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1.
Lancet Oncol ; 18(2): 230-240, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28089635

RESUMO

BACKGROUND: Selective BCL2 inhibition with venetoclax has substantial activity in patients with relapsed or refractory chronic lymphocytic leukaemia. Combination therapy with rituximab enhanced activity in preclinical models. The aim of this study was to assess the safety, pharmacokinetics, and activity of venetoclax in combination with rituximab. METHODS: Adult patients with relapsed or refractory chronic lymphocytic leukaemia (according to the 2008 Modified International Workshop on CLL guidelines) or small lymphocytic lymphoma were eligible for this phase 1b, dose-escalation trial. The primary outcomes were to assess the safety profile, to determine the maximum tolerated dose, and to establish the recommended phase 2 dose of venetoclax when given in combination with rituximab. Secondary outcomes were to assess the pharmacokinetic profile and analyse efficacy, including overall response, duration of response, and time to tumour progression. Minimal residual disease was a protocol-specified exploratory objective. Central review of the endpoints was not done. Venetoclax was dosed daily using a stepwise escalation to target doses (200-600 mg) and then monthly rituximab commenced (375 mg/m2 in month 1 and 500 mg/m2 in months 2-6). Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for adverse events version 4.0. Protocol-guided drug cessation was allowed for patients who achieved complete response (including complete response with incomplete marrow recovery) or negative bone marrow minimal residual disease. Analyses were done per protocol for all patients who commenced drug and included all patients who received at least one dose of venetoclax. Data were pooled across dose cohorts. Patients are still receiving therapy and follow-up is ongoing. The trial is registered at ClinicalTrials.gov, number NCT01682616. FINDINGS: Between Aug 6, 2012, and May 28, 2014, we enrolled 49 patients. Common grade 1-2 toxicities included upper respiratory tract infections (in 28 [57%] of 49 patients), diarrhoea (27 [55%]), and nausea (25 [51%]). Grade 3-4 adverse events occurred in 37 (76%) of 49 patients; most common were neutropenia (26 [53%]), thrombocytopenia (eight [16%]), anaemia (seven [14%]), febrile neutropenia (six [12%]), and leucopenia (six [12%]). The most common serious adverse events were pyrexia (six [12%]), febrile neutropenia (five [10%]), lower respiratory tract infection, and pneumonia (each three [6%]). Clinical tumour lysis syndrome occurred in two patients (resulting in one death) who initiated venetoclax at 50 mg. After enhancing tumour lysis syndrome prophylaxis measures and commencing venetoclax at 20 mg, clinical tumour lysis syndrome did not occur. The maximum tolerated dose was not identified; the recommended phase 2 dose of venetoclax in combination with rituximab was 400 mg. Overall, 42 (86%) of 49 patients achieved a response, including a complete response in 25 (51%) of 49 patients. 2 year estimates for progression-free survival and ongoing response were 82% (95% CI 66-91) and 89% (95% CI 72-96), respectively. Negative marrow minimal residual disease was attained in 20 (80%) of 25 complete responders and 28 (57%) of 49 patients overall. 13 responders ceased all therapy; among these all 11 minimal residual disease-negative responders remain progression-free off therapy. Two with minimal residual disease-positive complete response progressed after 24 months off therapy and re-attained response after re-initiation of venetoclax. INTERPRETATION: A substantial proportion of patients achieved an overall response with the combination of venetoclax and rituximab including 25 (51%) of 49 patients who achieved a complete response and 28 (57%) of 49 patients who achieved negative marrow minimal residual disease with acceptable safety. The depth and durability of responses observed with the combination offers an attractive potential treatment option for patients with relapsed or refractory chronic lymphocytic leukaemia and could allow some patients to maintain response after discontinuing therapy, a strategy that warrants further investigation in randomised studies. FUNDING: AbbVie Inc and Genentech Inc.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Terapia de Salvação , Adulto , Idoso , Idoso de 80 Anos ou mais , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Estudos de Coortes , Feminino , Seguimentos , Humanos , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Gradação de Tumores , Recidiva Local de Neoplasia/patologia , Prognóstico , Indução de Remissão , Rituximab/administração & dosagem , Sulfonamidas/administração & dosagem , Taxa de Sobrevida
2.
Pharmacogenet Genomics ; 23(7): 374-81, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23670235

