RESUMEN
BACKGROUND: Epertinib (S-222611) is a potent reversible inhibitor of HER2, EGFR and HER4. This trial evaluated the safety, tolerability, pharmacokinetics and antitumour activity of daily oral epertinib combined with trastuzumab (arm A), with trastuzumab plus vinorelbine (arm B) or with trastuzumab plus capecitabine (arm C), in patients with HER2-positive metastatic breast cancer (MBC). METHODS: Eligible patients, with or without brain metastases, had received prior HER2-directed therapy. A dose-escalation phase determined the tolerability of each combination and established a dose for further study. Further, patients were recruited to expansion cohorts in each of the 3 arms to further explore efficacy and safety. RESULTS: The recommended doses of epertinib were 600 mg, 200 mg and 400 mg in arms A, B and C, respectively. The most frequent grade 3/4 adverse event (AE) was diarrhoea in all arms, which was manageable with medical intervention and dose modification. The objective response rate (complete response [CR] plus partial response [PR]) in heavily pre-treated HER2-positive MBC patients at the recommended doses of epertinib combined with trastuzumab was 67% (N = 9), with trastuzumab plus vinorelbine was 0% (N = 5) and with trastuzumab plus capecitabine was 56% (N = 9). Notably, 4 of 6 patients previously treated with T-DM1 responded in the arm A expansion cohort (epertinib plus trastuzumab). In the arm C expansion cohort (epertinib plus trastuzumab plus capecitabine), 4 of 7 patients responded despite previous exposure to capecitabine. Measurable regression of brain metastases was observed in patients with CNS target lesions treated in both arms A and C. CONCLUSION: We observed safety, tolerability and encouraging antitumour activity of epertinib combined with trastuzumab, or with trastuzumab plus capecitabine. This supports further evaluation of these combinations in patients with pre-treated HER2-positive MBC, with or without brain metastases. TRIAL REGISTRATION: EudraCT Number: 2013-003894-87; registered 09-September-2013.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Quinazolinas/uso terapéutico , Receptor ErbB-2/metabolismo , Trastuzumab/uso terapéutico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/secundario , Neoplasias de la Mama/patología , Capecitabina/administración & dosificación , Capecitabina/efectos adversos , Capecitabina/uso terapéutico , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Quinazolinas/administración & dosificación , Quinazolinas/efectos adversos , Receptor ErbB-2/antagonistas & inhibidores , Trastuzumab/administración & dosificación , Trastuzumab/efectos adversos , Resultado del Tratamiento , Vinorelbina/administración & dosificación , Vinorelbina/efectos adversos , Vinorelbina/uso terapéuticoRESUMEN
The reaction of ethyl 2-ethynylphenylcarbamate derivative with alkenes in the presence of a palladium(II) catalyst, copper dichloride and tetrabutylammonium fluoride (TBAF) produced 2-substituted 3-ethenylindoles during refluxing. The intramolecular cyclization reaction of ethyl 2-ethynylphenylcarbamates, which have an ethenyl part in the ethynyl group, was also used to produce carbazole derivatives.