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1.
Cancer Chemother Pharmacol ; 88(3): 485-497, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34097100

RESUMO

PURPOSE: Trifluridine/tipiracil (FTD/TPI) is approved for advanced colorectal and gastric/gastroesophageal cancer; however, data in patients with renal impairment (RI) are limited. This phase I study evaluated FTD/TPI in patients with advanced solid tumors and varying degrees of RI to develop dosing guidance. METHODS: Patients were enrolled into normal renal function (CrCl ≥ 90 mL/min), mild RI (CrCl 60-89 mL/min), or moderate RI (CrCl 30-59 mL/min) cohorts and administered the recommended FTD/TPI dose (35 mg/m2 twice daily, days 1-5 and 8-12; 28-day cycle). Based on interim pharmacokinetics/safety data, patients with severe RI (CrCl 15-29 mL/min) were enrolled and received FTD/TPI 20 mg/m2 twice daily. RESULTS: Forty-three patients (normal renal function [n = 12]; mild RI [n = 12]; moderate RI [n = 11]; severe RI [n = 8]) were enrolled and treated. At steady state, compared to values in patients with normal renal function, FTD area under the curve (AUC) was not significantly different in patients with RI, but TPI AUC was significantly higher and increased with RI severity. FTD/TPI safety profile was consistent with prior experience, but grade ≥ 3 adverse events (AEs) were more frequent in the RI cohorts (83.3% [mild], 90.9% [moderate], 75.0% [severe], and normal [50.0%]). Hematologic AEs (anemia and neutropenia) were more frequent with RI. Overall, seven patients discontinued because of unrelated, nonhematologic AEs. CONCLUSION: FTD/TPI is safe and tolerable at the recommended 35 mg/m2 dose in patients with mild/moderate RI and at the reduced 20 mg/m2 dose in patients with severe RI. TRIAL REGISTRATION: NCT02301117, registration date: November 21, 2014.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Nefropatias/fisiopatologia , Neoplasias/tratamento farmacológico , Pirrolidinas/administração & dosagem , Timina/administração & dosagem , Trifluridina/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Anemia/induzido quimicamente , Anemia/epidemiologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Área Sob a Curva , Estudos de Coortes , Combinação de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Neutropenia/epidemiologia , Pirrolidinas/efeitos adversos , Pirrolidinas/farmacocinética , Índice de Gravidade de Doença , Timina/efeitos adversos , Timina/farmacocinética , Trifluridina/efeitos adversos , Trifluridina/farmacocinética
2.
Cancer Chemother Pharmacol ; 88(3): 393-402, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34028598

RESUMO

PURPOSE: The current study aimed to determine the efficacy of trifluridine/tipiracil for elderly patients with advanced colorectal cancer. METHODS: This single-arm, open-label, multicenter, phase II study included elderly patients aged 65 years or more who had fluoropyrimidine-refractory advanced colorectal cancer and received trifluridine/tipiracil (70 mg/m2, days 1-5 and 8-12, every 4 weeks). The primary endpoint was progression-free survival (PFS), while secondary endpoints included overall survival (OS), overall response rate (ORR), toxicities, association between efficacy and geriatric assessment scores, and association between toxicity and plasma drug concentrations. RESULTS: A total of 30 patients with a mean age of 73 years were enrolled. Median PFS was 2.3 months (95% confidence interval, 1.9-4.3 months), while median OS was 5.7 months (95% confidence interval, 3.7-8.9 months). Patients had an ORR of 0%, with 57% having stable disease. Grade 4 neutropenia was observed in 13% of the patients. Patients with a higher G8 score (15 or more) showed longer PFS than those with a lower G8 score (median 4.6 vs. 2.0 months; p = 0.047). Moreover, patients with grade 3 or 4 neutropenia showed higher maximum trifluridine concentrations than those with grade 1 or 2 neutropenia (mean 2945 vs. 2107 ng/mL; p = 0.036). DISCUSSION: The current phase II trial demonstrated that trifluridine/tipiracil was an effective and well-tolerated option for elderly patients with advanced colorectal cancer. Moreover, geriatric assessment tools and/or plasma drug concentration monitoring might be helpful in predicting the efficacy and toxicities in elderly patients receiving this drug. TRIAL REGISTRATION NUMBER: UMIN000017589, 15/May/2015 (The University Hospital Medical Information Network).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Avaliação Geriátrica/métodos , Pirrolidinas/administração & dosagem , Timina/administração & dosagem , Trifluridina/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Biomarcadores Tumorais/metabolismo , Combinação de Medicamentos , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Masculino , Neutropenia/induzido quimicamente , Intervalo Livre de Progressão , Pirrolidinas/efeitos adversos , Pirrolidinas/farmacocinética , Taxa de Sobrevida , Timina/efeitos adversos , Timina/farmacocinética , Trifluridina/efeitos adversos , Trifluridina/farmacocinética
3.
Anticancer Res ; 41(5): 2553-2561, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33952483

