RESUMO
PURPOSE: The primary aim of this study was to measure the objective tumor response rate following treatment with indisulam [E7070; N-(3-chloro-7-indolyl)-1,4-benzenedisulfonamide] as second-line therapy in patients with advanced non-small cell lung cancer. The secondary aims were to determine progression-free survival, to assess the safety and tolerability of indisulam, and to study its pharmacokinetic and pharmacodynamic profile. EXPERIMENTAL DESIGN: Patients were randomized to receive indisulam every 3 weeks either as a single i.v. dose of 700 mg/m(2) on day one (dx1) or 130 mg/m(2) given on days 1 to 5 inclusive as a daily infusion (dx5). All patients had previously received platinum-based chemotherapy. RESULTS: Forty-four patients were randomized. Only minor responses were seen. Myelosuppression, gastrointestinal symptoms, and lethargy were the most common toxicities and were more frequent in the dx1 arm. The pharmacokinetics of indisulam in each treatment schedule were adequately described using a previously developed population pharmacokinetic model and were mostly consistent with the results of the phase I program. Flow cytometric analysis of endobronchial and metastatic disease revealed a reduction in the fraction of cycling cells and an increase in apoptosis following indisulam compared with pretreatment levels. CONCLUSIONS: We conclude that, despite evidence of tumor-specific indisulam-induced apoptosis, neither of these treatment schedules has single-agent activity as second-line treatment of non-small cell lung cancer.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Sulfonamidas/administração & dosagem , Sulfonamidas/farmacocinética , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Relação Dose-Resposta a Droga , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Sulfonamidas/efeitos adversos , Análise de Sobrevida , Resultado do TratamentoRESUMO
PURPOSE: The purpose of our study was to determine whether variation in cyclophosphamide metabolism influences the incidence of recurrence among children receiving chemotherapy for B-cell non-Hodgkin's lymphoma. EXPERIMENTAL DESIGN: The pharmacokinetics and metabolism of cyclophosphamide were studied during a single course of treatment in 36 children receiving a uniform chemotherapy regimen for B-cell non-Hodgkin's lymphoma and were analyzed in terms of disease recurrence and hematological toxicity. RESULTS: At a median follow-up of 43 months (range, 17-98 months), six children had developed recurrent disease, giving an overall disease-free survival of 83%. The median clearance of cyclophosphamide in patients who remain free of B-cell non-Hodgkin's lymphoma was 3.7 liter/h/m(2) (range, 2.3-5.0 liter/h/m(2)), compared with 2.2 (range, 1.5-2.5 liter/h/m(2)) in those with disease recurrence. Likelihood of recurrence was higher in patients with low clearance (<3.5 liter/h/m(2)) of cyclophosphamide (P < 0.01) and positively related to detection of the inactive metabolites carboxyphosphamide and dechloroethylcyclophosphamide in plasma (P = 0.01). There was no correlation between cyclophosphamide metabolism and hematological toxicity. CONCLUSIONS: Inadequate clearance of cyclophosphamide to active metabolites is associated with increased risk of recurrence of B-cell non-Hodgkin's lymphoma in children. Modified chemotherapy strategies should be considered in patients who exhibit low rates of clearance of the parent drug and/or extensive production of inactive metabolites.
Assuntos
Ciclofosfamida/farmacocinética , Linfoma não Hodgkin/tratamento farmacológico , Adolescente , Antineoplásicos Alquilantes/farmacocinética , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/metabolismo , Linfoma de Células B/patologia , Linfoma não Hodgkin/metabolismo , Linfoma não Hodgkin/patologia , Masculino , Mostardas de Fosforamida/farmacologia , Recidiva , Fatores de TempoRESUMO
Indisulam is a new anticancer drug with a unique mechanism of action, arresting the cell cycle at the G1/S transition. The major excretory pathway of indisulam is via the urine, accounting for 63% of the radioactive dose ([(14)C]indisulam) administered in a human mass balance study. Radiochromatographic profiling of urine samples resulted in the detection of several radioactive peaks. The purpose of the present investigation was to elucidate the chemical structures of these observed indisulam metabolites. We collected fractions after chromatographic separation of the urine samples. These fractions were analysed using tandem mass spectrometry. We propose the chemical structure of 15 indisulam metabolites in urine. The metabolism of indisulam is very complex, consisting of oxidative dechlorination, hydroxylation, hydrolysis, acetylation, sulphation and glucuronidation. The clinical relevance of the observed indisulam metabolites needs further investigation.