RESUMO

OBJECTIVE: ABT-751, a novel orally available antitubulin agent, is mainly eliminated as inactive glucuronide (ABT-751G) and sulfate (ABT-751S) conjugates. We performed a pharmacogenetic investigation of ABT-751 pharmacokinetics using in-vitro data to guide the selection of genes for genotyping in a phase I trial of ABT-751. METHODS: UDP-glucuronosyltransferase (UGT) and sulfotransferase (SULT) enzymes were screened for ABT-751 metabolite formation in vitro. Forty-seven cancer patients treated with ABT-751 were genotyped for 21 variants in these genes. RESULTS: UGT1A1, UGT1A4, UGT1A8, UGT2B7, and SULT1A1 were found to be involved in the formation of inactive ABT-751 glucuronide (ABT-751G) and sulfate (ABT-751S). SULT1A1 copy number (>2) was associated with an average 34% increase in ABT-751 clearance (P=0.044), an 18% reduction in ABT-751 AUC (P=0.045), and a 50% increase in sulfation metabolic ratios (P=0.025). UGT1A8 rs6431558 was associated with a 28% increase in glucuronidation metabolic ratios (P=0.022), and UGT1A4*2 was associated with a 65% decrease in ABT-751 C trough (P=0.009). CONCLUSION: These results might represent the first example of a clinical pharmacokinetic effect of the SULT1A1 copy number variant on the clearance of a SULT1A1 substrate. A-priori selection of candidate genes guided by in-vitro metabolic screening enhanced our ability to identify genetic determinants of interpatient pharmacokinetic variability.


Assuntos
Antineoplásicos/farmacocinética , Sulfonamidas/farmacocinética , Moduladores de Tubulina/farmacocinética , Adulto , Idoso , Arilsulfotransferase/genética , Feminino , Dosagem de Genes , Variação Genética , Glucuronosiltransferase/genética , Glucuronosiltransferase/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Sulfotransferases/genética , Sulfotransferases/metabolismo
3.
Support Care Cancer ; 20(8): 1797-804, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21964618

RESUMO

PURPOSE: Misoprostol, a synthetic analog of prostaglandin E1, has anti-inflammatory and mucosa-protecting properties. The objective of this study was to evaluate the efficacy of misoprostol oral rinse in reducing the severity of oral mucosal injury caused by high-dose chemotherapy. METHODS: The study used a randomized, double-blind, placebo-controlled, parallel-group design. Oncology patients receiving myeloablative high-dose chemotherapy, in preparation for a hematopoietic stem cell transplant, were randomized to misoprostol or placebo rinse. The primary outcome measure was the severity of oral mucositis, measured using the modified Oral Mucositis Index. Additional outcome measures included the severity of mouth pain (measured using a Visual Analog Scale and the Pain Affect Faces Scale), duration of hospital stay, and days on total parenteral nutrition. RESULTS: This study was originally planned to accrue 160 subjects but was terminated early due to revised sponsor research priorities. The intent-to-treat population consisted of 22 subjects randomized to misoprostol rinse and 26 subjects randomized to placebo rinse. There was no significant difference between the two groups in mucositis or pain severity. In both groups, duration of hospital stay was approximately 19 days, and number of days on total parenteral nutrition was 17-18 days. There were no serious adverse events attributable to misoprostol rinse. CONCLUSIONS: Although this study did not find a beneficial effect of a misoprostol rinse in mucositis secondary to high-dose chemotherapy, the small sample size limits the strength of this conclusion. Given the proposed importance of the prostaglandin pathway in the pathogenesis of oral mucositis, additional studies are warranted.


Assuntos
Antiulcerosos/uso terapêutico , Antineoplásicos/efeitos adversos , Misoprostol/uso terapêutico , Estomatite/induzido quimicamente , Estomatite/tratamento farmacológico , Análise de Variância , Método Duplo-Cego , Feminino , Humanos , Tempo de Internação/estatística & dados numéricos , Masculino , Medição da Dor , Nutrição Parenteral Total/estatística & dados numéricos , Placebos , Resultado do Tratamento , Estados Unidos
4.
Chemotherapy ; 58(4): 321-9, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23147218

RESUMO

BACKGROUND: ABT-751 is a novel antimitotic agent that exerted cytotoxic effects in preclinical studies. Carboplatin has efficacy in treating advanced non-small cell lung cancer (NSCLC) in combination with other drugs. METHODS: Lung cancer cell lines were treated with ABT-751 and/or carboplatin to investigate their impact on cell growth. A phase I study with an expansion cohort was conducted in previously treated NSCLC patients. The primary objective was the maximum tolerated dose (MTD); secondary objectives were objective response rates, median survival, time to tumor progression, dose-limiting toxicities (DLTs), and pharmacodynamic evaluation of buccal swabs. RESULTS: Combining ABT-751 with carboplatin significantly reduced growth and induced apoptosis of lung cancer cell lines. Twenty advanced NSCLC patients were enrolled. MTD was ABT-751 125 mg orally twice daily for 7 days with carboplatin AUC 6. DLTs included fatigue, ileus, neutropenia and pneumonitis. Two patients had confirmed partial responses. Median overall survival was 11.7 months (95% CI 5.9-27.0). Time to tumor progression was 2.8 months (95% CI 2.0-2.7). Four of 6 patients showed decreased cyclin D1 protein in posttreatment versus pretreatment buccal swabs. CONCLUSION: Combining ABT-751 with carboplatin suppressed growth of lung cancer cell lines and had modest clinical antitumor activity in advanced NSCLC previously treated predominantly with carboplatin. Further studies of this combination are not recommended while investigations of biomarkers in different patient populations, alternative schedules and combinations may be pursued.


