RESUMO
BACKGROUND: To determine the MTD of Seneca Valley Virus (NTX-010) in children with relapsed/refractory solid tumors. Patients (≥ 3-≤ 21 years) with neuroblastoma, rhabdomyosarcoma, or rare tumors with neuroendocrine features were eligible. PROCEDURE: Part A (single dose of NTX-010) enrolled 13 patients at three dose levels (1 × 10(9) viral particles (vp)/kg [n = 6], 1 × 10(10) vp/kg [n = 3], 1 × 10(11) vp/kg [n = 4]). Diagnoses included neuroblastoma (n = 9), rhabdomyosarcoma (n = 2), carcinoid tumor (n = 1), and adrenocorticocarcinoma (n = 1). Part B added cyclophosphamide (CTX) (oral CTX (25 mg/m(2) /day) days 1-14 and IV CTX (750 mg/m(2) ) days 8 and 29) to two doses of NTX-010 (1 × 10(11) vp/kg, days 8 and 29). Nine patients enrolled to Part B. Diagnoses included neuroblastoma (n = 3), rhabdomyosarcoma (n = 1), Wilms tumor (n = 3), and adrenocorticocarcinoma (n = 2). RESULTS: Twelve patients on Part A were evaluable for toxicity. There was a single DLT (grade 3 pain) at dose level 1. Additional grade ≥ 3 related adverse events (AEs) included leukopenia (n = 1), neutropenia (n = 3), lymphopenia (n = 3), and tumor pain (n = 1). No DLTs occurred on part B. Other grade ≥ 3 related AEs on Part B included: Leukopenia (n = 3), nausea (n = 1), emesis (n = 1), anemia (n = 1), neutropenia (n = 4), platelets (n = 1), alanine aminotransferase (n = 1), and lymphopenia (n = 2). All patients cleared NTX-010 from blood and stool by 3 weeks with 17/18 patients developing neutralizing antibodies. CONCLUSION: NTX-010 is feasible and tolerable at the dose levels tested in pediatric patients with relapsed/refractory solid tumors either alone or in combination with cyclophosphamide. However, despite the addition of cyclophosphamide, neutralizing antibodies appeared to limit applicability.
Assuntos
Ciclofosfamida/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Recidiva Local de Neoplasia/terapia , Neoplasias/terapia , Terapia Viral Oncolítica , Picornaviridae , Terapia de Salvação , Adolescente , Adulto , Anticorpos Neutralizantes/sangue , Antineoplásicos Alquilantes/uso terapêutico , Criança , Pré-Escolar , Terapia Combinada , Feminino , Seguimentos , Humanos , Masculino , Dose Máxima Tolerável , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/virologia , Estadiamento de Neoplasias , Neoplasias/patologia , Neoplasias/virologia , Prognóstico , Adulto JovemRESUMO
BACKGROUND: Reovirus is a naturally occurring human virus that is cytopathic to malignant cells possessing an activated Ras signaling pathway. We conducted a phase I trial of Reolysin, a manufactured, proprietary isolate of purified reovirus, in children with relapsed/refractory extracranial solid tumors to define the recommended phase 2 dose (RP2D), toxicities, and pharmacokinetic properties when administered as a single agent or in combination with cyclophosphamide. PROCEDURES: Reolysin was administered intravenously for 5 consecutive days, every 28 days. Using a 3 + 3 design, the following dose levels were evaluated: 3 × 10(8) Tissue Culture Inhibitory Dose 50% (TCID50 )/kg; 5 × 10(8) TCID50 /kg (maximum dose was 3 × 10(10) TCID50 ); and 5 × 10(8) TCID50 /kg plus oral cyclophosphamide (50 mg/m(2) /day × 21 days). RESULTS: Twenty-nine patients were enrolled; 28 were eligible and 24 were evaluable for toxicity and response. There were no hematologic dose-limiting toxicities. Grade 5 respiratory failure and a Grade 5 thromboembolic event were reported, both in the setting of progressive disease. The median time to clear the reovirus viremia was 6.5 days. Eight of 24 patients were viremic beyond the 5 days of therapy, all were negative by day 17. No patient had detectable viral RNA in saliva or stool. There were no objective responses. CONCLUSIONS: Reolysin at a dose of 5 × 10(8) TCID50 /kg daily for 5 days was well tolerated in children alone and in combination with oral cyclophosphamide. Virus was cleared rapidly from the serum and shedding in stool and saliva was not detectable.
Assuntos
Ciclofosfamida/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Recidiva Local de Neoplasia/terapia , Neoplasias/terapia , Terapia Viral Oncolítica , Reoviridae , Terapia de Salvação , Adolescente , Adulto , Antineoplásicos Alquilantes/uso terapêutico , Criança , Pré-Escolar , Terapia Combinada , Feminino , Seguimentos , Humanos , Masculino , Dose Máxima Tolerável , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/virologia , Estadiamento de Neoplasias , Neoplasias/patologia , Neoplasias/virologia , Prognóstico , Adulto JovemRESUMO
BACKGROUND: Ruxolitinib, an orally bioavailable JAK1/JAK2 inhibitor, may treat cancers with CRLF2 and/or JAK pathway mutations. PROCEDURE: A phase 1 trial of ruxolitinib was performed to determine the maximum tolerated or recommended phase 2 dose, dose-limiting toxicities (DLTs), pharmacokinetics (PK), and pharmacodynamics (PD) in children with recurrent/refractory solid tumors (STs). Ruxolitinib was administered twice daily (BID) in 28-day cycles at five dose levels (15, 21, 29, 39, and 50 mg/m(2)/dose). PK and PD studies were performed during cycle 1. Toxicity, preliminary efficacy, and PK/PD were also assessed in children with relapsed/refractory hematologic malignancies (HMs). RESULTS: Forty-nine patients were enrolled, 28 with STs (dose escalation cohort) and 21 with HMs. Ruxolitinib was well-tolerated with one DLT per cohort of six patients at dose levels (DLs) 2-5. One patient with an ST had grade 5 multi-organ failure at DL2. One patient each at DL3 and DL4 had a grade 4 neutropenia, and one patient at DL5 had a grade 4 creatinine phosphokinase elevation. No objective responses were observed in patients with STs. One patient with polycythemia vera achieved a partial response and received 18 cycles of ruxolitinib. The PK of ruxolitinib were similar to that in adults. Partial inhibition of phosphorylated JAK2, STAT5, and S6 was observed in in vitro plasma inhibitory activity PD assay. CONCLUSION: Ruxolitinib was well tolerated in children with refractory cancer. The recommended phase 2 dose for continuous BID oral administration is 50 mg/m(2)/dose. Subsequent evaluation of ruxolitinib in combination with cytotoxic chemotherapy in children, adolescents, and young adults with JAK-mutant leukemias is planned.
