Pooled safety analysis from phase III studies of trifluridine/tipiracil in patients with metastatic gastric or gastroesophageal junction cancer and metastatic colorectal cancer.

BACKGROUND: Trifluridine/tipiracil (FTD/TPI) showed clinical benefit, including improved survival and manageable safety in previously treated patients with metastatic colorectal (mCRC) or gastric/gastroesophageal junction (mGC/GEJC) cancer in the phase III RECOURSE and TAGS trials, respectively. A pooled analysis was conducted to further characterize FTD/TPI safety, including management of haematologic toxicities and use in patients with renal or hepatic impairment. PATIENTS AND METHODS: Adults with ≥2 prior regimens for advanced mGC/GEJC or mCRC were randomized (2 : 1) to FTD/TPI [35 mg/m2 twice daily days 1-5 and 8-12 (28-day cycle); same dosage in both trials] or placebo plus best supportive care. Adverse events (AEs) were summarized in the safety population (patients who received ≥1 dose) and analysed by renal/hepatic function. RESULTS: TAGS and RECOURSE included 335 and 533 FTD/TPI-treated and 168 and 265 placebo-treated patients, respectively. Overall safety of FTD/TPI was similar in TAGS and RECOURSE. Haematologic (neutropenia, anaemia) and gastrointestinal (nausea, diarrhoea) AEs were most commonly observed. Laboratory-assessed grade 3-4 neutropenia occurred in 37% (TAGS)/38% (RECOURSE) of FTD/TPI-treated patients (median onset: 29 days/55 days), and 96% (TAGS)/97% (RECOURSE) of cases resolved regardless of renal/hepatic function. Supportive medications for neutropenia were received by 17% (TAGS) and 9% (RECOURSE); febrile neutropenia was reported in 2% and 4%, respectively. Overall grade ≥3 AEs were more frequent in patients with moderate renal impairment [81% (TAGS); 85% (RECOURSE)] versus normal renal function (74%; 67%); anaemia and neutropenia were more common in patients with renal impairment. FTD/TPI safety (including haematologic AEs) was consistent across patients with normal and mildly impaired hepatic function. CONCLUSIONS: These results support FTD/TPI as a well-tolerated treatment in patients with mGC/GEJC or mCRC, with a consistent safety profile. Safety was largely similar in patients with normal or mildly impaired renal/hepatic function; however, patients with renal impairment should be monitored for haematologic toxicities.

Efficacy, safety and quality-of-life data from patients with pre-treated metastatic colorectal cancer receiving trifluridine/tipiracil: results of the TALLISUR trial.

INTRODUCTION: Trifluridine/tipiracil (FTD/TPI) improved both overall and progression-free survival (OS, PFS) of patients with pre-treated metastatic colorectal cancer (mCRC) in the pivotal phase III RECOURSE trial. However, health-related quality of life (HRQoL) was not assessed directly. To this end and to generate post-authorisation data, the TALLISUR trial was conducted. METHODS: In this prospective, multi-centre, Germany-wide, phase IV study, patients with pre-treated mCRC were given the choice to receive either FTD/TPI or best supportive care (BSC). A validated questionnaire, EORTC QLQ-C30, was employed to assess HRQoL. Secondary endpoints included OS, PFS and safety. RESULTS: Of 194 eligible patients, 185 decided to receive FTD/TPI and 9 to receive BSC. The low number of patients in the BSC-arm did not allow statistically meaningful analyses. On the other hand, treatment with FTD/TPI was associated with maintained HRQoL. Median OS was 6.9 months [95% confidence interval (CI) 6.1-8.2 months] and median PFS was 2.5 months (95% CI 2.1-2.9 months). The most frequent treatment-emergent adverse events were neutropenia (27.6%) and anaemia (22.7%). Febrile neutropenia occurred in 1.1%. CONCLUSIONS: Treatment of patients suffering from pre-treated mCRC with FTD/TPI was associated not only with prolonged survival and delayed progression but also with maintained HRQoL.

A phase I, open-label study evaluating the safety and pharmacokinetics of trifluridine/tipiracil in patients with advanced solid tumors and varying degrees of renal impairment.

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.

Regorafenib-to-trifluridine/tipiracil Versus the Reverse Sequence for Refractory Metastatic Colorectal Cancer Patients: A Multicenter Retrospective Real-life Experience.

