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Takayuki Yoshino - One of the best experts on this subject based on the ideXlab platform.
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relationship between thymidine kinase 1 expression and Trifluridine tipiracil therapy in refractory metastatic colorectal cancer a pooled analysis of 2 randomized clinical trials
Clinical Colorectal Cancer, 2018Co-Authors: Takayuki Yoshino, Tomohiro Nishina, Kentaro Yamazaki, Hideo Baba, Eiji Shinozaki, Yoshito Komatsu, Akihito Tsuji, Yasushi Tsuji, Kensei Yamaguchi, Naotoshi SugimotoAbstract:Abstract Background High thymidine kinase 1 (TK1) activity increases the incorporation of Trifluridine (FTD) into DNA; thus, FTD antitumor activity is likely to increase in patients with high tumoral TK1 activity. To date, no established predictive biomarker to indicate the clinical benefit of FTD/tipiracil (TPI) has been identified. We aimed to determine the relationship between TK1 expression and FTD/TPI efficacy in refractory metastatic colorectal cancer. Patients and Methods Individual patient data from 2 randomized placebo-controlled trials were analyzed. We measured TK1 protein expression in tumor tissue samples and its relationship with FTD/TPI clinical efficacy using overall survival (OS), progression-free survival, and disease control rate. Results This study comprised 329 patients (FTD/TPI, 224; placebo, 105). FTD/TPI significantly improved OS versus placebo in the high-expression (cutoff ≥ 15%) TK1 group (median OS, 7.8 vs. 6.8 months; hazard ratio = 0.65; 95% confidence interval, 0.46-0.93; P = .018). The low-expression (cutoff Conclusion Patients with high TK1 expression showed an improvement in OS when treated with FTD/TPI. Further investigations are warranted to confirm this relationship.
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rationale and design of the trusty study a randomised multicentre open label phase ii iii study of Trifluridine tipiracil plus bevacizumab versus irinotecan fluoropyrimidine plus bevacizumab as second line treatment in patients with metastatic colore
ESMO open, 2018Co-Authors: Takayuki Yoshino, Eiji Oki, Hiroya Taniguchi, Hiroaki Nozawa, Takako Eguchinakajima, Satoshi Morita, Naruhito Takenaka, Daisuke Ozawa, Kuniaki ShiraoAbstract:Background Trifluridine/tipiracil is an oral agent approved for the treatment of patients with metastatic colorectal cancer (mCRC). Trifluridine is an antineoplastic thymidine analogue, and tipiracil improves its bioavailability. A phase I/II C-TASK FORCE study of Trifluridine/tipiracil plus bevacizumab for patients with refractory mCRC demonstrated promising efficacy results with mild toxicity profile. It is important that quality of life be preserved in patients with mCRC without compromising their prognosis. Here, we outline the Trifluridine/tipiracil in Second-line sTudY phase II/III study (JapicCTI-173618), designed to demonstrate non-inferiority in overall survival of Trifluridine/tipiracil plus bevacizumab compared with irinotecan, fluoropyrimidine and bevacizumab combination regimens as second-line treatment in patients with mCRC. Patients and methods Eligible patients have confirmed unresectable advanced or recurrent colorectal adenocarcinoma and have failed to respond to first-line oxaliplatin-based chemotherapy. A total of 524 patients are to be randomly assigned (1:1 ratio) to Trifluridine/tipiracil plus bevacizumab or irinotecan, fluoropyrimidine and bevacizumab and stratified according to RAS status (wild type vs mutant). The primary endpoint of the phase II part is disease control rate with Trifluridine/tipiracil plus bevacizumab therapy. Secondary endpoints are response rate and safety with Trifluridine/tipiracil plus bevacizumab therapy. In the phase III part, the primary endpoint is overall survival, and secondary endpoints include quality of life, progression-free survival, response rate, disease control rate, safety, time to treatment failure, time to post-study treatment failure and the proportion of patients receiving post-study treatment. The first patient was enrolled in October 2017 and the study is anticipated to be completed in 2022. Clinical trial registration JapicCTI-173618 (JapicCTI).
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trusty a randomized multicenter phase ii iii study of Trifluridine tipiracil and bevacizumab versus irinotecan fluoropyrimidine and bevacizumab as second line treatment in patients with metastatic colorectal cancer progressive during or following fir
Journal of Clinical Oncology, 2018Co-Authors: Takayuki Yoshino, Eiji Oki, Hiroya Taniguchi, Hiroaki Nozawa, Satoshi Morita, Naruhito Takenaka, Daisuke Ozawa, Takako Eguchi Nakajima, Kuniaki ShiraoAbstract:TPS881Background: Trifluridine/tipiracil is an oral combination preparation approved for the treatment of patients with metastatic colorectal cancer (mCRC). Trifluridine is a thymidine analog, and ...
