RESUMEN
PURPOSE: This is a phase-I study of gefitinib in combination with temozolomide in patients with gliomas. The goal of the study was to define the maximum tolerated dose (MTD) and to characterize the pharmacokinetics of gefitinib when combined with temozolomide. PATIENTS AND METHODS: Patients were stratified according to co-administration of enzyme-inducing anti-epileptic drugs (EIAEDs). There were 26 evaluable patients enrolled (16 on EIAEDs, 10 not on EIAEDs). All but seven patients had Glioblastoma Multiforme (GBM), and only six cases had a Karnosfsky Performance Status (KPS) of less than 80; median age was 51 years. All had received prior radiotherapy and 14 patients had no prior chemotherapy. The starting dose of temozolomide was 150 mg/m(2)/day for 5 days every 28 days and could be escalated to a maximum dose of 200 mg/m(2)/day in subsequent cycles. The starting dose of gefitinib was 500 mg/day given by mouth on a continuous basis. Dose-limiting toxicity was assessed in cycle one only. RESULTS: For patients on EIAEDs, the MTD of gefitinib was 1,000 mg/day in combination with temozolomide. Dose-limiting toxicity (DLT) was due to diarrhea, nausea and vomiting. For patients not on EIAEDs, the MTD was 250 mg/day in combination with temozolomide. The DLT was due to increases in liver transaminases. Rash was not a significant toxicity at these dose levels. The peak concentration and AUC(0-24hr) at the 500 mg dose level was 1.8 and 2.5-fold lower, respectively, in the EIAED group compared to the non-EIAED group; trough levels of gefitinib increased in both groups consistent with the reported terminal half-life ranging from 27 to 51 h. CONCLUSION: The recommended phase-2 dose of gefitinib when used in combination with temozolomide is 1,000 and 250 mg/day, respectively, for patients on or not on EIAEDs.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Glioma/tratamiento farmacológico , Corticoesteroides/uso terapéutico , Adulto , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos Alquilantes/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Área Bajo la Curva , Edema Encefálico/tratamiento farmacológico , Edema Encefálico/etiología , Neoplasias Encefálicas/complicaciones , Dacarbazina/administración & dosificación , Dacarbazina/análogos & derivados , Relación Dosis-Respuesta a Droga , Femenino , Gefitinib , Glioblastoma/complicaciones , Glioblastoma/tratamiento farmacológico , Glioma/complicaciones , Humanos , Estado de Ejecución de Karnofsky , Masculino , Persona de Mediana Edad , Quinazolinas/administración & dosificación , TemozolomidaRESUMEN
PURPOSE: Preclinical activity of irinotecan has been seen in glioma models, but only modest efficacy has been noted in clinical studies, perhaps related to drug distribution and/or pharmacokinetic limitations. In preclinical testing, irinotecan liposome injection (nal-IRI) results in prolongation of drug exposure and higher tissue levels of drug due to slower metabolism and the effect of enhanced permeability and retention. The objective of the current study was to assess the safety and pharmacokinetics (PK) of nal-IRI and to determine the maximum tolerated dose (MTD) in patients with recurrent high-grade glioma stratified based on UGT1A1 genotyping. METHODS: This phase I study stratified patients with recurrent high-grade glioma into 2 groups by UGT1A1 status: homozygous WT ("WT") vs heterozygous WT/*28 ("HT"). Patients who were homozygous *28 were ineligible. The design was a standard 3 + 3 phase I design. WT patients were started at 120 mg/m2 intravenously every 3 weeks with dose increases in 60 mg/m2 increments. HT patients were started at 60 mg/m2, with dose increases in 30 mg/m2 increments. The assessment period for dose-limiting toxicity was 1 cycle (21 days). RESULTS: In the WT cohort (n = 16), the MTD was 120 mg/m2. In the HT cohort (n = 18), the MTD was 150 mg/m2. Dose-limiting toxicity in both cohorts included diarrhea, some with associated dehydration and/or fatigue. PK results were comparable to those seen in other PK studies of nal-IRI; UGT1A1*28 genotype (WT vs. HT) did not affect PK parameters. CONCLUSIONS: Nal-IRI had no unexpected toxicities when given intravenously. Of note, UGT1A1 genotype did not correlate with toxicity or affect PK profile.
