RESUMEN
PURPOSE: This phase I trial is to determine the recommended dose of the TAS-102, irinotecan plus bevacizumab regimen and assess its safety and efficacy in patients with metastatic colorectal cancer refractory to fluoropyrimidine and oxaliplatin treatment. METHODS: A 3 + 3 designed dose escalation was performed. Patients were administered TAS-102 (30-35 mg/m2 twice daily on days 1-5) and irinotecan (150-165 mg/m2 on day 1) combined with a fixed dose of bevacizumab (5 mg/kg on day 1) every two weeks. The primary endpoint was the determination of the recommended phase II dose. RESULTS: Eighteen patients were enrolled: 6 at the Level 1 (TAS-102 30 mg/m2 twice daily, irinotecan 150 mg/m2 plus bevacizumab 5 mg/kg), six at the Level 2 (TAS-102 35 mg/m2 twice daily, irinotecan 150 mg/m2 plus bevacizumab 5 mg/kg), and six at the Level 3 (TAS-102 30 mg/m2 twice daily, irinotecan 165 mg/m2 plus bevacizumab 5 mg/kg). Five dose-limiting toxicities occurred: one observed at Level 1 (thrombocytopenia), two at Level 2 (neutropenia and diarrhea), and two at Level 3 (fatigue and neutropenia). The RP2D was established as TAS-102 30 mg/m2 twice daily and irinotecan 150 mg/m2 plus bevacizumab 5 mg/kg. The most frequent grade 3/4 treatment-related adverse events were neutropenia (33.3%), diarrhea (16.7%), and thrombocytopenia (11.1%). No treatment-related death occurred. Two patients (11.1%) experienced partial responses and 14 (77.8%) had stable disease. CONCLUSION: The regimen of TAS-102, irinotecan, and bevacizumab is tolerable with antitumor activity for metastatic colorectal cancer patients refractory to first-line fluoropyrimidines and oxaliplatin treatment.
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Protocolos de Quimioterapia Combinada Antineoplásica , Bevacizumab , Neoplasias Colorrectales , Combinación de Medicamentos , Irinotecán , Pirrolidinas , Timina , Trifluridina , Uracilo , Humanos , Timina/administración & dosificación , Trifluridina/administración & dosificación , Trifluridina/uso terapéutico , Trifluridina/efectos adversos , Bevacizumab/administración & dosificación , Bevacizumab/efectos adversos , Bevacizumab/uso terapéutico , Masculino , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Femenino , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Persona de Mediana Edad , Pirrolidinas/administración & dosificación , Pirrolidinas/efectos adversos , Pirrolidinas/uso terapéutico , Anciano , Irinotecán/administración & dosificación , Irinotecán/efectos adversos , Irinotecán/uso terapéutico , Uracilo/análogos & derivados , Uracilo/administración & dosificación , Uracilo/uso terapéutico , Uracilo/efectos adversos , Adulto , Metástasis de la NeoplasiaRESUMEN
BACKGROUND: TAS-102 is effective against unresectable advanced or recurrent colorectal and gastric cancer. However, its effect on oral squamous cell carcinoma (OSCC) is still unknown. Here, we tried to clarify the possible effect of TAS-102 against angiogenesis and proliferation of human OSCC cells. MATERIALS AND METHODS: 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, migration assay and mice xenograft models were used to determine the effect of TAS-102 on growth and migration of OSCC. The activity of phosphorylated nuclear factor kappa light-chain-enhancer of activated B-cells (NF-κB) (p-p65) in cells was detected by immunocytochemistry. The expression of p-AKT serine/threonine kinase 1 (p-AKT), p-p65, vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF2) and CD31 in mouse tumors were detected by immunohistochemistry. RESULTS: TAS-102 significantly inhibited growth and migration of OSCC both in vitro and in vivo. It suppressed the activity of NF-κB in cells. TAS-102 down-regulated the expression of p-AKT, VEGF, FGF2 and CD31, which was associated with reduced vascularization of HSC2 tumor lesions. CONCLUSION: These findings suggest that TAS-102 might inhibit angiogenesis and proliferation of OSCC cells.