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integrated safety summary for Trifluridine tipiracil tas 102
Anti-Cancer Drugs, 2018Co-Authors: Alfredo Falcone, Atsushi Ohtsu, Eric Van Cutsem, Robert J Mayer, Michele Buscaglia, Johanna C Bendell, Scott Kopetz, Paul Bebeau, Takayuki YoshinoAbstract:Trifluridine/tipiracil, an oral treatment combining Trifluridine (an antineoplastic thymidine-based nucleoside analog) and tipiracil hydrochloride (a thymidine phosphorylase inhibitor), led to significant improvement in overall survival in metastatic colorectal cancer (mCRC) patients refractory to standard therapy in the phase III RECOURSE trial. Here, we report an integrated summary of the safety of Trifluridine/tipiracil. The main safety analysis includes integrated data from the RECOURSE and J003 studies (safety data group 2) of patients with refractory mCRC receiving Trifluridine/tipiracil at the recommended starting dose: 35 mg/m twice daily for 5 days with 2 days' rest for 2 weeks, followed by a 14-day rest (one cycle). Integrated data from a larger group of mCRC patients receiving Trifluridine/tipiracil at the recommended starting dose (group 1) and nonintegrated data on serious adverse events (SAEs) representing all clinical experience with Trifluridine/tipiracil as of the data cutoff date (group 3) are also summarized. In group 2, myelosuppressive and all-grade gastrointestinal adverse events (AEs) were more frequent in Trifluridine/tipiracil patients than in placebo patients. The Trifluridine/tipiracil and placebo patients had similar frequencies of AEs leading to discontinuation (9.0 vs. 11.5%) and SAEs (27.7 vs. 29.2%); fatal AEs were more frequent in placebo patients than in Trifluridine/tipiracil patients (9.3 vs. 2.8%). AEs leading to interruptions/delays/reductions were more frequent in Trifluridine/tipiracil patients (56.3 vs. 12.7%). Trifluridine/tipiracil was generally well tolerated, but over 50% of patients required interruptions/delays/reductions. There was a low rate of discontinuations, SAEs, and fatal AEs. This analysis confirms the safety profile observed in RECOURSE.
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effect of thymidine kinase 1 expression on prognosis and treatment outcomes in refractory metastatic colorectal cancer results from two randomized studies of tas 102 versus a placebo
Journal of Clinical Oncology, 2017Co-Authors: Takayuki Yoshino, Tomohiro Nishina, Kentaro Yamazaki, Hideo Baba, Eiji Shinozaki, Yoshito Komatsu, Akihito Tsuji, Yasushi Tsuji, Kensei Yamaguchi, Naotoshi SugimotoAbstract:529Background: TAS-102 is an oral nucleoside antitumor agent, comprising Trifluridine (FTD) and tipiracil. FTD is incorporated into DNA after phosphorylation by thymidine kinase 1 (TK1). This study aimed to investigate the association between TK1 expression and TAS-102 efficacy in refractory metastatic colorectal cancer (mCRC) patients (pts). Methods: Data from two randomized phase 2 and phase 3 studies of mCRC pts refractory to standard therapies were analyzed for treatment outcomes in relation to TK1 expression. Expression was measured using immunohistochemistry, and staining was classified according to intensity and scored 0, 1+, 2+, or 3+. Occupancy rates of the areas scored 2+ and 3+ in tumor cells were calculated in 5% intervals, and divided into two groups (high or low TK1) at each cut-off point. Results: TK1 expression was evaluated in 329 pts. Baseline characteristics and treatment outcomes were comparable between the TK1-refined and intention-to-treat populations. Pts with high TK1 expression wh...
Eric Van Cutsem - One of the best experts on this subject based on the ideXlab platform.
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Trifluridine tipiracil plus bevacizumab for third line management of metastatic colorectal cancer sunlight study design
Future Oncology, 2021Co-Authors: Josep Tabernero, Fortunato Ciardiello, Nadia Amellal, Ronan Fougeray, Julien Taieb, Gerald W Prager, Marwan Fakih, Catherine Leger, Eric Van CutsemAbstract: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.
