Dataset Information

Efficacy of Combination Chemotherapy Using a Novel Oral Chemotherapeutic Agent, FTD/TPI, with Ramucirumab Murine Version DC101 in a Mouse Syngeneic Cancer Transplantation Model.

ABSTRACT: Trifluridine/tipiracil (FTD/TPI) (a.k.a. TAS-102) is a combination drug for metastatic colorectal cancer (CRC) and severely pretreated metastatic gastric/gastroesophageal junction (GEJ) cancers, comprising FTD, a thymidine-based antineoplastic nucleoside analog, and TPI, which enhances FTD bioavailability. Herein, in KRAS mutant murine colorectal cancer CT26 syngeneic models, we investigate whether combination therapy with DC101 (a surrogate ramucirumab antibody, rat antimouse vascular endothelial growth factor receptor (VEGFR)-2 monoclonal antibody (mAb)) improves FTD/TPI efficacy. Tumor growth inhibition (TGI) on day 15 was 38.0% and 30.6% upon DC101 monotherapy and FTD/TPI monotherapy respectively, and 60.3% upon combination therapy. Tumor volume was significantly lower (p < 0.001) upon combination treatment than upon FTD/TPI or DC101 monotherapy, indicating the additive effects of FTD/TPI and DC101. DNA-incorporated FTD levels on Day 8 were significantly higher in combination therapy with FTD/TPI (for 5 consecutive days) and DC101 (on alternate days for 7days) than in FTD/TPI monotherapy. Furthermore, vascular endothelial cell-specific marker CD31 was downregulated in DC101-treated tumors on day 8. These results indicate that combination therapy with FTD/TPI and DC101 is a promising treatment alternative regardless of KRAS mutations.

SUBMITTER: Tsunekuni K

PROVIDER: S-EPMC7765280 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Efficacy of Combination Chemotherapy Using a Novel Oral Chemotherapeutic Agent, FTD/TPI, with Ramucirumab Murine Version DC101 in a Mouse Syngeneic Cancer Transplantation Model.

Tsunekuni Kenta K Kawakami Hisato H Matsuoka Kazuaki K Nagase Hideki H Mitani Seiichiro S Nakagawa Kazuhiko K

Journal of clinical medicine 20201215 12

Trifluridine/tipiracil (FTD/TPI) (a.k.a. TAS-102) is a combination drug for metastatic colorectal cancer (CRC) and severely pretreated metastatic gastric/gastroesophageal junction (GEJ) cancers, comprising FTD, a thymidine-based antineoplastic nucleoside analog, and TPI, which enhances FTD bioavailability. Herein, in <i>KRAS</i> mutant murine colorectal cancer CT26 syngeneic models, we investigate whether combination therapy with DC101 (a surrogate ramucirumab antibody, rat antimouse vascular en ...[more]

PMID: 33333866

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Project description:BackgroundTrifluridine/tipiracil (FTD/TPI) prolongs survival in the third- or later-line treatment for advanced gastric cancer (GC), esophagogastric junction (EGJ) adenocarcinoma, and colorectal cancer. While single-arm phase II trials showed promising outcomes of FTD/TPI plus ramucirumab (RAM) as third- or later-line treatments for advanced GC or EGJ cancer, there have been no clinical trials to directly compare FTD/TPI plus RAM with FTD/TPI monotherapy. Therefore, we have started a randomised phase II trial to evaluate the efficacy and safety of FTD/TPI plus RAM compared with FTD/TPI monotherapy as third- or later-line treatments in patients with advanced GC and EGJ adenocarcinoma.MethodsThis RETREVE trial (WJOG15822G) is a prospective, open-label, randomised, multicentre phase II trial comparing FTD/TPI plus RAM versus FTD/TPI monotherapy in a third- or later-line setting. Eligibility criteria include age of > 20 years; performance status of 0 or 1; unresectable or recurrent gastric or EGJ adenocarcinoma; confirmed HER2 status; refractory or intolerant to fluoropyrimidine, taxane or irinotecan; refractory to RAM (not intolerant); and at least a measurable lesion per RECIST 1.1. FTD/TPI (35 mg/m2 twice daily, evening of day 1 to morning of day 6 and evening of day 8 to morning of day 13) was administered orally every 4 weeks, and RAM (8 mg/kg) was administered intravenously every 2 weeks. The primary endpoint is progression-free survival (PFS), and the secondary endpoints are overall survival, objective response rate, disease control rate, and safety. The expected hazard ratio of PFS is set as 0.7, assuming 4-month PFS rate of 27% in FTD/TPI monotherapy and 40% in FTD/TPI plus RAM. The number of subjects was 110, with a one-sided alpha error of 0.10 and power of 0.70.DiscussionThis study will clarify the additional effect of RAM continuation beyond disease progression on FTD/TPI in the third- or later-line setting for patients with advanced GC or EGJ cancer.Trial registrationjRCTs041220120.

