RESUMEN
SevenChildren's Oncology Group phase 2 trials for patients with relapsed/progressive solid tumors were analyzed to estimate the event-free survival (EFS) for relapsed/progressive Ewing sarcoma. One hundred twenty-eight Ewing sarcoma patients were enrolled and 124 events occurred. The 6-month EFS was 12.7%, demonstrating the poor outcome of these patients. Only docetaxel achieved its protocol-specified radiographic response rate for activity; however, the EFS for docetaxel was similar to other agents, indicating that a higher radiographic response rate may not translate into superior disease control. This EFS benchmark could be utilized as an additional endpoint in trials for recurrent Ewing sarcoma.
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Neoplasias Óseas , Tumores Neuroectodérmicos Periféricos Primitivos , Sarcoma de Ewing , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Óseas/patología , Niño , Docetaxel/uso terapéutico , Humanos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Sarcoma de Ewing/patologíaRESUMEN
BACKGROUND: Infants with acute lymphoblastic leukemia (ALL) treated with high-dose methotrexate may have reduced methotrexate clearance (CL) due to renal immaturity, which may predispose them to toxicity. OBJECTIVE: The aim of this study was to develop a population pharmacokinetic (PK) model of methotrexate in infants with ALL. METHODS: A total of 672 methotrexate plasma concentrations were obtained from 71 infants enrolled in the Children's Oncology Group (COG) Clinical Trial P9407. Infants received methotrexate 4 g/m2 intravenously for four cycles during weeks 4-12 of intensification. A population PK analysis was performed using NONMEM® version 7.4. The final model was evaluated using a non-parametric bootstrap and a visual predictive check. Simulations were performed to evaluate methotrexate dose and the utility of a bedside algorithm for dose individualization. RESULTS: Methotrexate was best characterized by a two-compartment model with allometric scaling. Weight was the only covariate included in the final model. The coefficient of variation for interoccasion variability (IOV) on CL was relatively high at 25.4%, compared with the interindividual variability for CL and central volume of distribution (10.7% and 13.2%, respectively). Simulations identified that 21.1% of simulated infants benefitted from bedside dose adjustment, and adjustment of methotrexate doses during infusions can avoid supratherapeutic concentrations. CONCLUSION: Infants treated with high-dose methotrexate demonstrated a relatively high degree of IOV in methotrexate CL. The magnitude of IOV in the CL of methotrexate suggests that use of a bedside algorithm may avoid supratherapeutic methotrexate concentrations resulting from high IOV in methotrexate CL.
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Antimetabolitos Antineoplásicos/farmacocinética , Metotrexato/farmacocinética , Modelos Biológicos , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Femenino , Humanos , Lactante , Masculino , Medicina de PrecisiónRESUMEN
Efficacious ventricular assist device (VAD) support in pediatric patients depends on successful antithrombotic management. The experience with antithrombotic management for the EXCOR Pediatric VAD Investigational Device Exemption (IDE) study is described. All 68 children in North America enrolled in the IDE study from May 9, 2007 to December 10, 2010 are included. The Edmonton Anticoagulation and Platelet Inhibition Protocol was provided for management guidance. Monitoring parameters, drug dosing, targeted serious adverse events, and pump changes were reviewed. Major bleeding occurred in 43% of all subjects with most events occurring within 14 days of implantation. Bleeding events were probably/definitely related in 24% to antithrombotic management. Neurologic events occurred in 28% of subjects and were probably/definitely related in 9% to antithrombotic therapy intensity. Most neurologic events occurred between 4 and 30 days postimplantation and sporadically thereafter. Pump change occurred in 56% of subjects. Use of an antithrombotic protocol for enrolled subjects was possible in this multicenter study. Incidence of significant bleeding and thromboembolic events was acceptable when balanced against life-saving benefits of VADs. Further studies are needed to optimize the antithrombotic management of this patient population.
