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We investigated the effectiveness of navtemadlin (KRT-232) in treating recurrent glioblastoma. A surgical window-of-opportunity trial ( NCT03107780 ) was conducted on 21 patients to determine achievable drug concentrations within tumor tissue and examine mechanisms of response and resistance. Both 120 mg and 240 mg daily dosing achieved a pharmacodynamic impact. Sequencing of three recurrent tumors revealed an absence of TP53 -inactivating mutations, indicating alternative mechanisms of resistance. In patient-derived GBM models, the lower range of clinically achieved navtemadlin concentrations induced partial tumor cell death as monotherapy. However, combining navtemadlin with temozolomide increased apoptotic rates while sparing normal bone marrow cells in vitro, which in return underwent reversible growth arrest. These results indicate that clinically achievable doses of navtemadlin generate significant pharmacodynamic effects and suggest that combined treatment with standard-of-care DNA damaging chemotherapy is a route to durable survival benefits. Statement of significance: Tissue sampling during this clinical trial allowed us to assess mechanisms of response and resistance associated with navtemadlin treatment in recurrent GBM. We report that clinically achievable doses of navtemadlin induce pharmacodynamic effects in tumor tissue, and suggest combinations with standard-of-care chemotherapy for durable clinical benefit.
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Background: Mibefradil (MIB), previously approved for treatment of hypertension, is a selective T-type calcium channel blocker with preclinical activity in high-grade gliomas (HGGs). To exploit its presumed mechanism of impacting cell cycle activity (G1 arrest), we designed a phase I study to determine safety and the maximum tolerated dose (MTD) of MIB when given sequentially with temozolomide (TMZ) in recurrent (r)HGG. Methods: Adult patients with rHGG ≥3 months from TMZ for initial therapy received MIB in 4 daily doses (q.i.d.) for 7 days followed by standard TMZ at 150-200 mg/m2 for 5 days per 28-day cycle. MIB dose escalation followed a modified 3 + 3 design, with an extension cohort of 10 patients at MTD who underwent 3'-deoxy-3'-18F-fluorothymidine (18F-FLT) PET imaging, to image proliferation before and after 7 days of MIB. Results: Twenty-seven patients were enrolled (20 World Health Organization grade IV, 7 grade III; median age 50 y; median KPS 90). The MTD of MIB was 87.5 mg p.o. q.i.d. Dose-limiting toxicities were elevation of alanine aminotransferase/aspartate aminotransferase (grade 3) and sinus bradycardia. The steady-state maximum plasma concentration of MIB at the MTD was 1693 ± 287 ng/mL (mean ± SD). 18F-FLT PET imaging showed a significant decline in standardized uptake value (SUV) signal in 2 of 10 patients after 7 days of treatment with MIB. Conclusions: MIB followed by TMZ was well tolerated in rHGG patients at the MTD. The lack of toxicity and presence of some responses in this selected patient population suggest that this regimen warrants further investigation.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Canales de Calcio Tipo T/química , Glioma/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Encefálicas/patología , Dacarbazina/administración & dosificación , Dacarbazina/análogos & derivados , Femenino , Estudios de Seguimiento , Glioma/patología , Humanos , Masculino , Dosis Máxima Tolerada , Mibefradil/administración & dosificación , Persona de Mediana Edad , Clasificación del Tumor , Recurrencia Local de Neoplasia/patología , Tasa de Supervivencia , Temozolomida , Adulto JovenRESUMEN
Quantitative 3'-deoxy-3'-18F-fluorothymidine (18F-FLT) PET has potential as a noninvasive tumor biomarker for the objective assessment of response to treatment. To guide interpretation of these quantitative data, we evaluated the repeatability of 18F-FLT PET as part of a multicenter trial involving patients with high-grade glioma. Methods:18F-FLT PET was performed on 10 patients with recurrent high-grade glioma at 5 different institutions within the Adult Brain Tumor Consortium trial ABTC1101. Data were acquired according to a double baseline protocol in which PET examinations were repeated within 2 d of each other with no intervening treatment. On each of the 2 imaging days, dedicated brain PET was performed at 2 time points, 1 and 3 h after 18F-FLT administration. Tumor SUVs and related parameters were measured at a central laboratory using various volumes of interest: isocontour at 30% of the maximum pixel (SUVmean_30%), gradient-based segmentation (SUVmean_gradient), the maximum pixel (SUVmax), and a 1-mL sphere at the region of highest uptake (SUVpeak). Repeatability coefficients (RCs) were calculated from the relative differences between corresponding SUV measurements obtained on the 2 d. Results: RCs for tumor SUVs were 22.5% (SUVmean_30%), 23.8% (SUVmean_gradient), 23.2% (SUVmax), and 18.5% (SUVpeak) at 1 h after injection. Corresponding data at 3 h were 22.4%, 25.0%, 27.3%, and 23.6%. Normalizing the tumor SUV data with reference to a background region improved repeatability, and the most stable parameter was the tumor-to-background ratio derived using SUVpeak (RC, 16.5%). Conclusion: SUV quantification of 18F-FLT uptake in glioma had an RC in the range of 18%-24% when imaging began 1 h after 18F-FLT administration. The volume-of-interest methodology had a small but not negligible influence on repeatability, with the best performance obtained using SUVpeak Although changes in 18F-FLT SUV after treatment cannot be directly interpreted as a change in tumor proliferation, we have established ranges beyond which SUV differences are likely due to legitimate biologic effects.
