RESUMO
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: 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
PURPOSE: To determine the maximum-tolerated dose, dose-limiting toxicities, and pharmacokinetics of the kinesin spindle protein inhibitor ispinesib in pediatric patients with recurrent or refractory solid tumors. SUBJECTS AND METHODS: Ispinesib was administered as 1-hr intravenous infusion weekly × 3, every 28 days. Cohorts of 3-6 patients were enrolled at 5, 7, 9, and 12 mg/m(2) /dose. Serial plasma samples for pharmacokinetic analyses were obtained after the first dose. RESULTS: Twenty-four (13 females) patients with a median (range) age of 10 years (1-19) were enrolled in the study. At the 12 mg/m(2) dose level dose-limiting neutropenia occurred in 2/6 patients and hyperbilirubinemia in 1/6 patients, while at the 9 mg/m(2) dose level 1/6 patients had dose-limiting neutropenia. There were no objective responses, but three patients (diagnoses of anaplastic astrocytoma, alveolar soft part sarcoma, and ependymoblastoma) had stable disease for 4-7 courses. There was substantial interpatient variation in drug disposition. The median (range) terminal elimination half-life was 16 (8-44) hr and the plasma drug clearance was 5 (1-14) L/hr/m(2) . CONCLUSIONS: The maximum tolerated and recommended phase II dose for ispinesib administered weekly × 3 every 28 days for children with solid tumors is 9 mg/m(2) /dose. Plans for a phase II trial in select pediatric solid tumors are in development.
Assuntos
Benzamidas/administração & dosagem , Cinesinas/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Quinazolinas/administração & dosagem , Adolescente , Benzamidas/efeitos adversos , Benzamidas/farmacocinética , Criança , Pré-Escolar , Esquema de Medicação , Feminino , Humanos , Hiperbilirrubinemia/induzido quimicamente , Lactente , Infusões Intravenosas , Dose Máxima Tolerável , Neutropenia/induzido quimicamente , Quinazolinas/efeitos adversos , Quinazolinas/farmacocinética , Adulto JovemRESUMO
BACKGROUND: In preclinical models, temozolomide, and vincristine are additive or synergistic with irinotecan. We examined this three-drug combination in children with relapsed solid tumors. Patients received orally administered irinotecan together with temozolomide and vincristine on two different schedules, using cefixime to reduce irinotecan-associated diarrhea. METHODS: Oral irinotecan was given daily on days 1-5 and 8-12 (Schedule A), or on days 1-5 (Schedule B). Temozolomide was given on days 1-5, with vincristine 1.5 mg/m(2) administered on days 1 and 8 (Schedule A) or day 1 (Schedule B) in 21-day courses. RESULTS: On Schedule A, the maximum tolerated dose of oral irinotecan was 35 mg/m(2)/day combined with temozolomide 100 mg/m(2)/day and vincristine on days 1 and 8. Dose-limiting toxicities in 4 of 12 patients included hepatotoxicity, abdominal pain, anorexia, hypokalemia, and thrombocytopenia at 50 mg/m(2)/day. Using Schedule B, 0 of 6 patients experienced dose-limiting toxicity (DLT) at the highest doses studied of oral irinotecan 90 mg/m(2)/day, temozolomide 150 mg/m(2)/day x 5, and vincristine on day 1. First-course and cumulative toxicity was greater with Schedule A. UGT1A1*28 genotype did not correlate with DLT. At the irinotecan dose of 90 mg/m(2)/day, the mean SN-38 AUC(inf) was 63 ng/ml hr. Activity was seen in sarcoma patients, and overall eight patients received >or=6 courses. CONCLUSIONS: The 5-day schedule of VOIT was well tolerated and provided SN-38 exposures similar to those achieved with intravenous IRN. Activity on this and prior studies suggests a potential role for VOIT in a spectrum of childhood solid tumors.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias/tratamento farmacológico , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Área Sob a Curva , Camptotecina/administração & dosagem , Camptotecina/efeitos adversos , Camptotecina/análogos & derivados , Camptotecina/farmacocinética , Criança , Pré-Escolar , Dacarbazina/administração & dosagem , Dacarbazina/efeitos adversos , Dacarbazina/análogos & derivados , Dacarbazina/farmacocinética , Feminino , Humanos , Lactente , Irinotecano , Masculino , Temozolomida , Vincristina/administração & dosagem , Vincristina/efeitos adversos , Vincristina/farmacocinética , Adulto JovemRESUMO
