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.

• Klíčová slova
• Pharmacokinetics, Renal impairment, Safety, TAS-102, Trifluridine/tipiracil,
• MeSH
• anemie chemicky indukované   epidemiologie   MeSH
• dospělí MeSH
• fixní kombinace léků MeSH
• kohortové studie MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory farmakoterapie   MeSH
• nemoci ledvin patofyziologie   MeSH
• neutropenie chemicky indukované   epidemiologie   MeSH
• plocha pod křivkou MeSH
• protokoly protinádorové kombinované chemoterapie aplikace a dávkování   škodlivé účinky   farmakokinetika   MeSH
• pyrrolidiny aplikace a dávkování   škodlivé účinky   farmakokinetika   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• stupeň závažnosti nemoci MeSH
• thymin aplikace a dávkování   škodlivé účinky   farmakokinetika   MeSH
• trifluridin aplikace a dávkování   škodlivé účinky   farmakokinetika   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze I MeSH
• práce podpořená grantem MeSH
• Názvy látek
• fixní kombinace léků MeSH
• pyrrolidiny MeSH
• thymin MeSH
• trifluridin MeSH
• trifluridine tipiracil drug combination MeSH Prohlížeč

BACKGROUND: Treatment with recombinant human granulocyte-colony stimulating factor (G-CSF) is accepted standard for prevention of chemotherapy-induced neutropenia. RGB-02 (Gedeon Richter) is a proposed biosimilar to pegylated G-CSF (Neulasta®, Amgen) with sustained release properties. This is a randomized, comparative, double-blind, multicenter study to evaluate efficacy and safety of RGB-02 in breast cancer patients receiving cytotoxic regimen. METHODS: Two hundred thirty-nine women presenting with breast cancer were randomized to RGB-02 (n = 121) and the reference product (n = 118). All patients received up to 6 cycles of docetaxel/doxorubicin chemotherapy combination and a once-per-cycle injection of a fixed 6 mg dose of pegfilgrastim. Primary endpoint was the duration of severe neutropenia (ANC < 0.5 × 109/L) in Cycle 1 (2-sided CI 95%). Secondary endpoints included incidence and duration of severe neutropenia (in cycles 2-4), incidence of febrile neutropenia, time to ANC recovery, depth of ANC nadir, and safety outcomes. RESULTS: The mean duration of severe neutropenia in Cycle 1 was 1.7 (RGB-02) and 1.6 days (reference), with a difference (LS Mean) of 0.1 days (95% CI -0.2, 0.4). Equivalence could be established as the CI for the difference in LS Mean lay entirely within the pre-defined range of ±1 day. This positive result was supported by the analysis of secondary endpoints, which also revealed no clinical meaningful differences. Safety profiles were comparable between groups. No neutralizing antibodies against pegfilgrastim were identified. CONCLUSIONS: Treatment equivalence in reducing the duration of chemotherapy induced neutropenia between RGB-02 and Neulasta® could be demonstrated. Similar efficacy and safety profiles of the once-per-cycle administration of RGB-02 and the pegfilgrastim reference were demonstrated. TRIAL REGISTRATION: The trial was registered prospectively, prior to study initiation. EudraCT number ( 2013-003166-14 ). The date of registration was 12 July, 2013.

• Klíčová slova
• Biosimilar, Breast Cancer, Chemotherapy-induced neutropenia, Clinical study, Pegfilgrastim, RGB-02, Therapeutic equivalence,
• MeSH
• biosimilární léčivé přípravky aplikace a dávkování   škodlivé účinky   normy   MeSH
• docetaxel aplikace a dávkování   škodlivé účinky   MeSH
• dospělí MeSH
• doxorubicin aplikace a dávkování   škodlivé účinky   MeSH
• dvojitá slepá metoda MeSH
• filgrastim aplikace a dávkování   škodlivé účinky   MeSH
• hematologické látky aplikace a dávkování   škodlivé účinky   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory prsu farmakoterapie   patologie   MeSH
• neutropenie chemicky indukované   prevence a kontrola   MeSH
• polyethylenglykoly aplikace a dávkování   škodlivé účinky   MeSH
• protokoly protinádorové kombinované chemoterapie aplikace a dávkování   škodlivé účinky   MeSH
• staging nádorů MeSH
• terapeutická ekvivalence MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH
• srovnávací studie MeSH
• Názvy látek
• biosimilární léčivé přípravky MeSH
• docetaxel MeSH
• doxorubicin MeSH
• filgrastim MeSH
• hematologické látky MeSH
• pegfilgrastim MeSH Prohlížeč
• polyethylenglykoly MeSH