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effect of Trifluridine tipiracil in patients treated in recourse by prognostic factors at baseline an exploratory analysis
ESMO Open, 2020Co-Authors: Josep Tabernero, Guillem Argiles, Atsushi Ohtsu, Robert J Mayer, Shanti Ricardo Moreno Vera, A Sobrero, Christophe Borg, Loick Vidot, Eric Van CutsemAbstract:Background The choice of treatment in patients with metastatic colorectal cancer (mCRC) is generally influenced by tumour and patient characteristics, treatment efficacy and tolerability, and quality of life. Better patient selection might lead to improved outcomes. Methods This post hoc exploratory analysis examined the effect of prognostic factors on outcomes in the Randomized, Double-blind, Phase 3 Study of Trifluridine tipiracil (FTD/TPI) plus Best Supportive Care (BSC) versus Placebo plus BSC in Patients with mCRC Refractory to Standard Chemotherapies (RECOURSE) trial. Patients were redivided by prognosis into two subgroups: those with Results GPC patients (n=386) had improved outcome versus PPC patients (n=414) in both the Trifluridine/tipiracil and placebo arms. GPC patients receiving Trifluridine/tipiracil (n=261) had an improved median overall survival (9.3 vs 5.3 months; HR (95% CI) 0.46 (0.37 to 0.57), p Conclusion Low tumour burden and indolent disease were factors of good prognosis in late-line mCRC, with patients experiencing longer progression-free survival and greater overall survival.
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quality of life at baseline in the international open label early access program of Trifluridine tipiracil in previously treated metastatic colorectal cancer phase iiib
Journal of Clinical Oncology, 2018Co-Authors: Alfredo Falcone, Timothy J. Price, Lucjan Wyrwicz, Martin Becquart, Julien Taieb, Jean Francois Seitz, Shanti Moreno, Nadjat Mounedji, Eric Van CutsemAbstract:803Background: Pivotal phase 3 RECOURSE trial evaluated efficacy and safety of Trifluridine/tipiracil (FTD/TPI, also known TAS-102) in metastatic colorectal cancer (mCRC) without collecting quality...
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baseline characteristics in the international open label early access program of Trifluridine tipiracil in previously treated metastatic colorectal cancer phase iiib
Journal of Clinical Oncology, 2018Co-Authors: Timothy J. Price, Alfredo Falcone, Lucjan Wyrwicz, Martin Becquart, Julien Taieb, Jean Francois Seitz, Shanti Moreno, Nadjat Mounedji, Eric Van CutsemAbstract:761Background: In the phase 3 RECOURSE trial, Trifluridine/tipiracil (FTD/TPI, also known as TAS-102) significantly improved overall and progression-free survival versus placebo in patients (pts) w...
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the subgroups of the phase iii recourse trial of Trifluridine tipiracil tas 102 versus placebo with best supportive care in patients with metastatic colorectal cancer
European Journal of Cancer, 2018Co-Authors: Eric Van Cutsem, Manuel Benavides, Robert J Mayer, Stephanie Laurent, Robert Winkler, Cristina Gravalos, Federico Longomunoz, Fabienne Portales, Fortunato Ciardiello, Salvatore SienaAbstract:Abstract Background In the phase III RECOURSE trial, Trifluridine/tipiracil (TAS-102) extended overall survival (OS) and progression-free survival (PFS) with an acceptable toxicity profile in patients with metastatic colorectal cancer refractory or intolerant to standard therapies. The present analysis investigated the efficacy and safety of Trifluridine/tipiracil in RECOURSE subgroups. Methods Primary and key secondary end-points were evaluated using a Cox proportional hazards model in prespecified subgroups, including geographical subregion (United States of America [USA], European Union [EU], Japan), age ( KRAS ) status (wild type, mutant). Safety and tolerability were reported with descriptive statistics. Results Eight-hundred patients were enrolled: USA, n = 99; EU, n = 403; Japan, n = 266. Patients aged ≥65 years and those with mutant KRAS tumours comprised 44% and 51% of all patients in the subregions, respectively. Final OS analysis (including 89% of events, compared with 72% in the initial analysis) confirmed the survival benefit associated with Trifluridine/tipiracil, with a hazard ratio (HR) of 0.69 (95% confidence interval [CI] 0.59–0.81; P = 0.0001). Median OS in the three regions was 6.5–7.8 months in the Trifluridine/tipiracil arm and 4.3–6.7 months in the placebo arm (USA: HR 0.56; 95% CI 0.34–0.94; P = 0.0277; EU: HR 0.62; 95% CI 0.48–0.80; P = 0.0002; Japan: HR 0.75; 95% CI 0.57–1.00; P = 0.0470). Median PFS was 2.0–2.8 months for Trifluridine/tipiracil and 1.7–1.8 months for placebo; HRs favoured Trifluridine/tipiracil in all regions. Similar clinical benefits of Trifluridine/tipiracil were observed in elderly patients and in those with mutant KRAS tumours. There were no marked differences among subregions in terms of safety and tolerability. Conclusions Trifluridine/tipiracil was effective in all subgroups, regardless of age, geographical origin or KRAS status. This trial is registered with ClinicalTrials.gov: NCT01607957 .
Eiji Oki - One of the best experts on this subject based on the ideXlab platform.