BACKGROUND: Despite the increasing cure rates for children with acute lymphoblastic leukemia (ALL), patients who relapse continue to have poor prognosis. The Children's Oncology Group (COG) conducted a limited institution Phase II trial of Campath-1H, a monoclonal antibody that targets CD52 on leukemic cells, in children with relapsed or refractory ALL. METHODS: From October 2005 to December 2006, 13 eligible patients were enrolled on the COG phase II study of Campath-1H (ADVL0222). Campath-1H was initially administered as an intravenous infusion over 2 hr, five times per week for 1 week, then three times per week for three additional weeks. Patients with stable disease or better on day 29 could continue on to combination therapy with Campath-1H, methotrexate, and 6-mercaptopurine for two additional cycles. RESULTS: One of 13 patients enrolled had a complete response to Campath-1H and 4 had stable disease. Dose limiting toxicity occurred in two out of nine fully evaluable patients (Grade IV pain and Grade III allergic reaction/hypersensitivity). No patients received combination therapy. Serum Campath-1H concentrations appeared to be somewhat lower in children with ALL compared with adult patients with chronic lymphocytic leukemia. CONCLUSION: Although a single complete response was observed, activity of single agent Campath-1H appears limited. Our study does not support future single agent evaluation of Campath-1H in children with relapsed ALL.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Anticorpos Antineoplásicos/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Alemtuzumab , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais/toxicidade , Anticorpos Monoclonais Humanizados , Anticorpos Antineoplásicos/toxicidade , Antineoplásicos/administração & dosagem , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Terapia de Salvação , Falha de Tratamento , Resultado do Tratamento , Adulto JovemRESUMO
A phase I trial was conducted to determine the maximum tolerated dose (MTD) of temozolomide given in combination with lomustine in newly diagnosed pediatric patients with high-grade gliomas. Response was assessed following two courses of therapy at the MTD. Temozolomide was administered to cohorts of patients at doses of 100, 125, 160, or 200 mg/m(2) on days 1-5, along with 90 mg/m(2) lomustine on day 1. Two courses of lomustine/temozolomide were given prior to radiation therapy (RT) and up to six courses were administered afterward. Thirty-two patients were enrolled. Dose-limiting myelosuppression was seen in two of three patients enrolled at the 200 mg/m(2) dose level. One of 14 patients in the expanded MTD cohort (160 mg/m(2)) experienced dose-limiting thrombocytopenia. After two courses at the MTD, one patient with a 5-mm enhancing nodule postoperatively had a complete response, one patient with a large residual temporal lobe glioblastoma had a partial response, and eight patients had stable disease. Several patients developed transient radiographic worsening after completing RT. Median 1- and 2-year overall survivals at the MTD were 60% +/- 13% and 40% +/- 13% with a median of 17.6 months. Thirteen of 20 patients (65%) who underwent MRI scans within 6 months prior to death developed metastatic disease. In conclusion, when administered with 90 mg/m(2) lomustine on day 1, the MTD of temozolomide is 160 mg/m(2)/day x 5. Radiographic changes following RT make determination of early tumor progression difficult. Metastatic disease is common prior to death.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Glioma/tratamento farmacológico , Adolescente , Adulto , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Alquilantes/efeitos adversos , Criança , Pré-Escolar , Dacarbazina/administração & dosagem , Dacarbazina/efeitos adversos , Dacarbazina/análogos & derivados , Humanos , Lomustina/administração & dosagem , Lomustina/efeitos adversos , Dose Máxima Tolerável , TemozolomidaRESUMO
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.
