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1.
Lancet Oncol ; 19(1): 101-114, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29169877

RESUMO

BACKGROUND: EGFR antibodies have shown promise in patients with advanced non-small-cell lung cancer (NSCLC), particularly with squamous cell histology. We hypothesised that EGFR copy number by fluorescence in-situ hybridisation (FISH) can identify patients most likely to benefit from these drugs combined with chemotherapy and we aimed to explore the activity of cetuximab with chemotherapy in patients with advanced NSCLC who are EGFR FISH-positive. METHODS: We did this open-label, phase 3 study (SWOG S0819) at 277 sites in the USA and Mexico. We randomly assigned (1:1) eligible patients with treatment-naive stage IV NSCLC to receive paclitaxel (200 mg/m2; every 21 days) plus carboplatin (area under the curve of 6 by modified Calvert formula; every 21 days) or carboplatin plus paclitaxel and bevacizumab (15 mg/kg; every 21 days), either with cetuximab (250 mg/m2 weekly after loading dose; cetuximab group) or without (control group), stratified by bevacizumab treatment, smoking status, and M-substage using a dynamic-balancing algorithm. Co-primary endpoints were progression-free survival in patients with EGFR FISH-positive cancer and overall survival in the entire study population. We analysed clinical outcomes with the intention-to-treat principle and analysis of safety outcomes included patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov (number NCT00946712). FINDINGS: Between Aug 13, 2009, and May 30, 2014, we randomly assigned 1313 patients to the control group (n=657; 277 with bevacizumab and 380 without bevacizumab in the intention-to-treat population) or the cetuximab group (n=656; 283 with bevacizumab and 373 without bevacizumab in the intention-to-treat population). EGFR FISH was assessable in 976 patients and 400 patients (41%) were EGFR FISH-positive. The median follow-up for patients last known to be alive was 35·2 months (IQR 22·9-39·9). After 194 progression-free survival events in the cetuximab group and 198 in the control group in the EGFR FISH-positive subpopulation, progression-free survival did not differ between treatment groups (hazard ratio [HR] 0·92, 95% CI 0·75-1·12; p=0·40; median 5·4 months [95% CI 4·5-5·7] vs 4·8 months [3·9-5·5]). After 570 deaths in the cetuximab group and 593 in the control group, overall survival did not differ between the treatment groups in the entire study population (HR 0·93, 95% CI 0·83-1·04; p=0·22; median 10·9 months [95% CI 9·5-12·0] vs 9·2 months [8·7-10·3]). In the prespecified analysis of EGFR FISH-positive subpopulation with squamous cell histology, overall survival was significantly longer in the cetuximab group than in the control group (HR 0·58, 95% CI 0·36-0·86; p=0·0071), although progression-free survival did not differ between treatment groups in this subgroup (0·68, 0·46-1·01; p=0·055). Overall survival and progression-free survival did not differ among patients who were EGFR FISH non-positive with squamous cell histology (HR 1·04, 95% CI 0·78-1·40; p=0·77; and 1·02, 0·77-1·36; p=0·88 respectively) or patients with non-squamous histology regardless of EGFR FISH status (for EGFR FISH-positive 0·88, 0·68-1·14; p=0·34; and 0·99, 0·78-1·27; p=0·96; respectively; and for EGFR FISH non-positive 1·00, 0·85-1·17; p=0·97; and 1·03, 0·88-1·20; p=0·69; respectively). The most common grade 3-4 adverse events were decreased neutrophil count (210 [37%] in the cetuximab group vs 158 [25%] in the control group), decreased leucocyte count (103 [16%] vs 74 [20%]), fatigue (81 [13%] vs 74 [20%]), and acne or rash (52 [8%] vs one [<1%]). 59 (9%) patients in the cetuximab group and 31 (5%) patients in the control group had severe adverse events. Deaths related to treatment occurred in 32 (6%) patients in the cetuximab group and 13 (2%) patients in the control group. INTERPRETATION: Although this study did not meet its primary endpoints, prespecified subgroup analyses of patients with EGFR FISH-positive squamous-cell carcinoma cancers are encouraging and support continued evaluation of anti-EGFR antibodies in this subpopulation. FUNDING: National Cancer Institute and Eli Lilly and Company.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Cetuximab/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Paclitaxel/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carboplatina/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Cetuximab/efeitos adversos , Progressão da Doença , Intervalo Livre de Doença , Receptores ErbB/genética , Feminino , Humanos , Hibridização in Situ Fluorescente , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , México , Pessoa de Meia-Idade , Mutação , Paclitaxel/efeitos adversos , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Estados Unidos
2.
Int J Gynecol Cancer ; 25(3): 484-92, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25594147

