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PURPOSE: Limited options exist for patients with advanced pancreatic cancer progressing after 1 or more lines of therapy. A phase II study in patients with previously treated metastatic pancreatic cancer showed that combining GVAX pancreas (granulocyte-macrophage colony-stimulating factor-secreting allogeneic pancreatic tumor cells) with cyclophosphamide (Cy) and CRS-207 (live, attenuated Listeria monocytogenes expressing mesothelin) resulted in median overall survival (OS) of 6.1 months, which compares favorably with historical OS achieved with chemotherapy. In the current study, we compared Cy/GVAX + CRS-207, CRS-207 alone, and standard chemotherapy in a three-arm, randomized, controlled phase IIb trial. PATIENTS AND METHODS: Patients with previously treated metastatic pancreatic adenocarcinoma were randomized 1:1:1 to receive Cy/GVAX + CRS-207 (arm A), CRS-207 (arm B), or physician's choice of single-agent chemotherapy (arm C). The primary cohort included patients who had failed ≥2 prior lines of therapy, including gemcitabine. The primary objective compared OS between arms A and C in the primary cohort. The second-line cohort included patients who had received 1 prior line of therapy. Additional objectives included OS between all treatment arms, safety, and tumor responses. RESULTS: The study did not meet its primary efficacy endpoint. At the final study analysis, median OS [95% confidence interval (CI)] in the primary cohort (N = 213) was 3.7 (2.9-5.3), 5.4 (4.2-6.4), and 4.6 (4.2-5.7) months in arms A, B, and C, respectively, showing no significant difference between arm A and arm C [P = not significant (NS), HR = 1.17; 95% CI, 0.84-1.64]. The most frequently reported adverse events in all treatment groups were chills, pyrexia, fatigue, and nausea. No treatment-related deaths occurred. CONCLUSIONS: The combination of Cy/GVAX + CRS-207 did not improve survival over chemotherapy. (ClinicalTrials.gov ID: NCT02004262)See related commentary by Salas-Benito et al., p. 5435.
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Adenocarcinoma , Neoplasias Pancreáticas , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica , Ciclofosfamida , Factor Estimulante de Colonias de Granulocitos y Macrófagos , HumanosRESUMEN
The genomes of cancers deficient in mismatch repair contain exceptionally high numbers of somatic mutations. In a proof-of-concept study, we previously showed that colorectal cancers with mismatch repair deficiency were sensitive to immune checkpoint blockade with antibodies to programmed death receptor-1 (PD-1). We have now expanded this study to evaluate the efficacy of PD-1 blockade in patients with advanced mismatch repair-deficient cancers across 12 different tumor types. Objective radiographic responses were observed in 53% of patients, and complete responses were achieved in 21% of patients. Responses were durable, with median progression-free survival and overall survival still not reached. Functional analysis in a responding patient demonstrated rapid in vivo expansion of neoantigen-specific T cell clones that were reactive to mutant neopeptides found in the tumor. These data support the hypothesis that the large proportion of mutant neoantigens in mismatch repair-deficient cancers make them sensitive to immune checkpoint blockade, regardless of the cancers' tissue of origin.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Biomarcadores de Tumor/antagonistas & inhibidores , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/terapia , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/terapia , Síndromes Neoplásicos Hereditarios/inmunología , Síndromes Neoplásicos Hereditarios/terapia , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Adulto , Anciano , Anciano de 80 o más Años , Antígenos de Neoplasias/inmunología , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidad , Puntos de Control del Ciclo Celular/efectos de los fármacos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/mortalidad , Reparación de la Incompatibilidad de ADN , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación , Síndromes Neoplásicos Hereditarios/genética , Síndromes Neoplásicos Hereditarios/mortalidad , Receptor de Muerte Celular Programada 1/inmunología , Linfocitos T/inmunología , Adulto JovenRESUMEN
BACKGROUND: The immune system plays an important role in cancer surveillance and therapy. Chemoradiation can cause severe treatment-related lymphopenia (TRL) (<500 cells/mm3) that is associated with reduced survival. MATERIALS AND METHODS: Data from 4 independent solid tumor studies on serial lymphocyte counts, prognostic factors, treatment, and survival were collected and analyzed. The data set included 297 patients with newly diagnosed malignant glioma (N=96), resected pancreatic cancer (N=53), unresectable pancreatic cancer (N=101), and non-small cell lung cancer (N=47). RESULTS: Pretreatment lymphocyte counts were normal in 83% of the patient population, and no patient had severe baseline lymphopenia. Two months after initiating chemoradiation, 43% developed severe and persistent lymphopenia (P=.001). An increased risk for death was attributable to TRL in each cancer cohort (gliomas: hazard rate [HR], 1.8; 95% CI, 1.13-2.87; resected pancreas: HR, 2.2; 95% CI, 1.17-4.12; unresected pancreas: HR, 2.9; 95% CI, 1.53-5.42; and lung: HR, 1.7; 95% CI, 0.8-3.61) and in the entire study population regardless of pathologic findings (HR, 2.1; 95% CI, 1.54-2.78; P<.0001). Severe TRL was observed in more than 40% of patients 2 months after initiating chemoradiation, regardless of histology or chemotherapy regimen, and was independently associated with shorter survival from tumor progression. CONCLUSIONS: Increased attention and research should be focused on the cause, prevention, and reversal of this unintended consequence of cancer treatment that seems to be related to survival in patients with solid tumors.