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dna replication stress induced by Trifluridine determines tumor cell fate according to p53 status
Molecular Cancer Research, 2020Co-Authors: Yuki Kataoka, Makoto Iimori, Shinichiro Niimi, Takeshi Wakasa, Hiroshi Saeki, Eiji Oki, Tomomi Morikawaichinose, Ryo Fujisawa, Daisuke MiuraAbstract:DNA replication stress (DRS) is a predominant cause of genome instability, a driver of tumorigenesis and malignant progression. Nucleoside analogue-type chemotherapeutic drugs introduce DNA damage and exacerbate DRS in tumor cells. However, the mechanisms underlying the antitumor effect of these drugs are not fully understood. Here, we show that the fluorinated thymidine analogue Trifluridine (FTD), an active component of the chemotherapeutic drug Trifluridine/tipiracil, delayed DNA synthesis by human replicative DNA polymerases by acting both as an inefficient deoxyribonucleotide triphosphate source (FTD triphosphate) and as an obstacle base (trifluorothymine) in the template DNA strand, which caused DRS. In cells, FTD decreased the thymidine triphosphate level in the dNTP pool and increased the FTD triphosphate level, resulting in the activation of DRS-induced cellular responses during S-phase. In addition, replication protein A-coated single-stranded DNA associated with FancD2 and accumulated after tumor cells completed S-phase. Finally, FTD activated the p53-p21 pathway and suppressed tumor cell growth by inducing cellular senescence via mitosis skipping. In contrast, tumor cells that lost wild-type p53 underwent apoptotic cell death via aberrant late mitosis with severely impaired separation of sister chromatids. These results demonstrate that DRS induced by a nucleoside analogue-type chemotherapeutic drug suppresses tumor growth irrespective of p53 status by directing tumor cell fate toward cellular senescence or apoptotic cell death according to p53 status. IMPLICATIONS: Chemotherapeutic drugs that increase DRS during S-phase but allow tumor cells to complete S-phase may have significant antitumor activity even when functional p53 is lost.
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detection of Trifluridine in tumors of patients with metastatic colorectal cancer treated with Trifluridine tipiracil
Cancer Chemotherapy and Pharmacology, 2020Co-Authors: Yoshiaki Fujimoto, Takeshi Wakasa, Eiji Oki, Yoshihiko Maehara, Hiroyuki Kitao, Kazuaki Matsuoka, Ryota Nakanishi, Mamoru Nukatsuka, Koji Ando, Masaki MoriAbstract:Trifluridine (FTD) is the active component of the nucleoside chemotherapeutic drug Trifluridine/tipiracil (FTD/TPI), which is approved worldwide for the treatment of patients with metastatic gastrointestinal cancer. FTD exerts cytotoxic effects via its incorporation into DNA, but FTD has not been detected in the tumor specimens of patients. The purpose of this study was to detect FTD in tumors resected from metastatic colorectal cancer (mCRC) patients who were administered FTD/TPI. Another purpose was to investigate the turnover rate of FTD in tumors and bone marrow in a mouse model. Tumors and normal tissue specimens were obtained from mCRC patients who were administered FTD/TPI or placebo at Kyushu University Hospital. Tumors and bone marrow were resected from mice with peritoneal dissemination treated with FTD/TPI. To detect and quantitate FTD incorporated into DNA, immunohistochemical staining of paraffin-embedded specimens (IHC-p staining) and slot-blot analysis of DNA purified from these tissues were performed using an anti-BrdU antibody. IHC-p staining of proliferation and apoptosis markers was also performed. FTD was detected in metastatic tumors obtained from mCRC patients who were administered FTD/TPI, but who had discontinued the treatment several weeks before surgery. In a peritoneal dissemination mouse model, FTD was still detected in tumors 13 days after the cessation of FTD/TPI treatment, but had disappeared from bone marrow within 6 days. These results indicate that FTD persists longer in tumors than in bone marrow, which may cause a sustained antitumor effect with tolerable hematotoxicity.
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Cytotoxicity of Trifluridine correlates with the thymidine kinase 1 expression level.
Scientific reports, 2019Co-Authors: Yuki Kataoka, Makoto Iimori, Shinichiro Niimi, Hiroshi Tsukihara, Takeshi Wakasa, Hiroshi Saeki, Eiji Oki, Yoshihiko Maehara, Hiroyuki KitaoAbstract:Trifluridine (FTD), a tri-fluorinated thymidine analogue, is a key component of the oral antitumor drug FTD/TPI (also known as TAS-102), which is used to treat refractory metastatic colorectal cancer. Thymidine kinase 1 (TK1) is thought to be important for the incorporation of FTD into DNA, resulting in DNA dysfunction and cytotoxicity. However, it remains unknown whether TK1 is essential for FTD incorporation into DNA and whether this event is affected by the expression level of TK1 because TK1-specific-deficient human cancer cell lines have not been established. Here, we generated TK1-knock-out human colorectal cancer cells using the CRISPR/Cas9 genome editing system and validated the specificity of TK1 knock-out by measuring expression of AFMID, which is encoded on the same locus as TK1. Using TK1-knock-out cells, we confirmed that TK1 is essential for cellular sensitivity to FTD. Furthermore, we demonstrated a correlation between the TK1 expression level and cytotoxicity of FTD using cells with inducible TK1 expression, which were generated from TK1-knock-out cells. Based on our finding that the TK1 expression level correlates with sensitivity to FTD, we suggest that FTD/TPI might efficiently treat cancers with high TK1 expression.