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Fibrinolíticos/uso terapéutico , Corazón Auxiliar/efectos adversos , Adolescente , Niño , Preescolar , Femenino , Hemorragia/etiología , Humanos , Lactante , Masculino , Estudios Prospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: Current warfarin dosing guidelines for pediatric patients do not account for obesity. Published data from adults suggest that obesity may affect warfarin dosing requirements. Obesity is prevalent in the pediatric population, and current warfarin dosing methods should be evaluated in obese pediatric patients. METHODS: Patients aged 2 to 18 years who were obese and initiated on warfarin therapy at our institution as inpatients from 2004 to 2010 were identified and matched in a 1:2 ratio by age and sex with nonobese patients who were initiated on warfarin therapy. Patients were categorized obese per Centers for Disease Control guidelines. Demographic and disease state information, warfarin dosing information, INR values, and interacting medications were collected. Warfarin was dosed according to the institutional guidelines adapted from the published literature. Time to therapeutic INR value was the primary endpoint and percent of patients with supratherapeutic INR values was the secondary endpoint. RESULTS: A total of 30 patients met the study criteria (10 obese, 20 nonobese), and baseline demographic variables were similar. No significant differences were noted in the number of INR values drawn, number of warfarin doses administered, or length of stay. Initial and maximum doses of warfarin per kg were significantly lower in obese patients compared with nonobese patients (P<0.05). Median time to therapeutic INR value was twice as long in obese patients as in nonobese patients (median=6 [range, 4 to 28 d] versus median=3 [range, 1 to 10 d]; P<0.01). CONCLUSIONS: Obese pediatric patients have an increased time to therapeutic INR value when traditional warfarin dosing guidelines are used.
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Anticoagulantes/uso terapéutico , Índice de Masa Corporal , Obesidad/complicaciones , Trombosis/complicaciones , Trombosis/tratamiento farmacológico , Warfarina/uso terapéutico , Adolescente , Niño , Preescolar , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Práctica Institucional , Masculino , Guías de Práctica Clínica como Asunto , Estudios RetrospectivosRESUMEN
BACKGROUND: Warfarin therapy in pediatric patients can be difficult to manage with bleeding as a primary adverse event. Therapy initiation can be difficult as doses to achieve therapeutic outcomes are being determined. Evaluation of readmission for bleeding in pediatric patients discharged on warfarin therapy may be useful to prevent adverse events. METHODS: The Pediatric Health Information System (PHIS) was queried to identify all patients <19 years of age who were discharged from a pediatric hospital on warfarin therapy. Patients who were readmitted with bleeding in the first 30 days after discharge were identified and patient variables, hospital stay variables, and medications at discharge were identified. Univariate and multivariate analysis was performed to identify independent risk factors for bleeding readmission. RESULTS: A total of 4,883 patients met study criteria (56% male, mean age 10.1 + 5.9 years). The two most common indications for warfarin therapy were cardiac valve replacement (23.6%) and Fontan procedure (19.5%). Ninety-seven patients (1.99%) were readmitted with bleeding within 30 days of discharge [median time 9 days (IQR 5-16 days)]. Multivariate analysis identified Asian race (OR 4.0, P < 0.01); mitral valve replacement (OR 2.5, P < 0.01); escitalopram at discharge (OR 4.2, P = 0.02); levofloxacin at discharge (OR 8.3, P < 0.01); lansoprazole at discharge (OR 1.7, P = 0.047); and length of stay (OR 1.01, P = 0.047) as significant for bleeding readmission. CONCLUSION: Pediatric patients discharged on warfarin may be readmitted for bleeding within 30 days if risk factors are present. Risk factors include patient genetic profile, drug interactions, and indications with higher goal INR values.
