RESUMO
PURPOSE: Poxviral vectors have a proven safety record and can be used to incorporate multiple transgenes. Prior clinical trials with poxviral vaccines have shown that immunologic tolerance to self-antigens can be broken. Carcinoembryonic antigen (CEA) and MUC-1 are overexpressed in a substantial proportion of common solid carcinomas. The primary end point of this study was vaccine safety, with immunologic and clinical responses as secondary end points. EXPERIMENTAL DESIGN: We report here a pilot study of 25 patients treated with a poxviral vaccine regimen consisting of the genes for CEA and MUC-1, along with a triad of costimulatory molecules (TRICOM; composed of B7.1, intercellular adhesion molecule 1, and lymphocyte function-associated antigen 3) engineered into vaccinia (PANVAC-V) as a prime vaccination and into fowlpox (PANVAC-F) as a booster vaccination. RESULTS: The vaccine was well tolerated. Apart from injection-site reaction, no grade > or =2 toxicity was seen in more than 2% of the cycles. Immune responses to MUC-1 and/or CEA were seen following vaccination in 9 of 16 patients tested. A patient with clear cell ovarian cancer and symptomatic ascites had a durable (18-month) clinical response radiographically and biochemically, and one breast cancer patient had a confirmed decrease of >20% in the size of large liver metastasis. CONCLUSIONS: This vaccine strategy seems to be safe, is associated with both CD8 and CD4 immune responses, and has shown evidence of clinical activity. Further trials with this agent, either alone or in combination with immunopotentiating and other therapeutic agents, are warranted.
Assuntos
Vacinas Anticâncer/uso terapêutico , Antígeno Carcinoembrionário/uso terapêutico , Mucina-1/uso terapêutico , Neoplasias/terapia , Poxviridae/imunologia , Adjuvantes Imunológicos/metabolismo , Adjuvantes Imunológicos/uso terapêutico , Adulto , Idoso , Antígeno B7-1/imunologia , Antígeno B7-1/uso terapêutico , Antígenos CD58/imunologia , Antígenos CD58/uso terapêutico , Vacinas Anticâncer/imunologia , Antígeno Carcinoembrionário/imunologia , Feminino , Vetores Genéticos , Humanos , Molécula 1 de Adesão Intercelular/imunologia , Molécula 1 de Adesão Intercelular/uso terapêutico , Masculino , Pessoa de Meia-Idade , Mucina-1/imunologia , Neoplasias/imunologia , Projetos Piloto , Vacinas Sintéticas/imunologia , Vacinas Sintéticas/uso terapêuticoRESUMO
PURPOSE: To determine the maximum-tolerated dose (MTD) and toxicity profile of the novel anticancer agent, 2-methoxyestradiol (2ME2) administered orally, in patients with solid tumors. MATERIALS AND METHODS: Twenty patients with refractory solid tumors were enrolled. 2ME2 was given orally starting at 400 mg bid with dose escalation until 3000 mg bid. Tumor biopsies were taken before and after starting the drug to assess for microvessel density by CD 31 and cell proliferation by Ki67 immunohistochemistry. Serial plasma samples collected up to 50 hours after first single oral dose for characterization of pharmacokinetics, were analyzed using liquid chromatography tandem mass-spectrometry. RESULTS: Eleven men and nine women received 2ME2 at dose levels of 400 mg bid (n = 3), 800 mg bid (n = 3), 1600 mg bid (n = 6), 2200 mg bid (n = 5) and 3000 mg bid (n = 3). There were no dose limiting toxicities, therefore the MTD was not defined. There was one episode of grade 4 angioedema in the 1600 mg bid dose level 38 days into 2ME2 treatment. Other toxicities were mild to moderate. A patient with clear cell carcinoma of the ovary had a partial response at 1600 mg bid dose level lasting over three years. CONCLUSION: MTD for 2ME2 was not reached at dose of 3000 mg bid. The trial was closed due to extremely low plasma concentrations of 2ME2 relative to the doses administered. 2ME2 treatment had no effect on microvessel density (CD31 immunostaining) and cell proliferation (Ki-67 immunostaining). A new formulation of 2ME2 with improved bioavailability is currently being developed.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Antineoplásicos/uso terapêutico , Estradiol/análogos & derivados , Dose Máxima Tolerável , Neoplasias/tratamento farmacológico , 2-Metoxiestradiol , Administração Oral , Adulto , Apoptose , Capilares/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Estradiol/efeitos adversos , Estradiol/sangue , Estradiol/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/diagnóstico por imagem , Tomografia Computadorizada por Raios XRESUMO