Assuntos
Antineoplásicos/uso terapêutico , Carboplatina/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Sulfonamidas/uso terapêutico , Administração Oral , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Área Sob a Curva , Carboplatina/efeitos adversos , Carboplatina/farmacologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Linhagem Celular Tumoral , Ciclina D1/metabolismo , Quimioterapia Combinada , Fadiga/etiologia , Feminino , Humanos , Íleus/etiologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Neutropenia/etiologia , Pneumonia/etiologia , Sulfonamidas/efeitos adversos , Sulfonamidas/farmacologia , Taxa de Sobrevida
5.
N Engl J Med ; 355(9): 873-84, 2006 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-16943400

RESUMO

BACKGROUND: Studies showing that drugs that inhibit cyclooxygenase-2 (COX-2) reduce the number of colorectal adenomas in animals and patients with familial adenomatous polyposis suggest that COX-2 inhibitors may also prevent sporadic colorectal neoplasia. METHODS: We randomly assigned patients who had adenomas removed before study entry to receive placebo (679 patients) or 200 mg (685 patients) or 400 mg (671 patients) of celecoxib twice daily. Randomization was stratified for the use of low-dose aspirin. Follow-up colonoscopies were performed at one and three years after randomization. The occurrence of newly detected colorectal adenomas was compared among the groups with the life-table extension of the Mantel-Haenszel test. RESULTS: Follow-up colonoscopies were completed at year 1 in 89.5 percent of randomized patients, and at year 3 in 75.7 percent. The estimated cumulative incidence of the detection of one or more adenomas by year 3 was 60.7 percent for patients receiving placebo, as compared with 43.2 percent for those receiving 200 mg of celecoxib twice a day (risk ratio, 0.67; 95 percent confidence interval, 0.59 to 0.77; P<0.001) and 37.5 percent for those receiving 400 mg of celecoxib twice a day (risk ratio, 0.55; 95 percent confidence interval, 0.48 to 0.64; P<0.001). Serious adverse events occurred in 18.8 percent of patients in the placebo group, as compared with 20.4 percent of those in the low-dose celecoxib group (risk ratio, 1.1; 95 percent confidence interval, 0.9 to 1.3; P=0.5) and 23.0 percent of those in the high-dose group (risk ratio, 1.2; 95 percent confidence interval, 1.0 to 1.5; P=0.06). As compared with placebo, celecoxib was associated with an increased risk of cardiovascular events (risk ratio for the low dose, 2.6; 95 percent confidence interval, 1.1 to 6.1; and risk ratio for the high dose, 3.4; 95 percent confidence interval, 1.5 to 7.9). CONCLUSIONS: These findings indicate that celecoxib is an effective agent for the prevention of colorectal adenomas but, because of potential cardiovascular events, cannot be routinely recommended for this indication. (ClinicalTrials.gov number, NCT00005094 [ClinicalTrials.gov].).


Assuntos
Adenoma/prevenção & controle , Neoplasias Colorretais/prevenção & controle , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Pirazóis/uso terapêutico , Sulfonamidas/uso terapêutico , Adenoma/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anti-Inflamatórios não Esteroides/administração & dosagem , Aspirina/administração & dosagem , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/mortalidade , Celecoxib , Neoplasias Colorretais/tratamento farmacológico , Inibidores de Ciclo-Oxigenase 2/administração & dosagem , Inibidores de Ciclo-Oxigenase 2/efeitos adversos , Quimioterapia Combinada , Feminino , Gastroenteropatias/induzido quimicamente , Humanos , Nefropatias/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Prevenção Secundária , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos
6.
Anticancer Drugs ; 20(6): 483-92, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19398903