Asunto(s)
Anticoagulantes/efectos adversos , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Sistemas de Información en Hospital , Readmisión del Paciente , Hemorragia Posoperatoria/inducido químicamente , Hemorragia Posoperatoria/epidemiología , Warfarina/efectos adversos , Adolescente , Antibacterianos/administración & dosificación , Antibacterianos/efectos adversos , Anticoagulantes/administración & dosificación , Asiático , Niño , Preescolar , Citalopram/administración & dosificación , Citalopram/efectos adversos , Femenino , Humanos , Relación Normalizada Internacional , Levofloxacino , Masculino , Ofloxacino/administración & dosificación , Ofloxacino/efectos adversos , Factores de Riesgo , Inhibidores Selectivos de la Recaptación de Serotonina/administración & dosificación , Inhibidores Selectivos de la Recaptación de Serotonina/efectos adversos , Factores de Tiempo , Warfarina/administración & dosificaciónRESUMEN
Romiplostim, a thrombopoietin-mimetic peptibody, increases and maintains platelet counts in adults with immune thrombocytopenia (ITP). In this first study of a thrombopoietic agent in children, patients with ITP of ≥ 6 months' duration were stratified by age 1:2:2 (12 months-< 3 years; 3-< 12 years; 12-< 18 years). Children received subcutaneous injections of romiplostim (n = 17) or placebo (n = 5) weekly for 12 weeks, with dose adjustments to maintain platelet counts between 50 × 10(9)/L and 250 × 10(9)/L. A platelet count ≥ 50 × 10(9)/L for 2 consecutive weeks was achieved by 15/17 (88%) patients in the romiplostim group and no patients in the placebo group (P = .0008). Platelet counts ≥ 50 × 10(9)/L were maintained for a median of 7 (range, 0-11) weeks in romiplostim patients and 0 (0-0) weeks in placebo patients (P = .0019). The median weekly dose of romiplostim at 12 weeks was 5 µg/kg. Fourteen responders received romiplostim for 4 additional weeks for assessment of pharmacokinetics. No patients discontinued the study. There were no treatment-related, serious adverse events. The most commonly reported adverse events in children, as in adults, were headache and epistaxis. In this short-term study, romiplostim increased platelet counts in 88% of children with ITP and was well-tolerated and apparently safe. The trial was registered with http://www.clinicaltrials.gov as NCT00515203.
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Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Receptores Fc/administración & dosificación , Receptores de Trombopoyetina/agonistas , Proteínas Recombinantes de Fusión/administración & dosificación , Trombopoyesis/efectos de los fármacos , Trombopoyetina/administración & dosificación , Adolescente , Niño , Preescolar , Método Doble Ciego , Femenino , Humanos , Lactante , Inyecciones Subcutáneas , Masculino , Proteínas Recombinantes de Fusión/efectos adversos , Proteínas Recombinantes de Fusión/farmacocinética , Trombopoyetina/efectos adversos , Trombopoyetina/farmacocinética , Resultado del TratamientoRESUMEN
PURPOSE: We studied the relationship between doxorubicin pharmacokinetics and body composition in children with cancer. PATIENTS AND METHODS: Children between 1 and 21 years of age, receiving doxorubicin as an infusion of any duration <24 h on either a 1-day or 2-day schedule were eligible if they had no significant abnormality of liver function tests, their dose of doxorubicin was not based on ideal body weight or otherwise "capped," and they weighed > or =12 kg. Body composition was measured by dual-energy X-ray absorptiometry. Doxorubicin and doxorubicinol concentration in plasma were measured by high pressure liquid chromatography. NONMEM was used to perform pharmacokinetic model fitting and S-PLUS was used to perform a post hoc analysis to examine the effect of body composition on pharmacokinetic parameters. RESULTS: Twenty-two subjects (16 male; 10 Hispanic, 10 Caucasian, 2 Asian) completed the study. The median age was 15.0 years (range 3.3-21.5), median weight was 51.5 kg (range 12.4-80), median BMI was 19.7 (range 13.2-30.0), and median body fat was 25% (range 15-36). The population mean clearance of doxorubicin was 420 ml/min/m(2). Doxorubicinol but not doxorubicin clearance was lower in patients with body fat greater than 30%. CONCLUSIONS: Doxorubicinol clearance is decreased in children with >30% body fat. This finding is potentially important clinically, because doxorubicinol may contribute significantly to cardiac toxicity after doxorubicin administration. Further study of the body composition on doxorubicin and doxorubicinol pharmacokinetics and on clinical outcomes is warranted.