PURPOSE: Carboxyamidotriazole (CAI) is a cytostatic inhibitor of nonvoltage-operated calcium channels and calcium channel-mediated signaling pathways. It inhibits angiogenesis, tumor growth, invasion, and metastasis. We hypothesized that CAI would promote disease stabilization lasting >/= 6 months in patients with relapsed ovarian cancer. PATIENTS AND METHODS: Patients with epithelial ovarian cancer, good end-organ function, measurable disease, and three or fewer prior regimens were eligible. Oral CAI was given daily using a pharmacokinetic-dosing approach to maintain plasma concentrations between 2 and 4 microg/mL. Radiographic imaging to assess response was performed every 8 weeks. Positive outcome included stabilization or improvement of disease lasting >/= 6 months. Plasma vascular endothelial growth factor (VEGF), interleukin (IL)-8, and matrix metalloproteinase (MMP)-2 were measured. RESULTS: Thirty-six patients were assessable for primary end point analysis, and 38 were assessable for toxicity. Forty-four percent of patients had three prior regimens, more than 50% had four or more disease sites, and 48% had liver metastases. Thirty-three patients reached the targeted concentration range during the first cycle. Eleven patients (31%) attained the >/= 6-month outcome end point, with one partial response (8 months) and three minor responses (8, 12+, and 13 months). Median time to progression was 3.6 months (range, 1.6 to 13.3 months). CAI was well tolerated, with mostly grade 1 to 2 toxicity. Grade 3 events included fatigue (5%), vomiting (2%), neutropenic fever (2%), and neutropenia (2%). There were no grade 4 adverse events. No associations between VEGF, IL-8, and MMP-2 with CAI concentration or clinical outcome were observed. CONCLUSION: CAI is a potential agent for additional study in the stabilization of relapsed ovarian cancer. Given a limited toxicity profile, it may have utility as a maintenance therapeutic agent for this disease.
Assuntos
Antineoplásicos/uso terapêutico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Triazóis/uso terapêutico , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Biomarcadores/análise , Bloqueadores dos Canais de Cálcio/efeitos adversos , Bloqueadores dos Canais de Cálcio/farmacocinética , Carcinoma Endometrioide/tratamento farmacológico , Carcinoma Endometrioide/metabolismo , Carcinoma Papilar/tratamento farmacológico , Carcinoma Papilar/metabolismo , Cistadenocarcinoma Seroso/tratamento farmacológico , Cistadenocarcinoma Seroso/metabolismo , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/metabolismo , Neoplasias Epiteliais e Glandulares/metabolismo , Neoplasias Ovarianas/metabolismo , Terapia de Salvação , Taxa de Sobrevida , Resultado do Tratamento , Triazóis/efeitos adversos , Triazóis/farmacocinéticaRESUMO
BACKGROUND: Benign metastasizing leiomyoma and lymphangioleiomyomatosis (LAM) both are characterized by abnormal proliferation of smooth muscle-like cells in the lung. CASE: A 32-year-old African woman with a diagnosis of LAM underwent myomectomy for uterine leiomyomas. An alternative diagnosis of benign metastasizing leiomyoma was made on repeat lung biopsy. Treatment with leuprolide acetate decreased pulmonary infiltrates and improved lung function and exercise tolerance. CONCLUSION: Accurately diagnosing benign metastasizing leiomyoma has important implications for clinical outcome. Because its clinical presentation may be misleading, immunohistochemical techniques may assist in differentiating benign metastasizing leiomyoma from LAM. This is important because, in benign metastasizing leiomyoma, reduced tumor burden and improved pulmonary function may be achieved by suppressing gonadal steroids.
