A Phase 1, Open-Label, Randomized, Crossover Study Evaluating the Bioavailability of TAS-102 (Trifluridine/Tipiracil) Tablets Relative to an Oral Solution Containing Equivalent Amounts of Trifluridine and Tipiracil.

TAS-102 (trifluridine/tipiracil) is composed of an antineoplastic thymidine-based nucleoside analogue trifluridine (FTD), and a thymidine phosphorylase inhibitor, tipiracil (TPI), at a molar ratio of 1:0.5 (weight ratio, 1:0.471). A phase 1 study evaluated relative bioavailability of TAS-102 tablets compared with an oral solution containing equivalent amounts of FTD and TPI. In an open-label, 2-sequence, 3-period, crossover bioavailability study (part 1), patients 18 years or older with advanced solid tumors were randomized to receive TAS-102 tablets (60 mg; 3 × 20-mg tablets) on day 1 and TAS-102 oral solution (60 mg) on days 8 and 15, or the opposite sequence. In an extension (part 2), all patients received TAS-102 tablets. Of the 46 patients treated in the crossover study, 38 were evaluable in the crossover bioavailability pharmacokinetic population. For area under the concentration-time curve (AUC)0-∞ and AUC0-last for FTD and TPI, and maximum plasma concentration (Cmax ) for TPI, the 90% confidence intervals (CIs) of the geometric mean ratios were within the 0.80 to 1.25 boundary for demonstration of bioequivalence; for FTD Cmax , the lower limit of the 90%CI was 0.786. The most frequently reported treatment-related grade 3 or 4 adverse events were neutropenia (7 patients) and decreased neutrophil count (3 patients). Although the lower limit of the 90%CI for the geometric mean ratio of FTD Cmax was slightly lower than 0.80, the bioavailability of the TAS-102 tablet is considered clinically similar to that of a TAS-102 oral solution. TAS-102 was well tolerated in this population of patients with advanced solid tumors.

Human mass balance study of TAS-102 using (14)C analyzed by accelerator mass spectrometry.

BACKGROUND: TAS-102 is an oral fluoropyrimidine prodrug composed of trifluridine (FTD) and tipiracil hydrochloride (TPI) in a 1:0.5 ratio. FTD is a thymidine analog, and it is degraded by thymidine phosphorylase (TP) to the inactive trifluoromethyluracil (FTY) metabolite. TPI inhibits degradation of FTD by TP, increasing systemic exposure to FTD. METHODS: Patients with advanced solid tumors (6 M/2 F; median age 58 years; PS 0-1) were enrolled on this study. Patients in group A (N = 4) received 60 mg TAS-102 with 200 nCi [(14)C]-FTD, while patients in group B (N = 4) received 60 mg TAS-102 with 1000 nCi [(14)C]-TPI orally. Plasma, blood, urine, feces, and expired air (group A only) were collected up to 168 h and were analyzed for (14)C by accelerator mass spectrometry and analytes by LC-MS/MS. RESULTS: FTD: 59.8% of the (14)C dose was recovered: 54.8% in urine mostly as FTY and FTD glucuronide isomers. The extractable radioactivity in the pooled plasma consisted of 52.7% FTD and 33.2% FTY. TPI: 76.8% of the (14)C dose was recovered: 27.0% in urine mostly as TPI and 49.7% in feces. The extractable radioactivity in the pooled plasma consisted of 53.1% TPI and 30.9% 6-HMU, the major metabolite of TPI. CONCLUSION: Absorbed (14)C-FTD was metabolized and mostly excreted in urine. The majority of (14)C-TPI was recovered in feces, and the majority of absorbed TPI was excreted in urine. The current data with the ongoing hepatic and renal dysfunction studies will provide an enhanced understanding of the TAS-102 elimination profile.

Phase 1 study of oral TAS-102 in patients with refractory metastatic colorectal cancer.