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Trifluridine tipiracil plus bevacizumab in elderly patients with previously untreated metastatic colorectal cancer kscc1602 a multicenter phase ii clinical trial
Journal of Clinical Oncology, 2019Co-Authors: Eiji Oki, Akitaka Makiyama, Yuji Miyamoto, Masahito Kotaka, Hirofumi Kawanaka, Keisuke Miwa, Akira Kabashima, Masahiro Hamanoue, Takafumi Ohchi, Tomomi KashiwadaAbstract:3548Background: Elderly patients are often intolerable in combination of cytotoxic agents. Recently, Trifluridine/tipiracil plus bevacizumab has been shown as good candidate for the vulnerable pati...
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rationale and design of the trusty study a randomised multicentre open label phase ii iii study of Trifluridine tipiracil plus bevacizumab versus irinotecan fluoropyrimidine plus bevacizumab as second line treatment in patients with metastatic colore
ESMO open, 2018Co-Authors: Takayuki Yoshino, Eiji Oki, Hiroya Taniguchi, Hiroaki Nozawa, Takako Eguchinakajima, Satoshi Morita, Naruhito Takenaka, Daisuke Ozawa, Kuniaki ShiraoAbstract:Background Trifluridine/tipiracil is an oral agent approved for the treatment of patients with metastatic colorectal cancer (mCRC). Trifluridine is an antineoplastic thymidine analogue, and tipiracil improves its bioavailability. A phase I/II C-TASK FORCE study of Trifluridine/tipiracil plus bevacizumab for patients with refractory mCRC demonstrated promising efficacy results with mild toxicity profile. It is important that quality of life be preserved in patients with mCRC without compromising their prognosis. Here, we outline the Trifluridine/tipiracil in Second-line sTudY phase II/III study (JapicCTI-173618), designed to demonstrate non-inferiority in overall survival of Trifluridine/tipiracil plus bevacizumab compared with irinotecan, fluoropyrimidine and bevacizumab combination regimens as second-line treatment in patients with mCRC. Patients and methods Eligible patients have confirmed unresectable advanced or recurrent colorectal adenocarcinoma and have failed to respond to first-line oxaliplatin-based chemotherapy. A total of 524 patients are to be randomly assigned (1:1 ratio) to Trifluridine/tipiracil plus bevacizumab or irinotecan, fluoropyrimidine and bevacizumab and stratified according to RAS status (wild type vs mutant). The primary endpoint of the phase II part is disease control rate with Trifluridine/tipiracil plus bevacizumab therapy. Secondary endpoints are response rate and safety with Trifluridine/tipiracil plus bevacizumab therapy. In the phase III part, the primary endpoint is overall survival, and secondary endpoints include quality of life, progression-free survival, response rate, disease control rate, safety, time to treatment failure, time to post-study treatment failure and the proportion of patients receiving post-study treatment. The first patient was enrolled in October 2017 and the study is anticipated to be completed in 2022. Clinical trial registration JapicCTI-173618 (JapicCTI).
Robert J Mayer - One of the best experts on this subject based on the ideXlab platform.
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effect of Trifluridine tipiracil in patients treated in recourse by prognostic factors at baseline an exploratory analysis
ESMO Open, 2020Co-Authors: Josep Tabernero, Guillem Argiles, Atsushi Ohtsu, Robert J Mayer, Shanti Ricardo Moreno Vera, A Sobrero, Christophe Borg, Loick Vidot, Eric Van CutsemAbstract:Background The choice of treatment in patients with metastatic colorectal cancer (mCRC) is generally influenced by tumour and patient characteristics, treatment efficacy and tolerability, and quality of life. Better patient selection might lead to improved outcomes. Methods This post hoc exploratory analysis examined the effect of prognostic factors on outcomes in the Randomized, Double-blind, Phase 3 Study of Trifluridine tipiracil (FTD/TPI) plus Best Supportive Care (BSC) versus Placebo plus BSC in Patients with mCRC Refractory to Standard Chemotherapies (RECOURSE) trial. Patients were redivided by prognosis into two subgroups: those with Results GPC patients (n=386) had improved outcome versus PPC patients (n=414) in both the Trifluridine/tipiracil and placebo arms. GPC patients receiving Trifluridine/tipiracil (n=261) had an improved median overall survival (9.3 vs 5.3 months; HR (95% CI) 0.46 (0.37 to 0.57), p Conclusion Low tumour burden and indolent disease were factors of good prognosis in late-line mCRC, with patients experiencing longer progression-free survival and greater overall survival.