Assuntos
Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Ácidos Borônicos/farmacocinética , Ácidos Borônicos/uso terapêutico , Leucemia/tratamento farmacológico , Pirazinas/farmacocinética , Pirazinas/uso terapêutico , Adolescente , Bortezomib , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Quinase I-kappa B/efeitos dos fármacos , Immunoblotting , Lactente , Masculino , Dose Máxima Tolerável , NF-kappa B/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacosRESUMO
PURPOSE: To determine the recommended phase 2 dose, dose-limiting toxicities (DLT), pharmacokinetic profile, and pharmacodynamics of the heat shock protein (Hsp) 90 inhibitor, 17-allylaminogeldanamycin (17-AAG). EXPERIMENTAL DESIGN: 17-AAG was administered as a 60-min infusion, on days 1, 4, 8, and 11 of a 21-day cycle at dose levels of 150, 200, 270, and 360 mg/m(2)/dose. Pharmacokinetic studies and evaluations for Hsp72 and Akt levels in peripheral blood mononuclear cells were done during the first course of therapy. RESULTS: Seventeen patients (7 males), median 7 years of age (range, 1-19 years), were enrolled using a standard dose escalation scheme. No DLTs were observed. Although there were no objective responses, three patients remain on therapy at 6+, 7+, and 9+ months with stable disease. One patient with hepatoblastoma had a reduction in alpha-fetoprotein and stable disease over three cycles. At 270 mg/m(2)/dose, the C(max) and areas under the plasma concentration-time curves of 17-AAG were 5,303 +/- 1,591 ng/mL and 13,656 +/- 4,757 ng/mL h, respectively, similar to the exposure in adults. The mean terminal half-life for 17-AAG was 3.24 +/- 0.80 h. Induction of Hsp72, a surrogate marker for inhibition of Hsp90, was detected at the 270 mg/m(2) dose level. CONCLUSIONS: Drug exposures consistent with those required for anticancer activity in preclinical models were achieved without DLT. Evidence for drug-induced modulation of Hsp90 systemically was also detected. The recommended phase II dose of 17-AAG is 360 mg/m(2)/d. Non-DMSO-containing formulations may improve acceptance of this drug by children and their families.
Assuntos
Benzoquinonas/administração & dosagem , Benzoquinonas/farmacocinética , Lactamas Macrocíclicas/administração & dosagem , Lactamas Macrocíclicas/farmacocinética , Neoplasias/tratamento farmacológico , Pediatria , Adolescente , Adulto , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Benzoquinonas/efeitos adversos , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Feminino , Proteínas de Choque Térmico HSP70/metabolismo , Humanos , Lactente , Lactamas Macrocíclicas/efeitos adversos , Masculino , Dose Máxima Tolerável , Neoplasias/metabolismo , Recidiva , Falha de TratamentoRESUMO
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: 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: To determine the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of sorafenib in children with refractory extracranial solid tumors and evaluate the tolerability of the solid tumor MTD in children with refractory leukemias. EXPERIMENTAL DESIGN: Sorafenib was administered orally every 12 hours for consecutive 28-day cycles. Pharmacokinetics (day 1 and steady-state) and pharmacodynamics were conducted during cycle 1. RESULTS: Of 65 patients enrolled, 60 were eligible. In the solid tumor cohort (n = 49), 4 of 6 patients experienced a DLT [hypertension, pain, rash/urticaria, thrombocytopenia, alanine aminotransferase (ALT)/aspartate aminotransferase (AST)] at the starting dose (150 mg/m(2)/dose) which resulted in de-escalation to 105 mg/m(2)/dose. After eligibility criteria modification and dose re-escalation, the MTD was 200 mg/m(2)/dose for solid tumors and 150 mg/m(2)/dose for leukemias. Sorafenib exposure was highly variable between patients but was within the ranges reported in adults. The apparent sorafenib clearance increased with patient age. Diarrhea, rash, fatigue, and increased ALT/AST were the most common sorafenib-related toxicities. Stable disease for 4 or more cycles was observed in 14 solid tumor patients, and 2 patients with acute myeloid leukemia (AML) and FLT3 internal tandem duplication (FLT3ITD) experienced a decrease in bone marrow blasts to less than 5%. CONCLUSIONS: The recommended phase II dose of sorafenib administered every 12 hours continuously for children with solid tumors is 200 mg/m(2)/dose and 150 mg/m(2)/dose for children with leukemias. Sorafenib toxicities and distribution in children are similar to adults. The activity of sorafenib in children with AML and FLT3ITD is currently being evaluated, and a phase II study for select solid tumors is ongoing.