RESUMO

ABT-751 is an orally bioavailable tubulin-binding agent that is currently under clinical development for cancer treatment. In preclinical studies, ABT-751 showed antitumor activity against a broad spectrum of tumor lines including those resistant to conventional chemotherapies. In this study, we investigated the antivascular properties of ABT-751 in a rat subcutaneous tumor model using dynamic contrast-enhanced magnetic resonance imaging. A single dose of ABT-751 (30 mg/kg, intravenously) induced a rapid, transient reduction in tumor perfusion. After 1 h, tumor perfusion decreased by 57% before recovering to near pretreatment levels within 6 h. In contrast, ABT-751 produced little change in muscle perfusion at either time point. To further elucidate mechanisms of drug action at the cellular level, we examined the effects of ABT-751 on endothelial cells using an in-vitro assay. ABT-751, at concentrations corresponding to plasma levels achieved in vivo, caused endothelial cell retraction and significant loss of microtubules within 1 h. The severity of these morphological changes was dose-dependent but reversible within 6 h after the discontinuation of the drug. Taken together, these results show that ABT-751 is a tubulin-binding agent with antivascular properties. Microtubule disruption and morphological changes in vascular endothelial cells may be responsible, at least in part, for the dysfunction of tumor blood vessels after ABT-751 treatment.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Neoplasias Experimentais/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Sulfonamidas/uso terapêutico , Tubulina (Proteína)/metabolismo , Citoesqueleto de Actina/efeitos dos fármacos , Citoesqueleto de Actina/metabolismo , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/farmacologia , Animais , Sítios de Ligação , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/patologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Microtúbulos/efeitos dos fármacos , Microtúbulos/metabolismo , Transplante de Neoplasias , Neoplasias Experimentais/irrigação sanguínea , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Ligação Proteica , Ratos , Ratos Endogâmicos F344 , Sulfonamidas/administração & dosagem , Sulfonamidas/farmacologia
7.
Clin Cancer Res ; 13(22 Pt 1): 6689-95, 2007 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-18006769

RESUMO

PURPOSE: Angiogenesis is a characteristic of renal cell carcinoma. ABT-510 is an angiogenesis inhibitor that mimics the antiangiogenic properties of thrombospondin-1. This study was designed to assess the safety and efficacy of ABT-510 in patients with advanced renal cell carcinoma. EXPERIMENTAL DESIGN: Patients with previously untreated metastatic or unresectable renal cell carcinoma were randomized to treatment with one of two doses of ABT-510, self-administered s.c. twice daily in 28-day treatment periods without intervening rest periods. End points were progression-free survival (PFS), objective response rate, overall survival, and toxicity. RESULTS: The objective response rate was 4% in the 10 mg twice daily group, and there were two unconfirmed PRs in the 100 mg twice daily group. Respective median PFS was 4.2 and 3.3 months, with a 6-month PFS of 39% and 32%. Median overall survival was 27.8 months (10 mg twice daily) and 26.1 months (100 mg twice daily). The most frequent adverse events were injection site reactions (84%), fatigue (50%), headache (20%), and nausea (19%). The incidence of treatment-related, grade 3/4 adverse events was low and included three bleeding episodes (gastrointestinal hemorrhage, intracranial hemorrhage, and hemoptysis) and one thrombotic event (deep vein thrombosis). No deaths were attributed to ABT-510. CONCLUSIONS: There was little evidence of clinical activity for ABT-510, and further evaluation as a single agent for treating advanced renal cell carcinoma is not warranted. The evidence of a favorable safety profile may justify further evaluation in combination therapy.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Oligopeptídeos/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oligopeptídeos/efeitos adversos , Resultado do Tratamento
8.
Clin Cancer Res ; 12(9): 2834-40, 2006 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-16675578

RESUMO

PURPOSE: Microtubules play a critical role in many cellular functions, including cell division and mitosis. ABT-751 is a novel sulfonamide antimitotic that binds to the colchicine site on beta-tubulin that leads to a block in the cell cycle at the G2M phase, resulting in cellular apoptosis. ABT-751 was investigated in this phase 1 trial designed to assess its maximum tolerated dose (MTD), dose-limiting toxicity (DLT), tolerability, and pharmacokinetics. EXPERIMENTAL DESIGN: ABT-751 was administered on a daily (q.d.) or twice daily (b.i.d.) oral schedule for 7 days every 3 weeks to 39 patients with refractory solid tumors. Toxicity was monitored weekly. Plasma and urine ABT-751 and metabolite pharmacokinetics were determined. RESULTS: The MTD for the q.d. schedule was 250 mg/d. DLTs during cycle 1 were abdominal pain, constipation, and fatigue. The MTD on the b.i.d. schedule was 150 mg. Cycle 1 of therapy with the 175 mg b.i.d. schedule was tolerated without DLT. However, six of seven patients reported grade 3 toxicity (ileus, constipation, abdominal pain, or fatigue), which occurred in cycle 2 or 3. ABT-751 was absorbed after oral administration with an overall mean T(max) of about 2 hours. The pharmacokinetics of ABT-751 were dose-proportional and time-independent. There was minimal accumulation of ABT-751 after multiple q.d. and b.i.d. doses. Efficacious concentrations, as determined from preclinical models (0.5-1.5 microg/mL), were achieved in all subjects. ABT-751 metabolism occurred primarily by glucuronidation and sulfation. No complete or partial tumor responses were noted, but one patient had a minor response, and four patients had stable disease lasting at least 6 months. CONCLUSIONS: The MTD and recommended phase 2 doses for ABT-751 were 250 mg q.d. and 150 mg b.i.d. on a 7-day schedule given every 3 weeks, due to subsequent cycle toxicities at 175 mg b.i.d. dosing. Toxicities were abdominal pain, constipation, and neuropathy.