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Carcinoma de Pulmón de Células no Pequeñas/complicaciones , Quimioradioterapia/efectos adversos , Glioma/complicaciones , Linfopenia/patología , Neoplasias Pancreáticas/complicaciones , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/radioterapia , Supervivencia sin Enfermedad , Femenino , Glioma/tratamiento farmacológico , Glioma/radioterapia , Humanos , Recuento de Linfocitos , Linfopenia/inducido químicamente , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/radioterapiaRESUMEN
BACKGROUND: Somatic mutations have the potential to encode "non-self" immunogenic antigens. We hypothesized that tumors with a large number of somatic mutations due to mismatch-repair defects may be susceptible to immune checkpoint blockade. METHODS: We conducted a phase 2 study to evaluate the clinical activity of pembrolizumab, an anti-programmed death 1 immune checkpoint inhibitor, in 41 patients with progressive metastatic carcinoma with or without mismatch-repair deficiency. Pembrolizumab was administered intravenously at a dose of 10 mg per kilogram of body weight every 14 days in patients with mismatch repair-deficient colorectal cancers, patients with mismatch repair-proficient colorectal cancers, and patients with mismatch repair-deficient cancers that were not colorectal. The coprimary end points were the immune-related objective response rate and the 20-week immune-related progression-free survival rate. RESULTS: The immune-related objective response rate and immune-related progression-free survival rate were 40% (4 of 10 patients) and 78% (7 of 9 patients), respectively, for mismatch repair-deficient colorectal cancers and 0% (0 of 18 patients) and 11% (2 of 18 patients) for mismatch repair-proficient colorectal cancers. The median progression-free survival and overall survival were not reached in the cohort with mismatch repair-deficient colorectal cancer but were 2.2 and 5.0 months, respectively, in the cohort with mismatch repair-proficient colorectal cancer (hazard ratio for disease progression or death, 0.10 [P<0.001], and hazard ratio for death, 0.22 [P=0.05]). Patients with mismatch repair-deficient noncolorectal cancer had responses similar to those of patients with mismatch repair-deficient colorectal cancer (immune-related objective response rate, 71% [5 of 7 patients]; immune-related progression-free survival rate, 67% [4 of 6 patients]). Whole-exome sequencing revealed a mean of 1782 somatic mutations per tumor in mismatch repair-deficient tumors, as compared with 73 in mismatch repair-proficient tumors (P=0.007), and high somatic mutation loads were associated with prolonged progression-free survival (P=0.02). CONCLUSIONS: This study showed that mismatch-repair status predicted clinical benefit of immune checkpoint blockade with pembrolizumab. (Funded by Johns Hopkins University and others; ClinicalTrials.gov number, NCT01876511.).