Assuntos
Antineoplásicos/uso terapêutico , Leucemia/tratamento farmacológico , Neoplasias/tratamento farmacológico , Niacinamida/análogos & derivados , Compostos de Fenilureia/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Adolescente , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Niacinamida/farmacocinética , Niacinamida/uso terapêutico , Compostos de Fenilureia/farmacocinética , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Sorafenibe , Resultado do Tratamento , 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.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Receptores de Fatores de Crescimento do Endotélio Vascular/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Adolescente , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Biomarcadores/sangue , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Masculino , Neoplasias/metabolismo , Receptores de Fatores de Crescimento do Endotélio Vascular/efeitos adversos , Receptores de Fatores de Crescimento do Endotélio Vascular/farmacocinética , Proteínas Recombinantes de Fusão/efeitos adversos , Proteínas Recombinantes de Fusão/farmacocinética , Resultado do Tratamento , Adulto JovemRESUMO
Both carboplatin and vinblastine have demonstrated single-agent activity in children with low-grade gliomas. A phase 1 trial evaluating 2 different schedules of these 2 agents in combination was performed: (1) Schedule A = carboplatin (140 mg/m(2)) weekly × 3 + vinblastine (4.5 or 3.5 mg/m(2)) weekly × 6, every 6 weeks; (2) Schedule B = carboplatin (300, 400, or 500 mg/m(2)) on day 1 + vinblastine (4.0 mg/m(2)) weekly × 3, every 4 weeks. Twenty-six patients, median (range) age 4.4 (0.7-14.8) years, were enrolled. Four of 9 patients enrolled on Schedule A had recurrent grade 4 neutropenia, suggesting that this schedule was not feasible. Seventeen patients were enrolled on Schedule B. At the 500 mg/m(2) carboplatin dose level, 2 of 3 patients developed dose-limiting toxicity (elevated alkaline phosphatase, neutropenia). At the 400 mg/m(2) carboplatin dose level, none of the 6 patients had dose-limiting toxicity. Ten of 16 patients who received treatment on Schedule B completed the prescribed 12 courses. Of the 21 patients evaluable for response, central review confirmed 1 partial response and 6 minor responses. Eleven patients had stable disease (>3 months) and 3 developed progressive disease. Seven of 9 patients with visual pathway tumors and acute visual changes prior to enrollment had documented improvement. The recommended phase 2 dose and schedule is carboplatin, 400 mg/m(2)/dose on day 1, and vinblastine, 4 mg/m(2)/dose, weekly × 3, repeated every 4 weeks. Further study of this regimen in patients with low-grade glioma is warranted.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Glioma/tratamento farmacológico , Adolescente , Neoplasias Encefálicas/patologia , Carboplatina/administração & dosagem , Criança , Pré-Escolar , Feminino , Seguimentos , Glioma/patologia , Humanos , Lactente , Masculino , Dose Máxima Tolerável , Estadiamento de Neoplasias , Taxa de Sobrevida , Resultado do Tratamento , Vimblastina/administração & dosagemRESUMO
