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Trifluridine/Tipiracil (TAS-102) With or Without Thalidomide for the Treatment of Metastatic Colorectal Cancer

ABSTRACT: Thalidomide has both anti-angiogenesis and antiemetic effects, and its combined use with TAS-102 may reduce the gastrointestinal reactions associated with TAS-102, while enhancing antitumor efficacy and reducing the side effects of chemotherapy, and its cost is significantly lower than that of bevacizumab, which has higher pharmacoeconomics and greater clinical research application value.

DISEASE(S): Metastatic Colorectal Cancer,Colorectal Neoplasms

PROVIDER: 2406756 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Thalidomide Exerts Distinct Molecular Antileukemic Effects

Project description:Thalidomide Exerts Distinct Molecular Antileukemic Effects and Combined Thalidomide/Fludarabine Therapy is Clinically Effective in High-Risk Chronic Lymphocytic Leukemia Background: Thalidomide represents a promising immunomodulatory drug that targets both leukemia cells and the tumor microenvironment. Methods: We treated chronic lymphocytic leukemia (CLL) patients with a combined thalidomide/fludarabine regimen and monitored cellular and molecular changes induced by thalidomide in-vivo prior to fludarabine treatment. Thalidomide was given daily (100mg p.o./day) and fludarabine was administered on days 7-11 (25 mg/m² i.v./day) within each 4-week cycle (maximum of 6 cycles). Twenty patients received thalidomide/fludarabine as first line therapy and 20 patients were previously treated. Unmutated IgVH mutation status was found in 36 cases and 13 had high-risk cytogenetic aberrations (deletion of 17p13 or 11q22-q23). Results: The overall response rate was 80% and 25% for untreated and previously treated patients, respectively. While thalidomide effectively reduced the number of CLL cells, the number of CD3 lymphocytes showed no significant change, but the number of CD4+CD25hiFOXP3+ T-regulatory cells was significantly decreased. Gene expression profiling revealed a thalidomide induced signature containing both targets known to play a role in immunomodulatory drug action as well as novel candidate genes. Conclusions: Combined thalidomide/fludarabine therapy demonstrated efficacy in high-risk CLL patients. Furthermore, our study provides novel biological insights into thalidomide effect, which might act by enhancing apoptosis of CLL cells and reducing Tregs, thereby enabling T-cell dependent anti-tumor effect.

2009-08-21 | GSE15913 | GEO

Trifluridine/Tipiracil Plus Bevacizumab Versus Trifluridine/Tipiracil Monotherapy in Refractory Metastatic Colorectal Cancer

Project description:This study is a retrospective study to compare the efficacy and safety between trifluridine/tipiracil (TAS-102) plus bevacizumab (BEV) with TAS-102 monotherapy in refractory metastatic colorectal cancer (mCRC) from November 2020 to October 2022 at the Hunan Cancer Hospital.

| 60837 | ecrin-mdr-crc

Biomarkers of Trifluridine-Tipiracil Efficacy.

Project description:Trifluridine/tipiracil (TAS-102) is a newer generation chemotherapy that has been approved for the later-line treatment of metastatic colorectal and gastric/gastroesophageal adenocarcinomas. The oral drug provides a modest benefit of prolongation of survival over placebo in pretreated patients with these cancers with acceptable toxicity. Studies have shown rare objective responses (2-4%), and the disease control rates were 44% in both colorectal and gastric cancer randomized trials. Thus, the majority of patients progress through treatment and are burdened by toxicities. To better characterize the sub-group of patients with a higher probability of benefit from trifluridine/tipiracil, predictive biomarkers have been sought using data from randomized trials as well as from non-randomized trials and real-world series. Biomarkers examined include clinical characteristics of the patients, laboratory tests, and tumor derived biomarkers. These studies show that early neutropenia on treatment, and ratios of leukocyte subsets, are potential biomarkers able to predict trifluridine/tipiracil benefit. Combinations of laboratory values and clinical characteristics and proteins involved in trifluridine transport and activation have been examined with initial positive results.

| S-EPMC8658167 | biostudies-literature

Study of Trifluridine/Tipiracil (TAS-102) in Patients With Metastatic Colorectal Cancer in Asia

Project description:To compare the effects of TAS-102 with placebo in patients with metastatic colorectal cancer refractory or intolerable to standard chemotherapies.

| 2152626 | ecrin-mdr-crc

Efficacy and safety of trifluridine/tipiracil plus bevacizumab and trifluridine/tipiracil or regorafenib monotherapy for chemorefractory metastatic colorectal cancer: a retrospective study.

Project description:BackgroundThe C-TASK-FORCE phase I/II and Danish randomized phase II trials reported the promising efficacy of trifluridine/tipiracil (TAS102) plus bevacizumab (BEV) in patients with chemorefractory metastatic colorectal cancer (mCRC). However, there had been no direct comparative phase III trial to compare the efficacy between TAS102 plus BEV and standard therapy with either TAS102 or regorafenib monotherapy.MethodsWe retrospectively reviewed the medical records of patients with mCRC who received TAS102 plus BEV, TAS102 monotherapy, or regorafenib monotherapy after standard chemotherapies during 2013-2019.ResultsPatients received TAS102 plus BEV (n = 139), TAS102 monotherapy (n = 153), or regorafenib monotherapy (n = 133). With a median follow-up of 25.3 months, median overall survival (OS) was 11.5 months [95% confidence interval (CI), 9.9-13.9] for TAS102 plus BEV, 8.1 months (95% CI, 6.8-9.2) for TAS102 monotherapy, and 6.8 months (95% CI, 5.7-8.5) for regorafenib monotherapy. The hazard ratios were 0.67 (95% CI, 0.51-0.88) for TAS102 plus BEV versus TAS102 monotherapy and 0.71 (95% CI, 0.54-0.94) for TAS102 plus BEV versus regorafenib monotherapy. Median progression-free survival (PFS) was 4.4 months (95% CI, 3.7-5.4) for TAS102 plus BEV, 2.5 months (95% CI, 1.6-2.3) for TAS102 monotherapy, and 2.1 months (95% CI, 1.6-2.3) for regorafenib monotherapy. The hazard ratios were 0.57 (95% CI, 0.45-0.73) for TAS102 plus BEV versus TAS102 monotherapy and 0.44 (95% CI, 0.34-0.58) for TAS102 plus BEV versus regorafenib monotherapy. On multivariate analysis, TAS102 plus BEV was independently correlated with better OS and PFS. No unexpected adverse events were observed in any group.ConclusionOur study shows that OS and PFS are longer in patients treated with TAS102 plus BEV than in those treated with TAS102 or regorafenib monotherapy.