Asunto(s)
Antineoplásicos/farmacología , Pirrolidinas/farmacología , Timina/farmacología , Trifluridina/farmacología , Animales , Antineoplásicos/administración & dosificación , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Combinación de Medicamentos , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Ratones , Neoplasias de la Boca , FN-kappa B/metabolismo , Neovascularización Patológica/tratamiento farmacológico , Pirrolidinas/administración & dosificación , Transducción de Señal , Carcinoma de Células Escamosas de Cabeza y Cuello , Timina/administración & dosificación , Trifluridina/administración & dosificación , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
PURPOSE: Antipsychotic medications, including olanzapine, are associated with substantial weight gain and metabolic disturbances. We sought to determine whether coadministration of miricorilant, a selective glucocorticoid receptor modulator, with olanzapine can ameliorate these effects. METHODS: Sixty-six healthy men were enrolled in a 2-week, randomized, double-blind, placebo-controlled trial. The primary objective was to evaluate changes in body weight after 14 days coadministration of olanzapine (10 mg) + miricorilant (600 mg) compared with olanzapine (10 mg) + placebo. Secondary objectives included evaluating (a) the safety and tolerability of the combination; (b) the effects of the combination on glucose, insulin, insulin resistance, and triglycerides; and (c) the impact of the combination on hepatic enzymes. RESULTS: Subjects administered olanzapine + miricorilant gained less weight than subjects administered olanzapine + placebo (mean weight gain on day 15, 3.91 kg vs 4.98 kg; difference between groups, -1.07 kg; 95% confidence interval, -1.94 to -0.19; P = 0.017]). Compared with the placebo group, coadministration of miricorilant with olanzapine was associated with smaller increases in insulin (difference, -3.74 mIU/L; P = 0.007), homeostatic model assessment of insulin resistance (difference, -0.47; P = 0.007), triglycerides (difference, -0.29 mmol/L; P = 0.057), aspartate aminotransferase (difference, -32.24 IU/L; P = 0.009), and alanine aminotransferase (difference, -49.99 IU/L; P = 0.030). CONCLUSIONS: Miricorilant may provide a promising option for ameliorating the detrimental effects of olanzapine, and investigation of this medication in patients affected by antipsychotic-induced weight gain is warranted. Two phase 2 studies of miricorilant in patients with recent and long-standing antipsychotic-induced weight gain are currently in progress.
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Antipsicóticos/farmacología , Olanzapina/farmacología , Receptores de Glucocorticoides/efectos de los fármacos , Timina/análogos & derivados , Aumento de Peso/efectos de los fármacos , Adulto , Antipsicóticos/administración & dosificación , Antipsicóticos/efectos adversos , Método Doble Ciego , Quimioterapia Combinada , Femenino , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Olanzapina/administración & dosificación , Olanzapina/efectos adversos , Prueba de Estudio Conceptual , Timina/administración & dosificación , Timina/efectos adversos , Timina/farmacología , Adulto JovenRESUMEN
Breast carcinomas commonly carry mutations in the tumor suppressor p53, although therapeutic efforts to target mutant p53 have previously been unfruitful. Here we report a selective combination therapy strategy for treatment of p53 mutant cancers. Genomic data revealed that p53 mutant cancers exhibit high replication activity and express high levels of the Base-Excision Repair (BER) pathway, whereas experimental testing showed substantial dysregulation in BER. This defect rendered accumulation of DNA damage in p53 mutant cells upon treatment with deoxyuridine analogues. Notably, inhibition of poly (ADP-ribose) polymerase (PARP) greatly enhanced this response, whereas normal cells responded with activation of the p53-p21 axis and cell cycle arrest. Inactivation of either p53 or p21/CDKN1A conferred the p53 mutant phenotype. Preclinical animal studies demonstrated a greater anti-neoplastic efficacy of the drug combination (deoxyuridine analogue and PARP inhibitor) than either drug alone. This work illustrates a selective combination therapy strategy for p53 mutant cancers that will improve survival rates and outcomes for thousands of breast cancer patients.