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Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/patología , Didesoxinucleósidos , Glioma/diagnóstico por imagen , Glioma/patología , Tomografía de Emisión de Positrones/métodos , Adulto , Femenino , Humanos , Interpretación de Imagen Asistida por Computador/métodos , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Variaciones Dependientes del Observador , Radiofármacos , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Estados UnidosRESUMEN
BACKGROUND: Cilengitide is a selective integrin inhibitor that is well tolerated and has demonstrated biologic activity in patients with recurrent malignant glioma. The primary objectives of this randomized phase 2 trial were to determine the safety and efficacy of cilengitide when combined with radiation and temozolomide for patients with newly diagnosed glioblastoma multiforme and to select a dose for comparative clinical testing. METHODS: In total, 112 patients were accrued. Eighteen patients received standard radiation and temozolomide with cilengitide in a safety run-in phase followed by a randomized phase 2 trial with 94 patients assigned to either a 500 mg dose group or 2000 mg dose group. The trial was designed to estimate overall survival benefit compared with a New Approaches to Brain Tumor Therapy (NABTT) Consortium internal historic control and data from the published European Organization for Research and Treatment of Cancer (EORTC) trial EORTC 26981. RESULTS: Cilengitide at all doses studied was well tolerated with radiation and temozolomide. The median survival was 19.7 months for all patients, 17.4 months for the patients in the 500 mg dose group, 20.8 months for patients in the 2000 mg dose group, 30 months for patients who had methylated O6-methylguanine-DNA methyltransferase (MGMT) status, and 17.4 months for patients who had unmethylated MGMT status. For patients aged ≤70 years, the median survival and survival at 24 months was superior to what was observed in the EORTC trial (20.7 months vs 14.6 months and 41% vs 27%, respectively; P = .008). CONCLUSIONS: Cilengitide was well tolerated when combined with standard chemoradiation and may improve survival for patients newly diagnosed with glioblastoma multiforme regardless of MGMT methylation status. The authors concluded that, from an efficacy and safety standpoint, future trials of this agent in this population should use the 2000 mg dose.