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos/uso terapéutico , Reparación de la Incompatibilidad de ADN , Metástasis de la Neoplasia/tratamiento farmacológico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/secundario , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/efectos adversos , Antineoplásicos/efectos adversos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia/genéticaRESUMEN
The balance between tumor-promoting and tumor-suppressing immune responses and the difference between them ultimately determine whether a cancer escapes immune recognition mechanisms. Defining the complex relationships between the tumor itself, the tumor environment, and the immune system has been critical in facilitating the development of successful immunotherapies. This review explores the role of oncogenes in inducing cancer-associated inflammation, the local and systemic factors that lead to immune suppression, and immunotherapy approaches to overcome immune privilege.
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Neoplasias Gastrointestinales/terapia , Inmunoterapia , Animales , Anticuerpos/uso terapéutico , Vacunas contra el Cáncer/uso terapéutico , Neoplasias Gastrointestinales/diagnóstico , Neoplasias Gastrointestinales/genética , Neoplasias Gastrointestinales/inmunología , Humanos , Inmunoterapia/métodos , Inmunoterapia Adoptiva , Mediadores de Inflamación/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Oncogenes/genética , Factores de Riesgo , Resultado del Tratamiento , Escape del Tumor , Microambiente TumoralRESUMEN
PURPOSE: CNS metastasis of pancreatic cancer is extremely rare, although systemic metastasis is very common. We present eight such cases with various forms of nervous system involvement. METHODS: Data was gathered from chart review of 800 patients with pancreatic cancer treated between 2004 and 2012 of which eight patients are described with CNS metastases. RESULTS: The median age of patients was 61.5 years and the median time to develop CNS metastasis was 29 months. Interestingly, two patients had no other sites of metastasis. The treatment modalities tried included resection followed by radiation, resection alone, or whole brain radiation.
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Adenocarcinoma/patología , Neoplasias del Sistema Nervioso Central/secundario , Neoplasias Pancreáticas/patología , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias PancreáticasRESUMEN
Management of patients with pancreatic cancer is a multidisciplinary approach that presents enormous challenges to the clinician. Overall 5-year survival for all patients remains <3%. Symptoms of early pancreas cancer are nonspecific. As such, only a fraction of patients are candidates for surgery. While surgical resection provides the only curative option, most patients will develop tumor recurrence and die of their disease. To date, the clinical benefits of chemotherapy and radiation therapy have been important but have led to modest improvements. Tumor vaccines have the potential to specifically target the needle of pancreas cancer cells amidst the haystack of normal tissue. The discovery of pancreas tumor-specific antigens and the subsequent ability to harness this technology has become an area of intense interest for tumor immunologists and clinicians alike. Without knowledge of specific antigen targets, the whole tumor cell represents the best source of immunizing antigens. This chapter will focus on the development of whole tumor cell vaccine strategies for pancreas cancer.
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Vacunas contra el Cáncer/inmunología , Citocinas/inmunología , Neoplasias Pancreáticas/inmunología , Animales , Vacunas contra el Cáncer/uso terapéutico , Línea Celular Tumoral , Citocinas/genética , Técnicas de Transferencia de Gen , Vectores Genéticos/genética , Humanos , Inmunoterapia , Ratones , Células 3T3 NIH , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/terapia , Retroviridae/genética , Transducción GenéticaRESUMEN
BACKGROUND: The role of adjuvant chemoradiation therapy for ampullary carcinoma is unknown. Previous literature suggests that certain populations with high risk factors for recurrence may benefit from adjuvant chemoradiation. We combined the experience of two institutions to better delineate which patients may benefit from adjuvant chemoradiation. METHODS: Patients who underwent curative surgery for ampullary carcinoma at the Johns Hopkins Hospital (n=290; 1992-2007) and at the Mayo Clinic (n=130; 1977-2005) were reviewed. Patients with <60 days of follow-up, metastatic disease at surgery, or insufficient pathologic data were excluded. The final combined study consisted of 186 patients (n=104 Johns Hopkins, n=82 Mayo). Most patients received 5-FU based chemoradiation with conformal radiation. Cox proportional hazards models were used for survival analysis. RESULTS: Median overall-survival was 39.9 months with 2- and 5-year survival rates of 62.4% and 39.1%. On univariate analysis, adverse prognostic factors for overall survival included T3/T4 stage disease (RR=1.86, p=0.002), node positive status (RR=3.18, p<0.001), and poor histological grade (RR=1.69, p=0.011). Patients who received adjuvant chemoradiation (n=66) vs. surgery alone (n=120) showed a higher rate of T3/T4 stage disease (57.6% vs. 30.8%, P<0.001), lymph node involvement (72.7% vs. 30.0%, P<0.001), and close or positive margins (4.6% vs. 0.0%, P=0.019). Five year survival rates among node negative and node positive patients were 58.7% and 18.4% respectively. When compared with surgery alone, use of adjuvant chemoradiation improved survival among node positive patients (mOS 32.1 vs. 15.7 mos, 5 yr OS: 27.5% vs. 5.9%; RR=0.47, P=0.004). After adjusting for adverse prognostic factors on multivariate analysis, patients treated with adjuvant chemoradiation demonstrated a significant survival benefit (RR=0.40, P<0.001). Disease relapse occurred in 37.1% of all patients, most commonly metastatic disease in the liver or peritoneum. CONCLUSIONS: Node-positive patients with resected ampullary adenocarcinoma may benefit from 5-FU based adjuvant chemoradiation. Since a significant proportion of patients develop metastatic disease, there is a need for more effective systemic treatment.