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Reparación del ADN/genética , Mutación , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Proteína p53 Supresora de Tumor/genética , Ensayos Antitumor por Modelo de Xenoinjerto/métodos , Células A549 , Animales , Línea Celular , Línea Celular Tumoral , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Combinación de Medicamentos , Femenino , Humanos , Ratones Endogámicos BALB C , Ratones SCID , Ftalazinas/administración & dosificación , Piperazinas/administración & dosificación , Inhibidores de Poli(ADP-Ribosa) Polimerasas/administración & dosificación , Pirrolidinas/administración & dosificación , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Timina/administración & dosificación , Trifluridina/administración & dosificación , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/metabolismo , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
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.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Enfermedades Renales/fisiopatología , Neoplasias/tratamiento farmacológico , Pirrolidinas/administración & dosificación , Timina/administración & dosificación , Trifluridina/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Anemia/inducido químicamente , Anemia/epidemiología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Área Bajo la Curva , Estudios de Cohortes , Combinación de Medicamentos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neutropenia/inducido químicamente , Neutropenia/epidemiología , Pirrolidinas/efectos adversos , Pirrolidinas/farmacocinética , Índice de Severidad de la Enfermedad , Timina/efectos adversos , Timina/farmacocinética , Trifluridina/efectos adversos , Trifluridina/farmacocinéticaRESUMEN
BACKGROUND/AIM: Our multicenter phase II TAS-CC3 study demonstrated favorable median progression-free survival (PFS) and overall survival (OS) of 32 metastatic colorectal cancer (mCRC) patients treated with TAS-102 + bevacizumab as 3rd-line treatment. PATIENTS AND METHODS: We investigated the predictive and prognostic values of pre-treatment blood inflammation-based scores, including the neutrophil-to-lymphocyte (NLR), platelet-to-lymphocyte (PLR) and lymphocyte-to-monocyte ratio (LMR) on disease-control (DC), PFS and OS by a post-hoc analysis. RESULTS: Receiver operating characteristic curve analyses of the 3 inflammation-based scores versus DC showed the best predictive performance for LMR, followed by NLR and PLR. The high-LMR group had a significantly higher DC rate than the low group (87.5 vs. 43.8%). The high-LMR group showed significantly longer survival than the low group (4.9 vs. 2.3 m for median PFS) (21.0 vs. 6.1 m for median OS). CONCLUSION: The pre-treatment LMR is a valid predictive and prognostic biomarker for mCRC patients undergoing TAS-102 and bevacizumab treatment.
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Antineoplásicos Inmunológicos/uso terapéutico , Bevacizumab/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Linfocitos/patología , Monocitos/patología , Metástasis de la Neoplasia/tratamiento farmacológico , Pirrolidinas/uso terapéutico , Timina/uso terapéutico , Trifluridina/uso terapéutico , Anciano , Antineoplásicos Inmunológicos/administración & dosificación , Bevacizumab/administración & dosificación , Neoplasias Colorrectales/patología , Combinación de Medicamentos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pirrolidinas/administración & dosificación , Timina/administración & dosificación , Trifluridina/administración & dosificaciónRESUMEN
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).