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Neoplasias Encefálicas/terapia , Quimioradioterapia , Metilasas de Modificación del ADN/metabolismo , Enzimas Reparadoras del ADN/metabolismo , Dacarbazina/análogos & derivados , Glioblastoma/terapia , Venenos de Serpiente/uso terapéutico , Proteínas Supresoras de Tumor/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos Alquilantes/farmacología , Antineoplásicos Alquilantes/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/radioterapia , Terapia Combinada , Metilación de ADN , Dacarbazina/farmacología , Dacarbazina/uso terapéutico , Supervivencia sin Enfermedad , Femenino , Glioblastoma/tratamiento farmacológico , Glioblastoma/genética , Glioblastoma/radioterapia , Humanos , Integrinas/antagonistas & inhibidores , Masculino , Persona de Mediana Edad , Venenos de Serpiente/farmacología , Temozolomida , Resultado del Tratamiento , Adulto JovenRESUMEN
COL-3 is a chemically modified tetracycline that targets multiple aspects of matrix metalloproteinase regulation. This phase I clinical trial was conducted to determine the maximum tolerated dose (MTD) of COL-3 in adults with recurrent high-grade glioma, to describe the effects of enzyme-inducing antiseizure drugs (EIADs) on its pharmacokinetics, and to obtain preliminary evidence of activity. Adults with recurrent high-grade glioma were stratified by EIAD use. COL-3 was given orally daily without interruption until disease progression or treatment-related dose-limiting toxicity (DLT). Three patients in each EIAD group were evaluated at each dose level beginning with 25 mg/m(2)/day and escalated by 25 mg/m(2)/day. Toxicity, response, and pharmacokinetics were assessed. Thirty-three patients were evaluated. The MTD was 75 mg/m(2)/day in the -EIAD patients while one was not determined in +EIAD patients. The common toxicities observed were anemia, ataxia, diarrhea, hypokalemia, CNS hemorrhage, and myalgia. One partial response was observed. -EIAD patients tended to have a higher steady-state trough concentration that was apparent only at the 100 mg/m(2)/day dose level (P = 0.01). This study suggests that: (a) EIAD use does affect the pharmacokinetics of COL-3 at higher doses; and (b) there was not enough suggestion of single-agent activity to warrant further study in recurrent high-grade gliomas.
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Anticonvulsivantes/farmacología , Neoplasias Encefálicas/tratamiento farmacológico , Glioma/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Tetraciclinas/farmacocinética , Tetraciclinas/uso terapéutico , Adulto , Anciano , Neoplasias Encefálicas/mortalidad , Femenino , Estudios de Seguimiento , Glioma/mortalidad , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Clasificación del Tumor , Recurrencia Local de Neoplasia/mortalidad , Pronóstico , Distribución TisularRESUMEN
Atrasentan is an oral selective endothelin-A receptor antagonist that may inhibit cell proliferation and interfere with angiogenesis during glioma growth. We conducted a dose-finding study to assess atrasentan's safety and toxicity and to gather preliminary evidence of efficacy. Patients with recurrent malignant glioma received oral atrasentan at >or=10 mg/day. We increased the dose among cohorts until the maximum tolerated dose (MTD) was defined. Patients were evaluated for response every 8 weeks and remained on the study until the tumor progressed or toxicities occurred. Twenty-five patients were enrolled, with a median age of 53 years (range, 25-70) and a median KPS of 90% (range, 60-100%). Twenty-two patients had glioblastoma multiforme (GBM), 2 had anaplastic astrocytoma, and 1 had an anaplastic oliogodendroglioma; 24 patients had received one prior chemo therapy regimen before being enrolled in the study. The most common atrasentan-related toxicities were grade 1 or 2 rhinitis, fatigue, and edema. One patient developed grade 3 hypoxia and peripheral edema at a dose of 90 mg/day. We observed no dose-limiting toxicities in an expanded cohort of 10 patients at 70 mg/day, which was declared the MTD. Two partial responses (8%) were seen in patients with GBM at the 70- and 90-mg/day dose levels, and 4 patients had stable disease before progressing. Nineteen patients have died, and median survival was 6.0 months (95% confidence interval, 4.2-9.5 months). We conclude that the MTD of daily oral atrasentan in patients with recurrent malignant glioma is 70 mg/day. Further study of atrasentan with radiation therapy and temozolomide in newly diagnosed GBM is warranted to evaluate the efficacy of this novel agent.