Assuntos
Antineoplásicos/administração & dosagem , Neoplasias Hematológicas/tratamento farmacológico , Pirazóis/administração & dosagem , Adolescente , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Recidiva Local de Neoplasia/tratamento farmacológico , Nitrilas , Pirazóis/efeitos adversos , Pirazóis/farmacocinética , Pirimidinas , Adulto JovemRESUMO
BACKGROUND: mTOR inhibitors have activity in pediatric tumor models. A phase I trial of the mTOR inhibitor temsirolimus (TEM) with irinotecan (IRN) and temozolomide (TMZ) was conducted in children with recurrent/refractory solid tumors, including central nervous system (CNS) tumors. METHODS: Escalating doses of intravenous (IV) TEM were administered on days 1 and 8 of 21-day cycles. IRN (50 mg/m(2)/dose escalated to a maximum of 90 mg/m(2)/dose) and TMZ (100 mg/m(2)/dose escalated to a maximum of 150 mg/m(2)/dose) were administered orally (PO) on days 1-5. When maximum tolerated doses (MTD) were identified, TEM frequency was increased to weekly. RESULTS: Seventy-one eligible pts (median age 10.9 years, range 1.0-21.5) with neuroblastoma (16), osteosarcoma (7), Ewing sarcoma (7), rhabdomyosarcoma (4), CNS (22) or other (15) tumors were enrolled. Dose-limiting hyperlipidemia occurred in two patients receiving oral corticosteroids. The protocol was subsequently amended to preclude chronic steroid use. The MTD was identified as TEM 35 mg/m(2) IV weekly, with IRN 90 mg/m(2) and TMZ 125 mg/m(2) PO on days 1-5. At higher dose levels, elevated serum alanine aminotransferase and triglycerides, anorexia, and thrombocytopenia were dose limiting. Additional ≥ grade 3 regimen-related toxicities included leukopenia, neutropenia, lymphopenia, anemia, and nausea/vomiting. Six patients had objective responses confirmed by central review; three of these had sustained responses through ≥ 14 cycles of therapy. CONCLUSION: The combination of TEM (35 mg/m(2)/dose IV weekly), IRN (90 mg/m(2)/dose days 1-5) and TMZ (125 mg/m(2)/dose days 1-5) administered PO every 21 days is well tolerated in children. Phase 2 trials of this combination are ongoing.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias/tratamento farmacológico , Adolescente , Adulto , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Criança , Pré-Escolar , Dacarbazina/administração & dosagem , Dacarbazina/análogos & derivados , Feminino , Seguimentos , Humanos , Lactente , Irinotecano , Masculino , Dose Máxima Tolerável , Recidiva Local de Neoplasia/tratamento farmacológico , Prognóstico , Indução de Remissão , Sirolimo/administração & dosagem , Sirolimo/análogos & derivados , Temozolomida , Adulto JovemRESUMO
BACKGROUND: We report results of a phase I trial designed to estimate the maximum tolerated dose (MTD), describe dose-limiting toxicities (DLT), and characterize the pharmacokinetic profile of MK-2206, an AKT inhibitor, in children with refractory or recurrent malignancies. PROCEDURE: MK-2206 was administered either every other day (Schedule 1), or once a week (Schedule 2) in a 28-day cycle. Dose escalations in increments of â¼30% were independently made in each part using the rolling-six design. Serial pharmacokinetic (PK) studies were obtained. Biological studies include analysis of PI3K/PTEN/AKT-cell signaling pathway in pre and post-therapy in PBMC and in tumors at diagnosis or recurrence. RESULTS: Fifty patients (26 males, median age 12.6 years [range, 3.1-21.9]) with malignant glioma (16), ependymoma (4), hepatocellular carcinoma (3), gliomatosis cereberi (2), or other tumors (22) were enrolled; 40 were fully evaluable for toxicity (Schedule 1, n = 23; Schedule 2, n = 17). Schedule 1 DLTs included: grade 3 dehydration in 1/6 patients at 28 mg/m(2) ; grade 4 hyperglycemia and neutropenia in 1/6 patients at 45 mg/m(2) ; and grade 3 rash in 3/6 patients at dose level 4 (58 mg/m(2) ). Schedule 2 DLTs included: grade 3 alkaline phosphatase in 1/6 patients at 90 mg/m(2) ; grade 3 rash in 1/6 patients at 120 mg/m(2) ; and grade 3 rash in 2/6 patients at 155 mg/m(2) . CONCLUSIONS: The recommended pediatric phase 2 dose of MK-2206 is 45 mg/m(2) /dose every other day or 120 mg/m(2) /dose weekly. PK appeared linear over the dose range studied.
