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1.
PLoS One ; 11(7): e0157548, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27390847

RESUMO

INTRODUCTION: Current treatment options for advanced esophagogastric cancer (AEGC) are still unsatisfactory. The aim of this prospective phase Ib/II study was to evaluate the safety and efficacy of a novel regimen, AVDCX, consisting of weekly docetaxel and cisplatin together with capecitabine and bevacizumab, in AEGC. METHODS: Patients with AEGC received treatment with different dose levels of AVDCX (cisplatin and docetaxel 25-35 mg/m2, days 1,8, capecitabine 1,600 mg/m2 days 1-14, bevacizumab 7.5 mg/kg, day 1, Q:21 days). The study's primary objectives were to establish the recommended phase II doses of docetaxel and cisplatin in AVDCX (phase Ib part) and to determine the tumor response rate (phase II part). RESULTS: The study was closed early, after the accrual of 22 patients, due to accumulating toxicity-related deaths. The median age was 59 years and 77% of patients had gastric or gastroesophageal adenocarcinomas. Grade ≥3 adverse events were documented in 18 patients (82%), usually neutropenia (36%), fatigue (54%) or diarrhea (23%). There were three fatal toxicities (14%): mesenteric thromboembolism, gastric perforation and pancytopenic sepsis. The recommended phase II doses of cisplatin and docetaxel were determined to be 25 mg/m2 and 30 mg/m2, respectively. Twenty-one patients were evaluable for response: 12 (54%) had partial response (PR), 4 (18%) had stable disease (SD) and none had complete response (CR). Hence, the objective response rate (CR+PR) was 54% and the disease control rate (CR+PR+SD) was 72%. For the 17 patients treated at the MTD, the objective response rate was 41% and the disease control rate was 88%. The median overall survival (OS) for these patients was 13.9 months (range, 1.5-52.2 months) and the median progression-free survival was 7.6 months (range, 1.3-26.6 months). The 2-year OS rate reached 23.7%. CONCLUSIONS: AVDCX was associated with a high rate of regimen related fatal adverse events and is not appropriate for further development in AEGC patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT00845884.


Assuntos
Bevacizumab/administração & dosagem , Capecitabina/administração & dosagem , Cisplatino/administração & dosagem , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Gástricas/tratamento farmacológico , Taxoides/administração & dosagem , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bevacizumab/efeitos adversos , Intervalo Livre de Doença , Docetaxel , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
2.
Oncologist ; 18(1): 25-6, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23299770

RESUMO

BACKGROUND: The A(3) adenosine receptor (A(3)AR) is overexpressed in the tumor and in the peripheral blood mononuclear cells of patients with hepatocellular carcinoma (HCC). The orally active drug candidate CF102, an A(3)AR agonist, induces apoptosis of HCC cells via deregulation of the Wnt signaling pathway. In this open label phase I/II trial, the safety and clinical effects of CF102 were assessed in patients with advanced unresectable HCC. METHODS: The primary objectives of this trial were to examine the safety and pharmacokinetic (PK) behavior of CF102 given orally (1, 5, and 25 mg BID) in 28-day cycles. Evaluation of anti-tumor effects and the utilization of A(3)AR as a biological predictive marker of response to CF102 were the secondary objectives. RESULTS: Eighteen patients received CF102-six at each dose level. No serious drug-related adverse events or dose-limiting toxicities were observed. CF102 demonstrated good oral bioavailability and linear PK behavior. Median overall survival in the study population, 67% of whom had received prior sorafenib, was 7.8 months, and for Child Pugh B patients (28%) it was 8.1 months. Stable disease by RECIST was observed in four patients for at least 4 months. CF102 maintained liver function over a 6-month period. A correlation between receptor overexpression levels at baseline and patients' overall survival was found. One of the patients who presented with skin nodules that were biopsy-proven to be HCC metastases prior to the trial showed complete metastasis regression during three months of treatment with CF102. CONCLUSIONS: CF102 is safe and well-tolerated, showing favorable PK characteristics in Child Pugh A and B HCC patients, justifying further clinical development.


Assuntos
Adenosina/análogos & derivados , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Agonistas do Receptor Purinérgico P1/administração & dosagem , Adenosina/administração & dosagem , Adulto , Idoso , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/patologia , Criança , Feminino , Humanos , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/patologia , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Niacinamida/administração & dosagem , Niacinamida/análogos & derivados , Compostos de Fenilureia/administração & dosagem , Agonistas do Receptor Purinérgico P1/efeitos adversos , Agonistas do Receptor Purinérgico P1/farmacocinética , Receptor A3 de Adenosina/metabolismo , Sorafenibe , Via de Sinalização Wnt
3.
Vaccine ; 29(29-30): 4676-86, 2011 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-21570434

RESUMO

An optimal cancer vaccine should be able to induce highly potent, long-lasting, tumor-specific responses in the majority of the cancer patient population. One approach for achieving this is to use synthetic peptide vaccines derived from widely expressed tumor-associated antigens, that promiscuously bind multiple MHC class I and class II alleles. MUC1-SP-L (ImMucin, VXL100) is a 21mer peptide encoding the complete signal peptide domain of MUC1, a tumor-associated antigen expressed by over 90% of solid and non-solid tumors. MUC1-SP-L was predicted in silico to bind various MHC class I and MHC class II alleles, covering the majority of the Caucasian population. PBLs obtained from 13 naïve donors all proliferated, with a Stimulation Index (SI≥2), to the MUC1-SP-L peptide, producing mixed CD4+ and CD8+ responses. Similar results were manifested by MUC1-SP-L in PBLs derived from 9 of 10 cancer patients with MUC1 positive tumors. CD4+ and CD8+ T cell populations exhibited CD45RO memory markers and secreted IFN-gamma and IL-2 following stimulation with MUC1-SP-L. These T cells also exhibited proliferation to the MUC1-SP-L inner 9mer epitopes and cytotoxicity against tumor cell lines expressing MUC1 and a concordant MHC class I allele. Cytotoxicity to MUC1-expressing human and murine tumors was shown also in T cells obtained from HLA-A2 transgenic mice and BALB/c syngeneic mice immunized with the MUC1-SP-L and GM-CSF. In an immunotherapy model, BALB/c mice inoculated with metastatic MUC1 transfected murine DA3 mammary tumor cells, exhibited significantly prolonged survival following vaccination with MUC1-SP-L. Our results indicate superior immunological and anti-tumor properties of MUC1-SP-L compared to previously published MUC1-derived epitopes.


Assuntos
Vacinas Anticâncer/administração & dosagem , Antígenos de Histocompatibilidade/imunologia , Antígenos de Histocompatibilidade/metabolismo , Imunoterapia/métodos , Mucina-1/biossíntese , Mucina-1/imunologia , Neoplasias/terapia , Idoso , Animais , Vacinas Anticâncer/imunologia , Proliferação de Células , Citotoxicidade Imunológica , Modelos Animais de Doenças , Feminino , Humanos , Leucócitos Mononucleares/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Pessoa de Meia-Idade , Ligação Proteica , Doenças dos Roedores/terapia , Análise de Sobrevida
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