RESUMEN
Background Plocabulin (PM060184) is a novel marine-derived microtubule inhibitor that acts as an antitumor agent. This first-in-human study evaluated dose-limiting toxicities (DLT) to define the maximum tolerated dose (MTD) and phase II recommended dose (RD) of plocabulin given as a 10-min infusion on Day (D) 1, D8 and D15 every four weeks. Patients and methods Forty-four patients with advanced solid tumors received plocabulin following an accelerated titration design. Results Plocabulin was escalated from 1.3 mg/m2 to 14.5 mg/m2, which was defined as the MTD. No RD was confirmed, because frequent dose delays and omissions resulted in low relative dose intensity (66%) at the 12.0 mg/m2 expansion cohort. The main DLT was grade 3 peripheral sensory neuropathy (PSN); other DLTs were grade 4 tumor lysis syndrome, grade 4 cardiac failure and grade 3 myalgia. Toxicities were mainly mild to moderate, and included abdominal pain, myalgia, fatigue, nausea, and vomiting. Myelosuppression was transient and manageable. Plocabulin had a half-life of ~4 h and a wide diffusion to peripheral tissues. Antitumor response was observed in cervix carcinoma and heavily pretreated metastatic non-small cell lung cancer patients, and disease stabilization (≥3 months) in patients with colorectal, thymic, gastrointestinal stromal and breast tumors, among others. The clinical benefit rate was 33%. Conclusion The main DLT of plocabulin was PSN, as anticipated for a tubulin-binding agent. Since encouraging antitumor activity was observed, efforts to improve toxicity and to find the RD were planned in other trials evaluating D1&D8 and D1-D3 plus D15-D17 schedules.
Asunto(s)
Antineoplásicos/administración & dosificación , Neoplasias/tratamiento farmacológico , Policétidos/administración & dosificación , Pironas/administración & dosificación , Moduladores de Tubulina/administración & dosificación , Adulto , Anciano , Antineoplásicos/efectos adversos , Antineoplásicos/sangre , Antineoplásicos/farmacocinética , Femenino , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Neoplasias/metabolismo , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Policétidos/efectos adversos , Policétidos/sangre , Policétidos/farmacocinética , Pironas/efectos adversos , Pironas/sangre , Pironas/farmacocinética , Resultado del Tratamiento , Moduladores de Tubulina/efectos adversos , Moduladores de Tubulina/sangre , Moduladores de Tubulina/farmacocinética , Adulto JovenRESUMEN
The biological activity and structural diversity of natural products are unsurpassed by any available synthetic screening libraries. As such, these privileged scaffolds serve as important, biologically prevalidated platforms for the design of compound libraries in the search for new drug candidates. Recent progress has focussed on improving the potency, selectivity and pharmacokinetics of bioactive natural products through structural modification, leading to the emergence of a number of drug-like lead compounds. Here, we review recent advances in the exploitation of terpenoid, polyketide, phenylpropanoid and alkaloid natural product scaffolds for inspiration in the design and development of important new drug candidates.