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1.
Br J Haematol ; 162(2): 191-201, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23647373

RESUMO

Tefinostat (CHR-2845) is a monocyte/macrophage targeted histone deacetylase inhibitor (HDACi). This first-in-human, standard 3 + 3 dose escalating trial of oral, once daily tefinostat was conducted to determine the safety, tolerability, pharmacokinetic and pharmacodynamic profile of tefinostat in relapsed/refractory haematological diseases. Eighteen patients were enrolled at doses of 20-640 mg. Plasma concentrations of tefinostat exceeded those demonstrated to give in vitro anti-proliferative activity. Flow cytometric pharmacodynamic assays demonstrated monocyte-targeted increases in protein acetylation, without corresponding changes in lymphocytes. Dose-limiting toxicities (DLTs) were not observed and dose escalation was halted at 640 mg without identification of the maximum tolerated dose. Drug-related toxicities were largely Common Toxicity Criteria for Adverse Events grade 1/2 and included nausea, anorexia, fatigue, constipation, rash and increased blood creatinine. A patient with chronic monomyelocytic leukaemia achieved a bone marrow response, with no change in peripheral monocytes. An acute myeloid leukaemia type M2 patient showed a >50% decrease in bone marrow blasts and clearance of peripheral blasts. In conclusion, tefinostat produces monocyte-targeted HDACi activity and is well tolerated, without the DLTs, e.g. fatigue, diarrhoea, thrombocytopenia, commonly seen with non-targeted HDACi. The early signs of efficacy and absence of significant toxicity warrant further evaluation of tefinostat in larger studies. (clinicaltrials.gov identifier: NCT00820508).


Assuntos
Anilidas/administração & dosagem , Anilidas/efeitos adversos , Neoplasias Hematológicas/tratamento farmacológico , Inibidores de Histona Desacetilases/administração & dosagem , Inibidores de Histona Desacetilases/efeitos adversos , Ácidos Hidroxâmicos/administração & dosagem , Ácidos Hidroxâmicos/efeitos adversos , Macrófagos/metabolismo , Monócitos/metabolismo , Anilidas/farmacocinética , Estudos de Coortes , Relação Dose-Resposta a Droga , Sistemas de Liberação de Medicamentos , Neoplasias Hematológicas/sangue , Neoplasias Hematológicas/metabolismo , Inibidores de Histona Desacetilases/farmacocinética , Humanos , Ácidos Hidroxâmicos/farmacocinética , Macrófagos/enzimologia , Monócitos/enzimologia
2.
Lancet Oncol ; 14(4): 354-62, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23453583

RESUMO

BACKGROUND: Tosedostat is a novel oral aminopeptidase inhibitor with clinical activity in a previous phase 1-2 study in elderly patients with relapsed or refractory acute myeloid leukaemia (AML). We aimed to compare two dosing regimens of tosedostat. METHODS: In this randomised phase 2 study, patients aged 60 years or older with AML that had relapsed after a first complete remission lasting less than 12 months, or had achieved no previous complete remission, were randomly assigned (1:1) to receive as first salvage tosedostat 120 mg once daily for 6 months or 240 mg once daily for 2 months followed by 120 mg for 4 months. Randomisation was by block method via an interactive web response system using a randomisation schedule generated by an external vendor, with no stratification. The study was open label. The primary endpoint was the proportion of patients who obtained a complete remission or complete remission with incomplete platelet recovery. Analyses included all patients randomly assigned to treatment groups who received at least one oral dose of tosedostat. The study is registered with ClinicalTrials.gov, number NCT00780598. FINDINGS: 38 patients were randomly assigned to receive tosedostat 120 mg and 38 to receive the tosedostat 240 mg to 120 mg regimen. 38 patients in the 120 mg group and 35 in the 240 mg to 120 mg group received tosedostat. Seven patients (10%) had complete remission or complete remission with incomplete platelet recovery: two (5%) in the 120 mg group and five (14%) in the 240 mg to 120 mg group. The most common grade 3 or worse adverse events were febrile neutropenia (11 [29%] patients in the 120 mg group and ten [29%] of the 240 mg to 120 mg group), thrombocytopenia (eight [21%] and eight [23%] patients), fatigue (seven [18%] and eight [23%] patients), dyspnoea (five [13%] and seven [20%] patients), and pneumonia (four [11%] and six [17%] patients). There were five fatal adverse events deemed to be treatment-related: three in the 120 mg group and two in the 240 mg to 120 mg group. The events were acute hepatitis, respiratory failure, pneumonia, atrial fibrillation, and left ventricular dysfunction. INTERPRETATION: Tosedostat, at either dose schedule, has activity in older patients with relapsed or refractory AML. Additional studies of tosedostat including combination with hypomethylating agents and low-dose cytarabine in patients with high-risk myelodysplastic syndromes and AML are ongoing or planned. FUNDING: Chroma Therapeutics.