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Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/radioterapia , Quimioradioterapia/métodos , Quimioterapia Adyuvante/métodos , Neoplasias del Conducto Colédoco/tratamiento farmacológico , Neoplasias del Conducto Colédoco/radioterapia , Adulto , Anciano , Anciano de 80 o más Años , Ampolla Hepatopancreática/patología , Antineoplásicos/uso terapéutico , Femenino , Fluorouracilo/uso terapéutico , Humanos , Masculino , Maryland , Persona de Mediana Edad , Minnesota , Metástasis de la Neoplasia , Modelos de Riesgos Proporcionales , Radioterapia Conformacional/métodos , Estudios Retrospectivos , Factores de Riesgo , Resultado del TratamientoRESUMEN
Primary pancreatic small cell carcinoma (SCC) is rare, with just over 30 cases reported in the literature. Only 7 of these patients underwent surgical resection with a median survival of 6 months. Prognosis of SCC is therefore considered to be poor, and the role of adjuvant therapy is uncertain. Here we report two institutions' experience with resectable pancreatic SCC. Six patients with pancreatic SCC treated at the Johns Hopkins Hospital (4 patients) and the Mayo Clinic (2 patients) were identified from prospectively collected pancreatic cancer databases and re-reviewed by pathology. All six patients underwent a pancreaticoduodenectomy. Clinicopathologic data were analyzed, and the literature on pancreatic SCC was reviewed. Median age at diagnosis was 50 years (range 27-60). All six tumors arose in the head of the pancreas. Median tumor size was 3 cm, and all cases had positive lymph nodes except for one patient who only had five nodes sampled. There were no perioperative deaths and three patients had at least one postoperative complication. All six patients received adjuvant therapy, five of whom were given combined modality treatment with radiation, cisplatin, and etoposide. Median survival was 20 months with a range of 9-173 months. The patient who lived for 9 months received chemotherapy only, while the patient who lived for 173 months was given chemoradiation with cisplatin and etoposide and represents the longest reported survival time from pancreatic SCC to date. Pancreatic SCC is an extremely rare form of cancer with a poor prognosis. Patients in this surgical series showed favorable survival rates when compared to prior reports of both resected and unresectable SCC. Cisplatin and etoposide appears to be the preferred chemotherapy regimen, although its efficacy remains uncertain, as does the role of combined modality treatment with radiation.
