Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 6 de 6
Filtrar
Mais filtros

Base de dados
País/Região como assunto
Tipo de documento
País de afiliação
Intervalo de ano de publicação
1.
Lancet Oncol ; 14(6): 472-80, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23598171

RESUMO

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 Jovem
2.
Lancet Oncol ; 13(10): 1011-9, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22954507

RESUMO

BACKGROUND: ALK fusion genes occur in a subset of non-small-cell lung cancers (NSCLCs). We assessed the tolerability and activity of crizotinib in patients with NSCLC who were prospectively identified to have an ALK fusion within the first-in-man phase 1 crizotinib study. METHODS: In this phase 1 study, patients with ALK-positive stage III or IV NSCLC received oral crizotinib 250 mg twice daily in 28-day cycles. Endpoints included tumour responses, duration of response, time to tumour response, progression-free survival (PFS), overall survival at 6 and 12 months, and determination of the safety and tolerability and characterisation of the plasma pharmacokinetic profile of crizotinib after oral administration. Responses were analysed in evaluable patients and PFS and safety were analysed in all patients. This study is registered with ClinicalTrials.gov, number NCT00585195. FINDINGS: Between Aug 27, 2008, and June 1, 2011, 149 ALK-positive patients were enrolled, 143 of whom were included in the response-evaluable population. 87 of 143 patients had an objective response (60·8%, 95% CI 52·3-68·9), including three complete responses and 84 partial responses. Median time to first documented objective response was 7·9 weeks (range 2·1-39·6) and median duration of response was 49·1 weeks (95% CI 39·3-75·4). The response rate seemed to be largely independent of age, sex, performance status, or line of treatment. Median PFS was 9·7 months (95% CI 7·7-12·8). Median overall survival data are not yet mature, but estimated overall survival at 6 and 12 months was 87·9% (95% CI 81·3-92·3) and 74·8% (66·4-81·5), respectively. 39 patients continued to receive crizotinib for more than 2 weeks after progression because of perceived ongoing clinical benefit from the drug (12 for at least 6 months from the time of their initial investigator-defined disease progression). Overall, 144 (97%) of 149 patients experienced treatment-related adverse events, which were mostly grade 1 or 2. The most common adverse events were visual effects, nausea, diarrhoea, constipation, vomiting, and peripheral oedema. The most common treatment-related grade 3 or 4 adverse events were neutropenia (n=9), raised alanine aminotransferase (n=6), hypophosphataemia (n=6), and lymphopenia (n=6). INTERPRETATION: Crizotinib is well tolerated with rapid, durable responses in patients with ALK-positive NSCLC. There seems to be potential for ongoing benefit after initial disease progression in this population, but a more formal definition of ongoing benefit in this context is needed.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Piridinas/uso terapêutico , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Quinase do Linfoma Anaplásico , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Crizotinibe , Feminino , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/efeitos adversos , Pirazóis/efeitos adversos , Piridinas/efeitos adversos , Receptores Proteína Tirosina Quinases/análise
3.
Leuk Lymphoma ; 48(9): 1728-35, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17786708

RESUMO

Between January 1990 and April 2001, 115 patients received high-dose chemotherapy (HDT) followed by autologous stem cell transplantation (ASCT) for relapsed or refractory Hodgkin lymphoma (HL). With a median follow-up of 58 months (range, 1 - 175 months), 5-year progression-free survival (PFS) and overall survival (OS) were 46% and 58%, respectively. Twelve patients with primary refractory disease had a 5-year PFS of 41% and OS of 58%, not significantly different from those of the remaining cohort. Early and overall regimen related mortality were 7% and 16%, respectively. Male gender (P = 0.04) and a time to relapse (TTR) < 12 months (P = 0.03) were associated with decreased OS by univariate analysis. In multivariate analysis, TTR < 12 months remained statistically significant (P = 0.04). We have confirmed that HDT and ASCT result in long-term survival for a proportion of patients with relapsed or refractory HL. All patients, including those with primary refractory disease, benefited from HDT and ASCT.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Doença de Hodgkin/terapia , Adolescente , Adulto , Terapia Combinada , Feminino , Doença de Hodgkin/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Segunda Neoplasia Primária/etiologia , Prognóstico , Recidiva , Transplante Autólogo , Transplante Homólogo , Resultado do Tratamento
5.
Biol Blood Marrow Transplant ; 13(10): 1207-15, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17889358

