RESUMEN
PURPOSE: To determine the maximum tolerated dose (MTD) dose-limiting toxicity, and pharmacokinetic and pharmacodynamic profile of TKI258 (formerly CHIR-258). EXPERIMENTAL DESIGN: A phase I dose escalating trial in patients with advanced solid tumors was performed. Treatment was initially as single daily doses on an intermittent 7-day on/7-day off schedule. Following a protocol amendment, a second schedule comprised, during cycle 1, 7-day on/7-day off treatment followed by 14 days of continuous daily dosing; subsequent cycles comprised 28 days of daily dosing. Pharmacokinetics and evaluation of phosphorylated extracellular signal-regulated kinase (ERK) in peripheral blood mononuclear cells were done during the first 28 days of each schedule. RESULTS: Thirty-five patients were treated in four intermittent (25-100 mg/d) and three continuous (100-175 mg/d) dosing cohorts. Observed drug-related toxicities were nausea and vomiting, fatigue, headache, anorexia, and diarrhea. Dose-limiting toxicities were grade 3 hypertension in one patient at 100 mg continuous dosing, grade 3 anorexia in a second patient at 175 mg, and grade 3 alkaline phosphatase elevation in a third patient at 175 mg. One patient had a partial response (melanoma) and two patients had stable disease >6 months. TKI258 pharmacokinetics were linear over the dose range of 25 to 175 mg. Five of 14 evaluable patients had modulation of phosphorylated ERK levels. CONCLUSIONS: The MTD was defined as 125 mg/d. Evidence of antitumor activity in melanoma and gastrointestinal stromal tumors warrants further investigation, and other phase I studies are ongoing. Further pharmacodynamic evaluation is required in these studies to evaluate the biological effects of TKI258.
Asunto(s)
Bencimidazoles/efectos adversos , Bencimidazoles/farmacocinética , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/farmacocinética , Quinolonas/efectos adversos , Quinolonas/farmacocinética , Administración Oral , Adulto , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Bencimidazoles/administración & dosificación , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/administración & dosificación , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/efectos de los fármacos , Quinolonas/administración & dosificación , Resultado del TratamientoRESUMEN
Rapid advances in our understanding of the molecular basis of cancer development and progression over the past three decades have led to the design of new potential cancer therapies. High throughput target validation and expression studies are expected to yield a powerful arsenal of new cancer treatments, but untangling the complex pathways underlying the major cancer phenotypes remains a significant challenge. A considerable body of evidence in recent years implicates deregulated expression of a single multi-component enzyme, telomerase, as a causative factor at the heart of immortalization in the vast majority of human tumors. This review highlights the potential of telomerase as a target for novel cancer therapies. The potential of exploiting the selectivity of the telomerase family of genes within cancer cells to develop gene therapy strategies is discussed, and the progress towards translating these novel therapeutics from the laboratory to the clinic is reviewed.