RESUMO
BACKGROUND: Olaparib (AZD2281) is an oral poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitor that has shown antitumor activity in patients with high-grade serous ovarian cancer with or without BRCA1 or BRCA2 germline mutations. METHODS: We conducted a randomized, double-blind, placebo-controlled, phase 2 study to evaluate maintenance treatment with olaparib in patients with platinum-sensitive, relapsed, high-grade serous ovarian cancer who had received two or more platinum-based regimens and had had a partial or complete response to their most recent platinum-based regimen. Patients were randomly assigned to receive olaparib, at a dose of 400 mg twice daily, or placebo. The primary end point was progression-free survival according to the Response Evaluation Criteria in Solid Tumors guidelines. RESULTS: Of 265 patients who underwent randomization, 136 were assigned to the olaparib group and 129 to the placebo group. Progression-free survival was significantly longer with olaparib than with placebo (median, 8.4 months vs. 4.8 months from randomization on completion of chemotherapy; hazard ratio for progression or death, 0.35; 95% confidence interval [CI], 0.25 to 0.49; P<0.001). Subgroup analyses of progression-free survival showed that, regardless of subgroup, patients in the olaparib group had a lower risk of progression. Adverse events more commonly reported in the olaparib group than in the placebo group (by more than 10% of patients) were nausea (68% vs. 35%), fatigue (49% vs. 38%), vomiting (32% vs. 14%), and anemia (17% vs. 5%); the majority of adverse events were grade 1 or 2. An interim analysis of overall survival (38% maturity, meaning that 38% of the patients had died) showed no significant difference between groups (hazard ratio with olaparib, 0.94; 95% CI, 0.63 to 1.39; P=0.75). CONCLUSIONS: Olaparib as maintenance treatment significantly improved progression-free survival among patients with platinum-sensitive, relapsed, high-grade serous ovarian cancer. Interim analysis showed no overall survival benefit. The toxicity profile of olaparib in this population was consistent with that in previous studies. (Funded by AstraZeneca; ClinicalTrials.gov number, NCT00753545.).
Assuntos
Antineoplásicos/uso terapêutico , Quimioterapia de Manutenção , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Ftalazinas/uso terapêutico , Piperazinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Intervalo Livre de Doença , Método Duplo-Cego , Feminino , Genes BRCA1 , Genes BRCA2 , Mutação em Linhagem Germinativa , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Gradação de Tumores , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Ftalazinas/efeitos adversos , Piperazinas/efeitos adversos , Adulto JovemRESUMO
Many oncology studies incorporate a blinded independent central review (BICR) to make an assessment of the integrity of the primary endpoint, progression free survival. Recently, it has been suggested that, in order to assess the potential for bias amongst investigators, a BICR amongst only a sample of patients could be performed; if evidence of bias is detected, according to a predefined threshold, the BICR is then assessed in all patients, otherwise, it is concluded that the sample was sufficient to rule out meaningful levels of bias. In this paper, we present an approach that adapts a method originally created for defining futility bounds in group sequential designs. The hazard ratio ratio, the ratio of the hazard ratio (HR) for the treatment effect estimated from the BICR to the corresponding HR for the investigator assessments, is used as the metric to define bias. The approach is simple to implement and ensures a high probability that a substantial true bias will be detected. In the absence of bias, there is a high probability of accepting the accuracy of local evaluations based on the sample, in which case an expensive BICR of all patients is avoided. The properties of the approach are demonstrated by retrospective application to a completed Phase III trial in colorectal cancer. The same approach could easily be adapted for other disease settings, and for test statistics other than the hazard ratio.
Assuntos
Viés , Ensaios Clínicos como Assunto/métodos , Neoplasias/terapia , Ensaios Clínicos Fase III como Assunto/métodos , Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , Progressão da Doença , Intervalo Livre de Doença , Humanos , Neoplasias/patologia , Tamanho da AmostraRESUMO
BACKGROUND: The aim of this phase I study was to determine the safety and tolerability and to establish the maximum tolerated dose (MTD) of orally administered olaparib (AZD2281) in combination with topotecan in patients with advanced solid tumors. PATIENTS AND METHODS: Patients aged ≥ 18 years with histologically or cytologically diagnosed advanced solid tumors for whom no suitable effective therapy exists were included. Patients in four cohorts received topotecan (0.5 mg/m(2)/day × 3 days or 1.0 mg/m(2)/day × 3 days) intravenously in combination with oral olaparib 50, 100 or 200 mg bid for six cycles. The primary objectives were to determine the safety and tolerability and to establish the MTD of olaparib in combination with topotecan. RESULTS: Twenty-one patients were enrolled and 19 received treatment. Dose-limiting toxicities were neutropenia and thrombocytopenia. The MTD was established as topotecan 1.0 mg/m(2)/day × 3 days plus olaparib 100 mg bid. The most common adverse events (AEs) included fatigue and gastrointestinal events. There was an olaparib and topotecan dose-related increase in neutropenia which was dose limiting. CONCLUSIONS: Further development of olaparib and topotecan in combination was not explored due to dose-limiting hematological AEs and the resulting sub-therapeutic MTD.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Inibidores Enzimáticos/efeitos adversos , Neoplasias/tratamento farmacológico , Ftalazinas/efeitos adversos , Piperazinas/efeitos adversos , Inibidores de Poli(ADP-Ribose) Polimerases , Topotecan/uso terapêutico , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Estudos de Coortes , Demografia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/uso terapêutico , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/diagnóstico por imagem , Ftalazinas/administração & dosagem , Ftalazinas/farmacocinética , Ftalazinas/uso terapêutico , Piperazinas/administração & dosagem , Piperazinas/farmacocinética , Piperazinas/uso terapêutico , Poli(ADP-Ribose) Polimerases/metabolismo , Tomografia Computadorizada por Raios X , Topotecan/administração & dosagem , Topotecan/efeitos adversos , Topotecan/farmacocinética , Resultado do TratamentoRESUMO