RESUMO

BACKGROUND/AIM: Regorafenib (REG) and trifluridine/tipiracil (FTD/TPI) have have been shown to improve overall survival in patients with refractory metastatic colorectal cancer. The aim of our study was to evaluate the efficacy and safety profiles of these agents administered in sequence in real world practice. PATIENTS AND METHODS: Clinical data of patients treated beyond the 2°line with REG or FTD/TPI between January 2016 and August 2020, were retrospectively collected from eight institutes in the Lazio Region. RESULTS: We included 49 patients treated with both drug sequences. A total of 28 G3/G4 toxicity events (53.8%) were recorded in the FTD/TPI-to-REG sequence vs. 24 (46.1%) in the reverse sequence. Median overall survival for the patients included in the FTP/TPI-to-REG group was 20 months (95%CI=16.7-23.3) vs. 27 months in the reverse group (95%CI=17.8-36.2). The disease control rate was 45.0% for patients treated with the REG-to-FTD/TPI sequence vs. 24.1% in those treated with the FTD/TPI-to-REG sequence (p=0.18). CONCLUSION: The sequence REG-to-FTD/TPI and vice versa can extend survival, whereas only REG-to-FTD/TPI stabilizes cancer growth.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Compostos de Fenilureia/administração & dosagem , Piridinas/administração & dosagem , Pirrolidinas/administração & dosagem , Timina/administração & dosagem , Trifluridina/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Esquema de Medicação , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Compostos de Fenilureia/efeitos adversos , Intervalo Livre de Progressão , Piridinas/efeitos adversos , Pirrolidinas/efeitos adversos , Timina/efeitos adversos , Trifluridina/efeitos adversos
4.
Anticancer Res ; 41(4): 2157-2163, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33813427

RESUMO

BACKGROUND: This study assessed the efficacy and safety of biweekly trifluridine and tipiracil hydrochloride (TAS-102) with bevacizumab combination therapy for patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: We included 19 patients with mCRC who received TAS-102 and bevacizumab combination therapy biweekly as third-line chemotherapy. The primary endpoint was progression-free survival. RESULTS: Patients had a median age of 73 years and most (73.4%) were men. The median progression-free and overall survival were 5.6 and 11.5 months, respectively. Five (26.3%) patients achieved a response and the disease control rate was 12/19 (63.1%). One patient (5.2%) experienced neutropenia grade 3 or more. The median time from baseline performance status 0/1 to worsening to 2 or more was 10.3 months. CONCLUSION: Biweekly TAS-102 plus bevacizumab facilitates tumor shrinkage by reducing the incidence of grade 3 or more neutropenia, improving survival, and maintaining performance status. This combination may represent a treatment option for patients with late-stage mCRC receiving third- or later-line therapy.


Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bevacizumab/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Pirrolidinas/administração & dosagem , Timina/administração & dosagem , Trifluridina/administração & dosagem , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/efeitos adversos , Neutropenia Febril Induzida por Quimioterapia/epidemiologia , Neutropenia Febril Induzida por Quimioterapia/etiologia , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Esquema de Medicação , Combinação de Medicamentos , Feminino , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Pirrolidinas/efeitos adversos , Análise de Sobrevida , Timina/efeitos adversos , Resultado do Tratamento , Trifluridina/efeitos adversos
5.
Anticancer Res ; 41(4): 2203-2207, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33813435

RESUMO

BACKGROUND/AIM: In later-line treatment of metastatic colorectal cancer (mCRC), trifluridine/tipiracil is often selected because regorafenib is difficult to use in patients with comorbidities such as thrombosis, hemorrhage, or cardiac events. However, the safety and efficacy of trifluridine/tipiracil in these patients is not clear. PATIENTS AND METHODS: The clinical outcomes of trifluridine/tipiracil were retrospectively investigated in patients who were ineligible for regorafenib because of comorbidities. RESULTS: Among the 27 patients who received trifluridine/tipiracil, many had comorbidities of deep venous thrombosis or hemorrhage. The median overall survival was 12.4 months, and the median progression-free survival was 2.8 months. The median overall survival was 7.7 months in 19 patients without subsequent regorafenib. Grade 3 or higher toxicities were found in 51% of patients. No treatment discontinuation because of comorbidities was observed. CONCLUSION: Trifluridine/tipiracil can be safely administered while maintaining efficacy in patients who were ineligible for regorafenib.