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.

Phase II study of trifluridine/tipiracil (TAS-102) therapy in elderly patients with colorectal cancer (T-CORE1401): geriatric assessment tools and plasma drug concentrations as possible predictive biomarkers.

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).

Prospective Multicenter Phase II Study of Biweekly TAS-102 and Bevacizumab for Metastatic Colorectal Cancer.

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.

Clinical Outcomes Following Trifluridine/Tipiracil Treatment for Patients With Metastatic Colorectal Cancer Ineligible for Regorafenib Treatment.

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.

Monitoring FTD in the peripheral blood mononuclear cells of elderly patients with metastatic colorectal cancer administered FTD plus bevacizumab as first-line treatment.

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.

A phase 2 trial of trifluridine/tipiracil plus nivolumab in patients with heavily pretreated microsatellite-stable metastatic colorectal cancer.

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.

Safety and activity of trifluridine/tipiracil and ramucirumab in previously treated advanced gastric cancer: an open-label, single-arm, phase 2 trial.

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.

Appropriateness of trifluridine/tipiracil in the clinical practice of third-line therapy in metastatic colorectal cancer.

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.

A phase 1b expansion study of TAS-102 with oxaliplatin for refractory metastatic colorectal cancer.

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.

Effectiveness and Safety of Regorafenib vs. Trifluridine/Tipiracil in Unresectable Colorectal Cancer: A Retrospective Cohort Study.

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.

IgA Nephropathy Associated with Trifluridine/Tipiracil: A Case Report.

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.

Phase 1 dose escalation trial of TAS-102 (trifluridine/tipiracil) and temozolomide in the treatment of advanced neuroendocrine tumors.

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.

Phase I dose-escalation of trifluridine/tipiracil in combination with oxaliplatin in patients with metastatic colorectal cancer.

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.

Safety profile of trifluridine/tipiracil monotherapy in clinical practice: results of the German compassionate-use program for patients with metastatic colorectal cancer.

BACKGROUND: Trifluridine/tipiracil (TAS-102, Lonsurf®), a novel oral anti-tumor agent combining an anti-neoplastic thymidine-based nucleoside analogue (trifluridine, FTD) with a thymidine phosphorylase inhibitor (tipiracil hydrochloride, TPI) presents a new treatment option for metastatic colorectal cancer (mCRC) patients refractory or intolerant to standard therapies. FTD/TPI was approved in the European Union (EU) in April 2016 and launched on the German market in August 15, 2016. METHODS: We investigated the characteristics of patients (pts) with mCRC treated with FTD/TPI at 118 centers in Germany from January 12 to August 14, 2016 and analyzed the safety in a clinical real-world setting. RESULTS: In Germany, a total of 226 mCRC patients were included into a compassionate-use-program (CUP) and received FTD/TPI. For 45.5% of patients (n = 101), 253 adverse events (AE) were documented, most of them drug-related (n = 135). From January 12 (2016) to March 2 (2017), 124 serious adverse events (SAE) were reported (74 drug related). The most common serious adverse drug reactions (SADR) were leukopenia (12 events), neutropenia (8 events), anemia (7 events), diarrhea and nausea (5 events each) (observation period January 12 2016 to October 7 2016). In total, 122 patients (54%) discontinued FTD/TPI treatment, mostly due to progression (n = 75) followed by AEs (n = 21), deaths (n = 16), and non-specified reasons (n = 16). Interestingly, 12 patients with ECOG PS ≥2 achieved up to 3 cycles of FTD/TPI and in this patient population only 3 treatment discontinuations due to AEs were documented and the safety profile was comparable to the entire population. CONCLUSION: The patient characteristics as well as the safety profile of FTD/TPI documented in the German CUP were consistent with those reported in the pivotal trial RECOURSE without unexpected safety signals.

Leukocytoclastic vasculitis with late-onset Henoch-Schönlein purpura after trifluridine/tipiracil treatment.

