RESUMO
OBJECTIVES: A6 is a novel peptide that interferes with single-chain urokinase plasminogen activator activity and has shown anti-angiogenic, anti-migratory, and anti-invasive properties. We evaluated clinical efficacy and safety of subcutaneously administered A6 in women with epithelial ovarian cancer. METHODS: Women with epithelial ovarian, fallopian tube, or primary peritoneal cancer in clinical remission after first-line chemotherapy with 2 consecutive increases of CA125 values above normal but with no disease on physical examination or imaging studies were randomly assigned to receive daily subcutaneous injections of placebo, low-dose A6 (150 mg), or high-dose A6 (300 mg) until disease progression or end of study participation. Primary endpoints were time to clinical progression of disease and safety of A6. Secondary endpoints were changes in serum CA125 and biomarkers of the urokinase system. RESULTS: Data are available for 24 women (placebo, n=12; low-dose, n=8; high-dose n=4). A6 therapy was associated with a statistically significant delay in time to clinical progression (log-rank p-value 0.01) with a median of 100 days (95% CI: 64,168) for women who received A6 compared with 49 days (95% CI: 29,67) for women who received placebo. The treatments appeared to be well tolerated. Treatment was not associated with CA125 response (p=0.44). On-treatment values for plasma urokinase plasminogen activator receptor were statistically significantly lower in the A6 groups compared with placebo (p=0.02). CONCLUSIONS: A6 therapy increases time to clinical disease progression and appears to be well tolerated in this patient population.
Assuntos
Antígeno Ca-125/sangue , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/tratamento farmacológico , Fragmentos de Peptídeos/administração & dosagem , Ativador de Plasminogênio Tipo Uroquinase/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Método Duplo-Cego , Neoplasias das Tubas Uterinas/sangue , Neoplasias das Tubas Uterinas/tratamento farmacológico , Feminino , Humanos , Injeções Subcutâneas , Pessoa de Meia-Idade , Fragmentos de Peptídeos/efeitos adversos , Neoplasias Peritoneais/sangue , Neoplasias Peritoneais/tratamento farmacológico , Placebos , Estudos Prospectivos , Receptores de Superfície Celular/metabolismo , Receptores de Ativador de Plasminogênio Tipo Uroquinase , Ativador de Plasminogênio Tipo Uroquinase/efeitos adversos , Ativador de Plasminogênio Tipo Uroquinase/metabolismoRESUMO
OBJECTIVES: The aim of this study was to define the toxicity, maximum feasible dose (MFD), and pharmacokinetics (PK) of A6, a peptide derived from human urokinase plasminogen activator (uPA), in patients with advanced gynecologic cancers, and to explore anti-tumor activity and the effects of A6 on biomarkers of the urokinase system. METHODS: A6 was administered subcutaneously daily, and doses were escalated in cohorts of three to six subjects. Serial blood specimens were obtained for pharmacokinetics and levels of urokinase plasminogen activator (uPA), uPA receptor (uPAR), and plasminogen activator inhibitor-1 (PAI-1). RESULTS: Sixteen patients were enrolled and eligible for evaluation. No serious drug-related adverse events or dose-limiting toxicity occurred. A6-related toxicities were limited to grades 1 and 2 adverse effects including local injection site reactions. Five patients had stable tumor measurements for at least 4 cycles, one of whom stayed on study for 12 months. One patient had a confirmed cancer antigen (CA)-125 response (decrease in CA-125 of >50%) with stable disease on CT scan after 14 cycles and continues on study. Time to peak plasma level of A6 was 1-2 h. C(max) is proportional to dose. The half-life of A6 was approximately 2 h. Baseline biomarker levels did not predict response and trends over time did not correlate with outcome. CONCLUSIONS: A6 given daily continuously is well tolerated at all dose levels, without any dose-limiting toxicity. Based on the preliminary activity of A6, a phase II trial is underway in ovarian cancer.