Assuntos
Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Dose Máxima Tolerável , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacocinética , Adolescente , Adulto , Criança , Pré-Escolar , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Humanos , Lactente , Neoplasias/enzimologia , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismoRESUMO
BACKGROUND: Various human cancers have ALK gene translocations, amplifications, or oncogenic mutations, such as anaplastic large-cell lymphoma, inflammatory myofibroblastic tumours, non-small-cell lung cancer (NSCLC), and neuroblastoma. Therefore, ALK inhibition could be a useful therapeutic strategy in children. We aimed to determine the safety, recommended phase 2 dose, and antitumour activity of crizotinib in children with refractory solid tumours and anaplastic large-cell lymphoma. METHODS: In this open-label, phase 1 dose-escalation trial, patients older than 12 months and younger than 22 years with measurable or evaluable solid or CNS tumours, or anaplastic large-cell lymphoma, refractory to therapy and for whom there was no known curative treatment were eligible. Crizotinib was given twice daily without interruption. Six dose levels (100, 130, 165, 215, 280, 365 mg/m(2) per dose) were assessed in the dose-finding phase of the study (part A1), which is now completed. The primary endpoint was to estimate the maximum tolerated dose, to define the toxic effects of crizotinib, and to characterise the pharmacokinetics of crizotinib in children with refractory cancer. Additionally, patients with confirmed ALK translocations, mutations, or amplification (part A2 of the study) or neuroblastoma (part A3) could enrol at one dose level lower than was currently given in part A1. We assessed ALK genomic status in tumour tissue and used quantitative RT-PCR to measure NPM-ALK fusion transcript in bone marrow and blood samples of patients with anaplastic large-cell lymphoma. All patients who received at least one dose of crizotinib were evaluable for response; patients completing at least one cycle of therapy or experiencing dose limiting toxicity before that were considered fully evaluable for toxicity. This study is registered with ClinicalTrials.gov, NCT00939770. FINDINGS: 79 patients were enrolled in the study from Oct 2, 2009, to May 31, 2012. The median age was 10.1 years (range 1.1-21.4); 43 patients were included in the dose escalation phase (A1), 25 patients in part A2, and 11 patients in part A3. Crizotinib was well tolerated with a recommended phase 2 dose of 280 mg/m(2) twice daily. Grade 4 adverse events in cycle 1 were neutropenia (two) and liver enzyme elevation (one). Grade 3 adverse events that occurred in more than one patient in cycle 1 were lymphopenia (two), and neutropenia (eight). The mean steady state peak concentration of crizotinib was 630 ng/mL and the time to reach this peak was 4 h (range 1-6). Objective tumour responses were documented in 14 of 79 patients (nine complete responses, five partial responses); and the anti-tumour activity was enriched in patients with known activating ALK aberrations (eight of nine with anaplastic large-cell lymphoma, one of 11 with neuroblastoma, three of seven with inflammatory myofibroblastic tumour, and one of two with NSCLC). INTERPRETATION: The findings suggest that a targeted inhibitor of ALK has antitumour activity in childhood malignancies harbouring ALK translocations, particularly anaplastic large-cell lymphoma and inflammatory myofibroblastic tumours, and that further investigation in the subset of neuroblastoma harbouring known ALK oncogenic mutations is warranted. FUNDING: Pfizer and National Cancer Institute grant to the Children's Oncology Group.
Assuntos
Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Linfoma Anaplásico de Células Grandes/tratamento farmacológico , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Piridinas/uso terapêutico , Adolescente , Fatores Etários , Quinase do Linfoma Anaplásico , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Criança , Pré-Escolar , Crizotinibe , Progressão da Doença , Esquema de Medicação , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Lactente , Linfoma Anaplásico de Células Grandes/enzimologia , Linfoma Anaplásico de Células Grandes/genética , Linfoma Anaplásico de Células Grandes/patologia , Masculino , Dose Máxima Tolerável , Terapia de Alvo Molecular , Mutação , Neoplasias/enzimologia , Neoplasias/genética , Neoplasias/patologia , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Pirazóis/efeitos adversos , Pirazóis/farmacocinética , Piridinas/efeitos adversos , Piridinas/farmacocinética , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/metabolismo , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Optimal management of children with centrally located low-grade glioma (LGG) is unclear. Initial interventions in most children are chemotherapy in younger and radiation therapy (RT) in older children. A better understanding of the inherent risk factors along with the effects of interventions on long-term outcome can lead to reassessment of the current approaches to minimize long-term morbidity. METHODS: To reassess the current treatment strategies of centrally located LGG, we compared the long-term survival and morbidity of different treatment regimens. Medical records of patients primarily treated at Texas Children's Cancer and Hematology Centers between 1987 and 2008 were reviewed. RESULTS: Forty-seven patients with a median follow-up of 79 months were included in the analysis. The 5-year overall survival and progression-free survival (PFS) for all patients were 96% and 53%, respectively. The 5-year PFS for those treated initially with RT (12 patients; median age, 11 years [range, 3-15 years]) and with chemotherapy (28 patients; median age, 2 years [range 0-8 years]) were 76% and 37%, respectively (log-rank test P = .02). Among children who progressed after chemotherapy, the 5-year PFS after salvage RT was 55%. Patients diagnosed at a younger age (<5 years) were more likely to experience endocrine abnormalities (Fisher exact test; P<.00001). CONCLUSIONS: Effective and durable tumor control was obtained with RT as initial treatment. In younger patients, chemotherapy can delay the use of RT; however, frequent progression and long-term morbidity are common. More effective and less toxic therapies are required in these patients, the majority of whom are long-term survivors.
