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Invest New Drugs ; 39(6): 1613-1623, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34264412

RESUMO

Background We report a Phase 1 study of LY3076226, an antibody-drug conjugate composed of human IgG1 monoclonal antibody against the human FGFR3 attached with a cleavable linker to the maytansine derivative DM4 in patients with advanced or metastatic cancer. Methods This study was comprised of two parts: (A) dose escalation in patients with advanced or metastatic cancer and (B) dose expansion in patients with urothelial carcinoma with locally determined FGFR3 alterations. The dose range of LY3076226 tested was 0.2-5.0 mg/kg as an intravenous infusion on Day 1 of each 21-day cycle. The primary objective was to determine a recommended phase 2 dose (RP2D). Results Twenty-five patients were enrolled (Part A: 22, Part B: 3) and received ≥ 1 dose of LY3076226. No dose-limiting toxicities were reported. LY3076226 was generally well tolerated; most of the toxicities were Grade 1 or 2. Two patients experienced treatment-related Grade 3 toxicity (embolism and decreased platelet count). Four patients experienced serious adverse events (not treatment-related), all in Part A. Dose-proportional exposure was observed, with an estimated half-life of 2-7 days. No responses were seen with LY3076226 treatment. Stable disease persisting for > 6 months was observed in 1 patient receiving 3.2 mg/kg of LY3076226. Conclusion The study demonstrates acceptable safety and tolerability of LY3076226 up to the 5.0 mg/kg dose. Recruitment was stopped due to pipeline prioritization. Dose escalation of LY3076226 beyond 5.0 mg/kg in patients with advanced tumors may be possible. The trial was registered on August 19, 2015 under identifier NCT02529553 with ClinicalTrials.gov.


Assuntos
Anticorpos Monoclonais Humanizados , Antineoplásicos , Imunoconjugados , Maitansina , Neoplasias , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Área Sob a Curva , Relação Dose-Resposta a Droga , Meia-Vida , Imunoconjugados/administração & dosagem , Imunoconjugados/efeitos adversos , Imunoconjugados/farmacocinética , Imunoconjugados/uso terapêutico , Dose Máxima Tolerável , Maitansina/administração & dosagem , Maitansina/efeitos adversos , Maitansina/farmacocinética , Taxa de Depuração Metabólica , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Neoplasias Urológicas/tratamento farmacológico , Neoplasias Urológicas/patologia , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/farmacocinética
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