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias Colorrectales/tratamiento farmacológico , Evaluación Geriátrica/métodos , Pirrolidinas/administración & dosificación , Timina/administración & dosificación , Trifluridina/administración & dosificación , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Biomarcadores de Tumor/metabolismo , Combinación de Medicamentos , Monitoreo de Drogas/métodos , Femenino , Humanos , Masculino , Neutropenia/inducido químicamente , Supervivencia sin Progresión , Pirrolidinas/efectos adversos , Pirrolidinas/farmacocinética , Tasa de Supervivencia , Timina/efectos adversos , Timina/farmacocinética , Trifluridina/efectos adversos , Trifluridina/farmacocinéticaRESUMEN
Aim: To determine a recommended Phase II dose of the oral fluoropyrimidine trifluridine/tipiracil (FTD/TPI) combined with the multi-kinase inhibitor regorafenib (REG) in refractory metastatic colorectal cancer patients. Materials & methods: A conventional 3 + 3 dose finding design was used. FTD/TPI was administered on days 1-5 and 8-12 of a 28-day cycle, REG on days 2-22. Two dose levels were used: FTD/TPI 25 mg/m2 b.i.d. + REG 120 mg/d, then escalated to FTD/TPI 35 mg/m2 b.i.d. + REG 120 mg/d. Results: In total, 12 patients were treated at two dose levels. Three dose-limiting toxicities were observed; all were grade 3 hypertension causally attributed to REG. Recommended Phase II dose is FTD/TPI 25 mg/m2 b.i.d. + REG 120 mg/d. Median progression-free survival was 3.81 months (95% CI: 1.51-5.29), median OS 11.1 months (95% CI: 2.3-18.2). Conclusion: The combination of REG and FTD/TPI is feasible and safe. Efficacy signals exceed that of the single agents at acceptable toxicity levels and are clinically meaningful.
Lay abstract Many patients with metastatic colorectal cancer need a sequence of different treatments over time. Regorafenib and trifluridine/tipiracil (also called TAS-102) are two drugs which are both used late in this sequence of treatments, but there is no rule as to which should be used first. Both drugs have very different mechanisms of action, and it might be beneficial to patients to administer them both at the same time as a combination treatment, instead of sequential treatment. We therefore conducted a Phase Ib study with a small number of patients to investigate whether this combined treatment would be feasible and safe. The study was designed to test the drug combination at different doses, and we found that treatment with trifluridine/tipiracil at 25 mg/m2 twice daily combined with regorafenib at 120 mg daily had acceptable side effects and is likely to be safe for use in future clinical trials. Efficacy results suggest that combined treatment with both drugs may extend patient's life span. However, these observations are preliminary and need testing in further clinical trials. Clinical trial registration: EudraCT 2016-001968-11; NCT03305913 (ClinicalTrials.gov).
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias Colorrectales/tratamiento farmacológico , Hipertensión/epidemiología , Compuestos de Fenilurea/administración & dosificación , Piridinas/administración & dosificación , Pirrolidinas/administración & dosificación , Timina/administración & dosificación , Trifluridina/administración & dosificación , Administración Oral , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidad , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Combinación de Medicamentos , Resistencia a Antineoplásicos , Estudios de Factibilidad , Femenino , Humanos , Hipertensión/inducido químicamente , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Compuestos de Fenilurea/toxicidad , Supervivencia sin Progresión , Piridinas/toxicidad , Pirrolidinas/toxicidad , Criterios de Evaluación de Respuesta en Tumores Sólidos , Timina/toxicidad , Trifluridina/toxicidadRESUMEN
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.