Assuntos
Adenocarcinoma/tratamento farmacológico , Neoplasias Colorretais/tratamento farmacológico , Pirrolidinas/uso terapêutico , Timina/uso terapêutico , Trifluridina/uso terapêutico , Adenocarcinoma/epidemiologia , Adenocarcinoma/patologia , Adulto , Idoso , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/patologia , Comorbidade , Combinação de Medicamentos , Feminino , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Seleção de Pacientes , Compostos de Fenilureia/uso terapêutico , Intervalo Livre de Progressão , Piridinas/uso terapêutico , Pirrolidinas/efeitos adversos , Estudos Retrospectivos , Terapia de Salvação , Análise de Sobrevida , Timina/efeitos adversos , Resultado do Tratamento , Trifluridina/efeitos adversos
6.
Int J Clin Oncol ; 26(7): 1238-1247, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33928486

RESUMO

BACKGROUND: We aimed to assess the safety and efficacy of combination treatment with panitumumab plus trifluridine/tipiracil (FTD/TPI) in patients with wild-type RAS metastatic colorectal cancer (mCRC) who were refractory/intolerant to standard therapies other than anti-epidermal growth factor receptor therapy. METHODS: APOLLON was an open-label, multicentre, phase 1/2 trial. In the phase 1 part, 3 + 3 de-escalation design was used to investigate the recommended phase 2 dose (RP2D); all patients in the phase 2 part received the RP2D. The primary endpoint was investigator-assessed progression-free survival (PFS) rate at 6 months. Secondary endpoints included PFS, overall survival (OS), overall response rate (ORR), disease control rate (DCR), time to treatment failure (TTF), and safety. RESULTS: Fifty-six patients were enrolled (phase 1, n = 7; phase 2, n = 49) at 25 Japanese centres. No dose-limiting toxicities were observed in patients receiving panitumumab (6 mg/kg every 2 weeks) plus FTD/TPI (35 mg/m2 twice daily; days 1-5 and 8-12 in a 28-day cycle), which became RP2D. PFS rate at 6 months was 33.3% (90% confidence interval [CI] 22.8-45.3). Median PFS, OS, ORR, DCR, and TTF were 5.8 months (95% CI 4.5-6.5), 14.1 months (95% CI 12.2-19.3), 37.0% (95% CI 24.3-51.3), 81.5% (95% CI 68.6-90.8), and 5.8 months (95% CI 4.29-6.21), respectively. Neutrophil count decreased (47.3%) was the most common Grade 3/4 treatment-emergent adverse event. No treatment-related deaths occurred. CONCLUSION: Panitumumab plus FTD/TPI exhibited favourable anti-tumour activity with a manageable safety profile and may be a therapeutic option for pre-treated mCRC patients.


Assuntos
Neoplasias Colorretais , Trifluridina , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Colorretais/tratamento farmacológico , Humanos , Panitumumabe , Pirrolidinas , Timina , Trifluridina/efeitos adversos
7.
Cancer Sci ; 112(6): 2436-2441, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33780084

RESUMO

Trifluridine/tipiracil (FTD/TPI) is an orally administrated anticancer drug with efficacy validated for patients with metastatic colorectal cancer (mCRC) or gastric cancer. FTD, a key component of FTD/TPI, exerts antitumor effects via its incorporation into DNA. Using specific antibodies against bromodeoxyuridine, FTD incorporation into DNA is detected in tumors and peripheral blood mononuclear cells (PBMC) of patients with mCRC who are administered FTD/TPI. The proportion of FTD-positive PBMC fluctuates according to the schedule of treatment, although the association between the proportion of FTD-positive PBMC and the clinical outcomes of patients is unknown. To answer this question, here we monitored the FTD-positive PBMC of 39 elderly patients with mCRC enrolled in KSCC1602, a single-arm phase 2 trial of FTD/TPI plus bevacizumab as a first-line treatment, for 1 month, during the first cycle of treatment. The median values and interquartile ranges of the percentage of FTD-positive PBMC on days 8, 15, and 29 were 39.3% (30.7%-52.2%), 66.9% (40.0%-75.3%), and 13.5% (5.7%-26.0%), respectively. Receiver operating characteristic analysis revealed that the percentage of FTD-positive PBMC on day 8 (the end of the first week of treatment) had moderate ability to accurately diagnose the occurrence of severe neutropenia and leukopenia within 1 month (area under the curve = 0.778 [95% confidence interval, 0.554-0.993]). This result suggests that excess FTD incorporation into PBMC at the initial phase of FTD/TPI plus bevacizumab treatment is a risk factor for early onset of severe hematological adverse events.