Assuntos
Biomarcadores Tumorais/análise , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Glioma/patologia , Glioma/terapia , Proteínas de Fusão Oncogênica/análise , Adolescente , Sintomas Afetivos/epidemiologia , Sintomas Afetivos/etiologia , Astrocitoma/patologia , Astrocitoma/terapia , Neoplasias Encefálicas/química , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/radioterapia , Criança , Pré-Escolar , Transtornos Cognitivos/epidemiologia , Transtornos Cognitivos/etiologia , Intervalo Livre de Doença , Doenças do Sistema Endócrino/epidemiologia , Doenças do Sistema Endócrino/etiologia , Feminino , Glioma/química , Glioma/tratamento farmacológico , Glioma/genética , Glioma/radioterapia , Humanos , Hibridização in Situ Fluorescente , Lactente , Estimativa de Kaplan-Meier , Masculino , Prontuários Médicos , Gradação de Tumores , Doenças do Sistema Nervoso/epidemiologia , Doenças do Sistema Nervoso/etiologia , Dosagem Radioterapêutica , Estudos Retrospectivos , Sobreviventes/estatística & dados numéricos , Texas/epidemiologia , Resultado do Tratamento , Transtornos da Visão/epidemiologia , Transtornos da Visão/etiologiaRESUMO
BACKGROUND: A pediatric Phase I trial was performed to determine the maximum-tolerated dose, dose-limiting toxicities (DLTs), and pharmacokinetics (PK) of vorinostat and bortezomib, in patients with solid tumors. PROCEDURE: Oral vorinostat was administered on days 1-5 and 8-12 of a 21-day cycle (starting dose 180 mg/m(2) /day with dose escalations to 230 and 300 mg/m(2) /day). Bortezomib (1.3 mg/m(2) i.v.) was administered on days 1, 4, 8, and 11 of the same cycle. PK and correlative biology studies were performed during Cycle 1. RESULTS: Twenty-three eligible patients [17 male, median age 12 years (range: 1-20)] were enrolled of whom 17 were fully evaluable for toxicity. Cycle 1 DLTs that occurred in 2/6 patients at dose level 3 (vorinostat 300 mg/m(2) /day) were Grade 2 sensory neuropathy that progressed to Grade 4 (n = 1) and Grade 3 nausea and anorexia (n = 1). No objective responses were observed. There was wide interpatient variability in vorinostat PK parameters. Bortezomib disposition was best described by a three-compartment model that demonstrated rapid distribution followed by prolonged elimination. We did not observe a decrease in nuclear factor-κB activity or Grp78 induction after bortezomib treatment in peripheral blood mononuclear cells from solid tumor patients. CONCLUSION: The recommended Phase 2 dose and schedule is vorinostat (230 mg/m(2) /day PO on days 1-5 and 8-12) in combination with bortezomib (1.3 mg/m(2) /day i.v. on days 1, 4, 8, and 11 of a 21-day cycle) in children with recurrent or refractory solid tumors.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias/tratamento farmacológico , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Ácidos Borônicos/administração & dosagem , Ácidos Borônicos/efeitos adversos , Ácidos Borônicos/farmacocinética , Bortezomib , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Chaperona BiP do Retículo Endoplasmático , Feminino , Humanos , Ácidos Hidroxâmicos/administração & dosagem , Ácidos Hidroxâmicos/efeitos adversos , Ácidos Hidroxâmicos/farmacocinética , Lactente , Masculino , Dose Máxima Tolerável , Pirazinas/administração & dosagem , Pirazinas/efeitos adversos , Pirazinas/farmacocinética , Vorinostat , Adulto JovemRESUMO
PURPOSE: We conducted a pediatric phase I study to estimate the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetic properties of vorinostat, a histone deacetylase (HDAC) inhibitor, when given in combination with temozolomide in children with refractory or recurrent CNS malignancies. PATIENTS AND METHODS: Vorinostat, followed by temozolomide approximately 1 hour later, was orally administered, once daily, for 5 consecutive days every 28 days at three dose levels using the rolling six design. Studies of histone accumulation in peripheral blood mononuclear cells were performed on Day 1 at 0, 6, and 24 hours after vorinostat dosing. Vorinostat pharmacokinetics (PK) and serum MGMT promoter status were also assessed. RESULTS: Nineteen eligible patients were enrolled and 18 patients were evaluable for toxicity. There were no DLTs observed at dose level 1 or 2. DLTs occurred in four patients at dose level 3: thrombocytopenia (4), neutropenia (3), and leucopenia (1). Non-dose limiting grade 3 or 4 toxicities related to protocol therapy were also hematologic and included neutropenia, lymphopenia, thrombocytopenia, anemia, and leucopenia. Three patients exhibited stable disease and one patient had a partial response. There was no clear relationship between vorinostat dosage and drug exposure over the dose range studied. Accumulation of acetylated H3 histone in PBMC was observed after administration of vorinostat. CONCLUSION: Five-day cycles of vorinostat in combination with temozolomide are well tolerated in children with recurrent CNS malignancies with myelosuppression as the DLT. The recommended phase II combination doses are vorinostat, 300 mg/m(2) /day and temozolomide, 150 mg/m(2) /day.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias da Medula Espinal/tratamento farmacológico , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Encefálicas/sangue , Criança , Pré-Escolar , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Dacarbazina/administração & dosagem , Dacarbazina/efeitos adversos , Dacarbazina/análogos & derivados , Relação Dose-Resposta a Droga , Feminino , Histonas/sangue , Humanos , Ácidos Hidroxâmicos/administração & dosagem , Ácidos Hidroxâmicos/efeitos adversos , Leucócitos Mononucleares/metabolismo , Masculino , Dose Máxima Tolerável , Neutropenia/sangue , Neutropenia/induzido quimicamente , Regiões Promotoras Genéticas , Recidiva , Neoplasias da Medula Espinal/sangue , Temozolomida , Trombocitopenia/sangue , Trombocitopenia/induzido quimicamente , Proteínas Supressoras de Tumor/metabolismo , VorinostatRESUMO