Project description:Background and study aims Worldwide, nearly 1.25 million patients are diagnosed with colorectal cancer each year. At least 50% of patients develop metastases, and most of these patients have unresectable tumours (unable to be removed). Standard treatment for these patients involves chemotherapy and monoclonal antibodies targeting vascular endothelial growth factor (VEGF the cells that stimulate formation of blood vessels). In patients with KRAS wild-type tumours (abnormal tumours), monoclonal antibodies targeting epidermal growth factor receptor (EGFR which stimulates cell growth) are also used. 5-year survival rates in patients with metastatic colorectal cancer (mCRC), representing Stage IV CRC, were reached by only about 15% of mCRC patients. Although the outcome of patients with mCRC has clearly improved during recent years with median survival now reaching more than 30 months in recent clinical trials, more treatment options are needed for patients with disease progression after fluoropyrimidine (e.g. 5-FU), irinotecan, oxaliplatin, applicable anti-VEGF agents and anti-EGFR agents or those unable to tolerate these agents. Trifluridine/tipiracil (FTD/TPI; Lonsurf®) has been authorized in the EU since April 2016 for treatment of these patients. On the basis of the severity of the tumour disease with rather limited treatment options within the context of a previously treated tumour disease in the end-of-life situation, the health-related quality of life (HRQoL) is very important to describe the impact of treatment on the patient’s functioning regarding physical health (including disease-related morbidity), social, emotional, cognitive and role aspects. Changes of HRQoL during and after treatment with FTD/TPI have not been investigated so far in clinical trials. The aim of this study is to investigate the HRQoL in patients treated with FTD/TPI and those who are treated with best-supportive-care (BSC) while being suitable for treatment with FTD/TPI according to the summary of product characteristics. Who can participate? Adults aged 18 and older who have colorectal cancer. What does the study involve? Participants who are eligible for FTD/TPI therapy are treated like mCRC cancer patients in regular medical service receiving FTD/TPI with the only exemption that these cancer patients have to fill out 2 questionnaires (in total 36 questions) concerning their quality of life at treatment baseline and at the end of each FTD/TPI treatment cycle until end-of-treatment (i.e. disease progression).

Project description:Adaptive immune system, principally governed by the T cells-dendritic cells (DCs) nexus, is an essential mediator of gestational fetal tolerance and protection against infection. However, the exact composition and dynamics of DCs and T cell subsets in gestational tissues are not well understood. These are controlled in human physiology by a complex interplay of alloantigen distribution and presentation, cellular/humoral active and passive tolerance, hormones/chemokines/angiogenic factors and their gradients, systemic and local microbial communities. Reductive discrimination of these factors in physiology and pathology of model systems and humans requires simplification of the model and increased resolution of interrogative technologies. As a baseline, we have studied the gestational tissue dynamics in the syngeneic C57BL/6 mice, as the simplest immunological environment, and focused on validating the approach to increased data density and computational analysis pipeline afforded by highly polychromatic flow cytometry and machine learning interpretation. We mapped DC and T cell subsets, and comprehensively examined their maternal (decidual)-fetal (placental) interface dynamics. Both frequency and composition of decidual DCs changed across gestation, with a dramatic increase in myeloid DCs in early pregnancy, and exclusion of plasmacytoid DCs. CD4+ T cells, in contrast, were lower at all gestational ages and an unusual CD4-CD8-TCRαβ+group was prominent at mid-pregnancy. Dimensionality reduction with machine learning-aided clustering revealed that CD4-CD8- T cells were phenotypically different from CD4+ and CD8+ T cells. Additionally, divergence between maternal decidual and fetal placental compartment was prominent, with absence of DCs from the placenta, but not decidua or embryo. These results provide a novel framework and a syngeneic baseline on which the specific role of alloantigen/tolerance, polymicrobial environment, and models of pregnancy pathology can be precisely modeled and analyzed.

Dataset Information

Efficacy of Combination Chemotherapy Using a Novel Oral Chemotherapeutic Agent, FTD/TPI, with Ramucirumab Murine Version DC101 in a Mouse Syngeneic Cancer Transplantation Model.

Publications

Efficacy of Combination Chemotherapy Using a Novel Oral Chemotherapeutic Agent, FTD/TPI, with Ramucirumab Murine Version DC101 in a Mouse Syngeneic Cancer Transplantation Model.

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