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1.
Br J Haematol ; 195(2): 201-209, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34341990

RESUMO

Fimepinostat (CUDC-907), a first-in-class oral small-molecule inhibitor of histone deacetylase and phosphatidylinositol 3-kinase, demonstrated efficacy in a phase 1 study of patients with relapsed/refractory (R/R) diffuse large and high-grade B-cell lymphomas (DLBCL/HGBL), particularly those with increased MYC protein expression and/or MYC gene rearrangement/copy number gain (MYC-altered disease). Therefore, a phase 2 study of fimepinostat was conducted in this patient population with 66 eligible patients treated. The primary end-point of overall response (OR) rate for patients with MYC-IHC ≥40% (n = 46) was 15%. Subsequently, exploratory pooled analyses were performed including patients treated on both the phase 1 and 2 studies based upon the presence of MYC-altered disease as well as a biomarker identified by Virtual Inference of Protein activity by Enriched Regulon analysis (VIPER). For these patients with MYC-altered disease (n = 63), the overall response (OR) rate was 22% with seven responding patients remaining on treatment for approximately two years or longer, and VIPER yielded a three-protein biomarker classification with positive and negative predictive values of ≥85%. Prolonged durations of response were achieved by patients with MYC-altered R/R DLBCL/HGBL treated with single-agent fimepinostat. Combination therapies and/or biomarker-based patient selection strategies may lead to higher response rates in future clinical trials.


Assuntos
Biomarcadores Tumorais/análise , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma não Hodgkin/tratamento farmacológico , Morfolinas/uso terapêutico , Pirimidinas/uso terapêutico , Feminino , Inibidores de Histona Desacetilases/administração & dosagem , Inibidores de Histona Desacetilases/uso terapêutico , Humanos , Linfoma Difuso de Grandes Células B/genética , Linfoma não Hodgkin/genética , Masculino , Pessoa de Meia-Idade , Morfolinas/administração & dosagem , Inibidores de Fosfoinositídeo-3 Quinase/administração & dosagem , Inibidores de Fosfoinositídeo-3 Quinase/uso terapêutico , Valor Preditivo dos Testes , Proteínas Proto-Oncogênicas c-myc/genética , Pirimidinas/administração & dosagem , Recidiva , Segurança , Resultado do Tratamento
2.
Int J Cancer ; 139(1): 177-86, 2016 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-26891420

RESUMO

Cetuximab in combination with an irinotecan-containing regimen is a standard treatment in patients with KRAS wild-type (KRAS WT), metastatic colorectal cancer (mCRC). We investigated the addition of the oral MET inhibitor tivantinib to cetuximab + irinotecan (CETIRI) based on preclinical evidence that activation of the MET pathway may confer resistance to anti-EGFR therapy. Previously treated patients with KRAS WT advanced or mCRC were enrolled. The phase 1, open-label 3 + 3, dose-escalation study evaluated the safety and maximally tolerated dose of tivantinib plus CETIRI. The phase 2, randomized, double-blinded, placebo-controlled study of biweekly CETIRI plus tivantinib or placebo was restricted to patients who had received only one prior line of chemotherapy. The phase 2 primary endpoint was progression-free survival (PFS). The recommended phase 2 dose was tivantinib (360 mg/m(2) twice daily) with biweekly cetuximab (500 mg/m(2)) and irinotecan (180 mg/m(2)). Among 117 patients evaluable for phase 2 analysis, no statistically significant PFS difference was observed: 8.3 months on tivantinib vs. 7.3 months on placebo (HR, 0.85; 95% confidence interval, 0.55-1.33; P = 0.38). Subgroup analyses trended in favor of tivantinib in patients with MET-High tumors by immunohistochemistry, PTEN-Low tumors, or those pretreated with oxaliplatin, but subgroups were too small to draw conclusions. Neutropenia, diarrhea, nausea and rash were the most frequent severe adverse events in tivantinib-treated patients. The combination of tivantinib and CETIRI was well tolerated but did not significantly improve PFS in previously treated KRAS WT mCRC. Tivantinib may be more active in specific subgroups.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Proteínas Proto-Oncogênicas p21(ras)/genética , Pirrolidinonas/administração & dosagem , Quinolinas/administração & dosagem , Adulto , Idoso , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Cetuximab/administração & dosagem , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Intervalo Livre de Doença , Feminino , Humanos , Irinotecano , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica
3.
J Clin Oncol ; 33(24): 2667-74, 2015 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-26169611