Asunto(s)
Antineoplásicos Fitogénicos/farmacocinética , Antineoplásicos Fitogénicos/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Camptotecina/análogos & derivados , Glioma/tratamiento farmacológico , Adulto , Anciano , Antineoplásicos Fitogénicos/efectos adversos , Camptotecina/efectos adversos , Camptotecina/farmacocinética , Camptotecina/uso terapéutico , Estudios de Cohortes , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Genotipo , Glucuronosiltransferasa/genética , Humanos , Inyecciones Intravenosas , Irinotecán , Liposomas , Masculino , Dosis Máxima Tolerada , Persona de Mediana EdadRESUMEN
BACKGROUND: Liposomal drug packaging is well established as an effective means for increasing drug half-life, sustaining drug activity, and increasing drug efficacy, whether administered locally or distally to the site of disease. However, information regarding the relative effectiveness of peripheral (distal) versus local administration of liposomal therapeutics is limited. This issue is of importance with respect to the treatment of central nervous system cancer, for which the blood-brain barrier presents a significant challenge in achieving sufficient drug concentration in tumors to provide treatment benefit for patients. METHODS: We compared the anti-tumor activity and efficacy of a nanoliposomal formulation of irinotecan when delivered peripherally by vascular route with intratumoral administration by convection-enhanced delivery (CED) for treating intracranial glioblastoma xenografts in athymic mice. RESULTS: Our results show significantly greater anti-tumor activity and survival benefit from CED of nanoliposomal irinotecan. In 2 of 3 efficacy experiments, there were animal subjects that experienced apparent cure of tumor from local administration of therapy, as indicated by a lack of detectable intracranial tumor through bioluminescence imaging and histopathologic analysis. Results from investigating the effectiveness of combination therapy with nanoliposomal irinotecan plus radiation revealed that CED administration of irinotecan plus radiation conferred greater survival benefit than did irinotecan or radiation monotherapy and also when compared with radiation plus vascularly administered irinotecan. CONCLUSIONS: Our results indicate that liposomal formulation plus direct intratumoral administration of therapeutic are important for maximizing the anti-tumor effects of irinotecan and support clinical trial evaluation of this therapeutic plus route of administration combination.
Asunto(s)
Antineoplásicos Fitogénicos/administración & dosificación , Neoplasias Encefálicas/tratamiento farmacológico , Camptotecina/análogos & derivados , Sistemas de Liberación de Medicamentos , Glioblastoma/tratamiento farmacológico , Liposomas , Nanopartículas , Animales , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/patología , Camptotecina/administración & dosificación , Convección , Vías de Administración de Medicamentos , Femenino , Glioblastoma/mortalidad , Glioblastoma/patología , Historia Antigua , Humanos , Técnicas para Inmunoenzimas , Inyecciones Intraperitoneales , Irinotecán , Ratones , Ratones Desnudos , Tasa de Supervivencia , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Achieving effective treatment outcomes for patients with glioblastoma (GBM) has been impeded by many obstacles, including the pharmacokinetic limitations of antitumor agents, such as topotecan (TPT). Here, we demonstrate that intravenous administration of a novel nanoliposomal formulation of TPT (nLS-TPT) extends the survival of mice with intracranial GBM xenografts, relative to administration of free TPT, because of improved biodistribution and pharmacokinetics of the liposome-formulated drug. In 3 distinct orthotopic GBM models, 3 weeks of biweekly intravenous therapy with nLS-TPT was sufficient to delay tumor growth and significantly extend animal survival, compared with treatment with free TPT (P ≤ .03 for each tumor tested). Analysis of intracranial tumors showed increased activation of cleaved caspase-3 and increased DNA fragmentation, both indicators of apoptotic response to treatment with nLS-TPT. These results demonstrate that intravenous delivery of nLS-TPT is a promising strategy in the treatment of GBM and support clinical investigation of this therapeutic approach.