Assuntos
Bevacizumab/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Leucócitos Mononucleares/química , Pirrolidinas/administração & dosagem , Timina/administração & dosagem , Trifluridina/administração & dosagem , Administração Intravenosa , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Bevacizumab/efeitos adversos , Neoplasias Colorretais/sangue , Neoplasias Colorretais/genética , DNA de Neoplasias/sangue , DNA de Neoplasias/química , Esquema de Medicação , Combinação de Medicamentos , Feminino , Humanos , Masculino , Metástase Neoplásica , Pirrolidinas/efeitos adversos , Curva ROC , Timina/efeitos adversos , Trifluridina/efeitos adversos
8.
Cancer Med ; 10(4): 1183-1190, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33544407

RESUMO

BACKGROUND: Microsatellite-stable (MSS) colorectal cancer (CRC) tends to be poorly immunogenic, with limited treatment options. In MSS CRC xenograft models, trifluridine/tipiracil (FTD/TPI) plus programed death 1 inhibitors resulted in synergistic antitumor activity and increased tumor immunogenicity. This phase 2 study evaluated FTD/TPI plus nivolumab in patients with MSS metastatic CRC. METHODS: This single-arm, safety lead-in study used a Simon's two-stage design (enrolling 6 patients in the safety lead-in, proceeding to stage 2 if ≥2 of the first 15 patients achieved a partial or complete response per immune-related response criteria [irRC] within 6 months). Patients with histologically proven MSS mCRC, and disease progression after ≥2 prior chemotherapy regimens received FTD/TPI (35 mg/m2 twice daily; days 1-5 and 8-12 every 28 days) plus nivolumab (3 mg/kg every 2 weeks). RESULTS: Between August 2016 and January 2017, 18 patients (50% men; median age 56.5 years) were enrolled; 72% had colon cancer and 56% had KRAS mutations. All patients received treatment (median, 2.5 cycles [range, 1-8]). No dose-limiting toxicities were observed in the study. The most frequent adverse events (AEs) of any cause and grade were nausea (67%), diarrhea (61%), and neutropenia (50%); 13 patients (72%) experienced grade ≥3 AEs. No patients discontinued treatment because of AEs. No patient achieved a tumor response (either per Response Evaluation Criteria in Solid Tumors [RECIST] or irRC), and the study did not progress to the second stage. Stable disease was achieved in 8 patients per irRC and in 10 patients per RECIST. Median progression-free survival was 2.2 months (95% CI, 1.8-6.0 months) per irRC and 2.8 months (95% CI, 1.8-5.1 months) per RECIST. CONCLUSION: Patients with refractory MSS metastatic CRC failed to experience clinical benefit with FTD/TPI plus nivolumab, although safety data in this population indicated tolerability and feasibility of this combination. TRIAL REGISTRATION NUMBER: NCT02860546.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Repetições de Microssatélites , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Combinação de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Nivolumabe/administração & dosagem , Pirrolidinas/administração & dosagem , Pirrolidinas/efeitos adversos , Taxa de Sobrevida , Timina/administração & dosagem , Timina/efeitos adversos , Trifluridina/administração & dosagem , Trifluridina/efeitos adversos
9.
Future Oncol ; 17(14): 1749-1759, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33464133

RESUMO

Aim: To help to remove misperception of an appropriate position of trifluridine/tipiracil (FTD/TPI) in the treatment of metastatic colorectal cancer. Materials & methods: The RAND Corporation/UCLA Appropriateness Method was used by a panel of Italian experts to develop recommendations concerning daily practice with FTD/TPI. Forty-three clinical scenarios were discussed in two rounds and the resulting statements were rated as appropriate, uncertain or inappropriate, according to the median score. Results: Several topics were dealt with, covering the profile of eligible patients, therapeutic options beyond the second line, the practice of treatment with FTD/TPI, evaluation and efficacy and toxicity, as well as costs and compliance. Conclusion: FTD/TPI is an important therapeutic resource in refractory metastatic colorectal cancer that combines manageability and safety.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Oncologia/normas , Guias de Prática Clínica como Assunto , Padrões de Prática Médica/normas , Pirrolidinas/administração & dosagem , Timina/administração & dosagem , Trifluridina/administração & dosagem , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Ensaios Clínicos como Assunto , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Consenso , Combinação de Medicamentos , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Pirrolidinas/efeitos adversos , Timina/efeitos adversos , Trifluridina/efeitos adversos
10.
Lancet Gastroenterol Hepatol ; 6(3): 209-217, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33508242