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Antineoplásicos/farmacocinética , Composición Corporal , Doxorrubicina/farmacocinética , Neoplasias/sangre , Obesidad/sangre , Adolescente , Adulto , Antineoplásicos/sangre , Niño , Preescolar , Doxorrubicina/análogos & derivados , Doxorrubicina/sangre , Femenino , Humanos , Lactante , Masculino , Tasa de Depuración Metabólica , Estadificación de Neoplasias , Neoplasias/diagnóstico , Pronóstico , Estudios Prospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
PURPOSE: A phase II study was performed to determine the efficacy of irinotecan (IRN) in children with refractory solid tumors. Secondary objectives were to evaluate toxicity, pharmacokinetics, pharmacodynamics, and UGT1A1 genotype. PATIENTS AND METHODS: A total of 181 patients were enrolled, of whom 171 were eligible. Patients received IRN 50 mg/m2/d for 5 days repeated every 3 weeks. Pharmacokinetic studies and UGT1A1 genotyping were performed. RESULTS: Of 161 patients assessable for response, one patient with hepatoblastoma had a complete response, with partial responses observed in patients with medulloblastoma (n = 4), rhabdomyosarcoma (n = 1), neuroblastoma (n = 1), and germinoma (n = 1), for an overall response rate of 5%. Grade 4 neutropenia and grade 3 to 4 diarrhea occurred in less than 7% of the courses administered. Pharmacokinetic studies were available for 79 patients. The mean +/- standard deviation IRN plasma clearance was 374 +/- 148 mL/min/m2, with median relative extent of conversion and relative extent of glucuronidation of 0.05 (range, 0.01 to 0.25) and 2.24 (range, 0.39 to 9.6), respectively. No association between UGT1A1 genotype (n = 61) and toxicity or pharmacokinetic parameters was observed. CONCLUSION: IRN 50 mg/m2/d for 5 days every 21 days is well tolerated, but was not effective as a single agent in a spectrum of solid tumors, with the possible exception of patients with medulloblastoma (16% response rate). There was no association between UGT1A1*28 genotype and toxicity or pharmacokinetic parameters.
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Antineoplásicos Fitogénicos/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Camptotecina/análogos & derivados , Neoplasias/tratamiento farmacológico , Adolescente , Adulto , Camptotecina/uso terapéutico , Niño , Preescolar , Femenino , Glucuronosiltransferasa/genética , Hepatoblastoma/tratamiento farmacológico , Humanos , Lactante , Irinotecán , Masculino , Meduloblastoma/tratamiento farmacológico , Neoplasias/genética , Resultado del TratamientoRESUMEN
PURPOSE: A phase 1 study to determine the maximum-tolerated dose, dose-limiting toxicity, pharmacokinetics, and biological effects of bortezomib in children with recurrent/refractory leukemia. EXPERIMENTAL DESIGN: Bortezomib was administered twice weekly for 2 consecutive weeks at either 1.3 or 1.7 mg/m(2) dose followed by a 1-week rest. Bortezomib pharmacokinetics and nuclear factor kappaB (NF-kappaB) binding activity were evaluated during the first treatment cycle. RESULTS: Twelve patients (nine with acute lymphoblastic leukemia, three with acute myelogenous leukemia), median age 11 years (range, 1-18 years), were enrolled between May 2004 and November 2005, of whom seven were not fully evaluable for toxicity due to rapidly progressive disease or uncontrolled infection. Dose-limiting toxicities occurred in two patients at the 1.7 mg/m(2) dose level. One patient experienced grade 3 confusion and the other patient had grade 4 febrile neutropenia associated with grade 4 hypotension and grade 3 creatinine. Pharmacokinetic analysis at 1.3 mg/m(2) revealed a clearance of 11 mL/h/m(2), a central volume of distribution of 6.7 L/m(2), and a terminal half-life of 12.6 h. NF-kappaB activity was examined in five patients and was noted to transiently increase and then decrease 4- to 6-fold by 24 h following bortezomib in two patients. There were no objective clinical responses. CONCLUSIONS: For children with leukemia, the recommended phase 2 dose of bortezomib, administered twice weekly for 2 weeks followed by a 1-week rest, is 1.3 mg/m(2)/dose. Although bortezomib treatment inhibited NF-kappaB activity, bortezomib had little activity as a single agent in this population.