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PURPOSE: Surgical resection provides the only possibility of cure for pancreas cancer. A standard adjuvant approach has not been established. We tested the safety and efficacy of a granulocyte-macrophage colony-stimulating factor (GM-CSF)-based immunotherapy administered in patients with resected pancreatic adenocarcinoma. PATIENTS AND METHODS: A single institution phase II study of 60 patients with resected pancreatic adenocarcinoma was performed. Each immunotherapy treatment consisted of a total of 5 × 108 GM-CSF-secreting cells distributed equally among 3 lymph node regions. The first immunotherapy treatment was administered 8 to 10 weeks after surgical resection. Subsequently, patients received 5-FU based chemoradiation. Patients who remained disease-free after completion of chemoradiotherapy received treatments 2 to 4, each 1 month apart. A fifth and final booster was administered 6 months after the fourth immunotherapy. The primary endpoint was disease free survival and secondary endpoints were overall survival and toxicity, and the induction of mesothelin specific T cell responses. RESULTS: The median disease-free survival is 17.3 months (95% CI, 14.6-22.8) with median survival of 24.8 months (95% CI, 21.2-31.6). The administration of immunotherapy was well tolerated. In addition, the post-immunotherapy induction of mesothelin-specific CD8+ T cells in HLA-A1+ and HLA-A2+patients correlates with disease-free survival. CONCLUSIONS: An immunotherapy approach integrated with chemoradiation is safe and demonstrates an overall survival that compares favorably with published data for resected pancreas cancer. These data suggest additional boost immunotherapies given at regular intervals beyond 1 year postsurgery should be tested in future studies, and provide the rationale for conducting a multicenter phase II study.
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Vacunas contra el Cáncer/uso terapéutico , Carcinoma Ductal Pancreático/terapia , Factor Estimulante de Colonias de Granulocitos y Macrófagos/uso terapéutico , Inmunoterapia , Neoplasias Pancreáticas/terapia , Adulto , Anciano , Anciano de 80 o más Años , Antígenos de Neoplasias/inmunología , Vacunas contra el Cáncer/efectos adversos , Vacunas contra el Cáncer/inmunología , Vacunas contra el Cáncer/efectos de la radiación , Carcinoma Ductal Pancreático/inmunología , Carcinoma Ductal Pancreático/mortalidad , Línea Celular Tumoral/metabolismo , Línea Celular Tumoral/efectos de la radiación , Terapia Combinada , Supervivencia sin Enfermedad , Femenino , Proteínas Ligadas a GPI/inmunología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Humanos , Hipersensibilidad Tardía/inmunología , Masculino , Mesotelina , Persona de Mediana Edad , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/mortalidad , Tasa de Supervivencia , Linfocitos T/inmunología , TransfecciónRESUMEN
PURPOSE: Positron emission tomography (PET) with [(18)F]fluorodeoxyglucose (FDG-PET) has increasingly been used to evaluate the efficacy of anticancer agents. We investigated the role of FDG-PET as a predictive marker for response to mammalian target of rapamycin (mTOR) inhibition in advanced solid tumor patients and in murine xenograft models. PATIENTS AND METHODS: Thirty-four rapamycin-treated patients with assessable baseline and treatment FDG-PET and computed tomography scans were analyzed from two clinical trials. Clinical response was evaluated according to Response Evaluation Criteria in Solid Tumors, and FDG-PET response was evaluated by quantitative changes and European Organisation for Research and Treatment of Cancer (EORTC) criteria. Six murine xenograft tumor models were treated with temsirolimus. Small animal FDG-PET scans were performed at baseline and during treatment. The tumors were analyzed for the expression of pAkt and GLUT1. RESULTS: Fifty percent of patients with increased FDG-PET uptake and 46% with decreased uptake had progressive disease (PD). No objective response was observed. By EORTC criteria, the sensitivity of progressive metabolic disease on FDG-PET in predicting PD was 19%. Preclinical studies demonstrated similar findings, and FDG-PET response correlated with pAkt activation and plasma membrane GLUT1 expression. CONCLUSION: FDG-PET is not predictive of proliferative response to mTOR inhibitor therapy in both clinical and preclinical studies. Our findings suggest that mTOR inhibitors suppress the formation of mTORC2 complex, resulting in the inhibition of Akt and glycolysis independent of proliferation in a subset of tumors. Changes in FDG-PET may be a pharmacodynamic marker for Akt activation during mTOR inhibitor therapy. FDG-PET may be used to identify patients with persistent Akt activation following mTOR inhibitor therapy.