BACKGROUND: Recent evidence suggests that the quantity of intra-abdominal fat may be a more important predictor of postoperative complications than body mass index (BMI). We hypothesized that increased intra-abdominal fat would be associated with longer operations, increased blood loss, more complications, and prolonged length of stay after pancreatic resection. METHODS: Retrospective cohort study. Intra-abdominal fat was quantified using CT imaging, and patients were divided into three groups (low, moderate, high). Unconditional multiple logistic regression was used to evaluate the relationship between obesity measures and complications. RESULTS: Between 2002 and 2010, 255 patients underwent pancreaticoduodenectomy or distal pancreatectomy, and 201 had preoperative CT imaging available for review. Operative time was significantly prolonged in patients with high quantities of intra-abdominal fat compared with those with low fat quantity (median 438 versus 354 min, P < 0.05), while BMI was not associated with changes in duration of surgery. Neither obesity defined by BMI (OR 0.90, 95% CI 0.36-2.21) nor visceral fat (OR 1.20, 95% CI 0.46-3.16) significantly predicted risk of complications. Median length of stay was similar in patients who were obese by BMI (7 versus 7.5 d) or amount of intra-abdominal fat (7 d). CONCLUSIONS: Intra-abdominal fat was a better predictor than BMI for determining length of procedure. However, in contrast to previous studies evaluating abdominal surgery, neither BMI nor intra-abdominal fat significantly predicted risk of complication or length of hospital stay. Further research is needed to determine the best measure to assist in risk prediction of obese patients undergoing pancreatic surgery.
Assuntos
Obesidade Abdominal/epidemiologia , Pancreatopatias/epidemiologia , Pancreatopatias/cirurgia , Pancreaticoduodenectomia/estatística & dados numéricos , Complicações Pós-Operatórias/epidemiologia , Gordura Abdominal , Adulto , Idoso , Índice de Massa Corporal , Estudos de Coortes , Comorbidade , Feminino , Humanos , Tempo de Internação/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Retrospectivos , Fatores de RiscoRESUMO
BACKGROUND: Most surgeons routinely place intraperitoneal drains at the time of pancreatic resection but this practice has recently been challenged. OBJECTIVE: Evaluate the outcome when pancreatic resection is performed without operatively placed intraperitoneal drains. METHODS: In all, 226 consecutive patients underwent pancreatic resection. In 179 patients drains were routinely placed at the time of surgery and in 47 no drains were placed. Outcomes for these two cohorts were recorded in a prospective database and compared using the χ(2) - /Fisher's exact test for categorical variables, and Wilcoxon's test for continuous variables. RESULTS: Demographic, surgical and pathological details were similar between the two cohorts. Elimination of routine intraperitoneal drainage did not increase the frequency or severity of serious complications. However, when all grades of complications were considered, the number of patients that experienced any complication (65% vs. 47%, P= 0.020) and the median complication severity grade (1 vs. 0, P= 0.027) were increased in the group that had drains placed at the time of surgery. Eliminating intra-operative drains was associated with decreased delayed gastric emptying (24% vs. 9%, P= 0.020) and a trend towards decreased wound infection (12% vs. 2%, P= 0.054). The readmission rate (9% vs. 17% P= 0.007) and number of patients requiring post-operative percutaneous drains (2% vs. 11%, P= 0.001) was higher in patients who did not have operatively placed drains but there was no difference in the re-operation rate (4% vs. 0%, P= 0.210). CONCLUSION: Abandoning the practice of routine intraperitoneal drainage after pancreatic resection may not increase the incidence or severity of severe post-operative complications.
Assuntos
Drenagem , Pancreatectomia/efeitos adversos , Pancreatectomia/métodos , Pancreatopatias/cirurgia , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Cavidade Peritoneal , Resultado do TratamentoRESUMO
PURPOSE: Breast cancer screening by mammography and clinical breast exam are commonly used for early tumor detection. Previous cost-effectiveness studies considered mammography alone or did not account for all relevant costs. In this study, we assessed the cost-effectiveness of screening schedules recommended by three major cancer organizations and compared them with alternative strategies. We considered costs of screening examinations, subsequent work-up, biopsy, and treatment interventions after diagnosis. METHODS: We used a microsimulation model to generate women's life histories, and assessed screening and treatment effects on survival. Using statistical models, we accounted for age-specific incidence, preclinical disease duration, and age-specific sensitivity and specificity for each screening modality. The outcomes of interest were quality-adjusted life years (QALY) saved and total costs with a 3% annual discount rate. Incremental cost-effectiveness ratios were used to compare strategies. Sensitivity analyses were done by varying some of the assumptions. RESULTS: Compared with guidelines from the National Cancer Institute and the U.S. Preventive Services Task Force, alternative strategies were more efficient. Mammography and clinical breast exam in alternating years from ages 40 to 79 years was a cost-effective alternative compared with the guidelines, costing $35,500 per QALY saved compared with no screening. The American Cancer Society guideline was the most effective and the most expensive, costing over $680,000 for an added QALY compared with the above alternative. CONCLUSION: Screening strategies with lower costs and benefits comparable with those currently recommended should be considered for implementation in practice and for future guidelines.