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Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Ácidos Borónicos/farmacocinética , Ácidos Borónicos/uso terapéutico , Leucemia/tratamiento farmacológico , Pirazinas/farmacocinética , Pirazinas/uso terapéutico , Adolescente , Bortezomib , Niño , Preescolar , Relación Dosis-Respuesta a Droga , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Quinasa I-kappa B/efectos de los fármacos , Immunoblotting , Lactante , Masculino , Dosis Máxima Tolerada , FN-kappa B/efectos de los fármacos , Complejo de la Endopetidasa Proteasomal/efectos de los fármacosRESUMEN
PURPOSE: We performed a pharmacokinetic evaluation of methotrexate (MTX) in infants with acute lymphoblastic leukemia enrolled on the Pediatric Oncology Group (POG) 9407 Infant Leukemia Study to evaluate the effects of age on MTX pharmacokinetics and pharmacodynamics. METHODS: A pharmacokinetic database of 61 patients was developed by combining MTX data obtained from 16 patients in a pharmacokinetic sub-study with data obtained for clinical care in other patients enrolled on the POG 9407 protocol. The data were analyzed for the first dose of MTX given to patients in induction/intensification therapy. Patients received MTX (4 g/m2) over 24 h at week 4 of therapy. Toxicity data were also reviewed to evaluate the incidence of common MTX toxicities during the first 6 weeks of therapy (the induction/intensification phase). RESULTS: Steady-state clearance (mean+/-standard deviation) for infants aged 0-6 months was 89+/-32 ml/min/m2 compared to 111+/-40 for infants aged 7-12 months (P=0.030). In the subgroup of infants aged 0-3 months the mean steady-state clearance was 84+/-30 ml/min/m2 (P=0.026 vs. the 7-12-month group). The incidence of renal toxicity (all grades) during induction/intensification therapy was 23% in the 0-3 months age group compared to 0% (for n=27) in the group 7-12 months of age (P=0.029). There were no significant differences in hepatoxicity or mucous membrane toxicity between age groups. CONCLUSIONS: A modest difference in steady-state MTX clearance is observed between younger infants (0-6 months) and older infants (7-12 months). Very young infants (0-3 months) also experienced a slightly higher incidence of renal toxicity during induction/intensification therapy. Steady-state clearance for the older infants is similar to values reported for children in other studies.
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Metotrexato/farmacocinética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Factores de Edad , Esquema de Medicación , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Metotrexato/efectos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismoRESUMEN
PURPOSE: To evaluate the efficacy and safety of clofarabine, a novel deoxyadenosine analog, in pediatric patients with refractory or relapsed acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: In a phase II, open-label, multicenter study, 61 pediatric patients with refractory or relapsed ALL received clofarabine 52 mg/m2 intravenously over 2 hours daily for 5 days, every 2 to 6 weeks. The median age was 12 years (range, 1 to 20 years), and the median number of prior regimens was three (range, two to six regimens). RESULTS: The response rate was 30%, consisting of seven complete remissions (CR), five CRs without platelet recovery (CRp), and six partial remissions. Remissions were durable enough to allow patients to proceed to hematopoietic stem-cell transplantation (HSCT) after clofarabine. Median CR duration in patients who did not receive HSCT was 6 weeks, with four patients maintaining CR or CRp for 8 weeks or more (8+, 12, 37+, and 48 weeks) on clofarabine therapy alone. The most common adverse events of grade > or = 3 were febrile neutropenia, anorexia, hypotension, and nausea. CONCLUSION: Clofarabine is active as a single agent in pediatric patients with multiple relapsed or refractory ALL. The toxicity profile is as expected in this heavily pretreated patient population. Studies exploring rational combinations of clofarabine with other agents are ongoing in an effort to maximize clinical benefit.