PURPOSE: The primary purpose of this trial was to define and describe the toxicities of oral valproic acid (VPA) at doses required to maintain trough concentrations of 100 to 150 mcg/mL or 150 to 200 mcg/mL in children with refractory solid or central nervous system (CNS) tumors. Secondary objectives included assessment of free and total VPA pharmacokinetics (PKs) and histone acetylation in peripheral blood mononuclear cells (PBMC) at steady state. PATIENTS AND METHODS: Oral VPA, initially administered twice daily and subsequently three times daily, was continued without interruption to maintain trough concentrations of 100 to 150 mcg/mL. First-dose and steady-state PKs were studied. Histone H3 and H4 acetylation in PBMCs was evaluated using an ELISA technique. RESULTS: Twenty-six children, sixteen of whom were evaluable for toxicity, were enrolled. Dose-limiting somnolence and intratumoral hemorrhage were associated with VPA troughs of 100 to 150 mcg/mL. Therefore, the final cohort of six children received VPA to maintain troughs of 75 to 100 mcg/mL and did not experience any dose-limiting toxicity. First-dose and steady-state VPA PK parameters were similar to values previously reported in children with seizures. Increased PBMC histone acetylation was documented in 50% of patients studied. One confirmed partial response (glioblastoma multiforme) and one minor response (brainstem glioma) were observed. CONCLUSIONS: VPA administered three times daily to maintain trough concentrations of 75 to 100 mcg/mL was well tolerated in children with refractory solid or CNS tumors. Histone hyperacetylation in PBMCs was observed in half of the patients at steady state. Future trials combining VPA with chemotherapy and/or radiation therapy should be considered, especially for CNS tumors.
Assuntos
Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Ácido Valproico/efeitos adversos , Acilação , Adolescente , Criança , Pré-Escolar , Resistencia a Medicamentos Antineoplásicos , Feminino , Histonas/metabolismo , Humanos , Leucócitos Mononucleares/metabolismo , Masculino , Ácido Valproico/administração & dosagem , Ácido Valproico/farmacocinética , Adulto JovemRESUMO
PURPOSE: Sunitinib is an oral multitargeted receptor tyrosine kinase inhibitor. The purpose of this study was to determine the recommended phase 2 dose, pharmacokinetics, pharmacodynamic effects, and preliminary antitumor activity of sunitinib in a pediatric population. EXPERIMENTAL DESIGN: Patients who were 2 to 21 years of age with refractory solid tumors were eligible if they had measurable or evaluable disease and met baseline organ function requirements. Patients received sunitinib once daily for 28 days followed by a 14-day break between each cycle. Dose levels of 15 and 20 mg/m(2)/d were evaluated, with dose escalation based on a 3 + 3 design. Sunitinib pharmacokinetics and biomarkers of angiogenesis were also evaluated during the first cycle. RESULTS: Twenty-three patients were treated (median age 13.9 years; range, 3.9-20.6 years). The most common toxicities were neutropenia, thrombocytopenia, elevated liver transaminases, gastrointestinal symptoms, and fatigue. Two patients developed dose-limiting reductions in cardiac ejection fraction prompting a protocol amendment to exclude patients with previous exposure to anthracyclines or cardiac radiation. In patients without these cardiac risk factors, the maximum tolerated dose (MTD) was 15 mg/m(2)/d. Steady-state plasma concentrations were reached by day 7. No objective responses were observed. Four patients with sarcoma and glioma had stable disease for 2 to 9 cycles. CONCLUSIONS: Cardiac toxicity precluded determination of a recommended dose for pediatric patients with previous anthracycline or cardiac radiation exposure. The MTD of sunitinib for patients without risk factors for cardiac toxicity is 15 mg/m(2)/d for 28 days followed by a 14-day break.