Assuntos
Leiomioma/diagnóstico , Leiomioma/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Linfangioleiomiomatose/diagnóstico , Neoplasias Uterinas/diagnóstico , Adulto , Antineoplásicos Hormonais/uso terapêutico , Diagnóstico Diferencial , Feminino , Humanos , Leiomioma/patologia , Leuprolida/uso terapêutico , Neoplasias Pulmonares/secundário , Neoplasias Uterinas/patologia , Neoplasias Uterinas/cirurgiaRESUMO
PURPOSE: To evaluate clinical activity and target modulation of vandetanib in women with recurrent ovarian cancer. EXPERIMENTAL DESIGN: A phase II trial of orally administered vandetanib 300 mg daily was designed to include analyses of target inhibition through paired biopsies and dynamic imaging. Core 18-gauge needle biopsies and dynamic contrast-enhanced magnetic resonance imaging were obtained before initiation of therapy and 6 weeks into therapy. Biopsy samples were subjected to reverse-phase protein lysate array endpoint analysis. Cytokine concentrations were measured by enzyme-linked immunosorbent assay in serially collected plasma samples. RESULTS: Twelve patients entered the study, and accrual was terminated in the first stage because of lack of response or disease stabilization beyond 6 months. Adverse events included rash, diarrhea, and prolonged QT interval corrected for heart rate, but not hypertension. Exploratory analyses showed that epidermal growth factor receptor (EGFR) phosphorylation was reduced in the eight paired biopsy sets obtained; vascular endothelial growth factor (VEGF) receptor-2 phosphorylation was not consistently affected nor were dynamic contrast-enhanced MRI permeability and flow parameters. Serial plasma VEGF concentrations were variable and did not significantly change in the 11 patients assessed. CONCLUSIONS: Vandetanib 300 mg daily monotherapy had no significant clinical benefit in this disease setting. Proteomic analysis of paired biopsies detected both phosphorylated-EGFR and phosphorylated-VEGF receptor-2 in ovarian tumor tissue, but only phosphorylated-EGFR was measurably inhibited by vandetanib.
Assuntos
Cistadenocarcinoma Seroso/tratamento farmacológico , Receptores ErbB/antagonistas & inibidores , Neoplasias Ovarianas/tratamento farmacológico , Piperidinas/uso terapêutico , Quinazolinas/uso terapêutico , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Administração Oral , Adulto , Idoso , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/patologia , Esquema de Medicação , Receptores ErbB/metabolismo , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Piperidinas/administração & dosagem , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinas/administração & dosagem , Quinazolinas/farmacologia , Recidiva , Transdução de Sinais/efeitos dos fármacos , Falha de Tratamento , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/administração & dosagem , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