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safety of Trifluridine tipiracil ftd tpi in elderly patients with metastatic colorectal cancer
Journal of Clinical Oncology, 2018Co-Authors: Robert J Mayer, Howard S Hochster, Robert Winkler, Steven J Cohen, Lukas Makris, Axel GrotheyAbstract:752Background: Elderly patients (≥65 yrs) with metastatic colorectal cancer (mCRC) are more likely to have comorbid conditions than younger patients ( < 65 yrs), limiting their therapeutic options....
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the subgroups of the phase iii recourse trial of Trifluridine tipiracil tas 102 versus placebo with best supportive care in patients with metastatic colorectal cancer
European Journal of Cancer, 2018Co-Authors: Eric Van Cutsem, Manuel Benavides, Robert J Mayer, Stephanie Laurent, Robert Winkler, Cristina Gravalos, Federico Longomunoz, Fabienne Portales, Fortunato Ciardiello, Salvatore SienaAbstract:Abstract Background In the phase III RECOURSE trial, Trifluridine/tipiracil (TAS-102) extended overall survival (OS) and progression-free survival (PFS) with an acceptable toxicity profile in patients with metastatic colorectal cancer refractory or intolerant to standard therapies. The present analysis investigated the efficacy and safety of Trifluridine/tipiracil in RECOURSE subgroups. Methods Primary and key secondary end-points were evaluated using a Cox proportional hazards model in prespecified subgroups, including geographical subregion (United States of America [USA], European Union [EU], Japan), age ( KRAS ) status (wild type, mutant). Safety and tolerability were reported with descriptive statistics. Results Eight-hundred patients were enrolled: USA, n = 99; EU, n = 403; Japan, n = 266. Patients aged ≥65 years and those with mutant KRAS tumours comprised 44% and 51% of all patients in the subregions, respectively. Final OS analysis (including 89% of events, compared with 72% in the initial analysis) confirmed the survival benefit associated with Trifluridine/tipiracil, with a hazard ratio (HR) of 0.69 (95% confidence interval [CI] 0.59–0.81; P = 0.0001). Median OS in the three regions was 6.5–7.8 months in the Trifluridine/tipiracil arm and 4.3–6.7 months in the placebo arm (USA: HR 0.56; 95% CI 0.34–0.94; P = 0.0277; EU: HR 0.62; 95% CI 0.48–0.80; P = 0.0002; Japan: HR 0.75; 95% CI 0.57–1.00; P = 0.0470). Median PFS was 2.0–2.8 months for Trifluridine/tipiracil and 1.7–1.8 months for placebo; HRs favoured Trifluridine/tipiracil in all regions. Similar clinical benefits of Trifluridine/tipiracil were observed in elderly patients and in those with mutant KRAS tumours. There were no marked differences among subregions in terms of safety and tolerability. Conclusions Trifluridine/tipiracil was effective in all subgroups, regardless of age, geographical origin or KRAS status. This trial is registered with ClinicalTrials.gov: NCT01607957 .
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integrated safety summary for Trifluridine tipiracil tas 102
Anti-Cancer Drugs, 2018Co-Authors: Alfredo Falcone, Atsushi Ohtsu, Eric Van Cutsem, Robert J Mayer, Michele Buscaglia, Johanna C Bendell, Scott Kopetz, Paul Bebeau, Takayuki YoshinoAbstract:Trifluridine/tipiracil, an oral treatment combining Trifluridine (an antineoplastic thymidine-based nucleoside analog) and tipiracil hydrochloride (a thymidine phosphorylase inhibitor), led to significant improvement in overall survival in metastatic colorectal cancer (mCRC) patients refractory to standard therapy in the phase III RECOURSE trial. Here, we report an integrated summary of the safety of Trifluridine/tipiracil. The main safety analysis includes integrated data from the RECOURSE and J003 studies (safety data group 2) of patients with refractory mCRC receiving Trifluridine/tipiracil at the recommended starting dose: 35 mg/m twice daily for 5 days with 2 days' rest for 2 weeks, followed by a 14-day rest (one cycle). Integrated data from a larger group of mCRC patients receiving Trifluridine/tipiracil at the recommended starting dose (group 1) and nonintegrated data on serious adverse events (SAEs) representing all clinical experience with Trifluridine/tipiracil as of the data cutoff date (group 3) are also summarized. In group 2, myelosuppressive and all-grade gastrointestinal adverse events (AEs) were more frequent in Trifluridine/tipiracil patients than in placebo patients. The Trifluridine/tipiracil and placebo patients had similar frequencies of AEs leading to discontinuation (9.0 vs. 11.5%) and SAEs (27.7 vs. 29.2%); fatal AEs were more frequent in placebo patients than in Trifluridine/tipiracil patients (9.3 vs. 2.8%). AEs leading to interruptions/delays/reductions were more frequent in Trifluridine/tipiracil patients (56.3 vs. 12.7%). Trifluridine/tipiracil was generally well tolerated, but over 50% of patients required interruptions/delays/reductions. There was a low rate of discontinuations, SAEs, and fatal AEs. This analysis confirms the safety profile observed in RECOURSE.