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Arabinonucleósidos/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Nucleótidos de Adenina , Adolescente , Adulto , Arabinonucleósidos/administración & dosificación , Arabinonucleósidos/efectos adversos , Niño , Preescolar , Clofarabina , Femenino , Humanos , Lactante , Infusiones Intravenosas , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Recurrencia , Resultado del TratamientoRESUMEN
PURPOSE: We performed a Phase I trial of irofulven (MGI 114) to determine the maximum tolerated dose (MTD), the dose-limiting toxicity (DLT), and the plasma pharmacokinetics of irofulven in children < or=21 years of age with refractory/recurrent malignancies. EXPERIMENTAL DESIGN: Thirty-five patients were entered into the study, of whom 34 were eligible. Patients received Irofulven daily x 5 days every 28 days over 10 min, following pre-treatment with ondansetron (0.45 mg/kg) and dexamethasone (12 mg/m(2)). The initial dose of irofulven was 8 mg/m(2) daily, with subsequent escalations to 10, 13, and 17 mg/m(2). Plasma pharmacokinetic samples were obtained in a subset patients. RESULTS: Thirty-two patients were assessable for toxicity, and 30 were assessable for response. In heavily pre-treated patients, dose-limiting thrombocytopenia was observed in two patients at the 8 mg/m(2)/day, and in one patient at the 6 mg/m(2)/day dose level. In less heavily pre-treated patients, proteinuria and elevated creatinine were dose limiting in two patients at the 17 mg/m(2)/day dose level. At 13 mg/m(2)/day, constipation, hyperkalemia with elevated creatinine, and thrombocytopenia was dose limiting in three patients. There were no complete or partial responses. One patient with poorly differentiated carcinoma had stable disease and received 11 courses of therapy. Patients demonstrated a lower systemic exposure and greater clearance than adults treated at similar dose levels. CONCLUSION: The MTD of irofulven administered daily x 5 every 28 days with concomitant ondansetron and dexamethasone is 6 mg/m(2)/day in heavily pre-treated patients and 10 mg/m(2)/day in less heavily pre-treated patients.
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Antineoplásicos Alquilantes/efectos adversos , Antineoplásicos Alquilantes/farmacocinética , Neoplasias/tratamiento farmacológico , Sesquiterpenos/efectos adversos , Sesquiterpenos/farmacocinética , Adolescente , Adulto , Antineoplásicos Alquilantes/administración & dosificación , Niño , Preescolar , Esquema de Medicación , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Femenino , Humanos , Masculino , Dosis Máxima Tolerada , Sesquiterpenos/administración & dosificaciónRESUMEN
PURPOSE: Tumor growth and metastasis is believed to depend on the tumor's ability to induce neovascularization. Recent studies have indicated that thalidomide inhibits angiogenesis. We performed a phase I and pharmacokinetic study of thalidomide with carboplatin in children with refractory solid tumors. PATIENTS AND METHODS: Carboplatin was administered as a single intravenous dose once every 21 days at a target area under the concentration-time curve of 6 mg/mL.min. Thalidomide was administered daily by mouth. The initial dose level was 100 mg/m(2)/d with intrapatient dose escalation to a maximum dose of 300 mg/m(2)/d. The next cohort of patients started at a dose of 300 mg/m(2)/d, with intrapatient dose escalation to a maximum dose of 500 mg/m(2)/d. Standard response and adverse event criteria were used. Serial blood samples for thalidomide pharmacokinetics studies were obtained after the first dose. RESULTS: Twenty-two patients received 56 cycles of therapy. The maximum tolerated thalidomide dose was 400 mg/m(2)/d. The dose-limiting toxicity was somnolence. There were no objective responses. Thalidomide's apparent clearance was 55 +/- 16 mL/min/m(2) and the terminal half-life was 5.9 +/- 2.8 hours. There was no evidence of dose-dependent pharmacokinetics in the narrow range studied. CONCLUSION: Thalidomide at a dose of 400 mg/m(2)/d can be safely administered to children with solid tumors in combination with carboplatin. Somnolence is the major toxicity. In addition, we have characterized the pharmacokinetic behavior of thalidomide in children. This study can serve as the basis for future investigation of thalidomide as an anticancer agent in children.