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Antineoplásicos/administración & dosificación , Neoplasias Encefálicas/tratamiento farmacológico , Glioma/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Pirrolidinas/administración & dosificación , Adulto , Anciano , Antineoplásicos/efectos adversos , Atrasentán , Neoplasias Encefálicas/mortalidad , Relación Dosis-Respuesta a Droga , Femenino , Glioma/mortalidad , Humanos , Estimación de Kaplan-Meier , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Recurrencia Local de Neoplasia/mortalidad , Pirrolidinas/efectos adversosRESUMEN
PURPOSE: Prognostic factor analyses have proven useful in predicting outcome in patients with newly diagnosed malignant glioma. Similar analyses in patients with recurrent glioma could affect the design and conduct of clinical trials substantially. PATIENTS AND METHODS: Between 1995 and 2002, 333 adults with recurrent gliomas were enrolled onto 10 phase I or II trials of systemic or local therapy. The studies had similar inclusion criteria and were conducted within the New Approaches to Brain Tumor Therapy CNS Consortium. Ninety-three percent of the patients have died. Cox proportional hazards (PH) regression and recursive partitioning analysis (RPA) were performed to identify prognostic factors. RESULTS: Factors associated with an increased risk of death were increased age, lower Karnofsky performance score (KPS), initial and on-study histologies of glioblastoma multiforme (GBM), corticosteroid use, shorter time from original diagnosis to recurrence, and tumor outside frontal lobe. The final PH model included initial histology of GBM (relative risk [RR] = 2.01), 10-year increase in age (RR = 1.23), KPS less than 80 (RR = 1.54), and corticosteroid use (RR = 1.49). RPA resulted in seven classes. Median survival time was poorest in non-GBM patients with KPS less than 80 or GBM patients, age 50 years, corticosteroid use (4.4 months; 95% CI, 3.6 to 5.4 months); median survival was best in patients with initial histology other than GBM with KPS 80 and tumor confined to the frontal lobe (25.7 months; 95% CI, 18.7 to 52.5), and was 7.0 months (95% CI, 6.2 to 8.0 months) for all patients. CONCLUSION: Initial histology, age, KPS, and corticosteroid use are prognostic for survival in recurrent glioma patients. To allow comparisons across phase II trials, enrollment criteria may need to be restricted.
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Glioma/mortalidad , Glioma/terapia , Factores de Edad , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , Terapia Combinada , Femenino , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Pronóstico , Modelos de Riesgos Proporcionales , Análisis de Regresión , Factores de Riesgo , Tasa de SupervivenciaRESUMEN
PURPOSE: This multi-institutional phase I trial was designed to determine the maximum-tolerated dose (MTD) of cilengitide (EMD 121974) and to evaluate the use of perfusion magnetic resonance imaging (MRI) in patients with recurrent malignant glioma. PATIENTS AND METHODS: Patients received cilengitide twice weekly on a continuous basis. A treatment cycle was defined as 4 weeks. Treatment-related dose-limiting toxicity (DLT) was defined as any grade 3 or 4 nonhematologic toxicity or grade 4 hematologic toxicity of any duration. RESULTS: A total of 51 patients were enrolled in cohorts of six patients to doses of 120, 240, 360, 480, 600, 1,200, 1,800, and 2,400 mg/m2 administered as a twice weekly intravenous infusion. Three patients progressed early and were inevaluable for toxicity assessment. The DLTs observed were one thrombosis (120 mg/m2), one grade 4 joint and bone pain (480 mg/m2), one thrombocytopenia (600 mg/m2) and one anorexia, hypoglycemia, and hyponatremia (800 mg/m2). The MTD was not reached. Two patients demonstrated complete response, three patients had partial response, and four patients had stable disease. Perfusion MRI revealed a significant relationship between the change in tumor relative cerebral blood flow (rCBF) from baseline and area under the plasma concentration versus time curve after 16 weeks of therapy. CONCLUSION: Cilengitide is well tolerated to doses of 2,400 mg/m2, durable complete and partial responses were seen in this phase I study, and clinical response appears related to rCBF changes.
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Antineoplásicos/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Glioma/tratamiento farmacológico , Venenos de Serpiente/uso terapéutico , Antineoplásicos/efectos adversos , Neoplasias Encefálicas/patología , Estudios de Cohortes , Glioma/patología , Humanos , Imagen por Resonancia Magnética , Dosis Máxima Tolerada , Recurrencia , Venenos de Serpiente/efectos adversosRESUMEN
PURPOSE: This phase I trial was designed to (1) establish the dose of O6-benzylguanine (O6-BG) administered intravenously as a continuous infusion that suppresses O6-alkylguanine-DNA alkyltransferase (AGT) levels in brain tumors, (2) evaluate the safety of extending continuous-infusion O6-BG at the optimal dose with intracranially implanted carmustine wafers, and (3) measure the pharmacokinetics of O6-BG and its metabolite. PATIENTS AND METHODS: The first patient cohort (group A) received 120 mg/m2 of O6-BG over 1 hour followed by a continuous infusion for 2 days at escalating doses presurgery. Tumor samples were evaluated for AGT levels. The continuous-infusion dose that resulted in undetectable AGT levels in 11 or more of 14 patients was used in the second patient cohort. Group B received the optimal dose of O6-BG for 2, 4, 7, or 14 days after surgical implantation of the carmustine wafers. The study end point was dose-limiting toxicity (DLT). RESULTS: Thirty-eight patients were accrued. In group A, 12 of 13 patients had AGT activity levels of less than 10 fmol/mg protein with a continuous-infusion O6-BG dose of 30 mg/m2/d. Group B patients were enrolled onto 2-, 4-, 7-, and 14-day continuous-infusion cohorts. One DLT of grade 3 elevation in ALT was seen. Other non-DLTs included ataxia and headache. For up to 14 days, steady-state levels of O6-BG were 0.1 to 0.4 micromol/L, and levels for O6-benzyl-8-oxoguanine were 0.7 to 1.3 micromol/L. CONCLUSION: Systemically administered O6-BG can be coadministered with intracranially implanted carmustine wafers, without added toxicity. Future trials are required to determine if the inhibition of tumor AGT levels results in increased efficacy.