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qtwist analysis of the recourse trial of Trifluridine tipiracil in metastatic colorectal cancer
ESMO Open, 2017Co-Authors: Josep Tabernero, Atsushi Ohtsu, Eric Van Cutsem, Nadia Amellal, Stephanie Cadour, Ronan Fougeray, Benjamin Haffemayer, Robert J MayerAbstract:Purpose A Quality-adjusted Time WIthout Symptoms of disease or Toxicity (QTWiST) analysis was carried out to assess quality-adjusted survival time in the RECOURSE trial of Trifluridine/tipiracil versus placebo in pretreated metastatic colorectal cancer (mCRC). Methods Duration of overall survival in the RECOURSE trial (n=798 patients) was partitioned into three discrete health states: toxicity (TOX), time without symptoms or toxicity (TWIST) and relapse (REL). TOX was defined as time spent with grade 3 or 4 treatment-related adverse events (AEs) after randomisation and before progression or censoring. AEs were limited to those related to Trifluridine/tipiracil and known to affect quality of life (QoL) (ie, nausea, vomiting, diarrhoea, fatigue/asthaenia, anorexia and febrile neutropaenia). The estimated mean duration of each state, weighted by a utility coefficient representing QoL, was combined into a global QTWiST score. Results In the RECOURSE trial, overall survival was 7.1 months with Trifluridine/tipiracil versus 5.3 months with placebo. Patients receiving Trifluridine/tipiracil spent longer in each health state than placebo recipients. Using assumed utility coefficients of 1 for TWIST and 0.5 for TOX and REL, the QTWiST was 5.48 months for the Trifluridine/tipiracil group and 3.98 months for the placebo group, a difference of 1.5 (95% CI 1.49 to 1.52) months in favour of Trifluridine/tipiracil. A sensitivity analysis using large variations in utility coefficients for TOX and REL produced a range of only approximately 0.5 months from minimum to maximum QTWiST. Conclusions Quality-adjusted survival, as measured by QTWiST, shows clinically meaningful improvements in patients treated with Trifluridine/tipiracil versus placebo in pretreated mCRC.
Josep Tabernero - One of the best experts on this subject based on the ideXlab platform.
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Trifluridine tipiracil plus bevacizumab for third line management of metastatic colorectal cancer sunlight study design
Future Oncology, 2021Co-Authors: Josep Tabernero, Fortunato Ciardiello, Nadia Amellal, Ronan Fougeray, Julien Taieb, Gerald W Prager, Marwan Fakih, Catherine Leger, Eric Van CutsemAbstract: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.
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effect of Trifluridine tipiracil in patients treated in recourse by prognostic factors at baseline an exploratory analysis
ESMO Open, 2020Co-Authors: Josep Tabernero, Guillem Argiles, Atsushi Ohtsu, Robert J Mayer, Shanti Ricardo Moreno Vera, A Sobrero, Christophe Borg, Loick Vidot, Eric Van CutsemAbstract:Background The choice of treatment in patients with metastatic colorectal cancer (mCRC) is generally influenced by tumour and patient characteristics, treatment efficacy and tolerability, and quality of life. Better patient selection might lead to improved outcomes. Methods This post hoc exploratory analysis examined the effect of prognostic factors on outcomes in the Randomized, Double-blind, Phase 3 Study of Trifluridine tipiracil (FTD/TPI) plus Best Supportive Care (BSC) versus Placebo plus BSC in Patients with mCRC Refractory to Standard Chemotherapies (RECOURSE) trial. Patients were redivided by prognosis into two subgroups: those with Results GPC patients (n=386) had improved outcome versus PPC patients (n=414) in both the Trifluridine/tipiracil and placebo arms. GPC patients receiving Trifluridine/tipiracil (n=261) had an improved median overall survival (9.3 vs 5.3 months; HR (95% CI) 0.46 (0.37 to 0.57), p Conclusion Low tumour burden and indolent disease were factors of good prognosis in late-line mCRC, with patients experiencing longer progression-free survival and greater overall survival.