Assuntos
Neoplasias da Mama/diagnóstico , Neoplasias da Mama/economia , Análise Custo-Benefício/economia , Mamografia/economia , Modelos Estatísticos , Exame Físico/economia , Adulto , Fatores Etários , Idoso , American Cancer Society , Biópsia , Neoplasias da Mama/terapia , Feminino , Humanos , Pessoa de Meia-Idade , Método de Monte Carlo , National Cancer Institute (U.S.) , Guias de Prática Clínica como Assunto , Modelos de Riscos Proporcionais , Anos de Vida Ajustados por Qualidade de Vida , Sensibilidade e Especificidade , Análise de Sobrevida , Estados UnidosRESUMO
Osteosarcoma (OS) is the primary bone tumor in children and young adults. Currently, there are no reliable, noninvasive biologic markers to detect the presence or progression of disease, assess therapy response, or provide upfront prognostic insights. MicroRNAs (miRNAs) are evolutionarily conserved, stable, small noncoding RNA molecules that are key posttranscriptional regulators and are ideal candidates for circulating biomarker development due to their stability in plasma, ease of isolation, and the unique expressions associated with specific disease states. Using a qPCR-based platform that analyzes more than 750 miRNAs, we analyzed control and diseased-associated plasma from a genetically engineered mouse model of OS to identify a profile of four plasma miRNAs. Subsequent analysis of 40 human patient samples corroborated these results. We also identified disease-specific endogenous reference plasma miRNAs for mouse and human studies. Specifically, we observed plasma miR-205-5p was decreased 2.68-fold in mice with OS compared to control mice, whereas, miR-214, and miR-335-5p were increased 2.37- and 2.69-fold, respectively. In human samples, the same profile was seen with miR-205-5p decreased 1.75-fold in patients with OS, whereas miR-574-3p, miR-214, and miR-335-5p were increased 3.16-, 8.31- and 2.52-fold, respectively, compared to healthy controls. Furthermore, low plasma levels of miR-214 in metastatic patients at time of diagnosis conveyed a significantly better overall survival. This is the first study to identify plasma miRNAs that could be used to prospectively identify disease, potentially monitor therapeutic efficacy and have prognostic implications for OS patients.
Assuntos
Neoplasias Ósseas/diagnóstico , Neoplasias Ósseas/genética , MicroRNAs/genética , Osteossarcoma/diagnóstico , Osteossarcoma/genética , Transcriptoma , Adolescente , Adulto , Aloenxertos , Animais , Biomarcadores Tumorais , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/terapia , Criança , Modelos Animais de Doenças , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Feminino , Seguimentos , Perfilação da Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Knockout , MicroRNAs/sangue , Estadiamento de Neoplasias , Osteossarcoma/mortalidade , Osteossarcoma/terapia , Prognóstico , Curva ROC , Reprodutibilidade dos Testes , Adulto JovemRESUMO
PURPOSE: To determine the MTD, dose-limiting toxicities (DLT), pharmacokinetics, and biologic effects of cixutumumab administered in combination with temsirolimus to children with refractory solid tumors. EXPERIMENTAL DESIGN: Cixutumumab and temsirolimus were administered intravenously once every 7 days in 28-day cycles. Pharmacokinetic and biology studies, including assessment of mTOR downstream targets in peripheral blood mononuclear cells, were performed during the first cycle. RESULTS: Thirty-nine patients, median age 11.8 years (range, 1-21.5), with recurrent solid or central nervous system tumors were enrolled, of whom 33 were fully assessable for toxicity. There were four dose levels, which included two dose reductions and a subsequent intermediated dose escalation: (i) IMC-A12 6 mg/kg, temsirolimus 15 mg/m(2); (ii) IMC-A12 6 mg/kg, temsirolimus 10 mg/m(2); (iii) IMC-A12 4 mg/kg, temsirolimus 8 mg/m(2); and (iv) IMC-A12 6 mg/kg, temsirolimus 8 mg/m(2). Mucositis was the predominant DLT. Other DLTs included hypercholesterolemia, fatigue, thrombocytopenia, and increased alanine aminotransferase. Target inhibition (decreased S6K1 and PAkt) in peripheral blood mononuclear cells was noted at all dose levels. Marked interpatient variability in temsirolimus pharmacokinetic parameters was noted. At 8 mg/m(2), the median temsirolimus AUC was 2,946 ng ⢠h/mL (range, 937-5,536) with a median sirolimus AUC of 767 ng ⢠h/mL (range, 245-3,675). CONCLUSIONS: The recommended pediatric phase II doses for the combination of cixutumumab and temsirolimus are 6 mg/kg and 8 mg/m(2), respectively.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias/tratamento farmacológico , Sirolimo/análogos & derivados , Adolescente , Adulto , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Feminino , Humanos , Lactente , Masculino , Dose Máxima Tolerável , Sirolimo/administração & dosagem , Sirolimo/efeitos adversos , Sirolimo/farmacocinética , Adulto JovemRESUMO
PURPOSE: Imetelstat is a covalently-lipidated 13-mer thiophosphoramidate oligonucleotide that acts as a potent specific inhibitor of telomerase. It binds with high affinity to the template region of the RNA component of human telomerase (hTERC) and is a competitive inhibitor of telomerase enzymatic activity. The purpose of this study was to determine the recommended phase II dose of imetelstat in children with recurrent or refractory solid tumors. EXPERIMENTAL DESIGN: Imetelstat was administered intravenously more than two hours on days 1 and 8, every 21 days. Dose levels of 225, 285, and 360 mg/m(2) were evaluated, using the rolling-six design. Imetelstat pharmacokinetic and correlative biology studies were also performed during the first cycle. RESULTS: Twenty subjects were enrolled (median age, 14 years; range, 3-21). Seventeen were evaluable for toxicity. The most common toxicities were neutropenia, thrombocytopenia, and lymphopenia, with dose-limiting myelosuppression in 2 of 6 patients at 360 mg/m(2). Pharmacokinetics is dose dependent with a lower clearance at the highest dose level. Telomerase inhibition was observed in peripheral blood mononuclear cells at 285 and 360 mg/m(2). Two confirmed partial responses, osteosarcoma (n = 1) and Ewing sarcoma (n = 1), were observed. CONCLUSIONS: The recommended phase II dose of imetelstat given on days 1 and 8 of a 21-day cycle is 285 mg/m(2).