RESUMO

PURPOSE: Tivantinib, a MET receptor tyrosine kinase inhibitor, demonstrated increased anticancer activity in preclinical and early clinical studies when combined with erlotinib. Our study aimed to confirm efficacy and safety of the combination in previously treated patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with advanced nonsquamous NSCLC previously treated with one to two systemic regimens, including a platinum doublet, were randomly assigned at a 1:1 ratio to receive erlotinib 150 mg daily plus oral tivantinib 360 mg twice daily (E + T) or erlotinib plus placebo (E + P) until disease progression. Tumor specimens were evaluated for EGFR and KRAS mutations, MET expression, and MET gene amplification. The primary end point was overall survival (OS). Secondary and exploratory objectives included progression-free survival (PFS), OS in molecular subgroups, and safety. RESULTS: The study enrolled 1,048 patients and was discontinued for futility at the interim analysis. OS did not improve with E + T versus E + P (median OS, 8.5 v 7.8 months, respectively; hazard ratio [HR], 0.98; 95% CI, 0.84 to 1.15; P = .81), even though PFS increased (median PFS, 3.6 v 1.9 months; HR, 0.74; 95% CI, 0.62 to 0.89; P < .001). Exploratory subgroup analyses suggested OS improvement in patients with high MET expression (HR, 0.70; 95% CI, 0.49 to 1.01). Most common adverse events occurring with E + T versus E + P were rash (33.1% v 37.3%, respectively), diarrhea (34.6% v 41.0%), asthenia or fatigue (43.5% v 38.1%), and neutropenia (grade 3 to 4; 8.5% v 0.8%). CONCLUSION: E + T was well tolerated and increased PFS but did not improve OS in the overall nonsquamous NSCLC population.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Quinazolinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/patologia , Cloridrato de Erlotinib , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Pirrolidinonas/administração & dosagem , Quinazolinas/administração & dosagem , Quinolinas/administração & dosagem , Adulto Jovem
4.
Clin Cancer Res ; 19(21): 5984-93, 2013 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-24045184

RESUMO

PURPOSE: CS-1008 (tigatuzumab; phase I/II), an antihuman death receptor 5 (DR5) agonist, induces apoptosis and has cytotoxic activity against human cancer cell lines. This study reports on the preclinical validation of (111)In-labeled anti-DR5 humanized antibody CS-1008 as a diagnostic tool to study the DR5 occupancy in patients with cancer and establish dose ranges for receptor saturation kinetics in vivo. EXPERIMENTAL DESIGN: CS-1008 was radiolabeled and characterized for DR5 binding and labeling efficiency on TRAIL-sensitive DR5-positive colorectal cancer cells (COLO 205 and WiDr). Pharmacokinetic and biodistribution studies were conducted in BALB/c nu/nu mice bearing COLO 205, WiDr, or DR5-negative CT26 colon tumors. Planar gamma camera imaging and computerized tomography (CT) images were obtained to study receptor occupancy in vivo. RESULTS: Scatchard analysis showed high and specific binding affinity (Kd, 1.05 ± 0.12 nmol/L) of (111)In-labeled CS-1008. (111)In-labeled CS-1008 was specifically taken up in mice bearing COLO 205 and WiDr tumors with prolonged tumor retention (26.25 ± 2.85%ID/g vs. 12.20 ± 2.24 at 168 hours post injection; n = 5, SD), and uptake correlated both with DR5 expression on tumor cells and antitumor activity. DR5 saturation was shown in vivo via both biodistribution studies and planar gamma camera imaging/CT imaging of (111)In-labeled CS-1008. Saturation of DR5 corresponded to maximal in vivo antitumor efficacy. CONCLUSIONS: Imaging of DR5 receptor occupancy in vivo correlates with tumor concentration and in vivo efficacy, and is a novel molecular imaging technique that can be used to determine receptor occupancy and effective dose levels of DR5 agonist antibodies in the clinic.