Asunto(s)
Neoplasias Colorrectales/tratamiento farmacológico , Compuestos de Fenilurea/administración & dosificación , Piridinas/administración & dosificación , Pirrolidinas/administración & dosificación , Timina/administración & dosificación , Trifluridina/administración & dosificación , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Esquema de Medicación , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Compuestos de Fenilurea/efectos adversos , Supervivencia sin Progresión , Piridinas/efectos adversos , Pirrolidinas/efectos adversos , Timina/efectos adversos , Trifluridina/efectos adversosRESUMEN
Adjuvant chemotherapy has reduced the risk of tumor recurrence and improved survival in patients with resected colorectal cancer. Potential utility of circulating tumor DNA (ctDNA) prior to and post surgery has been reported across various solid tumors. We initiated a new type of adaptive platform trials to evaluate the clinical benefits of ctDNA analysis and refine precision adjuvant therapy for resectable colorectal cancer, named CIRCULATE-Japan including three clinical trials. The GALAXY study is a prospectively conducted large-scale registry designed to monitor ctDNA for patients with clinical stage II to IV or recurrent colorectal cancer who can undergo complete surgical resection. The VEGA trial is a randomized phase III study designed to test whether postoperative surgery alone is noninferior to the standard therapy with capecitabine plus oxaliplatin for 3 months in patients with high-risk stage II or low-risk stage III colon cancer if ctDNA status is negative at week 4 after curative surgery in the GALAXY study. The ALTAIR trial is a double-blind, phase III study designed to establish the superiority of trifluridine/tipiracil as compared with placebo in patients with resected colorectal cancer who show circulating tumor-positive status in the GALAXY study. Therefore, CIRCULATE-Japan encompasses both "de-escalation" and "escalation" trials for ctDNA-negative and -positive patients, respectively, and helps to answer whether measuring ctDNA postoperatively has prognostic and/or predictive value. Our ctDNA-guided adaptive platform trials will accelerate clinical development toward further precision oncology in the field of adjuvant therapy. Analysis of ctDNA status could be utilized as a predictor of risk stratification for recurrence and to monitor the effectiveness of adjuvant chemotherapy. ctDNA is a promising, noninvasive tumor biomarker that can aid in tumor monitoring throughout disease management.
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ADN Tumoral Circulante/sangre , Neoplasias Colorrectales/sangre , Recurrencia Local de Neoplasia/sangre , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Capecitabina/administración & dosificación , Quimioterapia Adyuvante , Neoplasias del Colon/sangre , Neoplasias del Colon/genética , Neoplasias del Colon/patología , Neoplasias del Colon/terapia , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/terapia , Método Doble Ciego , Humanos , Japón , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/terapia , Oxaliplatino/administración & dosificación , Estudios Prospectivos , Pirrolidinas/administración & dosificación , Timina/administración & dosificación , Trifluridina/administración & dosificaciónRESUMEN
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.
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Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Bevacizumab/administración & dosificación , Neoplasias Colorrectales/tratamiento farmacológico , Pirrolidinas/administración & dosificación , Timina/administración & dosificación , Trifluridina/administración & dosificación , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bevacizumab/efectos adversos , Neutropenia Febril Inducida por Quimioterapia/epidemiología , Neutropenia Febril Inducida por Quimioterapia/etiología , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Esquema de Medicación , Combinación de Medicamentos , Femenino , Humanos , Japón/epidemiología , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Pirrolidinas/efectos adversos , Análisis de Supervivencia , Timina/efectos adversos , Resultado del Tratamiento , Trifluridina/efectos adversosRESUMEN
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.
Asunto(s)
Bevacizumab/administración & dosificación , Neoplasias Colorrectales/tratamiento farmacológico , Leucocitos Mononucleares/química , Pirrolidinas/administración & dosificación , Timina/administración & dosificación , Trifluridina/administración & dosificación , Administración Intravenosa , Administración Oral , Anciano , Anciano de 80 o más Años , Bevacizumab/efectos adversos , Neoplasias Colorrectales/sangre , Neoplasias Colorrectales/genética , ADN de Neoplasias/sangre , ADN de Neoplasias/química , Esquema de Medicación , Combinación de Medicamentos , Femenino , Humanos , Masculino , Metástasis de la Neoplasia , Pirrolidinas/efectos adversos , Curva ROC , Timina/efectos adversos , Trifluridina/efectos adversosRESUMEN
