A phase II study of an oral nucleoside antitumor agent consisting trifluridine and tipiracil hydrochloride for previously fluoropyrimidine-treated elderly patients with unresectable or recurrent colorectal cancer (T-CORE1401)
Ontology highlight
ABSTRACT:
DISEASE(S): Colorectal Cancer
PROVIDER: 2632902 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
Similar Datasets
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
Project description:Interventions: A: FTD/TPI monotherapy
FTD/TPI (35 mg/m2 given orally twice daily on days 1-5 and 8-12 in a 28-day cycle)
B: Bi-weekly FTD/TPI+BEV combination
Bi-weekly FTD/TPI (35 mg/m2 given orally twice daily on days 1-5 in a 14-day cycle) with BEV (5 mg/kg on day1, every 2 weeks)
Primary outcome(s): Overall survival
Study Design: randomized controlled trial, open(masking not used), active control, parallel assignment, treatment purpose
| 2614546 | ecrin-mdr-crc
Project description:Intervention name : trifluridine/tipiracil
INN of the intervention : trifluridine/tipiracil
Dosage And administration of the intervention : Trifluridine/tipiracil was given in a dose of 35-75 mg twice daily (after breakfast and dinner) (70-150 mg/day) from after dinner on Day 1 to after breakfast on Day 6 and from after dinner on Day 8 to after breakfast on Day 13. Treatment was given orally for 5 consecutive days followed by a 2-day rest. This treatment was repeated twice, followed by a 14-day rest. This 28-day cycle was repeated until the criteria for withdrawal of the study treatment were met.
Intervention name : bevacizumab
INN of the intervention : bevacizumab
Dosage And administration of the intervention : Bevacizumab 5 mg/kg was given as a 30-min continuous intravenous infusion on Day 1 and Day 15.
Control intervention name : fluorouracil
INN of the control intervention : fluorouracil
Dosage And administration of the control intervention : [Treatment with FOLFIRI + bevacizumab] Fluorouracil 400 mg/m2 was given by rapid intravenous injection on Day 1, followed by a 46-h continuous intravenous infusion of 2400 mg/m2. Each cycle was 14 days, and treatment was repeated until the criteria for withdrawal of the study treatment were met.
Control intervention name : TS-1(tegafur + gimeracil + oteracil potassium)
INN of the control intervention : TS-1(tegafur + gimeracil + oteracil potassium)
Dosage And administration of the control intervention : [Treatment with TS-1+ irinotecan +bevacizumab (3-week cycles) ] TS-1 is given orally in a dose of 40-60 mg twice daily (after breakfast and dinner) in accordance with body-surface area (80-120 mg/day), starting from after dinner on Day 1 to after breakfast on Day 15, followed by a 7-day rest. Each cycle was 21 days, and treatmen
Primary outcome(s): efficacy
Overall survival
Study Design: Randomized, open-label, comparative study
| 2611617 | ecrin-mdr-crc
Project description:Interventions: investigational material(s)
Generic name etc : trifluridine/tipiracil
INN of investigational material : trifluridine/tipiracil
Therapeutic category code : 429 Other antitumor agents
Dosage and Administration for Investigational material : Trifluridine/tipiracil was given in a dose of 35-75 mg twice daily (after breakfast and dinner) (70-150 mg/day) from after dinner on Day 1 to after breakfast on Day 6 and from after dinner on Day 8 to after breakfast on Day 13. Treatment was given orally for 5 consecutive days followed by a 2-day rest. This treatment was repeated twice, followed by a 14-day rest. This 28-day cycle was repeated until the criteria for withdrawal of the study treatment were met.
Generic name etc : bevacizumab
INN of investigational material : bevacizumab
Therapeutic category code : 429 Other antitumor agents
Dosage and Administration for Investigational material : Bevacizumab 5 mg/kg was given as a 30-min continuous intravenous infusion on Day 1 and Day 15.
control material(s)
Generic name etc : fluorouracil
INN of investigational material : fluorouracil
Therapeutic category code : 422 Antimetabolic agents
Dosage and Administration for Investigational material : [Treatment with FOLFIRI + bevacizumab] Fluorouracil 400 mg/m2 was given by rapid intravenous injection on Day 1, followed by a 46-h continuous intravenous infusion of 2400 mg/m2. Each cycle was 14 days, and treatment was repeated until the criteria for withdrawal of the study treatment were met.
Generic name etc : TS-1(tegafur + gimeracil + oteracil potassium)
INN of investigational material : TS-1(tegafur + gimeracil + oteracil potassium)
Therapeutic category code : 422 Antimetabolic agents
Dosage and Administration for Investigational material : [Treatment with TS-1+ irinotecan +bevacizumab (3-
Primary outcome(s): efficacy
Overall survival
Study Design: Randomized, open-label, comparative study
| 98099 | ecrin-mdr-crc
Project description:Interventions: FOLFIRI plus ziv-aflibercept
(Day 1) Ziv-aflibercept, 4 mg/kg, intravenously (IV) over 60 min
(Day 1) Irinotecan, 150 mg/m2, IV over 90 min
(Day 1) Leucovorin (l-LV), 200 mg/m2, IV over 120 min
(Day 1) 5-FU, 400 mg/m2, bolus
(Day 1-3) 5-FU, 2400 mg/m2, continuous infusion over 46 h
Repeat the above every two weeks
The dose of irinotecan can be reduced to 120 mg/m2 if patients are homozygous for UGT1A1*28 or UGT1A1*6, or heterozygous for both UGT1A1*28 and UGT1A1*6.;C480833,C533178;FOLFIRI, ziv-aflibercept
Primary outcome(s): progression free survival
Study Design: single arm study, open(masking not used), historical control, single assignment, treatment purpose
| 2614963 | ecrin-mdr-crc
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
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
Project description:Low-dose regorafenib (5 mg/kg/day, corresponding to about half of human clinical dosage) inhibited tumor growth and angiogenesis in vivo similarly to DC-101 (anti-VEGFR antibody) but produced higher T cell activation and M1 macrophage polarization, Regorafenib increased M1/M2 ratio of BMDMs polarization and proliferation/activation of co-cultured T cells in vitro, indicating angiogenesis-independent immunomodulatory effects. Suppression of p38 kinase phosphorylation and downstream CREB-KLF4 activity in BMDMs by regorafenib reversed M2 polarization. Regorafenib enhanced antitumor efficacy of adoptively transferred antigen-specific T cells, whereas macrophage deletion negated regorafenib’s antitumor effects. Synergistic antitumor efficacy between low-dose regorafenib and anti-PD1 was associated with multiple immune-related pathways in the tumor microenvironment.
2021-01-27 | GSE148947 | GEO
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.
| S-EPMC10403909 | biostudies-literature
Project description:Interventions: S-1+CPT-11+bevacizumab+Placebo S-1 80-120mg/day day1-14 q4w CPT-11 100mg/m2 day1,15 q4w Bevacizumab 5mg/kg day1, 15 q4w Placebo day1-28 q4w
S-1+CPT-11+bevacizumab+hange-shashin-to S-1 80-120mg/day day1-14 q4w CPT-11 100mg/m2 day1,15 q4w Bevacizumab 5mg/kg day1, 15 q4w Hange-shashin-to 7.5g/day day1-28 q4w
Primary outcome(s): Incidence of grade 3 or more diarrhea until the end of 3rd cycle
Study Design: Parallel Randomized
| 2627635 | ecrin-mdr-crc