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health related quality of life associated with Trifluridine tipiracil in heavily pretreated metastatic gastric cancer results from tags
Gastric Cancer, 2020Co-Authors: Josep Tabernero, Kohei Shitara, Toshihiko Doi, M Dvorkin, Wasat Mansoor, Hendriktobias Arkenau, Aliaksandr Prokharau, Maria Alsina, Michele Ghidini, C FaustinoAbstract:In TAGS, an international, double-blind, phase 3 trial, Trifluridine/tipiracil significantly improved overall survival and progression-free survival compared with placebo in heavily pretreated metastatic gastric cancer patients. This paper reports pre-specified quality of life (QoL) outcomes for TAGS. Patients were randomized 2:1 to Trifluridine/tipiracil (35 mg/m2 twice daily on days 1–5 and 8–12 of each 28-day cycle) plus best supportive care (BSC) or placebo plus BSC. QoL was evaluated at baseline and at each treatment cycle, using the EORTC QLQ-C30 and EORTC QLQ-STO22 questionnaires; results were considered valid for analysis only if ≥ 10% of patients completed the questionnaires. Key QoL outcomes were mean changes from baseline and time to deterioration in QoL. A post hoc analysis assessed the association between QoL and time to deterioration of Eastern Cooperative Oncology Group performance score (ECOG PS) to ≥ 2. Of 507 randomized patients, 496 had baseline QoL data available. The analysis cut-off was 6 cycles for Trifluridine/tipiracil and 3 cycles for placebo. In both treatment groups, there were no clinically significant deteriorations in the mean QLQ-C30 Global Health Status (GHS) score, or in most subscale scores. In a sensitivity analysis including death and disease progression as events, there was a trend towards Trifluridine/tipiracil reducing the risk of deterioration of QoL scores compared with placebo. Deterioration in the GHS score was associated with deterioration in ECOG PS. QoL was maintained in TAGS, and there was a trend towards Trifluridine/tipiracil reducing the risk of QoL deterioration compared with placebo. Trial registration ClinicalTrials.gov number: NCT02500043
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phase i dose escalation of Trifluridine tipiracil in combination with oxaliplatin in patients with metastatic colorectal cancer
European Journal of Cancer, 2019Co-Authors: Guillem Argiles, Nadia Amellal, Ronan Fougeray, Andres Cervantes, Catherine Leger, Thierry Andre, Antoine Hollebecque, Aitana Calvo, Laetitia Dahan, Josep TaberneroAbstract:Abstract Background and objectives Pre-clinical data have shown that combining Trifluridine/tipiracil with oxaliplatin enhances anti-tumour activity compared with either monotherapy. A phase I dose-escalation study was conducted to determine the maximum tolerated dose (MTD), recommended dose (RD) for phase II and pharmacokinetic profile of this combination in patients with metastatic colorectal cancer (mCRC) who had progressed after at least 1 prior line of treatment. Methods Using a 3 + 3 design, patients received escalating Trifluridine/tipiracil doses from 25, then 30 and to 35 mg/m2 twice daily, days 1–5, q14 days, together with a fixed dose of 85 mg/m2 of oxaliplatin day 1, q14 days. An intermediate cohort with a lower oxaliplatin dose (65 mg/m2) was also investigated. After MTD determination, additional patients were treated to define the RD. Results Twenty-four patients were enrolled. One dose-limiting toxicity of grade 3 febrile neutropenia was observed at the highest dose level, which was established as the MTD and subsequently the RD. The most common drug-related adverse events (AEs) were asthenia, nausea, diarrhoea, peripheral neuropathy, neutropenia, decreased appetite, thrombocytopenia, vomiting, anaemia and peripheral sensory neuropathy. Most drug-related AEs (93.0%) were of grade 1–2. Pharmacokinetic parameters of Trifluridine/tipiracil were not influenced by oxaliplatin co-administration. Best overall responses at the RD (n = 14) included 1 patient with partial response (7.1%) and 7 patients with stable disease (50.0%). Conclusion The combination of Trifluridine/tipiracil and oxaliplatin in patients with mCRC has a manageable safety profile with some efficacy. The RD is 35 mg/m2 of Trifluridine/tipiracil twice daily, days 1–5, q14 days and 85 mg/m2 of oxaliplatin day 1, q14 Clinicaltrials.gov number NCT02848443 .
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phase i multicenter open label study to establish the maximum tolerated dose mtd of Trifluridine tipiracil tas 102 and oxaliplatin combination in patients pts with metastatic colorectal cancer mcrc
Journal of Clinical Oncology, 2018Co-Authors: Antoine Hollebecque, Guillem Argiles, Nadia Amellal, Ronan Fougeray, Andres Cervantes, Catherine Leger, Thierry Andre, Aitana Calvo, Aude Valette, Josep TaberneroAbstract:816Background: Preclinical evidence suggests improved efficacy when combining Trifluridine/tipiracil with oxaliplatin compared to each monotherapy (Nukatsuka, 2015). The primary objective was to de...