Trifluridine/tipiracil (FTD/TPI) is an orally active formulation of trifluridine, a thymidine-based nucleoside analog, and tipiracil hydrochloride, a thymidine phosphorylase inhibitor that increases the bioavailability of trifluridine. Preliminary studies of FTD/TPI plus bevacizumab have produced encouraging results in the treatment of refractory metastatic colorectal cancer. Here, we describe the design of the multinational Phase III SUNLIGHT, an open-label study of FTD/TPI plus bevacizumab as third-line treatment for patients with unresectable metastatic colorectal cancer. A total of 490 patients will be randomized 1:1 to receive either FTD/TPI plus bevacizumab, or FTD/TPI monotherapy. The primary objective is to significantly improve overall survival with FTD/TPI plus bevacizumab compared with FTD/TPI monotherapy. The first patient was enrolled in November 2020.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Bevacizumab/administración & dosificación , Ensayos Clínicos Fase III como Asunto , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Combinación de Medicamentos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Metástasis de la Neoplasia , Pirrolidinas/administración & dosificación , Ensayos Clínicos Controlados Aleatorios como Asunto , Timina/administración & dosificación , Trifluridina/administración & dosificación , Adulto JovenRESUMEN
The analysis was conducted to assess the pharmacological costs of regorafenib and trifluridine/tipiracil in the treatment of refractory metastatic colorectal cancer (mCRC). Pivotal phase III randomized controlled trials (RCTs) of regorafenib and trifluridine/tipiracil in the treatment of refractory mCRC were considered. We have also considered the ReDOS trial, in order to verify if the dose-escalation strategy (practice changing for regorafenib) could influences the results. Differences in OS (expressed in months) between the different arms were calculated and compared with the pharmacological costs (at the Pharmacy of our Hospital and expressed in euros ()) needed to get one month of OS. Trifluridine/tipiracil resulted the less expensive, with 1167.50 per month OS-gained. The ReDOS trial further reduce costs with 510.41 per month OS-gained in favour of regorafenib with the escalation-dose strategy. Both regorafenib and trifluridine/tipiracil can be considered economically sustainable treatments for refractory mCRC, apparently with a lower cost of trifluridine/tipiracil. The adoption of a dose-escalation strategy (ReDOS trial) could reverse the situation making regorafenib more cost-effective than trifluridine/tipiracil.
Asunto(s)
Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/economía , Análisis Costo-Beneficio/métodos , Costos de los Medicamentos/tendencias , Compuestos de Fenilurea/economía , Piridinas/economía , Pirrolidinas/economía , Timina/economía , Trifluridina/economía , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/economía , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Humanos , Compuestos de Fenilurea/administración & dosificación , Piridinas/administración & dosificación , Pirrolidinas/administración & dosificación , Timina/administración & dosificación , Trifluridina/administración & dosificaciónRESUMEN
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.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Resistencia a Antineoplásicos , Repeticiones de Microsatélite , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Combinación de Medicamentos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Nivolumab/administración & dosificación , Pirrolidinas/administración & dosificación , Pirrolidinas/efectos adversos , Tasa de Supervivencia , Timina/administración & dosificación , Timina/efectos adversos , Trifluridina/administración & dosificación , Trifluridina/efectos adversosRESUMEN
BACKGROUND/AIM: This study aimed to describe the chemotherapy effects after trifluridine/tipiracil (TFTD) and/or regorafenib treatment in colorectal cancer (CRC) patients. PATIENTS AND METHODS: Patients receiving regorafenib or TFTD for metastatic CRC during 2013-2018 were selected and divided into two groups: one with additional chemotherapy after regorafenib or TFTD (CTX group) and one without additional chemotherapy (Non-CTX group). Patients were followed up from a landmark point (90 days from the last day of administration of regorafenib or TFTD). We compared overall survival (OS) between the groups. RESULTS: The median OS was 7.7 months in the CTX group and 4.1 months in the non-CTX groups. Several sensitivity analyses did not negate the survival advantage detected in the CTX group. CONCLUSION: The chemotherapy after regorafenib or TFTD was associated with prolonged OS in advanced CRC patients. Further study is required to determine appropriate treatment choice.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias Colorrectales/tratamiento farmacológico , Compuestos de Fenilurea/administración & dosificación , Piridinas/administración & dosificación , Pirrolidinas/administración & dosificación , Timina/administración & dosificación , Trifluridina/administración & dosificación , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/mortalidad , Combinación de Medicamentos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Compuestos de Fenilurea/uso terapéutico , Piridinas/uso terapéutico , Pirrolidinas/uso terapéutico , Estudios Retrospectivos , Terapia Recuperativa , Análisis de Supervivencia , Timina/uso terapéutico , Resultado del Tratamiento , Trifluridina/uso terapéuticoRESUMEN
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.