PURPOSE: To evaluate safety of TAS-102 administered twice daily (bid) on days 1-5 and 8-12 of a 4-week cycle, confirm feasibility of the Japanese recommended dose (RD), 35 mg/m(2), in Western patients with metastatic colorectal cancer (mCRC) refractory to standard chemotherapies, and describe preliminary antitumor activity. METHODS: This open-label, dose-escalation phase 1 study was conducted at four US centers. Patients were enrolled into two sequential cohorts [30 (cohort 1) or 35 mg/m(2)/dose bid (cohort 2)]; dose-limiting toxicities (DLT) were evaluated during cycle 1 in dose-escalation cohorts. At RD, 15 additional patients were enrolled in an expansion cohort. RESULTS: Patients (N = 27) with refractory mCRC received TAS-102; 74 % had received ≥4 prior regimens. DLT was not observed in three patients in cohort 1, and was in one out of nine patients in cohort 2 (grade 3 febrile neutropenia). Therefore, RD was identified as 35 mg/m(2) bid. At RD, fatigue (63 %), gastrointestinal disturbances and nausea (46 %), vomiting (46 %), and diarrhea (42 %) were common but rarely grade 3/4. Grade 3/4 nausea, vomiting, and diarrhea occurred at 4 % each. Grade 3/4 toxicity was predominantly hematologic [neutropenia (71 %), anemia (25 %)]; febrile neutropenia was observed in two patients. Stable disease lasting ≥6 weeks was achieved by 16 evaluable patients (70 %); median progression-free survival and overall survival were 5.3 and 7.5 months, respectively. CONCLUSIONS: TAS-102 has an acceptable safety profile and preliminary evidence of disease stabilization in Western patients with refractory mCRC. Results from a randomized phase 3 study have shown survival benefit with disease stabilization evidence in this population.

Randomized trial of TAS-102 for refractory metastatic colorectal cancer.

BACKGROUND: Early clinical trials conducted primarily in Japan have shown that TAS-102, an oral agent that combines trifluridine and tipiracil hydrochloride, was effective in the treatment of refractory colorectal cancer. We conducted a phase 3 trial to further assess the efficacy and safety of TAS-102 in a global population of such patients. METHODS: In this double-blind study, we randomly assigned 800 patients, in a 2:1 ratio, to receive TAS-102 or placebo. The primary end point was overall survival. RESULTS: The median overall survival improved from 5.3 months with placebo to 7.1 months with TAS-102, and the hazard ratio for death in the TAS-102 group versus the placebo group was 0.68 (95% confidence interval [CI], 0.58 to 0.81; P<0.001). The most frequently observed clinically significant adverse events associated with TAS-102 were neutropenia, which occurred in 38% of those treated, and leukopenia, which occurred in 21%; 4% of the patients who received TAS-102 had febrile neutropenia, and one death related to TAS-102 was reported. The median time to worsening performance status (a change in Eastern Cooperative Oncology Group performance status [on a scale of 0 to 5, with 0 indicating no symptoms and higher numbers indicating increasing degrees of disability] from 0 or 1 to 2 or more) was 5.7 months with TAS-102 versus 4.0 months with placebo (hazard ratio, 0.66; 95% CI, 0.56 to 0.78; P<0.001). CONCLUSIONS: In patients with refractory colorectal cancer, TAS-102, as compared with placebo, was associated with a significant improvement in overall survival. (Funded by Taiho Oncology-Taiho Pharmaceutical; RECOURSE ClinicalTrials.gov number, NCT01607957.).

Prothrombin activation during carbon tetrachloride-induced acute liver injury in mice.

Serine protease thrombin is a central factor for blood coagulation and is an integral part of inflammatory reactions. Prothrombin activation of the liver homogenates during carbon tetrachloride-induced liver injury was investigated. At 72 h after administration of carbon tetrachloride, the prothrombin activation activity reached the maximal value, and then decreased to the basal level at 168 h. The alanine transaminase (ALT) activity, an index of tissue injury, was dramatically elevated at 36 h after treatment, and almost recovered to normal levels at 72 h. Histochemical analysis revealed that the proliferation of hepatocytes and remarkable phagocytosis by macrophages was observed at 72 h, in contrast to severe tissue damage at 36 h. Finally, we showed that prothrombinase activity, composed of factor Xa and factor Va, was involved in the injury-associated prothrombin activation. Taken together, these results strongly suggest that prothrombin activation by the prothrombinase complex occurred following tissue destruction in carbon tetrachloride-induced liver injury.