RESUMO

BACKGROUND: Findings of preclinical and clinical trials in colorectal cancer have shown promising antitumour effects of the co-formulation trifluridine/tipiracil and VEGF inhibition. We aimed to investigate the safety and activity of trifluridine/tipiracil and ramucirumab for previously treated advanced gastric cancer. METHODS: We did an open-label, single-arm, two-cohort, phase 2 study at eight centres in Japan. We enrolled patients with unresectable advanced gastric cancer or gastro-oesophageal junction adenocarcinoma. Cohort A included patients previously treated with one line of chemotherapy without ramucirumab and cohort B included patients previously treated with two to four lines of chemotherapy, including ramucirumab. Patients received trifluridine/tipiracil (35 mg/m2) orally twice daily on days 1-5 and days 8-12 of each 28-day treatment cycle, plus intravenous ramucirumab (8 mg/kg) on days 1 and 15. The primary endpoint was the disease control rate, assessed by investigators and defined as the proportion of patients with a confirmed best overall response, according to Response Evaluation Criteria in Solid Tumors version 1.1. This trial is registered on JapicCTI (JapicCTI-194596) and is ongoing but not recruiting. FINDINGS: Between April 8 and Oct 11, 2019, 64 patients were enrolled and included in the safety and activity analyses, 33 in cohort A and 31 in cohort B. In cohort A, the disease control rate was 85% (95% CI 68-95; 28 of 33 patients) and in cohort B it was 77% (59-90; 24 of 31 patients). Common treatment-related adverse events of grade 3 or worse were neutrophil count decreased (27 [82%] in cohort A and 23 [74%] in cohort B), white blood cell count decreased (eight [24%] and seven [23%]), and platelet count decreased (eight [24%] and four [13%]). Serious treatment-related adverse events were recorded in three patients in cohort A (fatigue and neutrophil count decreased; large intestine perforation; and febrile neutropenia, platelet count decreased, and anaemia). No patients in cohort B had a serious treatment-related adverse event, and no treatment-related deaths were reported in either cohort. INTERPRETATION: Trifluridine/tipiracil and ramucirumab showed an acceptable safety profile and clinical activity in patients with previously treated advanced gastric cancer regardless of previous ramucirumab exposure. FUNDING: Taiho Pharmaceutical and Eli Lilly.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Pirrolidinas/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Timina/uso terapêutico , Trifluridina/uso terapêutico , Adenocarcinoma/tratamento farmacológico , Administração Intravenosa , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Estudos de Casos e Controles , Combinação de Medicamentos , Neoplasias Esofágicas/tratamento farmacológico , Feminino , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Intervalo Livre de Progressão , Pirrolidinas/administração & dosagem , Pirrolidinas/efeitos adversos , Segurança , Timina/administração & dosagem , Timina/efeitos adversos , Trifluridina/administração & dosagem , Trifluridina/efeitos adversos
11.
Cancer ; 127(9): 1417-1424, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33351187

RESUMO

BACKGROUND: TAS-102, a novel antimetabolite, is approved for treatment of refractory metastatic colorectal cancer (CRC). This study sought to determine whether the addition of TAS-102 to oxaliplatin (TAS-OX) was safe and effective in metastatic CRC previously treated with oxaliplatin. METHODS: This investigator-initiated, open-label, single-arm phase 1b study enrolled patients with metastatic CRC previously treated with 5-fluorouracil, irinotecan, and oxaliplatin. In dose escalation, TAS-102 was given at 3 dose levels: 25, 30, and 35 mg/m2 twice daily on day 1 to day 5 with 85 mg/m2 oxaliplatin on day 1 in 14-day cycles. The primary endpoint of dose escalation was the recommended dose for expansion, and in dose expansion, the primary endpoint was overall response rate (ORR) according to the Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1). RESULTS: Forty-one patients were treated with TAS-OX. No dose-limiting toxicities were observed in the 11 patients treated in escalation. The recommended dose for expansion was 35 mg/m2 TAS-102 twice daily on day 1 to day 5 in combination with 85 mg/m2 oxaliplatin on day 1 in 14-day cycles. In the intention-to-treat population, the ORR was 2.4% (95% CI, 0%-12.9%) with 1 of 41 patients having a partial response, although 12 (29%) had tumor shrinkage. The median progression-free survival was 2.7 months (95% CI, 2.4-4.8 months) and median overall survival was 6.8 months (95% CI, 5.7-10 months). CONCLUSIONS: TAS-OX is safe with no unexpected toxicities at standard doses of each agent. The combination did not result in a clinically meaningful ORR, although progression-free survival and overall survival were encouraging in this heavily pretreated population. LAY SUMMARY: For metastatic colorectal cancer, the treatment combination of TAS-102 and oxaliplatin was found to be well-tolerated and revealed no unexpected side effects. Twelve of 41 patients had reductions in the size of their tumor, and the study treatment delayed the time to tumor growth as opposed to what would be expected.