Lay abstract To remove misperception of trifluridine/tipiracil (FTD/TPI) in the treatment of metastatic colorectal cancer. An established Method for evaluating appropriateness of new drugs was used. 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. Several topics were dealt with, covering the profile of eligible patients, therapeutic options beyond the second line, efficacy and toxicity, as well as compliance. FTD/TPI is an important therapeutic resource in refractory metastatic colorectal cancer that combines manageability and safety.
Asunto(s)
Neoplasias Colorrectales/tratamiento farmacológico , Oncología Médica/normas , Guías de Práctica Clínica como Asunto , Pautas de la Práctica en Medicina/normas , Pirrolidinas/administración & dosificación , Timina/administración & dosificación , Trifluridina/administración & dosificación , Factores de Edad , Anciano , Anciano de 80 o más Años , Ensayos Clínicos como Asunto , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Consenso , Combinación de Medicamentos , Resistencia a Antineoplásicos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Supervivencia sin Progresión , Pirrolidinas/efectos adversos , Timina/efectos adversos , Trifluridina/efectos adversosRESUMEN
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.
Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Pirrolidinas/uso terapéutico , Neoplasias Gástricas/tratamiento farmacológico , Timina/uso terapéutico , Trifluridina/uso terapéutico , Adenocarcinoma/tratamiento farmacológico , Administración Intravenosa , Anciano , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Estudios de Casos y Controles , Combinación de Medicamentos , Neoplasias Esofágicas/tratamiento farmacológico , Femenino , Humanos , Japón/epidemiología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Supervivencia sin Progresión , Pirrolidinas/administración & dosificación , Pirrolidinas/efectos adversos , Seguridad , Timina/administración & dosificación , Timina/efectos adversos , Trifluridina/administración & dosificación , Trifluridina/efectos adversos , RamucirumabRESUMEN
BACKGROUND: A previous Phase I/II study demonstrated that TAS-102 (trifluridine/tipiracil [FTD/TPI]) plus bevacizumab (Bev) has encouraging efficacy and controllable safety for patients with previously treated metastatic colorectal cancer. Therefore, we designed for assessing the efficacy and safety of FTD/TPI plus Bev in elderly patients with previously untreated metastatic colorectal cancer. METHODS: This is a multicenter, single-arm Phase II study included patients ≥70 years old with previously untreated, unresectable metastatic colorectal cancer. Treatment consisted of FTD/TPI plus Bev given every 4 weeks. The primary endpoint was progression-free survival (PFS), assuming a null hypothesis of a PFS of 5 months. The secondary endpoints were the overall survival (OS), overall response rate (ORR), and adverse events (AEs). RESULTS: Between 5 January 2017 and 13 March 2018, 39 patients were enrolled from 18 institutions. The median patient age was 76.0 years (range, 70-88); the ECOG-PS was 0 in 24 patients and 1 in 15 patients. The median PFS was 9.4 months as a primary endpoint, and the median OS was 22.4 months. The ORR was 40.5% and the disease control rate was 86.5%. Grade 3-4 AEs included neutropenia (71.8%), leukopenia (51.3%), anorexia (15.4%), febrile neutropenia (10.3%), and fatigue (10.3%). CONCLUSIONS: FTD/TPI plus Bev is an effective and well-tolerated regimen for elderly patients with previously untreated metastatic colorectal cancer. Capecitabine/bevacizumab can be selected as a subsequent maintenance therapy without irinotecan and oxaliplatin because FTD/TPI has no cross-resistance with 5-fluorouracil. CLINICAL TRIAL REGISTRATION: UMIN clinical trials registry (UMIN000025241).
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Bevacizumab/administración & dosificación , Neoplasias Colorrectales/patología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Pronóstico , Pirrolidinas/administración & dosificación , Tasa de Supervivencia , Timina/administración & dosificación , Trifluridina/administración & dosificaciónRESUMEN
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.