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Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Glioma/tratamiento farmacológico , Guanina/análogos & derivados , Recurrencia Local de Neoplasia/tratamiento farmacológico , Adulto , Anciano , Antineoplásicos/efectos adversos , Carmustina/administración & dosificación , Sistemas de Liberación de Medicamentos , Femenino , Guanina/administración & dosificación , Guanina/efectos adversos , Guanina/farmacocinética , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , O(6)-Metilguanina-ADN Metiltransferasa/antagonistas & inhibidores , O(6)-Metilguanina-ADN Metiltransferasa/metabolismoRESUMEN
INTRODUCTION: Carboxyamido-triazole (CAI) is a synthetic inhibitor of non-voltage-gated calcium channels that reversibly inhibits angiogenesis, tumor cell proliferation, and metastatic potential. This study examined the efficacy, safety and pharmacokinetics of oral CAI in the treatment of patients with newly diagnosed glioblastoma multiforme (GBM) in an open-label, single arm non-randomized phase 2 trial. METHODS: Eligible patients with histologically confirmed GBM started CAI therapy (250 mg daily) on the first day of radiation (6000 cGy in 30 fractions) and continued until progression, unless side effects became intolerable. The primary outcome was survival compared to historical controls within the NABTT CNS Consortium database. Secondary outcomes included toxicity and pharmacokinetic parameters. RESULTS: Fifty-five patients were enrolled with a median Karnofsky performance status of 90 and age of 56 years. Forty-six (84%) of these patients had debulking surgeries and 52 have died. The median survival was 10.3 months (95% confidence interval (CI), 8.5-12.8) compared to 12.1 months (95% CI, 10.3-13.3) in the NABTT reference group (p = 0.97). Significant toxicities included 2 incidents of reversible vision loss. The mean CAI plasma concentration for patients taking enzyme inducing antiepileptic drugs (EIAED) was 1.35 +/-1.22 compared to 4.06 +/- 1.50 (p < 0.001) for subjects not taking these agents. Overall survival and grade > or = 3 toxicities were comparable by EIAED status. CONCLUSIONS: This study demonstrated that (1) CAI can be administered safely with concomitant cranial irradiation, (2) the pharmacokinetics of CAI are significantly affected by co-administration of EIAED, and (3) the survival of patients with newly diagnosed GBM was not improved with this novel agent, despite achieving adequate drug levels.