BACKGROUND: Carboxyamido-triazole (CAI) is a calcium influx inhibitor with anti-angiogenic and anti-invasive properties and stabilizes tumor progression in patients. We hypothesized daily oral micronized CAI with q3 week paclitaxel would be well-tolerated and active. RESULTS: Twenty-nine heavily pretreated patients [median 3 [0-7]] were enrolled on five dose levels. No additive or cumulative toxicity was observed, and grade III nonhematological toxicity was rare. Neutropenia was the most common hematologic toxicity, seen in 79% of patients, with a trend towards increasing grade with higher paclitaxel doses. The recommended phase II dose defined by the maximum tolerated dose (MTD) was CAI 250 mg daily and paclitaxel 200 mg/m(2) q3weeks. Pharmacokinetic analysis revealed paclitaxel increases CAI trough concentration at all dose levels by over 100% (p < 0.0001). A trend towards higher steady-state CAI trough concentrations was found in patients with a partial response (PR; p = 0.09). Six patients had confirmed PR (24%; 4-67 cycles, median 10); two patients had minor responses. PATIENTS AND METHODS: Eligible patients with solid tumors received micronized CAI daily (150-250 mg PO) and paclitaxel intravenously q3weeks (175-250 mg/m(2)), sequentially escalating each drug. CAI preceded paclitaxel by one week to permit pharmacokinetic analysis. Patients were assessed for toxicity, pharmacokinetics and disease outcome. CONCLUSIONS: The MTD of the combination of CAI and paclitaxel is 250 mg daily and 200 mg/m(2) q3weeks, respectively. The combination is tolerable and has potential antitumor activity.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Relação Dose-Resposta a Droga , Esquema de Medicação , Interações Medicamentosas , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/metabolismo , Neoplasias/patologia , Paclitaxel/administração & dosagem , Resultado do Tratamento , Triazóis/administração & dosagem , Adulto JovemRESUMO
BACKGROUND: CA125 is an accepted indicator of epithelial ovarian cancer (EOC) response and is used to monitor patients treated with cytotoxic chemotherapy. It is uncertain how CA125 is affected by molecularly targeted drugs. In this pilot study, the authors analyzed the utility of CA125 to predict disease behavior in patients who were receiving sorafenib, a Raf-kinase/VEGFR2 inhibitor, and bevacizumab, an anti-VEGF monoclonal antibody. METHODS: Fifteen of 42 patients had recurrent EOC. Patients received sorafenib 200 mg orally twice daily or D1-5 of 7 and bevacizumab 5 mg/kg to 10 mg/kg intravenously every 2 weeks for 28-day cycles. Computed tomography (CT) scans were performed every 2 cycles for restaging, and CA125 was measured monthly. CA125 concentrations were retrospectively analyzed as a function of clinical behavior. RESULTS: Fourteen of 15 patients had abnormal CA125 concentrations at study entry (median 1056 U/mL; range, 67 U/mL to 9813 U/mL). Seven (47%) patients had partial response by imaging criteria. Five of these 7 patients had partial response by CA125 criteria (71% sensitivity). Eight (53%) patients would have had partial responses if CA125 criteria were used; only 5 were confirmed by CT (63 % specificity). Imaging and CA125 criteria combined yielded a higher total response rate of 10 of 15 (67%). Three patients with objective partial response by imaging lasting >20, >22, and >24 cycles would have terminated treatment prematurely if CA125 had been used. CONCLUSIONS: CA125 changes may not correspond to imaging response criteria for EOC patients who are receiving sorafenib and bevacizumab. Caution is recommended when using CA125 as a response criterion of molecularly targeted agents until prospective studies validate CA125 changes with objective imaging response results.
