RESUMO
PURPOSE: AGS-1C4D4 is a human monoclonal antibody against prostate stem cell antigen (PSCA), a cell-surface protein expressed by most prostate cancers. AGS-1C4D4 is produced in Chinese hamster ovary (CHO) cells and has an identical sequence to AGS-PSCA, an anti-PSCA antibody produced in mouse hybridoma cells that has completed Phase I testing. Preclinical studies demonstrated comparability of AGS-1C4D4 to AGS-PSCA with respect to pharmacokinetics (PK) and tumor inhibition. However, because of differences in antibody-dependent cellular cytotoxicity between AGS-PSCA and AGS-1C4D4, a limited Phase I trial using AGS-1C4D4 was performed evaluating safety and PK. PATIENTS AND METHODS: Thirteen patients with metastatic castration-resistant prostate cancer were enrolled. AGS-1C4D4 was administered intravenously every 3 weeks for four planned doses at 6, 12, 24, or 48 mg/kg. Primary endpoints were safety and PK. Secondary endpoints were immunogenicity and clinical activity. Disease assessments were conducted every 12 weeks and included radiographic and PSA evaluations. Patients with stable disease could receive extended treatment beyond four infusions. RESULTS: Adverse events were primarily grade 1-2, without any grade 3-4 drug-related toxicities or infusion reactions. Anti-AGS-1C4D4 antibodies were not detected. Similar to AGS-PSCA, serum AGS-1C4D4 concentrations declined biphasically and elimination was characterized by slow clearance (CL) and a long terminal half-life (t (1/2)). Median CL for the four dose levels ranged from 0.10 to 0.14 ml/h kg, and t (1/2) ranged from 2.2 to 2.9 weeks. No PSA reductions ≥50% were observed. Six patients (46%) had radiographically stable disease, lasting a median of 24 weeks. CONCLUSION: AGS-1C4D4 was well-tolerated and demonstrated linear PK. Despite preclinical differences in antibody-dependent cellular cytotoxicity, AGS-1C4D4 and AGS-PSCA have similar safety and PK profiles. The recommended Phase II dose is 48 mg/kg.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Antineoplásicos/administração & dosagem , Proteínas de Neoplasias/antagonistas & inibidores , Neoplasias da Próstata/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Antagonistas de Androgênios/administração & dosagem , Antagonistas de Androgênios/uso terapêutico , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais/uso terapêutico , Antígenos de Neoplasias , Antineoplásicos/efeitos adversos , Antineoplásicos/imunologia , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Estudos de Coortes , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos , Proteínas Ligadas por GPI/antagonistas & inibidores , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Resultado do TratamentoRESUMO
BACKGROUND: A phase III study of filgrastim as an adjunct to combination chemotherapy in previously untreated patients with limited- or extensive-stage small-cell lung cancer was conducted. This final analysis explores baseline factors that might predict febrile neutropenia and also reports the results of 463 open-label filgrastim cycles that were delivered after patients' initial episode of the primary endpoint, ie, febrile neutropenia. PATIENTS AND METHODS: A total of 244 patients were randomized to receive placebo or filgrastim in = 6 cycles of chemotherapy (cyclophosphamide/doxorubicin/etoposide). RESULTS: The cumulative percent of patients receiving filgrastim who experienced febrile neutropenia was approximately 50% lower than those given placebo (38% vs. 74%, respectively; P < 0.0001). Significant treatment-related reductions were also seen in the incidence and duration of grade 4 neutropenia. Cycle 1 displayed the highest incidence of neutropenia with or without fever and the longest duration of neutropenia relative to later cycles. Patients crossing over to open-label filgrastim from their blinded treatment assignment displayed event rates similar to those in the blinded filgrastim group. Patients who experienced febrile neutropenia in cycle 1 were at a significantly higher risk for subsequent events compared with those who were event-free in cycle 1. Women displayed a higher risk for febrile neutropenia than men, but no other baseline risk factors were detected. CONCLUSION: Given the high rate of febrile neutropenia in cycle 1 and the higher risk for subsequent events in patients with a cycle 1 event, we conclude that growth factor administration starting in cycle 1 should be considered for patients receiving moderately to highly myelosuppressive chemotherapy regimens.