BACKGROUND: Olaparib (AZD2281) is a small-molecule, potent oral poly(ADP-ribose) polymerase (PARP) inhibitor. We aimed to assess the safety and tolerability of this drug in patients without BRCA1 or BRCA2 mutations with advanced triple-negative breast cancer or high-grade serous and/or undifferentiated ovarian cancer. METHODS: In this phase 2, multicentre, open-label, non-randomised study, women with advanced high-grade serous and/or undifferentiated ovarian carcinoma or triple-negative breast cancer were enrolled and received olaparib 400 mg twice a day. Patients were stratified according to whether they had a BRCA1 or BRCA2 mutation or not. The primary endpoint was objective response rate by Response Evaluation Criteria In Solid Tumors (RECIST). All patients who received treatment were included in the analysis of toxic effects, and patients who had measurable lesions at baseline were included in the primary efficacy analysis. This trial is registered at ClinicalTrials.gov, number NCT00679783. FINDINGS: 91 patients were enrolled (65 with ovarian cancer and 26 breast cancer) and 90 were treated between July 8, 2008, and Sept 24, 2009. In the ovarian cancer cohorts, 64 patients received treatment. 63 patients had target lesions and therefore were evaluable for objective response as per RECIST. In these patients, confirmed objective responses were seen in seven (41%; 95% CI 22-64) of 17 patients with BRCA1 or BRCA2 mutations and 11 (24%; 14-38) of 46 without mutations. No confirmed objective responses were reported in patients with breast cancer. The most common adverse events were fatigue (45 [70%] of patients with ovarian cancer, 13 [50%] of patients with breast cancer), nausea (42 [66%] and 16 [62%]), vomiting (25 [39%] and nine [35%]), and decreased appetite (23 [36%] and seven [27%]). INTERPRETATION: Our study suggests that olaparib is a promising treatment for women with ovarian cancer and further assessment of the drug in clinical trials is needed. FUNDING: AstraZeneca.
Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/análise , Neoplasias da Mama/tratamento farmacológico , Carcinoma/tratamento farmacológico , Diferenciação Celular , Inibidores Enzimáticos/uso terapêutico , Recidiva Local de Neoplasia , Neoplasias Ovarianas/tratamento farmacológico , Ftalazinas/uso terapêutico , Piperazinas/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/química , Neoplasias da Mama/enzimologia , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Canadá , Carcinoma/enzimologia , Carcinoma/genética , Carcinoma/mortalidade , Carcinoma/secundário , Intervalo Livre de Doença , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/efeitos adversos , Feminino , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Mutação , Neoplasias Ovarianas/enzimologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Ftalazinas/administração & dosagem , Ftalazinas/efeitos adversos , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos , Poli(ADP-Ribose) Polimerases/metabolismo , Receptor ErbB-2/análise , Receptores de Estrogênio/análise , Receptores de Progesterona/análise , Fatores de Tempo , Resultado do TratamentoRESUMO
The application of reversed-phase ultra-performance liquid chromatography, based on the use of sub 2 microm particles, combined with time-of-flight mass spectrometry has been investigated for the production of global metabolite profiles from human urine. The stability and repeatability of the methodology, which employed gradient elution, was determined by the repeat analysis of a pooled quality control (QC) sample. As seen in previous studies conducted with conventional LC-MS an element of system conditioning was required to obtain reproducible data, as the initial injections were unrepresentative. However, once the system had equilibrated excellent repeatability in terms of retention time, signal intensity and mass accuracy was seen providing confidence that for this matrix, the within-day repeatability of UPLC-TOF-MS was sufficient to assure data quality in global metabolic profiling applications.
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Espectrometria de Massas/métodos , Urina/química , Humanos , Análise de Componente Principal , Reprodutibilidade dos TestesRESUMO
PURPOSE: To compare the clinical activity of the pure antiestrogen fulvestrant at 500 mg/mo (double the approved dose) with the aromatase inhibitor anastrozole as first-line endocrine therapy for advanced hormone receptor-positive breast cancer in postmenopausal women. PATIENTS AND METHODS: FIRST (Fulvestrant First-Line Study Comparing Endocrine Treatments) is a phase II, randomized, open-label, multicenter study of a fulvestrant high-dose (HD) regimen (500 mg/mo plus 500 mg on day 14 of month 1) versus anastrozole (1 mg/d). The primary efficacy end point was clinical benefit rate (CBR), defined as the proportion of patients experiencing an objective response (OR) or stable disease for > or = 24 weeks. The primary analysis was performed 6 months after the last patient was randomly assigned. RESULTS: CBR was similar for fulvestrant HD (n = 102) and anastrozole (n = 103), 72.5% v 67.0%, respectively (odds ratio, 1.30; 95% CI, 0.72 to 2.38; P = .386). Objective response rate (ORR) was also similar between treatments: fulvestrant HD, 36.0%; anastrozole, 35.5%. Time to progression (TTP) was significantly longer for fulvestrant versus anastrozole (median TTP not reached for fulvestrant HD v 12.5 months for anastrozole; hazard ratio, 0.63; 95% CI, 0.39 to 1.00; P = .0496). Duration of OR and CB also numerically favored fulvestrant HD. Both treatments were well tolerated, with no significant differences in the incidence of prespecified adverse events. CONCLUSION: First-line fulvestrant HD was at least as effective as anastrozole for CBR and ORR and was associated with significantly longer TTP. Fulvestrant HD was generally well tolerated, with a safety profile similar to that of anastrozole.