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Antineoplásicos/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/radioterapia , Bloqueadores de los Canales de Calcio/uso terapéutico , Glioblastoma/tratamiento farmacológico , Glioblastoma/radioterapia , Triazoles/uso terapéutico , Administración Oral , Adulto , Anciano , Anticonvulsivantes/uso terapéutico , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/mortalidad , Bloqueadores de los Canales de Calcio/administración & dosificación , Bloqueadores de los Canales de Calcio/efectos adversos , Bloqueadores de los Canales de Calcio/farmacocinética , Estudios de Casos y Controles , Quimioterapia Adyuvante , Interacciones Farmacológicas , Glioblastoma/diagnóstico , Glioblastoma/mortalidad , Humanos , Estimación de Kaplan-Meier , Persona de Mediana Edad , Radioterapia Adyuvante , Resultado del Tratamiento , Triazoles/administración & dosificación , Triazoles/efectos adversos , Triazoles/farmacocinética , Estados Unidos/epidemiologíaRESUMEN
PURPOSE: Procarbazine hydrochloride (PCB) is one of the few anticancer drugs with activity against high-grade gliomas. This study was conducted to determine if the maximum tolerated dose and pharmacokinetics of PCB are affected by the concurrent use of enzyme-inducing antiseizure drugs (EIASD). EXPERIMENTAL DESIGN: Adults with recurrent high-grade glioma were divided into cohorts who were (+) and were not (-) taking EIASDs. PCB was given orally for 5 consecutive days each month. Six patients were evaluated at each dose level beginning with 200 mg/m2/d and escalated using the modified continual reassessment method. Toxicity and response were assessed. Pharmacokinetic studies were done with a new electrospray ionization mass spectrometry assay. RESULTS: Forty-nine patients were evaluated. The maximum tolerated dose was 393 mg/m2/d for the +EIASD group and the highest dose evaluated in -EIASD patients was 334 mg/m2/d. Myelosuppression was the primary dose-limiting toxicity. Significant hepatic dysfunction occurred in three patients in the +EIASD cohort. Four partial responses (8%) and no complete responses were observed. PCB exhibited linear pharmacokinetics with no significant differences between the two cohorts. A marked increase in peak PCB levels was noted on day 5 relative to day 1, which was not attributable to drug accumulation. CONCLUSIONS: This study suggests that (a) EIASD use does not significantly affect the pharmacokinetics of PCB; (b) changes in the peak plasma concentration of PCB, consistent with decreased apparent oral clearance due to autoinhibition of hepatic metabolism, occur with daily dosing; and (c) severe hepatic dysfunction may accompany this administration schedule.
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Anticonvulsivantes/farmacología , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Glioma/tratamiento farmacológico , Procarbazina/efectos adversos , Procarbazina/farmacocinética , Administración Oral , Adulto , Anciano , Anticonvulsivantes/administración & dosificación , Antineoplásicos/administración & dosificación , Estudios de Cohortes , Progresión de la Enfermedad , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Inducción Enzimática/efectos de los fármacos , Femenino , Estudios de Seguimiento , Glioma/enzimología , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Procarbazina/administración & dosificación , Espectrometría de Masa por Ionización de Electrospray/métodos , Factores de Tiempo , Resultado del TratamientoRESUMEN
Penicillamine is an oral agent used to treat intracerebral copper overload in Wilson's disease. Copper is a known regulator of angiogenesis; copper reduction inhibits experimental glioma growth and invasiveness. This study examined the feasibility, safety, and efficacy of creating a copper deficiency in human glioblastoma multiforme. Forty eligible patients with newly diagnosed glioblastoma multiforme began radiation therapy (6000 cGy in 30 fractions) in conjunction with a low-copper diet and escalating doses of penicillamine. Serum copper was measured at baseline and monthly. The primary end point of this study was overall survival compared to historical controls within the NABTT CNS Consortium database. The 25 males and 15 females who were enrolled had a median age of 54 years and a median Karnofsky performance status of 90. Surgical resection was performed in 83% of these patients. Normal serum copper levels at baseline (median, 130 microg/dl; range, 50-227 microg/dl) fell to the target range of <50 microg/dl (median, 42 microg/dl; range, 12-118 microg/dl) after two months. Penicillamine-induced hypocupremia was well tolerated for months. Drug-related myelosuppression, elevated liver function tests, and skin rash rapidly reversed with copper repletion. Median survival was 11.3 months, and progression-free survival was 7.1 months. Achievement of hypocupremia did not significantly increase survival. Although serum copper was effectively reduced by diet and penicillamine, this antiangiogenesis strategy did not improve survival in patients with glioblastoma multiforme.