Assuntos
Neoplasias/sangue , Sulfonamidas/farmacocinética , Sulfonamidas/toxicidade , Administração Oral , Adulto , Idoso , Disponibilidade Biológica , Divisão Celular/efeitos dos fármacos , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/urina , Segurança , Sulfonamidas/uso terapêutico
9.
J Clin Oncol ; 35(8): 826-833, 2017 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-28095146

RESUMO

Purpose B-cell leukemia/lymphoma-2 (BCL-2) overexpression is common in many non-Hodgkin lymphoma (NHL) subtypes. A phase I trial in patients with NHL was conducted to determine safety, pharmacokinetics, and efficacy of venetoclax, a selective, potent, orally bioavailable BCL-2 inhibitor. Patients and Methods A total of 106 patients with relapsed or refractory NHL received venetoclax once daily until progressive disease or unacceptable toxicity at target doses from 200 to 1,200 mg in dose-escalation and safety expansion cohorts. Treatment commenced with a 3-week dose ramp-up period for most patients in dose-escalation cohorts and for all patients in safety expansion. Results NHL subtypes included mantle cell lymphoma (MCL; n = 28), follicular lymphoma (FL; n = 29), diffuse large B-cell lymphoma (DLBCL; n = 34), DLBCL arising from chronic lymphocytic leukemia (Richter transformation; n = 7), Waldenström macroglobulinemia (n = 4), and marginal zone lymphoma (n = 3). Venetoclax was generally well tolerated. Clinical tumor lysis syndrome was not observed, whereas laboratory tumor lysis syndrome was documented in three patients. Treatment-emergent adverse events were reported in 103 patients (97%), a majority of which were grade 1 to 2 in severity. Grade 3 to 4 events were reported in 59 patients (56%), and the most common were hematologic, including anemia (15%), neutropenia (11%), and thrombocytopenia (9%). Overall response rate was 44% (MCL, 75%; FL, 38%; DLBCL, 18%). Estimated median progression-free survival was 6 months (MCL, 14 months; FL, 11 months; DLBCL, 1 month). Conclusion Selective targeting of BCL-2 with venetoclax was well tolerated, and single-agent activity varied among NHL subtypes. We determined 1,200 mg to be the recommended single-agent dose for future studies in FL and DLBCL, with 800 mg being sufficient to consistently achieve durable response in MCL. Additional investigations including combination therapy to augment response rates and durability are ongoing.


Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Linfoma não Hodgkin/tratamento farmacológico , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Compostos Bicíclicos Heterocíclicos com Pontes/farmacocinética , Estudos de Coortes , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Linfoma não Hodgkin/metabolismo , Masculino , Pessoa de Meia-Idade , Sulfonamidas/farmacocinética
10.
Clin Cancer Res ; 11(18): 6615-24, 2005 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-16166440

RESUMO

PURPOSE: ABT-751 is an oral antimitotic agent that binds to the colchicine site on beta-tubulin. A phase 1 study was conducted to determine the maximum tolerated dose and toxicities of ABT-751 in patients with advanced myelodysplastic syndrome and relapsed or refractory acute leukemias. STUDY DESIGN: Thirty-two patients were treated: nine with 100 (n = 3), 125 (n = 3), or 150 mg/m(2) (n = 3) of ABT-751 given orally once daily for 7 days every 3 weeks and 23 with 75 (n = 3), 100 (n = 3), 125 (n = 5), 150 (n = 5), 175 (n = 3), or 200 mg/m(2) (n = 4) of ABT-751 given orally once daily for 21 days every 4 weeks. Consenting patients had pharmacogenetic sampling and enumeration of circulating endothelial cells (CEC). RESULTS: Dose-limiting toxicity consisted of ileus in one patient at 200 mg/m(2), with a subsequent patient developing grade 2 constipation at the same dose level. One patient with relapsed acute myelogenous leukemia achieved a complete remission that was sustained for 2 months. Four other patients had transient hematologic improvements, consisting of a decrease in peripheral blood blasts and improvements in platelet counts. CEC number was reduced in three patients with a concomitant reduction in peripheral blasts. A previously undescribed nonsynonymous single nucleotide polymorphism, encoding Ala(185)Thr, was identified in exon 4 of the beta-tubulin gene, TUBB, in three other patients. The recommended phase 2 dose in hematologic malignancies is 175 mg/m(2) daily orally for 21 days every 4 weeks. CONCLUSION: Further assessment of ABT-751, especially in combination with other agents, in patients with acute leukemias is warranted.