Assuntos
Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Oxaliplatina/administração & dosagem , Pirrolidinas/administração & dosagem , Timina/administração & dosagem , Trifluridina/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Colorretais/mortalidade , Esquema de Medicação , Combinação de Medicamentos , Resistencia a Medicamentos Antineoplásicos , Feminino , Fluoruracila/administração & dosagem , Humanos , Irinotecano/administração & dosagem , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina/efeitos adversos , Intervalo Livre de Progressão , Pirrolidinas/efeitos adversos , Critérios de Avaliação de Resposta em Tumores Sólidos , Timina/efeitos adversos , Trifluridina/efeitos adversos
12.
Clin Colorectal Cancer ; 19(4): e208-e225, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32912821

RESUMO

INTRODUCTION: Compared with the best supportive care, a survival benefit of using regorafenib and trifluridine/tipiracil (TFTD) in patients with colorectal cancer has been shown in previous randomized controlled trials (RCTs). However, there is no RCT or large-scale observational study directly comparing regorafenib and TFTD. PATIENTS AND METHODS: We used a nationwide claims database in Japan and compared the effectiveness of regorafenib and TFTD for metastatic colorectal cancer during 2013 to 2018. The patients were divided into 4 groups (regorafenib monotherapy, regorafenib/TFTD: regorafenib followed by TFTD, TFTD monotherapy, and TFTD/regorafenib: TFTD followed by regorafenib). Overall survival (OS) and adverse events were compared between the groups. In a subgroup analysis, we also compared treatment effectiveness between the group in which regorafenib was administered first and the group in which TFTD was administered first. RESULTS: We identified 7279 patients (regorafenib: 1501, regorafenib/TFTD: 973, TFTD: 3777, and TFTD/regorafenib: 1028). The corresponding median OS was 6.4, 16.4, 10.2, and 16.9 months, respectively. A log-rank test showed significant intergroup differences (P < .001). In the subgroup analysis, the group in which TFTD was administered first showed significantly longer OS. The incidences of most adverse events were the lowest in the TFTD group. The TFTD group showed longer OS than the regorafenib group, and sequential drug use resulted in the most prolonged OS. CONCLUSION: Our findings indicate that it might be better to prescribe TFTD first. Furthermore, owing to the longer OS than monotherapy, sequential administration of regorafenib and TFTD ought to be considered.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Compostos de Fenilureia/administração & dosagem , Piridinas/administração & dosagem , Pirrolidinas/administração & dosagem , Terapia de Salvação/métodos , Timina/administração & dosagem , Trifluridina/administração & dosagem , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Combinação de Medicamentos , Feminino , Humanos , Japão/epidemiologia , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Compostos de Fenilureia/efeitos adversos , Piridinas/efeitos adversos , Pirrolidinas/efeitos adversos , Estudos Retrospectivos , Terapia de Salvação/efeitos adversos , Terapia de Salvação/estatística & dados numéricos , Análise de Sobrevida , Timina/efeitos adversos , Resultado do Tratamento , Trifluridina/efeitos adversos
13.
Nephron ; 144(10): 506-508, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32799198

RESUMO

Kidney diseases during chemotherapy treatment are variable, with different manifestations depending on the drugs used. Trifluridine/tipiracil is a treatment used in refractory metastatic digestive cancers. Its renal toxicity is poorly described. We report here the onset of a severe IgA nephropathy requiring hemodialysis which occurred several weeks after trifluridine/tipiracil treatment.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Glomerulonefrite por IGA/induzido quimicamente , Pirrolidinas/efeitos adversos , Timina/efeitos adversos , Trifluridina/efeitos adversos , Idoso , Neoplasias do Colo/tratamento farmacológico , Glomerulonefrite por IGA/fisiopatologia , Glomerulonefrite por IGA/terapia , Humanos , Masculino
14.
J Int Med Res ; 48(7): 300060520926408, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32660291

RESUMO

OBJECTIVE: We performed this meta-analysis to compare the efficacy and toxicity of regorafenib and TAS-102. METHODS: Electronic databases were searched to identify studies comparing the efficacy and safety of regorafenib and TAS-102 in patients with chemotherapy-refractory metastatic colorectal cancer using pooled analyses. RESULTS: Three clinical trials were included in this analysis. Regarding the reasons for treatment discontinuation, regorafenib was significantly associated with disease progression (odds ratio [OR] = 0.33, 95% confidence interval [CI] = 0.21-0.50) and adverse events (OR = 4.38, 95% CI = 2.69-7.13). However, overall (OR = 0.97, 95% CI = 0.81-1.17) and progression-free survival (OR = 1.01, 95% CI = 0.86-1.18) did not significantly differ between the groups. The most common treatment-related adverse events in the regorafenib group were neutropenia (OR = 0.06, 95% CI = 0.03-0.11), hand-foot syndrome (OR = 50.34, 95% CI = 10.44-242.84), and liver dysfunction (OR = 34.51, 95% CI = 8.30-143.43). Conversely, the incidence of thrombocytopenia did not differ between the two groups. CONCLUSIONS: Regorafenib and TAS-102 have similar efficacy but different adverse event profiles. Differences in the toxicity profiles of the two drugs will help guide treatment selection.