Assuntos
Antineoplásicos/administração & dosagem , Neoplasias Ósseas/tratamento farmacológico , Indóis/administração & dosagem , Recidiva Local de Neoplasia/tratamento farmacológico , Neuroblastoma/tratamento farmacológico , Niacinamida/análogos & derivados , Sarcoma de Ewing/tratamento farmacológico , Adolescente , Antineoplásicos/farmacocinética , Área Sob a Curva , Criança , Pré-Escolar , Esquema de Medicação , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Indóis/farmacocinética , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/enzimologia , Masculino , Niacinamida/administração & dosagem , Niacinamida/farmacocinética , Oligonucleotídeos , Telomerase/antagonistas & inibidores , Telomerase/metabolismo , Resultado do Tratamento , Adulto JovemRESUMO
PURPOSE: Pazopanib, an oral multikinase angiogenesis inhibitor, prolongs progression-free survival in adults with soft tissue sarcoma (STS). A phase I pharmacokinetic and pharmacodynamic study of two formulations of pazopanib was performed in children with STS or other refractory solid tumors. PATIENTS AND METHODS: Pazopanib (tablet formulation) was administered once daily in 28-day cycles at four dose levels (275 to 600 mg/m(2)) using the rolling-six design. Dose determination for a powder suspension was initiated at 50% of the maximum-tolerated dose (MTD) for the intact tablet. Ten patients with STS underwent dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) scanning at baseline and 15 ± 2 days after initiation of pazopanib at the tablet MTD. RESULTS: Fifty-three patients were enrolled; 51 were eligible (26 males; median age, 12.9 years; range, 3.8 to 23.9 years). Hematologic and nonhematologic toxicities were generally mild, with dose-limiting lipase, amylase, and ALT elevation, proteinuria, and hypertension. One patient with occult brain metastasis had grade 4 intracranial hemorrhage. The MTD was 450 mg/m(2) for tablet and 160 mg/m(2) for suspension. Steady-state trough concentrations were reached by day 15 and did not seem to be dose dependent. One patient each with hepatoblastoma or desmoplastic small round cell tumor achieved a partial response; eight patients had stable disease for ≥ six cycles, seven of whom had sarcoma. All patients with evaluable DCE-MRI (n = 8) experienced decreases in tumor blood volume and permeability (P < .01). Placental growth factor increased, whereas endoglin and soluble vascular endothelial growth factor receptor-2 decreased (P < .01; n = 41). CONCLUSION: Pazopanib is well tolerated in children, with evidence of antiangiogenic effect and potential clinical benefit in pediatric sarcoma.
Assuntos
Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Pirimidinas/administração & dosagem , Pirimidinas/farmacocinética , Sarcoma/tratamento farmacológico , Sarcoma/metabolismo , Sulfonamidas/administração & dosagem , Sulfonamidas/farmacocinética , Adolescente , Adulto , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/efeitos adversos , Inibidores da Angiogênese/sangue , Inibidores da Angiogênese/farmacocinética , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Indazóis , Masculino , Neoplasias/sangue , Pirimidinas/efeitos adversos , Pirimidinas/sangue , Sarcoma/sangue , Sulfonamidas/efeitos adversos , Sulfonamidas/sangue , Adulto JovemRESUMO
PURPOSE: MLN8237, a selective small-molecule inhibitor of Aurora kinase A, has activity in a broad range of preclinical pediatric cancer models. We conducted a phase I trial in children with refractory/recurrent solid tumors to define the maximum-tolerated dose, toxicities, and pharmacokinetic properties of MLN8237. EXPERIMENTAL DESIGN: MLN8237 was administered orally either once daily or divided twice daily for seven days, every 21 days. Using a rolling-six design, four dose levels (45, 60, 80, and 100 mg/m(2)/day) were evaluated on the once-daily schedule, and two dose levels (60 and 80 mg/m(2)/d) on the twice-daily schedule. Pharmacokinetic studies were conducted with the initial dose and trough drug concentrations also measured at the steady state. RESULTS: Thirty-seven patients were enrolled. On the once-daily dosing schedule, myelosuppression was dose limiting in three of four patients at 100 mg/m(2), and one of six patients had dose-limiting mood alteration at 80 mg/m(2). At 45 mg/m(2), one of six patients experienced dose-limiting mucositis. Mucositis and myelosuppression were dose limiting at 80 mg/m(2) on the twice-daily schedule, and one of five patients at 60 mg/m(2) on the twice-daily schedule experienced a dose-limiting alkaline phosphatase. Five of 11 patients experienced hand-foot-skin syndrome with twice-daily dosing versus one of 21 after once-daily dosing. There was one partial response and six with prolonged stable disease among 33 evaluable subjects. CONCLUSION: The twice-daily dose regimen is well tolerated in adults; however, children experienced a greater frequency of myelosuppression and hand-foot-skin syndrome on this schedule. Children tolerated a higher dose and the recommended pediatric phase II dose is 80 mg/m(2)/d once daily for seven days.