| S-EPMC8064512 | biostudies-literature

Thalidomide combined with Trifluridine-Tipiracil Hydrochloride Mixture versus Trifluridine-Tipiracil Hydrochloride Mixture in the third-line or higher treatment of advanced colorectal cancer: a randomized, controlled, multicenter phase II clinical study

Project description:Interventions: Ttreatment group:Thalidomide;Control group:None Primary outcome(s): toxic and side effect;overall survival;progression-free survival;objective remission rate;Disease Control Rate Study Design: Parallel

| 2734760 | ecrin-mdr-crc

Trifluridine/tipiracil(TAS-102)-induced nausea and vomiting in patients with colorectal cancer: a prospective, observational, multicenter study

Project description:Primary outcome(s): Incidence of vomiting during the 14 days after starting TAS-102

| 2653963 | ecrin-mdr-crc

Monitoring trifluridine incorporation in the peripheral blood mononuclear cells of colorectal cancer patients under trifluridine/tipiracil medication.

Project description:Trifluridine/tipiracil (TFTD, TAS-102) is an orally administrated anti-cancer drug with efficacy validated for patients with metastatic colorectal cancer (mCRC). Trifluridine (FTD) is an active cytotoxic component of TFTD and mediates the anticancer effect via its incorporation into DNA. However, it has not been examined whether FTD is incorporated into the tissues of patients who received TFTD medication. By detecting FTD incorporation into DNA by a specific antibody, we successfully detected FTD in the bone marrow and spleen cells isolated from FTD-challenged mice as well as human peripheral blood mononuclear cells (PBMCs) activated with phytohemagglutinin-P and exposed to FTD in vitro. FTD was also detected in PBMCs isolated from mCRC patients who had administrated TFTD medication. Intriguingly, weekly evaluation of PBMCs from mCRC patients revealed the percentage of FTD-positive PBMCs increased and decreased in parallel with the administration and cessation of TFTD medication, respectively. To our knowledge, this is the first report to detect an active cytotoxic component of a chemotherapeutic drug in clinical specimens using a specific antibody. This technique may enable us to predict the clinical benefits or the adverse effects of TFTD in mCRC patients.

| S-EPMC5717244 | biostudies-literature

Next Generation Sequencing to study Thalidomide mechanism in Cutaneous Lupus

Project description:Thalidomide has been shown to be effective in patients with refractory cutaneous lupus erythematosus (CLE). However, its use is still limited by its potential severe side-effects. We conducted an RNA-sequencing study using CLE skin biopsies before and after thalidomide treatment to discover its mechanism of action. Methods: Total mRNA from skin biopsies from 10 CLE patient have been processed by RNA-seq in duplicate using Illumina Hiseq 2000 sequencing platform version 3. Application was stranded mRNA-Seq, paired-end and read length was 75bp. The sequence reads that passed quality filters were analyzed at the transcript isoform level using STAR program, RSEM program and DESeq2. Mapping was done with STAR (version 2.5.2a), quantification by RSEM (1.2.28) and differential analysis by DESeq. Results: Using an optimized data analysis workflow, we mapped about 30 million sequence reads per sample to human genome (hs37d5). Average un-mapped was between 11,40-7,05 %, average unique was 80.48-76,62% and average alignment insert size was 170,00-155,00 in the 20 samples. Conclusions: Plausibles mechanisms of action for thalidomide in lupus cutaneous were discovered using this study; however, in vitro and in vivo experiments would be performed to demostrate them.

2021-12-07 | GSE162424 | GEO

Emerging combination therapies for metastatic colorectal cancer - impact of trifluridine/tipiracil.

Project description:Patients with metastatic colorectal cancer (mCRC) are surviving longer now than ever before, but mortality rates are still high and more effective therapies are clearly needed. For patients with disease that is refractory to fluoropyrimidines, oxaliplatin, irinotecan, and biologic agents targeting the vascular endothelial growth factor and epidermal growth factor receptor pathways, novel treatment options trifluridine/tipiracil (TAS-102) and regorafenib can be effective disease stabilizers. However, objective clinical responses are rare and toxicities are manageable but common. In order to tackle poor clinical responses to TAS-102, there is an ongoing effort to effectively combine this drug with other agents, particularly those targeting angiogenesis. Certain subpopulations appear to benefit more than others from TAS-102; those that benefit often have underlying genetic defects in DNA repair pathways and/or develop neutropenia. In this review, we focus on the role of TAS-102 in the treatment of mCRC, including its use in combination with other agents, potential predictive biomarkers of response to TAS-102, and possible future directions.

| S-EPMC5635852 | biostudies-literature

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