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Neoplasias Encefálicas/terapia , Quelantes/toxicidad , Cobre/sangre , Glioblastoma/terapia , Neovascularización Patológica/tratamiento farmacológico , Penicilamina/toxicidad , Neoplasias Encefálicas/mortalidad , Dietoterapia , Femenino , Glioblastoma/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Análisis de SupervivenciaRESUMEN
We determined the maximum tolerated dose (MTD), toxicity profile, pharmacokinetic parameters, and preliminary efficacy data of oral sodium phenylbutyrate (PB) in patients with recurrent malignant gliomas. Twenty-three patients with supratentorial recurrent malignant gliomas were enrolled on this dose escalation trial. Four dose levels of PB were studied: 9, 18, 27, and 36 g/day. Data were collected to assess toxicity, response, survival, and pharmacokinetics. All PB doses of 9, 18, and 27 g/day were well tolerated. At 36 g/day, two of four patients developed dose-limiting grade 3 fatigue and somnolence. At the MTD of 27 g/day, one of seven patients developed reversible grade 3 somnolence. Median survival from time of study entry was 5.4 months. One patient had a complete response for five years, and no partial responses were noted, which yielded an overall response rate of 5%. Plasma concentrations of 706, 818, 1225, and 1605 muM were achieved with doses of 9, 18, 27, and 36 g/day, respectively. The mean value for PB clearance in this patient population was 22 liters/h, which is significantly higher than the 16 liters/h reported in patients with other malignancies who were not receiving P450 enzyme-inducing anticonvulsant drugs (P = 0.038). This study defines the MTD and recommended phase 2 dose of PB at 27 g/day for heavily pretreated patients with recurrent gliomas. The pharmacology of PB appears to be affected by concomitant administration of P450-inducing anticonvulsants.
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Antineoplásicos/farmacología , Glioma/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Fenilbutiratos/farmacología , Neoplasias Supratentoriales/tratamiento farmacológico , Administración Oral , Adulto , Anciano , Anticonvulsivantes/uso terapéutico , Antineoplásicos/efectos adversos , Antineoplásicos/sangre , Área Bajo la Curva , Sistema Enzimático del Citocromo P-450/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Femenino , Glioma/mortalidad , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Recurrencia Local de Neoplasia/mortalidad , Fenilbutiratos/efectos adversos , Fenilbutiratos/sangre , Neoplasias Supratentoriales/mortalidadRESUMEN
ONYX-015 is an oncolytic virus untested as a treatment for malignant glioma. The NABTT CNS Consortium conducted a dose-escalation trial of intracerebral injections of ONYX-015. Cohorts of six patients at each dose level received doses of vector from 10(7) plaque-forming units (pfu) to 10(10) pfu into a total of 10 sites within the resected glioma cavity. Adverse events were identified on physical exams and testing of hematologic, renal, and liver functions. Efficacy data were obtained from serial MRI scans. None of the 24 patients experienced serious adverse events related to ONYX-015. The maximum tolerated dose was not reached at 10(10) pfu. The median time to progression after treatment with ONYX-015 was 46 days (range 13 to 452 + days). The median survival time was 6.2 months (range 1.3 to 28.0 + months). One patient has not progressed and 1 patient showed regression of interval-increased enhancement. With more than 19 months of follow-up, 1/6 recipients at a dose of 10(9) and 2/6 at a dose of 10(10) pfu remain alive. In 2 patients who underwent a second resection 3 months after ONYX-015 injection, a lymphocytic and plasmacytoid cell infiltrate was observed. Injection of ONYX-015 into glioma cavities is well tolerated at doses up to 10(10) pfu.
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Adenoviridae/genética , Neoplasias Encefálicas/terapia , Terapia Genética/métodos , Glioma/terapia , Recurrencia Local de Neoplasia/terapia , Proteínas E1B de Adenovirus/genética , Adulto , Anciano , Encéfalo/patología , Neoplasias Encefálicas/patología , Relación Dosis-Respuesta a Droga , Femenino , Terapia Genética/efectos adversos , Vectores Genéticos/administración & dosificación , Glioma/patología , Humanos , Inyecciones Intralesiones , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Vacunas Virales , Replicación Viral/genéticaRESUMEN
OBJECT: In this study the authors evaluated the safety and performance of the GliaSite Radiation Therapy System (RTS) in patients with recurrent malignant brain tumors who were undergoing tumor resection. METHODS: The GliaSite is an inflatable balloon catheter that is placed in the resection cavity at the time of tumor debulking. Low-dose-rate radiation is delivered with an aqueous solution of organically bound iodine-125 (lotrex [sodium 3-(125I)-iodo-4-hydroxybenzenesulfonate]), which are temporarily introduced into the balloon portion of the device via a subcutaneous port. Adults with recurrent malignant glioma underwent resection and GliaSite implantation. One to 2 weeks later, the device was filled with Iotrex for 3 to 6 days, following which the device was explanted. Twenty-one patients with recurrent high-grade astrocytomas were enrolled in the study and received radiation therapy. There were two end points: 1) successful implantation and delivery of brachytherapy; and 2) safety of the device. Implantation of the device, delivery of radiation, and the explantation procedure were well tolerated. At least 40 to 60 Gy was delivered to all tissues within the target volume. There were no serious adverse device-related events during brachytherapy. One patient had a pseudomeningocele, one patient had a wound infection, and three patients had meningitis (one bacterial, one chemical, and one aseptic). No symptomatic radiation necrosis was identified during 21.8 patient-years of follow up. The median survival of previously treated patients was 12.7 months (95% confidence interval 6.9-15.3 months). CONCLUSIONS: The GliaSite RTS performs safely and efficiently. It delivers a readily quantifiable dose of radiation to tissue at the highest risk for tumor recurrence.