Assuntos
Antígeno Ca-125/análise , Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Adulto , Inibidores da Angiogênese/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzenossulfonatos/administração & dosagem , Bevacizumab , Estudos de Coortes , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Niacinamida/análogos & derivados , Compostos de Fenilureia , Projetos Piloto , Piridinas/administração & dosagem , Indução de Remissão , Reprodutibilidade dos Testes , Estudos Retrospectivos , Sorafenibe , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Quinases raf/antagonistas & inibidoresRESUMO
PURPOSE: Sorafenib inhibits Raf kinase and vascular endothelial growth factor (VEGF) receptor. Bevacizumab is a monoclonal antibody targeted against VEGF. We hypothesized that the complementary inhibition of VEGF signaling would have synergistic therapeutic effects. PATIENTS AND METHODS: Patients had advanced solid tumors, Eastern Cooperative Oncology Group performance status of 0 to 1, and good end-organ function. A phase I dose-escalation trial of sorafenib and bevacizumab was initiated at below-recommended single-agent doses because of possible overlapping toxicity: sorafenib 200 mg orally twice daily and bevacizumab intravenously at 5 mg/kg (dose level [DL] 1) or 10 mg/kg (DL2) every 2 weeks. Additional patients were enrolled at the maximum-tolerated dose (MTD). RESULTS: Thirty-nine patients were treated. DL1 was the MTD and administered in cohort 2 (N = 27). Dose-limiting toxicity in DL2 was grade 3 proteinuria and thrombocytopenia. Adverse events included hypertension, hand-foot syndrome, diarrhea, transaminitis, and fatigue. Partial responses (PRs) were seen in six (43%) of 13 patients with ovarian cancer (response duration range, 4 to 22+ months) and one of three patients with renal cell cancer (response duration, 14 months). PR or disease stabilization >or= 4 months (median, 6 months; range, 4 to 22+ months) was seen in 22 (59%) of 37 assessable patients. The majority (74%) required sorafenib dose reduction to 200 mg/d at a median of four cycles (range, one to 12 cycles). CONCLUSION: Combination therapy with sorafenib and bevacizumab has promising clinical activity, especially in patients with ovarian cancer. The rapidity and frequency of sorafenib dose reductions indicates that sorafenib at 200 mg twice daily with bevacizumab 5 mg/kg every 2 weeks may not be tolerable long term, and alternate sorafenib dosing schedules should be explored.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias/tratamento farmacológico , Administração Oral , Adulto , Idoso , Inibidores da Angiogênese/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Benzenossulfonatos/administração & dosagem , Bevacizumab , Esquema de Medicação , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias/enzimologia , Neoplasias/patologia , Niacinamida/análogos & derivados , Neoplasias Ovarianas/tratamento farmacológico , Compostos de Fenilureia , Inibidores de Proteínas Quinases/administração & dosagem , Piridinas/administração & dosagem , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Sorafenibe , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/sangue , Quinases raf/antagonistas & inibidoresRESUMO
BACKGROUND: c-Kit and platelet-derived growth factor receptor (PDGFR) are potential molecular targets in epithelial ovarian cancer (EOC). Imatinib inhibits the kinase domain and subsequent downstream signaling of these receptor tyrosine kinases. The objective of this study was to investigate biochemical and biologic effects of imatinib on EOC. METHODS: Patients with recurrent EOC who had received no more than 4 prior regimens and who had good end-organ function were eligible. Imatinib was administered orally at a dose of 400 mg twice daily in continuous, 28-day cycles with reassessment imaging studies obtained every other cycle. Tumor core biopsies were obtained prior to and at 4 weeks into therapy; microdissected tumor and stroma were subjected to protein lysate array analysis. Blood samples were obtained monthly for cytokine measurements. RESULTS: Twenty-three patients were enrolled, including 16 patients who received imatinib 600 mg daily because of gastrointestinal (GI) toxicity and fluid accumulation at the starting dose. The median time to disease progression was 2 months (range, 2-14 months). Common grade 3 toxicities included edema/ascites/pleural effusions in 11 patients (48%), GI complaints in 8 patients (35%), fatigue in 3 patients (13%), and grade 2 and 3 cytopenias in 10 patients and 3 patients (43% and 13%), respectively. Increased circulating levels of interleukin 6 were associated with grade >/=2 fluid collection (P = .02). A statistically significant trend was observed between pretreatment phosphorylated-kit levels in microdissected tumor and stroma and GI toxicity (P < .01), between tumor levels of epidermal growth factor receptor (EGFR) and PDGFR with grade of fatigue (P = .005), and EGFR and phosphorylated-AKT levels with grade of ascites and edema (P = .01). CONCLUSIONS: The results of this study indicated imatinib had minimal activity as a single agent in EOC. Its ability to modulate its molecular targets suggests that it may be considered in combinatorial therapy.