RESUMO

PURPOSE: The aim of this study was to evaluate the tolerability and efficacy of poly(ADP-ribose) polymerase (PARP) inhibition by veliparib during cytotoxic topotecan administration with filgrastim or pegfilgrastim neutrophil support in women with persistent or recurrent uterine cervix cancer. EXPERIMENTAL DESIGN: This phase I-II trial examined twice-daily oral veliparib (10 mg) given during once-daily intravenous topotecan (0.6 mg/m²) on days 1 to 5 of each treatment cycle. Cycles were repeated every 21 days until disease progression or until toxicity prohibited further therapy. Toxicity and objective response rate were primary endpoints. RESULTS: Twenty-seven women were enrolled. Frequently reported grade 3 or higher treatment-related toxicities were anemia (59%), thrombocytopenia (44%), leukopenia (22%), and neutropenia (19%). There were 2 partial responses (7% [90% confidence interval, 1%-22%]). Four patients had a disease progression date more than 6 months after the start of veliparib-topotecan therapy. Patients with low immunohistochemical expression (0-1+) of PARP-1 in their primary uterine cervix cancer were more likely to have a longer progression-free interval (hazard ratio, 0.25; P = 0.02) and survival (hazard ratio, 0.12; P = 0.005) after veliparib-topotecan therapy. CONCLUSIONS: Clinical activity of a veliparib-topotecan combination was minimal in women with persistent or recurrent uterine cervix cancer. Women whose uterine cervix cancers express PARP-1 at low levels may benefit preferentially from PARP inhibitors combined with cytotoxic therapies, suggesting further study of PARP expression as an integral triage biomarker.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias do Colo do Útero/tratamento farmacológico , Adulto , Idoso , Anemia/induzido quimicamente , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Carcinoma/química , Proteínas de Ciclo Celular/análise , Progressão da Doença , Feminino , Filgrastim/uso terapêutico , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/química , Neutropenia/induzido quimicamente , Neutropenia/prevenção & controle , Poli(ADP-Ribose) Polimerase-1 , Poli(ADP-Ribose) Polimerases/análise , Polietilenoglicóis , Proteínas Recombinantes/uso terapêutico , Ribonucleotídeo Redutases/análise , Trombocitopenia/induzido quimicamente , Topotecan/administração & dosagem , Topotecan/efeitos adversos , Neoplasias do Colo do Útero/química
3.
J Clin Oncol ; 28(20): 3330-5, 2010 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-20498388

RESUMO

PURPOSE: We conducted a phase II trial to evaluate the efficacy and safety of single-agent sorafenib in chemotherapy-naïve patients with metastatic or recurrent squamous cell carcinoma of the head and neck (SCCHN). The primary end point was response probability (ie, confirmed complete and partial response [PR]). PATIENTS AND METHODS: Chemotherapy-naïve patients with metastatic, persistent, or recurrent SCCHN who received one induction or fewer or received an adjuvant chemotherapy regimen, who had adequate organ function, and who had a performance status

Assuntos
Antineoplásicos/uso terapêutico , Benzenossulfonatos/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Piridinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzenossulfonatos/efeitos adversos , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Intervalo Livre de Doença , Avaliação de Medicamentos , Feminino , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Niacinamida/análogos & derivados , Compostos de Fenilureia , Piridinas/efeitos adversos , Sorafenibe
4.
J Thorac Oncol ; 1(9): 996-1001, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17409985

RESUMO

BACKGROUND: In preclinical models, the proteasome inhibitor bortezomib (PS-341) inhibits the growth of small cell lung cancer (SCLC) by inhibiting the antiapoptotic Bcl-2 signaling pathway. We conducted a phase II trial of PS-341 in previously treated patients with platinum-sensitive and -refractory extensive stage SCLC to determine response rate, toxicity, and survival. METHODS: Patients with histologically confirmed SCLC, measurable disease, Zubrod performance status 0-1, and previous treatment with platinum-based therapy were enrolled. They were stratified by platinum-sensitivity status: sensitive (relapse >90 days after platinum) or refractory (progression during or < or =90 days after platinum). PS-341 was administered at 1.3 mg/m intravenously on days 1, 4, 8, and 11 every 21 days. RESULTS: Of 56 eligible patients, 28 were platinum sensitive and 28 refractory. Twenty-nine patients (52%) had received two or more previous chemotherapy regimens. One platinum-refractory patient had a confirmed partial response. A majority of assessable patients (91%) progressed. Median progression-free survival and overall survival were 1 month and 3 months, respectively. Ten patients (18%) discontinued treatment due to adverse events or side effects. CONCLUSION: Although PS-341 induced a response in a patient with platinum-refractory disease, it has limited single-agent activity in this heavily pretreated cohort. As shown in preclinical models, testing of PS-341 in combination with an apoptotic trigger such as chemotherapy, is a rational clinical approach. A trial of topotecan plus PS-341 has been initiated to test this concept.


Assuntos
Ácidos Borônicos/administração & dosagem , Carcinoma de Células Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Pirazinas/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Ácidos Borônicos/efeitos adversos , Bortezomib , Carcinoma de Células Pequenas/mortalidade , Carcinoma de Células Pequenas/patologia , Intervalos de Confiança , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Esquema de Medicação , Seguimentos , Humanos , Infusões Intravenosas , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Dose Máxima Tolerável , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Probabilidade , Pirazinas/efeitos adversos , Indução de Remissão , Medição de Risco , Análise de Sobrevida
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