RESUMO

Chronic graft-versus-host disease (cGVHD), a common complication after stem cell transplant (SCT), has an impact on morbidity and survival. Previous classification of cGVHD has not been reproducible or prognostic for nonrelapse mortality (NRM). Recently the National Institutes of Health (NIH) consensus criteria were proposed, but the ability of this classification to predict outcome of various subtypes of cGVHD is unknown. Patients (N = 110) undergoing an SCT for a hematologic malignancy and surviving until day 100 posttransplant from 2001 to 2003 were studied. The overall survival (OS) using a landmark analysis at day 100 was 44% versus 66% (no GVHD vs. GVHD, P = .026). The OS of patients with various types of GVHD as proposed by the NIH criteria were significantly different (P < .0001). In a univariate analyses, this was more apparent when patients with any acute features of GVHD were compared to classic cGVHD (3-year OS 46% vs. 68%, P = .033). The 3-year NRM for the entire cohort was 21%, and was not affected by presence or absence of GVHD or subtypes of GVHD. In a multivariable analysis, extensive cGVHD (hazard ratio [HR] 0.35, P = .015) and having any acute feature of GVHD after day 100 (HR 3.36, P = .0144) were significant independent predictors of survival. The OS with different NIH subtypes of GVHD after day 100 from SCT varies, and is superior for patients with classic cGVHD.


Assuntos
Doença Enxerto-Hospedeiro/classificação , Doença Enxerto-Hospedeiro/epidemiologia , Guias de Prática Clínica como Assunto , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Doença Crônica , Estudos de Coortes , Feminino , Humanos , Incidência , Lactente , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , National Institutes of Health (U.S.) , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Tennessee/epidemiologia , Estados Unidos
6.
Blood ; 107(5): 2184-91, 2006 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-16254140

RESUMO

In an attempt to improve outcomes for patients with acute myeloid leukemia (AML) after allogeneic hematopoietic cell transplantation (HCT), we conducted a phase 1/2 study in which targeted irradiation delivered by 131I-anti-CD45 antibody was combined with targeted busulfan (BU; area-under-curve, 600-900 ng/mL) and cyclophosphamide (CY; 120 mg/kg). Fifty-two (88%) of 59 patients receiving a trace 131I-labeled dose of 0.5 mg/kg anti-CD45 murine antibody had higher estimated absorbed radiation in bone marrow and spleen than in any other organ. Forty-six patients were treated with 102 to 298 mCi (3774-11 026 MBq) 131I, delivering an estimated 5.3 to 19 (mean, 11.3) Gy to marrow, 17-72 (mean, 29.7) Gy to spleen, and 3.5 Gy (n = 4) to 5.25 Gy (n = 42) to the liver. The estimated 3-year nonrelapse mortality and disease-free survival (DFS) were 21% and 61%, respectively. These results were compared with those from 509 similar International Bone Marrow Transplant Registry patients who underwent transplantation using BU/CY alone. After adjusting for differences in age and cytogenetics risk, the hazard of mortality among all antibody-treated patients was 0.65 times that of the Registry patients (95% CI 0.39-1.08; P = .09). The addition of targeted hematopoietic irradiation to conventional BU/CY is feasible and well tolerated, and phase 2 results are sufficiently encouraging to warrant further study.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/terapia , Adolescente , Adulto , Fatores Etários , Anticorpos Monoclonais/administração & dosagem , Medula Óssea/patologia , Bussulfano/administração & dosagem , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Isótopos de Iodo/administração & dosagem , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Radioterapia/métodos , Indução de Remissão , Fatores de Risco , Baço/patologia , Transplante Homólogo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA