS between CT-P10 and rituximab in AFL patients. The B-cell kinetics and immunogenicity were comparable between the two treatment groups. CT-P10 was well tolerated with a safety profile comparable to that of rituximab up to and including Core Cycle 4 (12 weeks). Table 1 Statistical Analysis of Rituximab Pharmacokinetic Primary Endpoints for Core Cycle 4 at Steady State: Pharmacokinetic Population Table 1. Statistical Analysis of Rituximab Pharmacokinetic Primary Endpoints for Core Cycle 4 at Steady State: Pharmacokinetic Population Figure 1 Mean (±SD) Serum Concentration of Rituximab Versus Time for Cycle 4 at Steady State (Linear Scale): Pharmacokinetic Population Figure 1. Mean (±SD) Serum Concentration of Rituximab Versus Time for Cycle 4 at Steady State (Linear Scale): Pharmacokinetic Population Table 2 The Incidence Rates of Adverse Events Special Interest: Safety Population Table 2. The Incidence Rates of Adverse Events Special Interest: Safety Population Disclosures Coiffier: Celltrion, Inc.: Consultancy, Honoraria. Sancho:Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celltrion, Inc: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Jurczak:Celltrion, Inc: Research Funding; Gilead Sciences: Research Funding; Acerta: Research Funding; Bayer: Research Funding; Janssen: Research Funding. Kim:Celltrion, Inc.: Research Funding. Nagarkar:Celltrion, Inc.: Research Funding. Zhavrid:Celltrion, Inc.: Research Funding. Hernandez Rivas:Celltrion, Inc.: Research Funding. Prokharau:Celltrion, Inc.: Research Funding. Zodelava:Celltrion, Inc.: Research Funding. Osmanov:Celltrion, Inc.: Research Funding. Ogura:SymBio Pharmaceuticals: Consultancy, Honoraria; Celltrion, Inc.: Consultancy, Honoraria. Buske:Celltrion, Inc.: Consultancy, Honoraria. Kwak:Celltrion, Inc.: Consultancy. Kim:Celltrion, Inc.: Consultancy, Honoraria.

In the present paper, a model for the early stages of peri-implant bone regeneration is developed. This model is able to capture some important characteristics of endosseous healing, which were not incorporated in the existing models. It is a well known fact, that during peri-implant osseointegration, bone forms only by apposition on the pre-existing rigid surface, which initially consists of the implant surface and the old bone surface. In order to track the movement of the front of the newly formed bone, a moving boundary problem is formulated. Another important feature of the current model, is that the cell differentiation is considered as a gradual process, evolving in time and being influenced by the presence of growth factors. Hence, the evolution of cell differentiation level is captured in the present approach. Numerical methods, used to solve the set of partial differential equations with hyperbolic terms, defined within the domain with the moving boundary, are described.

We investigate stability of the solution of the equations proposed in [Moreo, 2008], which model peri-implant osseointegration process. For certain parameter values, the solution has a ’wave-like’ profile, which appears in the distribution of osteogenic cells, osteoblasts, growth factor and bone matrix. That is in contradiction with experimental observations. In our study we investigate the conditions, under which such profile appears in the solution. Those conditions are determined in terms of model parameters, by means of linear stability analysis, carried out at one of the homogeneous steady-state solutions of the simplified system. The analysis is validated with finite element simulations. The simulations show, that stability of the homogeneous steady-state could determine the behavior of the solution of the whole system, when certain initial conditions are considered.