Assuntos
Neoplasias Colorretais , Trifluridina , Neoplasias Colorretais/tratamento farmacológico , Combinação de Medicamentos , Humanos , Compostos de Fenilureia , Piridinas , Pirrolidinas , Timina , Trifluridina/efeitos adversos
15.
Oncologist ; 25(12): e1855-e1863, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32666647

RESUMO

LESSONS LEARNED: A biweekly TAS-102 plus BEV schedule in patients with heavily pretreated mCRC showed equivalent efficacy with less toxicity compared with the current schedule of TAS-102 plus BEV combination. Biweekly TAS-102 plus BEV combination could reduce unnecessary dose reduction of TAS-102, maintain higher doses, and possibly be effective even in cases without chemotherapy-induced neutropenia (CIN). The prespecified subgroup analysis of this study showed an obvious association between CIN within the first two cycles and prognosis of biweekly TAS-102 plus BEV. BACKGROUND: TAS-102 (trifluridine/tipiracil) plus bevacizumab (BEV) combination therapy has shown promising activity in patients with metastatic colorectal cancer (mCRC). However, the previously reported dose and schedule for the TAS-102 (70 mg/m2 /day on days 1-5 and 8-12, every 4 weeks) plus BEV (5 mg/kg on day 1, every 2 weeks) regimen is complicated by severe hematological toxicities and difficult administration schedules. Here, we evaluated the efficacy and safety of a more convenient biweekly TAS-102 plus BEV combination. METHODS: Patients with mCRC who were refractory or intolerant to standard chemotherapies were enrolled. Patients received biweekly TAS-102 (twice daily on days 1-5, every 2 weeks) with BEV (5mg/kg on day 1, every 2 weeks). The primary endpoint was progression-free survival rate at 16 weeks (16-w PFS rate). RESULTS: From October 2017 to January 2018, 46 patients were enrolled. The recommended phase II dose was determined to be TAS-102 (70 mg/m2 /day). Of the 44 eligible patients, the 16-w PFS rate was 40.9% (95% confidence interval, 26.3%-56.8%), and the null hypothesis was rejected (p < .0001). Median progression-free survival (PFS) and overall survival were 4.29 months and 10.86 months, respectively. Disease control rate was 59.1%. Common grade 3 or higher adverse events were hypertension (40.9%), neutropenia (15.9%), and leucopenia (15.9%). CONCLUSION: Biweekly TAS-102 plus BEV showed promising antitumor activity with safety.


Assuntos
Neoplasias Colorretais , Trifluridina , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Combinação de Medicamentos , Humanos , Pirrolidinas , Timina , Trifluridina/efeitos adversos
16.
Ann Oncol ; 31(9): 1160-1168, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32497736

RESUMO

BACKGROUND: We designed an open-label, noncomparative phase II study to assess the safety and efficacy of first-line treatment with trifluridine/tipiracil plus bevacizumab (TT-B) and capecitabine plus bevacizumab (C-B) in untreated patients with unresectable metastatic colorectal cancer (mCRC) who were not candidates for combination with cytotoxic chemotherapies. PATIENTS AND METHODS: From 29 April 2016 to 29 March 2017, 153 patients were randomly assigned (1:1) to either TT-B (N = 77) or C-B (N = 76). The primary end point was progression-free survival (PFS). The primary PFS analysis was performed after 100 events (radiological progression or death) were observed. Secondary end points included overall survival (OS), quality of life (QoL; QLQ-C30 and QLQ-CR29 questionnaires), and safety. RESULTS: Median (range) duration of treatment was 7.8 (6.0-9.7) months and 6.2 (4.1-9.1) months in the TT-B and C-B groups, respectively. Median (range) PFS was 9.2 (7.6-11.6) and 7.8 (5.5-10.1) months, respectively. Median (range) OS was 18 (15.2 to NA) and 16.2 (12.5 to NA) months, respectively. QoL questionnaires showed no relevant changes over time for either treatment. Therapies were well tolerated. Patients receiving TT-B had more grade ≥3 neutropenia (47% versus 5% with C-B). Patients receiving C-B had more grade ≥3 hand-foot syndrome (12% versus 0% with TT-B) and grade ≥3 diarrhea (8% versus 1% with TT-B), consistent with the known safety profiles of these agents. CONCLUSION: TT-B treatment showed promising clinical activity in untreated patients with unresectable mCRC ineligible for intensive therapy, with an acceptable safety profile and no clinically relevant changes in QoL. CLINICAL TRIAL INFORMATION: NCT02743221 (ClinicalTrials.gov).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Bevacizumab , Capecitabina , Neoplasias Colorretais , Trifluridina , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/efeitos adversos , Capecitabina/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Fluoruracila/uso terapêutico , Humanos , Pirrolidinas , Qualidade de Vida , Timina , Trifluridina/efeitos adversos
18.
Invest New Drugs ; 38(5): 1520-1525, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32253554