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Bencenosulfonatos , Braquiterapia/efectos adversos , Braquiterapia/instrumentación , Neoplasias Encefálicas/radioterapia , Cateterismo/instrumentación , Glioma/radioterapia , Radioisótopos de Yodo , Adulto , Anciano , Bencenosulfonatos/administración & dosificación , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/cirugía , Catéteres de Permanencia , Diseño de Equipo , Estudios de Factibilidad , Femenino , Glioma/patología , Glioma/cirugía , Humanos , Radioisótopos de Yodo/administración & dosificación , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Estadificación de Neoplasias , Dosis de RadiaciónRESUMEN
PURPOSE: A preliminary evaluation of the efficacy of irinotecan in patients with malignant glioma demonstrated modest activity. A markedly lower than expected incidence of drug-related toxicity was also noted. This was consistent with pharmacokinetic data indicating that the total body clearance (CL) of irinotecan in this patient population was considerably greater than in colorectal cancer patients. Concomitant medications used chronically in brain cancer patients, especially glucocorticoids and anticonvulsants that induce hepatic enzymes involved in the metabolism or excretion of drugs, were believed to be the cause of the alteration in pharmacokinetic behavior. A Phase I study was therefore undertaken in patients with recurrent malignant gliomas to independently determine the maximum tolerated dose (MTD) of irinotecan in patients stratified according to the use of enzyme-inducing anticonvulsants (EIAs). EXPERIMENTAL DESIGN: Patients with recurrent malignant gliomas received irinotecan as a weekly 90-min i.v. infusion for four consecutive weeks, with additional cycles of treatment repeated every 6 weeks. The starting dose was 125 mg/m(2)/week for both groups of patients (+/-EIA). Groups of >/==" BORDER="0">3 patients were evaluated at each dose level, and the modified continual reassessment method was used for dose adjustments. The plasma pharmacokinetics of irinotecan, its active metabolite, 7-ethyl-10-hydroxy-camptothecin (SN-38), and the glucuronide conjugate of SN-38, SN-38 glucuronide, were determined in all patients during treatment with the first weekly dose. RESULTS: Forty patients were enrolled into the study and treated with a total of 135 cycles of irinotecan. The MTD was determined to be 411 mg/m(2)/week in the +EIA cohort and 117 mg/m(2)/week in the -EIA cohort for the weekly x 4 every 6 weeks schedule. Pharmacokinetic studies showed that the CL of irinotecan was distinctly dose dependent in the patients receiving EIAs, decreasing from approximately 50 liters/h/m(2) at the lower dose levels (125-238 mg/m(2)) to a mean +/- SD value of 29.7 +/- 9.0 liters/h/m(2) (n = 7) at the MTD. The grand mean CL for a group of 13 patients who were not taking EIAs, 18.8 +/- 10.6 liters/h/m(2), was significantly different from the mean CL at the MTD of the +EIA cohort (P = 0.033). Mean values of the AUC of SN-38 (P = 0.4) and SN-38 glucuronide (P = 0.55) were not significantly different at the MTDs for the two cohorts of patients. CONCLUSIONS: The MTD of irinotecan was 3.5 times greater in patients with malignant glioma who were concurrently receiving EIAs than in those who were not. This study has also served to confirm that the concomitant administration of EIAs results in marked enhancement in the CL of irinotecan. These findings have important implications for subsequent clinical trials to further evaluate irinotecan in brain cancer patients and underscore the importance of assessing the potential for pharmacokinetic interactions between concurrent medications and chemotherapeutic agents.