Assuntos
Neoplasias Hematológicas/tratamento farmacológico , Sulfonamidas/uso terapêutico , Antígeno AC133 , Doença Aguda , Adulto , Idoso , Antígenos CD/análise , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Antígeno CD146 , Constipação Intestinal/induzido quimicamente , Diarreia/induzido quimicamente , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos , Células Endoteliais/química , Feminino , Glicoproteínas/análise , Neoplasias Hematológicas/sangue , Neoplasias Hematológicas/genética , Humanos , Leucemia/sangue , Leucemia/tratamento farmacológico , Leucemia/genética , Antígenos Comuns de Leucócito/análise , Masculino , Microtúbulos/metabolismo , Pessoa de Meia-Idade , Mutação , Síndromes Mielodisplásicas/sangue , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/genética , Náusea/induzido quimicamente , Recidiva Local de Neoplasia , Células Neoplásicas Circulantes/química , Moléculas de Adesão de Célula Nervosa/análise , Peptídeos/análise , Molécula-1 de Adesão Celular Endotelial a Plaquetas/análise , Sulfonamidas/efeitos adversos , Resultado do Tratamento , Tubulina (Proteína)/genética , Vômito/induzido quimicamente
11.
Clin Cancer Res ; 8(2): 314-46, 2002 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-11839647

RESUMO

Precancer or intraepithelial neoplasia (IEN) is a noninvasive lesion that has genetic abnormalities, loss of cellular control functions, and some phenotypic characteristics of invasive cancer and that predicts for a substantial likelihood of developing invasive cancer. The AACR Task Force on the Treatment and Prevention of IEN has delineated the relationship between IEN and cancer risk as well as the clinical benefit that can be derived from reducing IEN burden. Although several effective endoscopic and surgical treatments for IEN have become standard medical practice, these interventions can confer morbidity and do not treat the entire epithelial field at risk. The incidence of many epithelial cancers is continuing to rise, the number of individuals at risk is increasing with the aging population, and the rapid advancement of imaging and molecular diagnostics is bringing to light precancers that were heretofore clinically silent. There is therefore an urgent need to rapidly develop new treatment and prevention agents for IEN. The AACR IEN Task Force recommends focusing on established precancers as the target for new agent development because of the close association between dysplasia and invasive cancer and because a convincing reduction in IEN burden provides patient benefit by reducing cancer risk and/or by decreasing the need for invasive interventions. The IEN Task Force proposes several clinical trial designs that provide practical and feasible approaches to the rapid development of new agents to treat and prevent precancer.


Assuntos
Carcinoma in Situ/prevenção & controle , Carcinoma in Situ/terapia , Antineoplásicos/farmacologia , Esôfago de Barrett/terapia , Carcinoma in Situ/etiologia , Carcinoma in Situ/metabolismo , Doenças Cardiovasculares/terapia , Ensaios Clínicos como Assunto , Neoplasias Colorretais/terapia , Feminino , Humanos , Ceratose/terapia , Masculino , Neoplasias Bucais/terapia , Neoplasias/prevenção & controle , Neoplasia Prostática Intraepitelial/terapia , Fatores de Tempo , Neoplasias da Bexiga Urinária/terapia , Displasia do Colo do Útero/terapia
12.
Mol Cancer Ther ; 3(7): 885-93, 2004 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15252150

RESUMO

Many genes, with products involved in the protection of cells against carcinogens, oxidants, and other toxic chemicals, are under the transcriptional control of a simple DNA regulatory element [i.e., the antioxidant response element (ARE)]. One or more functional AREs have been confirmed or are believed to exist in the upstream region of many anticarcinogenic/antioxidant genes and have been shown to mediate the coordinate transcriptional up-regulation of these genes by many chemical agents [i.e., the ARE-mediated inducers]. There is strong evidence that increased expression of ARE-regulated genes inhibits cancer development. The signaling system leading to ARE activation has been partly elucidated, and nuclear factor erythroid 2-related factor 2 (Nrf2) has been identified as the key transcriptional factor that serves to transmit the inducer signal to ARE. It is now known that nuclear factor erythroid 2-related factor 2, which is normally sequestered in the cytoplasm by Kelch-like ECH-associated protein 1, dissociates from Kelch-like ECH-associated protein 1 on exposure to ARE-mediated inducers, translocates to the nucleus, complexes with other nuclear factors, and binds to ARE. Rapid and simple assays have been devised to identify chemical agents that can stimulate this signaling pathway. Moreover, many ARE-mediated inducers have been identified, and several of them have shown promising cancer preventive activity.