RESUMO

Neuroendocrine tumors (NETs) are understudied and have limited systemic treatment options. Prior studies for patients with advanced NETs have demonstrated promising results when antimetabolite agents, including fluoropyrimidines, were combined with temozolomide TMZ. TAS-102 (trifluridine/tipiracil) is an antineoplastic agent that is non-cross resistant with 5-fluorouracil and capecitabine and that has a different toxicity profile. This study evaluated the safety of TAS-102 in combination with TMZ in patients in neuroendocrine tumors. Escalating doses of TMZ (100, 150 and 200 mg/m2) on days 8-12 were given in combination with TAS-102 (35 mg/m2 twice a day) on days 1-5 and 8-12 of a 28 day cycle in subjects with advanced NETs. Primary endpoints were safety and determination of maximum tolerated dose (MTD). Growth factor support was mandated starting with level 2 to avoid treatment delays. Fifteen evaluable subjects were enrolled in the phase 1 study. No dose limiting toxicities (DLTs) were observed on level 1. One DLT was observed on level 2 (grade 3 fatigue and inability to resume treatment), and 1 on level 3 (grade 4 thrombocytopenia). The most common grade ≥ 3 adverse events included neutropenia (33%), lymphopenia (27%), and thrombocytopenia (27%). Disease control rate of 92% and partial response rate of 8% were observed in 13 evaluable subjects. This study established MTD of TAS-102 (35 mg/m2 twice daily) and TMZ (200 mg/m2 daily). This regimen was well tolerated. Early signs of clinically meaningful activity were observed. Further evaluation of the efficacy of this regimen is warranted.


Assuntos
Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Tumores Neuroendócrinos/tratamento farmacológico , Pirrolidinas/administração & dosagem , Temozolomida/administração & dosagem , Timina/administração & dosagem , Trifluridina/administração & dosagem , Adulto , Idoso , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Combinação de Medicamentos , Feminino , Doenças Hematológicas/induzido quimicamente , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Pirrolidinas/efeitos adversos , Temozolomida/efeitos adversos , Timina/efeitos adversos , Resultado do Tratamento , Trifluridina/efeitos adversos
20.
Ann Oncol ; 31(1): 88-95, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31912801

RESUMO

BACKGROUND: The phase II J003 (N = 169) and phase III RECOURSE (N = 800) trials demonstrated a significant improvement in survival with trifluridine (FTD)/tipiracil (TPI) versus placebo in patients with refractory metastatic colorectal cancer. This post hoc analysis investigated pharmacokinetic data of FTD/TPI exposure and pharmacodynamic markers, such as chemotherapy-induced neutropenia (CIN) and clinical outcomes. PATIENTS AND METHODS: A total of 210 patients from RECOURSE were enrolled in this substudy. A limited sampling approach was used, with three pharmacokinetic samples drawn on day 12 of cycle 1. Patients were categorized as being above or below the median area under the plasma concentration-time curve (AUC) for FTD and TPI. We conducted a post hoc analysis using the entire RECOURSE population to determine the correlations between CIN and clinical outcome. We then carried out a similar analysis on the J003 trial to validate the results. RESULTS: In the RECOURSE subset, patients in the high FTD AUC group had a significantly increased CIN risk. Analyses of the entire population demonstrated that FTD/TPI-treated patients with CIN of any grade in cycles 1 and 2 had significantly longer median overall survival (OS) and progression-free survival (PFS) than patients who did not develop CIN and patients in the placebo group. Patients who required an FTD/TPI treatment delay had increased OS and PFS versus those in the placebo group and those who did not develop CIN. Similar results were obtained in the J003 cohort. CONCLUSIONS: In RECOURSE, patients with higher FTD drug exposure had an increased CIN risk. FTD/TPI-treated patients who developed CIN had improved OS and PFS versus those in the placebo group and those who did not develop CIN. Similar findings were reported in the J003 cohort, thus validating the RECOURSE results. The occurrence of CIN may be a useful predictor of treatment outcomes for FTD/TPI-treated patients. CLINICALTRIALS. GOV IDENTIFIER: NCT01607957 (RECOURSE). JAPAN PHARMACEUTICAL INFORMATION CENTER NUMBER: JapicCTI-090880 (J003).


Assuntos
Neoplasias Colorretais , Neutropenia , Neoplasias Colorretais/tratamento farmacológico , Combinação de Medicamentos , Humanos , Japão , Pirrolidinas , Timina , Trifluridina/efeitos adversos , Uracila/efeitos adversos
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