Assuntos
Anticorpos Monoclonais Humanizados/metabolismo , Imagem Molecular , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Animais , Anticorpos Monoclonais Humanizados/farmacocinética , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Humanos , Radioisótopos de Índio , Marcação por Isótopo , Cinética , Camundongos , Ligação Proteica , Cintilografia , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/antagonistas & inibidores , Distribuição Tecidual
5.
Cancer Med ; 2(6): 925-32, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24403266

RESUMO

Tigatuzumab is the humanized version of the agonistic murine monoclonal antibody TRA-8 that binds to the death receptor 5 and induces apoptosis of human cancer cell lines via the caspase cascade. The combination of tigatuzumab and gemcitabine inhibits tumor growth in murine pancreatic xenografts. This phase 2 trial evaluated the efficacy of tigatuzumab combined with gemcitabine in 62 chemotherapy-naive patients with histologically or cytologically confirmed unresectable or metastatic pancreatic cancer. Patients received intravenous tigatuzumab (8 mg/kg loading dose followed by 3 mg/kg weekly) and gemcitabine (1000 mg/m(2) once weekly for 3 weeks followed by 1 week of rest) until progressive disease (PD) or unacceptable toxicity occurred. The primary end point was progression-free survival (PFS) at 16 weeks. Secondary end points included objective response rate (ORR) (complete responses plus partial responses), duration of response, and overall survival (OS). Safety of the combination was also evaluated. Mean duration of treatment was 18.48 weeks for tigatuzumab and 17.73 weeks for gemcitabine. The PFS rate at 16 weeks was 52.5% (95% confidence interval [CI], 39.3-64.1%). The ORR was 13.1%; 28 (45.9%) patients had stable disease and 14 (23%) patients had PD. Median PFS was 3.9 months (95% CI, 2.2-5.4 months). Median OS was 8.2 months (95% CI, 5.1-9.6 months). The most common adverse events related to tigatuzumab were nausea (35.5%), fatigue (32.3%), and peripheral edema (19.4%). Tigatuzumab combined with gemcitabine was well tolerated and may be clinically active for the treatment of chemotherapy-naive patients with unresectable or metastatic pancreatic cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/imunologia
6.
Lancet Oncol ; 14(1): 55-63, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23182627

RESUMO

BACKGROUND: Tivantinib (ARQ 197), a selective oral inhibitor of MET, has shown promising antitumour activity in hepatocellular carcinoma as monotherapy and in combination with sorafenib. We aimed to assess efficacy and safety of tivantinib for second-line treatment of advanced hepatocellular carcinoma. METHODS: In this completed, multicentre, randomised, placebo-controlled, double-blind, phase 2 study, we enrolled patients with advanced hepatocellular carcinoma and Child-Pugh A cirrhosis who had progressed on or were unable to tolerate first-line systemic therapy. We randomly allocated patients 2:1 to receive tivantinib (360 mg twice-daily) or placebo until disease progression. The tivantinib dose was amended to 240 mg twice-daily because of high incidence of treatment-emergent grade 3 or worse neutropenia. Randomisation was done centrally by an interactive voice-response system, stratified by Eastern Cooperative Oncology Group performance status and vascular invasion. The primary endpoint was time to progression, according to independent radiological review in the intention-to-treat population. We assessed tumour samples for MET expression with immunohistochemistry (high expression was regarded as ≥2+ in ≥50% of tumour cells). This study is registered with ClinicalTrials.gov, number NCT00988741. FINDINGS: 71 patients were randomly assigned to receive tivantinib (38 at 360 mg twice-daily and 33 at 240 mg twice-daily); 36 patients were randomly assigned to receive placebo. At the time of analysis, 46 (65%) patients in the tivantinib group and 26 (72%) of those in the placebo group had progressive disease. Time to progression was longer for patients treated with tivantinib (1·6 months [95% CI 1·4-2·8]) than placebo (1·4 months [1·4-1·5]; hazard ratio [HR] 0·64, 90% CI 0·43-0·94; p=0·04). For patients with MET-high tumours, median time to progression was longer with tivantinib than for those on placebo (2·7 months [95% CI 1·4-8·5] for 22 MET-high patients on tivantinib vs 1·4 months [1·4-1·6] for 15 MET-high patients on placebo; HR 0·43, 95% CI 0·19-0·97; p=0·03). The most common grade 3 or worse adverse events in the tivantinib group were neutropenia (ten patients [14%] vs none in the placebo group) and anaemia (eight [11%] vs none in the placebo group). Eight patients (21%) in the tivantinib 360 mg group had grade 3 or worse neutropenia compared with two (6%) patients in the 240 mg group. Four deaths related to tivantinib occurred from severe neutropenia. 24 (34%) patients in the tivantinib group and 14 (39%) patients in the placebo group had serious adverse events. INTERPRETATION: Tivantinib could provide an option for second-line treatment of patients with advanced hepatocellular carcinoma and well-compensated liver cirrhosis, particularly for patients with MET-high tumours. Confirmation in a phase 3 trial is needed, with a starting dose of tivantinib 240 mg twice-daily. FUNDING: ArQule, Daiichi Sankyo (Daiichi Sankyo Group).