Assuntos
Anemia Refratária/tratamento farmacológico , Glicina/análogos & derivados , Ácidos Hidroxâmicos/administração & dosagem , Leucemia Monocítica Aguda/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Anemia Refratária/patologia , Citarabina/administração & dosagem , Intervalo Livre de Doença , Feminino , Glicina/administração & dosagem , Glicina/efeitos adversos , Humanos , Ácidos Hidroxâmicos/efeitos adversos , Leucemia Monocítica Aguda/patologia , Masculino , Pessoa de Meia-Idade , Recidiva , Indução de Remissão
3.
Clin Cancer Res ; 18(9): 2687-94, 2012 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-22553374

RESUMO

PURPOSE: This clinical trial investigated the safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) profile of CHR-3996, a selective class I histone deacetylase inhibitor. PATIENTS AND METHODS: CHR-3996 was administered orally once a day. This phase I trial used a 3+3 dose-escalation design. PK profiles were analyzed by liquid chromatography-tandem mass spectroscopic methods and PD studies were conducted using ELISA studying histone H3 acetylation in peripheral blood mononuclear cells. RESULTS: Thirty-nine patients were treated at dose levels of 5 mg (n = 3), 10 mg (n = 4), 20 mg (n = 3), 40 mg (n = 10), 80 mg (n = 10), 120 mg (n = 4), and 160 mg (n = 5) administered orally once daily. The dose-limiting toxicities seen were thrombocytopenia (160 mg), fatigue (80 and 120 mg), plasma creatinine elevation (80 and 120 mg), and atrial fibrillation (40 mg). The area under the curve was proportional to the administered dose and a maximal plasma concentration of 259 ng/mL at a dose of 40 mg exceeded the concentrations required for antitumor efficacy in preclinical models. Target inhibition measured by quantification of histone acetylation was shown at doses of 10 mg/d and was maximal at 40 mg. A partial response was seen in one patient with metastatic acinar pancreatic carcinoma. CONCLUSIONS: Taking the toxicity and PK/PD profile into consideration, the recommended phase II dose (RP2D) is 40 mg/d. At this dose, CHR-3996 has a favorable toxicologic, PK, and PD profile. CHR-3996 has shown preliminary clinical activity and should be evaluated in further clinical trials.


Assuntos
Compostos Azabicíclicos/uso terapêutico , Inibidores de Histona Desacetilases/uso terapêutico , Histona Desacetilases/química , Neoplasias/tratamento farmacológico , Pirimidinas/uso terapêutico , Acetilação , Administração Oral , Adulto , Idoso , Compostos Azabicíclicos/farmacocinética , Ensaios Clínicos Fase II como Assunto , Feminino , Seguimentos , Inibidores de Histona Desacetilases/farmacocinética , Humanos , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/efeitos dos fármacos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Prognóstico , Pirimidinas/farmacocinética , Distribuição Tecidual
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