Assuntos
Antineoplásicos/uso terapêutico , Azepinas/uso terapêutico , Neoplasias/tratamento farmacológico , Pirimidinas/uso terapêutico , Adolescente , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Azepinas/efeitos adversos , Azepinas/farmacocinética , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pirimidinas/efeitos adversos , Pirimidinas/farmacocinética , Resultado do Tratamento , Adulto JovemRESUMO
PURPOSE: Sunitinib is an oral tyrosine kinase inhibitor of VEGF, PDGF, c-KIT, and flt-3 receptors. A pediatric phase I study of sunitinib capsules identified the maximum tolerated dose as 15 mg/m(2)/day. This study was conducted to evaluate sunitinib given as a powder formulation. METHODS: Sunitinib 15 mg/m(2) was administered orally daily for 4 weeks on/2 weeks off to patients <21 years old with refractory solid tumors. Sunitinib capsules were opened, and the powder sprinkled onto applesauce or yogurt. Plasma levels of sunitinib and an active metabolite, SU12662, were measured, and pharmacokinetic parameters were estimated. RESULTS: 12 patients, median age 13 (range 4-21) years, were treated. The most common first-cycle toxicities were leucopenia (n = 6), fatigue (n = 5), neutropenia (n = 4), and hypertension (n = 4). Three patients had dose-limiting toxicities (DLTs) in cycle 1 (dizziness/back pain, hand-foot syndrome, and intratumoral hemorrhage/hypoxia). A median peak plasma sunitinib concentration of 21 (range 6-36) ng/ml was reached at a median of 4 (range 4-8) h after the first dose. The median exposure (AUC(0-48)) was 585 (range 196-1,059) h ng/l. The median half-life was 23 (range 13-36) h. The median trough concentration measured before day 14 dosing was 32 (range 12-58) ng/ml. CONCLUSIONS: The pharmacokinetic profile of sunitinib appears similar between a powder formulation and published data using capsules. The powder formulation allows patients unable to swallow capsules to receive sunitinib.
Assuntos
Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Indóis/efeitos adversos , Indóis/farmacocinética , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Pirróis/efeitos adversos , Pirróis/farmacocinética , Adolescente , Antineoplásicos/administração & dosagem , Criança , Pré-Escolar , Humanos , Indóis/administração & dosagem , Indóis/química , Neoplasias/patologia , Pós/administração & dosagem , Pós/química , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirróis/administração & dosagem , Pirróis/química , Sunitinibe , Adulto JovemRESUMO
PURPOSE: A phase I/II study of cixutumumab (IMC-A12) in children with refractory solid tumors was conducted. This study was designed to assess the toxicities, pharmacokinetics, and pharmacodynamics of cixutumumab in children to determine a recommended phase II dose and to assess antitumor activity in Ewing sarcoma (ES). PATIENTS AND METHODS: Pediatric patients with relapsed or refractory solid tumors were treated with cixutumumab as a 1-hour intravenous infusion once per week. Two dose levels-6 and 9 mg/kg-were evaluated using a standard three-plus-three cohort design. Patients with refractory ES were treated in an expanded phase II cohort at each dose level. RESULTS: Forty-seven eligible patients with a median age of 15 years (range, 4 to 28 years) were enrolled. Twelve patients were treated in the dose-finding phase. Hematologic and nonhematologic toxicities were generally mild and infrequent. Dose-limiting toxicities included grade 4 thrombocytopenia at 6 mg/kg and grade 3 dehydration at 9 mg/kg. Mean trough concentration (± standard deviation) at 9 mg/kg was 106 ± 57 µg/mL, which exceeded the effective trough concentration of 60 µg/mL observed in xenograft models. Three patients with ES had confirmed partial responses: one of 10 at 6 mg/kg and two of 20 at 9 mg/kg. Serum insulin-like growth factor I (IGF-I) levels consistently increased after one dose of cixutumumab. Tumor IGF-I receptor expression by immunohistochemistry did not correlate with response in patients with ES. CONCLUSION: Cixutumumab is well tolerated in children with refractory solid tumors. The recommended phase II dose is 9 mg/kg. Limited single-agent activity of cixutumumab was seen in ES.
Assuntos
Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/metabolismo , Sarcoma de Ewing/tratamento farmacológico , Sarcoma de Ewing/metabolismo , Adolescente , Adulto , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Masculino , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Resultado do Tratamento , Adulto JovemRESUMO
PURPOSE: Aflibercept is a novel decoy receptor that efficiently neutralizes circulating VEGF. A pediatric phase I trial was conducted to define the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), and pharmacokinetics (PK) of aflibercept. EXPERIMENTAL DESIGN: Cohorts of three to six children with refractory solid tumors received aflibercept intravenously over 60 minutes every 14 days, at 2.0, 2.5, or 3.0 mg/kg/dose. PK sampling and analysis of peripheral blood biomarkers were conducted with the initial dose. RESULTS: Twenty-one eligible patients were enrolled; 18 were fully evaluable for toxicity. One of six patients receiving 2.0 mg/kg/dose developed dose-limiting intratumoral hemorrhage and two of six receiving 3.0 mg/kg/dose developed either dose-limiting tumor pain or tissue necrosis. None of the six patients receiving 2.5 mg/kg/dose developed DLTs, defining this as the MTD. The most common non-DLTs were hypertension and fatigue. Three patients with hepatocellular carcinoma, hepatoblastoma and clear cell sarcoma had stable disease for >13 weeks. At the MTD, the ratio of free-to-bound aflibercept serum concentration was 2.10 on day 8 but only 0.44 by day 15. A rapid decrease in VEGF (P < 0.05) and increase in placental growth factor (PlGF; P < 0.05) from baseline was observed in response to aflibercept by day 2. CONCLUSIONS: The aflibercept MTD in children of 2.5 mg/kg/dose every 14 days is lower than the adult recommended dose of 4.0 mg/kg. This dose achieves, but does not sustain, free aflibercept concentrations in excess of bound. Tumor pain and hemorrhage may be evidence of antitumor activity but were dose-limiting.