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Neoplasias Hepáticas/tratamento farmacológico , Pirrolidinonas/administração & dosagem , Quinolinas/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/patologia , Intervalo Livre de Doença , Método Duplo-Cego , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/induzido quimicamente , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/classificação , Feminino , Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Proto-Oncogênicas c-met/metabolismo , Pirrolidinonas/efeitos adversos , Quinolinas/efeitos adversos
7.
Clin Lung Cancer ; 13(5): 391-5, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22440336

RESUMO

We present the rationale and design for MARQUEE, a phase III, randomized, double-blind, placebo-controlled study of ARQ 197 plus erlotinib versus placebo plus erlotinib in previously treated subjects with locally advanced or metastatic, nonsquamous, non-small-cell lung cancer (NSCLC). The design of MARQUEE is based on preclinical data, the current understanding of the role of cellular N-methyl-N'-nitroso-guanidine human osteosarcoma (MNNG HOS) transforming gene (MET) in NSCLC, and clinical data from a randomized phase II study. The available evidence suggests that dual inhibition of MET and the epidermal growth factor receptor (EGFR) may overcome resistance to EGFR inhibitors. In the phase II study, the combination of tivantinib plus erlotinib significantly improved progression-free survival (PFS) and overall survival (OS) compared with placebo plus erlotinib in the subset of patients with nonsquamous histology, a population enriched for MET overexpression. The primary endpoint in MARQUEE is OS. Secondary and exploratory objectives include determination of PFS, OS in molecular subgroups (defined by EGFR and KRAS mutation status, amplification or overexpression of MET, and serum hepatocyte growth factor), and safety. All patients will be tested for biomarkers, and the results will provide a wealth of information on the role of tivantinib in treating nonsquamous NSCLC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Pirrolidinonas/uso terapêutico , Quinazolinas/uso terapêutico , Quinolinas/uso terapêutico , Projetos de Pesquisa , Terapia de Salvação , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/secundário , Método Duplo-Cego , Cloridrato de Erlotinib , Seguimentos , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Estadiamento de Neoplasias , Prognóstico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Taxa de Sobrevida
8.
Ther Deliv ; 2(3): 333-44, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22834004

RESUMO

Monoclonal antibodies are increasingly being used as protein therapeutics for cancer. They offer very specific binding to target molecules on the surface of cancer cells, relatively few side effects and predictable pharmacokinetics. Tumor shrinkage is seen in some patients, and an incremental improvement in survival occurs in the group. However, due to their large size and consequent slow diffusion, antibody penetration deep into tumors may be inhomogeneous. Even if only a few cells, deep in tumors, escape therapy, they can regrow and lead to clinical relapse, limiting the significant potential of monoclonal antibody therapy. This leads to questions about optimal dosing for monoclonal antibodies. Methods to determine monoclonal antibody dose include maximum-tolerated dose studies, pharmacokinetically and pharmacodynamically guided dosing, randomized dose-ranging studies, imaging of antibody biodistribution and competitive-binding studies. Limitations of these methods, and future directions to possibly overcome these limitations will be discussed.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/farmacocinética , Neoplasias/tratamento farmacológico , Animais , Humanos , Dose Máxima Tolerável , Neoplasias/metabolismo , Distribuição Tecidual , Tomografia Computadorizada de Emissão de Fóton Único
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