Assuntos
Anticarcinógenos/farmacologia , Antioxidantes/farmacologia , Proteínas de Ligação a DNA/metabolismo , Neoplasias/prevenção & controle , Elementos de Resposta , Transdução de Sinais/efeitos dos fármacos , Transativadores/metabolismo , Anticarcinógenos/química , Proteínas de Ligação a DNA/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Fator 2 Relacionado a NF-E2 , Neoplasias/genética , Transdução de Sinais/genética , Transativadores/genética , Ativação Transcricional
13.
Anticancer Res ; 34(7): 3739-46, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24982396

RESUMO

BACKGROUND: Biopharmaceutical studies for anti-cancer drugs are typically conducted in cancer patients due to unacceptable toxicities to healthy volunteers. Navitoclax is a first-in-class, orally bioavailable, targeted Bcl-2 family protein inhibitor that has been studied in cancer patients. METHODS: A strategy that integrated the evaluation of non-clinical toxicology data and clinical data in cancer patients was employed to assess the feasibility, determine doses and establish risk management plans for studying navitoclax in healthy volunteers. Two relative bioavailability/food effect studies with either a 25 mg dose or 50 and 100 mg doses of navitoclax were conducted sequentially in healthy female volunteers of non-childbearing potential. RESULTS/CONCLUSION: Navitoclax was well-tolerated in both studies in healthy volunteers, and did not impose risks beyond the minimal levels expected in healthy volunteer studies. Compared to a similar study in cancer patients, the studies in healthy volunteers generated higher quality data in a short period of time to support formulation selection.


Assuntos
Compostos de Anilina/administração & dosagem , Compostos de Anilina/efeitos adversos , Biofarmácia/ética , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Administração Oral , Adulto , Compostos de Anilina/farmacocinética , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Disponibilidade Biológica , Biofarmácia/métodos , Estudos de Coortes , Estudos Cross-Over , Feminino , Interações Alimento-Droga , Humanos , Masculino , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Medição de Risco , Sulfonamidas/farmacocinética
17.
J Natl Cancer Inst ; 102(24): 1835-44, 2010 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-21115882

RESUMO

BACKGROUND: Preclinical studies indicate that the enzyme cyclooxygenase 2 plays an important role in ultraviolet-induced skin cancers. We evaluated the efficacy and safety of celecoxib, a cyclooxygenase 2 inhibitor, as a chemopreventive agent for actinic keratoses, the premalignant precursor of nonmelanoma skin cancers, and for nonmelanoma skin cancers, including cutaneous squamous cell carcinomas (SCCs) and basal cell carcinomas (BCCs). METHODS: A double-blind placebo-controlled randomized trial involving 240 subjects aged 37-87 years with 10-40 actinic keratoses was conducted at eight US academic medical centers. Patients were randomly assigned to receive 200 mg of celecoxib or placebo administered orally twice daily for 9 months. Subjects were evaluated at 3, 6, 9 (ie, completion of treatment), and 11 months after randomization. The primary endpoint was the number of new actinic keratoses at the 9-month visit as a percentage of the number at the time of randomization. In an intent-to-treat analysis, the incidence of actinic keratoses was compared between the two groups using t tests. In exploratory analyses, we evaluated the number of nonmelanoma skin cancers combined and SCCs and BCCs separately per patient at 11 months after randomization using Poisson regression, after adjustment for patient characteristics and time on study. The numbers of adverse events in the two treatment arms were compared using χ(2) or Fisher exact tests. All statistical tests were two-sided. RESULTS: There was no difference in the incidence of actinic keratoses between the two groups at 9 months after randomization. However, at 11 months after randomization, there were fewer nonmelanoma skin cancers in the celecoxib arm than in the placebo arm (mean cumulative tumor number per patient 0.14 vs 0.35; rate ratio [RR] = .43, 95% confidence interval [CI] = 0.24 to 0.75; P = .003). After adjusting for age, sex, Fitzpatrick skin type, history of actinic keratosis at randomization, nonmelanoma skin cancer history, and patient time on study, the number of nonmelanoma skin cancers was lower in the celecoxib arm than in the placebo arm (RR = 0.41, 95% CI = 0.23 to 0.72, P = .002) as were the numbers of BCCs (RR = 0.40, 95% CI = 0.18 to 0.93, P = .032) and SCCs (RR = 0.42, 95% CI = 0.19 to 0.93, P = .032). Serious and cardiovascular adverse events were similar in the two groups. CONCLUSIONS: Celecoxib may be effective for prevention of SCCs and BCCs in individuals who have extensive actinic damage and are at high risk for development of nonmelanoma skin cancers.