Trifluridine/tipiracil has been approved for the treatment of refractory metastatic colorectal cancer. Adverse effects of this drug combination include leukopenia, neutropenia, fatigue, diarrhea, and vomiting. We present a case of trifluridine/tipiracil-induced leukocytoclastic vasculitis (LCV) with late-onset Henoch-Schönlein purpura (HSP) in a 42-year-old man with metastatic appendiceal cancer. The patient's biopsy-proven LCV developed one month after he began trifluridine/tipiracil treatment and resolved after discontinuation of the drug. He presented to the emergency department two months after the appearance of his LCV with shortness of breath, elevated blood pressure, elevated creatinine, hematuria, and proteinuria. A kidney biopsy was performed and the presence of IgA deposits and cellular crescents indicated rapidly progressive glomerulonephritis secondary to Henoch-Schönlein purpura (HSP). Neither LCV nor HSP have been reported as adverse effects of trifluridine/tipiracil treatment. Malignancy as a cause of our patient's HSP is another possibility. The delay between our patient's skin findings and acute renal failure indicates that suspected HSP should be monitored by urinalysis for a period of time owing to the risk of life-threatening renal disease.

A phase 1 study of the pharmacokinetics of nucleoside analog trifluridine and thymidine phosphorylase inhibitor tipiracil (components of TAS-102) vs trifluridine alone.

Background Trifluridine, a thymidine-based chemotherapeutic, has limited bioavailability after clinical administration as it is rapidly degraded via thymidine phosphorylase. An oral combination tablet combines trifluridine with a potent thymidine phosphorylase inhibitor, tipiracil hydrochloride. This study's objective was to evaluate whether trifluridine/tipiracil (TAS-102) administration increases trifluridine exposure vs trifluridine alone. Methods This open-label pharmacokinetic study randomly assigned patients with advanced solid tumors into two groups. On the morning of day 1, one group received a single 35 mg/m2 dose of trifluridine/tipiracil and the other group received a single 35-mg/m2 dose of trifluridine. Both groups received trifluridine/tipiracil 35 mg/m2 on the evening of day 1, then twice daily on days 2-5 and 8-12 in a 28-day cycle. Results Twenty patients received an initial one-time dose of trifluridine alone and 19 other patients received an initial dose of trifluridine/tipiracil. Trifluridine area under the curve (AUC0-last) and maximum observed plasma concentrations (Cmax) were approximately 37- and 22-fold higher, respectively, with trifluridine/tipiracil vs trifluridine alone. Plasma concentrations of the major metabolite of trifluridine were lower following the administration of trifluridine/tipiracil vs trifluridine alone. Conclusion Tipiracil administered in combination with trifluridine significantly increased exposure to trifluridine compared with trifluridine alone.

Effect of food on the pharmacokinetics of TAS-102 and its efficacy and safety in patients with advanced solid tumors.

TAS-102, a novel oral antitumor agent, consists of trifluridine and tipiracil hydrochloride (molar ratio, 1:0.5). We investigated the effects of food on trifluridine and tipiracil hydrochloride. The efficacy and safety of TAS-102 were evaluated in patients with advanced solid tumors. We analyzed drug pharmacokinetics using a randomized, single-dose, two-treatment (fed versus fasting), two-period, two-sequence cross-over design, followed by repeated administration. Patients were given single doses of TAS-102 (35 mg/m(2) ) in the pharmacokinetic phase and received twice-daily doses of TAS-102 in 28-day cycles in the repeated administration phase for evaluating efficacy and safety. Food showed no effect on the area under the curve from 0 to 12 h or 0 h-infinity values of trifluridine following administration of TAS-102 under fasting and fed conditions, whereas those of tipiracil hydrochloride decreased by approximately 40%. Maximum concentrations of both drugs decreased by approximately 40%, indicating that food influenced the absorption and bioavailability of trifluridine and tipiracil hydrochloride, respectively. During the repeated administration, stable disease was observed in nine patients with rectal, small-cell lung, breast, thymic, duodenal, and prostate cancers. Major adverse events were neutropenia, leukopenia, anemia, and nausea. Postprandial administration was optimal for TAS-102 because trifluridine's area under the curve was not changed by food, indicating that its clinical efficacy would not be affected. Additionally, postprandial administration was reasonable because the maximum concentration of trifluridine decreased in neutrophils, which correlated with previous studies. These results suggest that TAS-102 would be an effective treatment for small-cell lung, thymic, and colorectal cancers. This trial is registered with the Japan Pharmaceutical Information Center (no. JapicCTI-111482).