Assuntos
Antineoplásicos/farmacocinética , Inibidores da Colinesterase/farmacocinética , Neoplasias/metabolismo , Sulfonamidas/farmacocinética , Urina/química , Antineoplásicos/urina , Biotransformação , Radioisótopos de Carbono , Fracionamento Químico , Inibidores da Colinesterase/urina , Cromatografia Líquida de Alta Pressão , Glucuronídeos/metabolismo , Humanos , Infusões Intravenosas , Neoplasias/urina , Espectrometria de Massas por Ionização por Electrospray , Sulfonamidas/urinaRESUMO
Indisulam (N-(3-chloro-7-indolyl)-1,4-benzenedisulfonamide, GOAL, E7070) is a novel anti-cancer drug currently in phase II clinical development for the treatment of solid tumors. Phase I dose-escalation studies were conducted comparing four treatment schedules. Neutropenia and thrombocytopenia were dose limiting in all schedules. The aim of this study was to describe the extent and the time course of the hematological toxicity and its possible schedule dependency using a semi-physiological model. Data from 142 patients were analyzed using NONMEM. The semi-physiological model comprised a progenitor blood cell compartment, linked to the central circulation compartment, through 3 transition compartments representing the maturation chain in the bone marrow. Plasma concentrations of the drug were assumed to reduce the proliferation rate in the progenitor compartment according to a linear function. A feedback mechanism was included in the model representing the rebound effect of endogenous growth factors. The model was validated using a posterior predictive check. The model adequately described the extent and time course of neutropenia and thrombocytopenia. The mean transition time (MTT, i.e. maturation time in bone marrow) of neutrophils was increased by 47% in patients who received indisulam as a weekly dose administered for four out of every six weeks. For platelets, MTT was increased by 33% in patients who received this schedule and also in patients who received a continuous 120-h infusion. The validation procedure indicated that the model adequately predicts the nadir value of neutrophils and platelets and the time to reach this nadir. A semi-physiological model was successfully applied to describe the time course and extent of the neutropenia and thrombocytopenia after indisulam administration for four treatment schedules.
Assuntos
Antineoplásicos/efeitos adversos , Modelos Biológicos , Neutropenia/induzido quimicamente , Sulfonamidas/efeitos adversos , Trombocitopenia/induzido quimicamente , Adulto , Idoso , Antineoplásicos/administração & dosagem , Ensaios Clínicos Fase I como Assunto , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sulfonamidas/administração & dosagemRESUMO
E7070 (indisulam) is a novel anticancer drug currently undergoing clinical investigation. We present a sensitive and specific method for the quantitative determination of E7070 and its metabolite M1 (1,4-benzenedisulphonamide) in human plasma, urine and faeces. The analytes and their tetra-deuterated analogues, which were used as internal standards, were isolated from the biological matrix by solid-phase extraction with OASIS cartridges (0.5 mL plasma or 1 mL urine) and by liquid-liquid extraction with ethyl acetate at pH 5 (1 mL faecal homogenate). The analytes were separated on a C8 reversed-phase chromatographic column and analyzed using electrospray ionization and tandem mass spectrometric detection in the negative ion mode. The validated concentration ranges in plasma were 0.1-20 microg/mL for E7070 and 0.01-2 microg/mL for M1. In urine and faecal homogenate, a concentration range from 0.05-10 microg/mL or microg/g, respectively, was validated for both analytes. Validation of the plasma assay was performed according to the most recent FDA guidelines. The assay fulfilled all generally accepted requirements for linearity (r > 0.99, residuals between -8 and 10%), accuracy (-13.5 to 1.4%) and precision (all less than 11%) in the tested matrices. We investigated recovery, stability (working solutions at -20 degrees C and at room temperature, biological matrices at -20 degrees C, room temperature and after 3 freeze/thaw cycles; final extracts at room temperature) and robustness. All these parameters were found acceptable. This method is suited for mass balance studies or therapeutic drug monitoring, as demonstrated by a case example showing plasma concentrations and cumulative excretion of E7070 and M1 in urine and faeces. Furthermore, we show the presence of E7070 metabolites in patient urine.