Assuntos
Anticarcinógenos/uso terapêutico , Carcinoma Basocelular/prevenção & controle , Carcinoma de Células Escamosas/prevenção & controle , Ceratose Actínica/tratamento farmacológico , Pirazóis/uso terapêutico , Neoplasias Cutâneas/prevenção & controle , Sulfonamidas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticarcinógenos/administração & dosagem , Anticarcinógenos/efeitos adversos , Celecoxib , Transformação Celular Neoplásica , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Método Duplo-Cego , Feminino , Humanos , Ceratose Actínica/patologia , Masculino , Pessoa de Meia-Idade , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Neoplasias Cutâneas/etiologia , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Resultado do Tratamento
19.
J Clin Oncol ; 26(34): 5583-8, 2008 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-18981463

RESUMO

PURPOSE: Sarcomas are among the most proangiogenic malignancies in preclinical models. Phase I study results for ABT-510, which inhibits angiogenesis via a novel thrombospondin-mimetic mechanism, suggested activity in soft tissue sarcoma (STS) patients. This phase II study further evaluated the safety and efficacy of ABT-510 in advanced STS patients. PATIENTS AND METHODS: Patients with metastatic or unresectable STS were randomly assigned to treatment with one of two ABT-510 dose schedules (20 mg once a day [20 mg], n = 42; or 100 mg twice a day [200 mg], n = 46), which were self-administered subcutaneously in 28-day treatment periods. End points included progression-free survival (PFS), objective response rate (ORR), overall survival (OS), and safety. RESULTS: Median PFS for the 20-mg arm was 94 days, with 4- and 6-month PFS rate estimates of 42% and 24%, respectively. Median PFS for the 200-mg arm was 64 days, with 4- and 6-month PFS rate estimates of 41% and 32%, respectively. Although only one objective response was noted, stable disease was observed in 52% (20 mg) and 48% (200 mg) of patients. Median OS was 431 days (20 mg) and 295 days (200 mg). ABT-510 was well tolerated. Rare treatment-related grade 3 or 4 adverse events were one event each of hypotension, deep vein thrombosis, and hypophosphatemia. ABT-510 pharmacokinetics were dose proportional, time independent, and consistent with those in previous studies. CONCLUSION: ABT-510 had a favorable safety profile, and the rate of disease control and OS times were encouraging. However, with low ORR and lack of dose response, the study failed to yield compelling evidence of strong single-agent activity in STS.


Assuntos
Inibidores da Angiogênese/farmacologia , Oligopeptídeos/farmacologia , Oligopeptídeos/farmacocinética , Sarcoma/tratamento farmacológico , Trombospondina 1/metabolismo , Adulto , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neovascularização Patológica , Razão de Chances , Estudos Retrospectivos , Resultado do Tratamento
20.
J Thorac Oncol ; 3(6): 631-6, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18520803

RESUMO

PURPOSE: To determine the tolerability and efficacy of ABT-751, an oral antimitotic agent that inhibits polymerization of microtubules, in patients with advanced taxane-refractory non-small cell lung carcinoma (NSCLC). PATIENTS AND METHODS: Eligibility was limited to patients with recurrent or metastatic NSCLC who had received one to two cytotoxic chemotherapy regimens, had a performance status of zero to one, and adequate organ function. Treatment included ABT-751 200 mg daily for 21 consecutive days, followed by 7 days off drug. Objectives were to determine response rate, time to tumor progression, survival, and tolerability of ABT-751. RESULTS: All 35 enrolled patients were assessable for survival, response, and tolerability. Median time to tumor progression and overall survival were 2.1 and 8.4 months, respectively. The objective response rate was 2.9%. One patient achieved a partial response that was ongoing 567 days after initial documentation. Treatment was well tolerated; fatigue, constipation, and dehydration were the only treatment related, grade three adverse events occurring in more than one patient. Incidence of grade 3/4 hematologic and blood chemistry toxicities was acceptable, and ABT-751 was not associated with myelosuppression. CONCLUSIONS: ABT-751 associated toxicity was acceptable. The median time to progression and overall survival as demonstrated for ABT-751 were comparable to other agents considered active in this patient population and to current treatments approved for second-line NSCLC. The novel antimitotic targeting of ABT-751 in combination with the compound's acceptable nonmyelosuppressive toxicity profile and efficacy similar to agents currently in use in this setting, warrant further evaluation of this compound in combination with other cytotoxic agents in advanced NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Sulfonamidas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Progressão da Doença , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Índice de Gravidade de Doença , Sulfonamidas/administração & dosagem , Inquéritos e Questionários , Taxa de Sobrevida/tendências , Resultado do Tratamento , Estados Unidos/epidemiologia
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