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Antibióticos Antineoplásicos/uso terapéutico , Fluorodesoxiglucosa F18 , Neoplasias/diagnóstico por imagen , Neoplasias/tratamiento farmacológico , Tomografía de Emisión de Positrones , Proteínas Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Radiofármacos , Sirolimus/uso terapéutico , Animales , Antibióticos Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Progresión de la Enfermedad , Femenino , Transportador de Glucosa de Tipo 1/metabolismo , Humanos , Ratones , Ratones Desnudos , Neoplasias/enzimología , Neoplasias/patología , Selección de Paciente , Fosforilación , Valor Predictivo de las Pruebas , Sirolimus/análogos & derivados , Sirolimus/farmacología , Serina-Treonina Quinasas TOR , Tomografía Computarizada por Rayos X , Resultado del Tratamiento , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
PURPOSE: To determine the maximum tolerated dose (MTD), characterize the principal toxicities, and assess the pharmacokinetics of EKB-569, an oral selective irreversible inhibitor of the epidermal growth factor receptor tyrosine kinase, in combination with capecitabine in patients with advanced colorectal cancer. EXPERIMENTAL DESIGN: Patients were treated with EKB-569 daily for 21 days and capecitabine twice daily for 14 days of a 21-day cycle. The dose levels of EKB-569 (mg/day) and capecitabine (mg/m(2) twice daily) assessed were 25/750, 50/750, 50/1,000 and 75/1,000. An expanded cohort was enrolled at the MTD to better study toxicity and efficacy. Samples of plasma were collected to characterize the pharmacokinetics of the agents. Treatment efficacy was assessed every other cycle. RESULTS: A total of 37 patients, the majority of whom had prior chemotherapy, received a total of 163 cycles of treatment. Twenty patients were treated at the MTD, 50 mg EKB-569, daily and 1,000 mg/m(2) capecitabine twice daily. Dose-limiting toxicities were diarrhea and rash. No patients had complete or partial responses but 48% had stable disease. The conversion of capecitabine to 5-fluorouracil was higher for the combination of EKB-569 and capecitabine (321+/-151 ng*h/mL) than for capecitabine alone (176+/-62 ng*hours/mL; P=0.0037). CONCLUSION: In advanced colorectal cancer, 50 mg EKB-569 daily can be safely combined with 1,000 mg/m(2) capecitabine twice a day. A statistically significant increase in plasma levels of 5-fluorouracil for the combination of EKB-569 and capecitabine may be due to the single-dose versus multiple-dose exposure difference, variability in exposure or a potential drug interaction.
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Aminoquinolinas/administración & dosificación , Compuestos de Anilina/administración & dosificación , Desoxicitidina/análogos & derivados , Fluorouracilo/análogos & derivados , Adulto , Anciano , Anciano de 80 o más Años , Aminoquinolinas/efectos adversos , Aminoquinolinas/farmacocinética , Compuestos de Anilina/efectos adversos , Compuestos de Anilina/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Capecitabina , Neoplasias Colorrectales/tratamiento farmacológico , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Desoxicitidina/farmacocinética , Esquema de Medicación , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Fluorouracilo/farmacocinética , Humanos , Masculino , Persona de Mediana EdadRESUMEN
A liquid chromatography/tandem mass spectrometric (LC/MS/MS) assay was developed for the quantitative determination of salirasib (S-trans,trans-farnesylthiosalicylic acid, FTS) in human plasma. Sample pretreatment involved liquid-liquid extraction with methyl t-butyl ether of 0.5-mL aliquots of lithium heparin plasma spiked with the internal standard, S-trans,trans-5-fluoro-farnesylthiosalicylic acid (5-F-FTS). Separation was achieved on Waters X-Terra C(18) (50 mm x 2.1 mm i.d., 3.5 microm) at room temperature using isocratic elution with acetonitrile/10 mM ammonium acetate buffer mobile phase (80:20, v/v) containing 0.1% formic acid at a flow rate of 0.20 mL/min. Detection was performed using electrospray MS/MS by monitoring the ion transitions from m/z 357.2-->153.0 (salirasib) and m/z 375.1-->138.8 (5-F-FTS). Calibration curves were linear in the concentration range of 1-1000 ng/mL. A 5000 ng/mL sample that was diluted 1:10 (v/v) with plasma was accurately quantitated. The values for both within day and between day precision and accuracy were well within the generally accepted criteria for analytical method (<8.0%). This assay was subsequently used for the determination of salirasib concentrations in plasma of cancer patients after oral administration of salirasib at a dose of 400 mg.
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Antineoplásicos/sangre , Cromatografía Liquida/métodos , Farnesol/análogos & derivados , Salicilatos/sangre , Espectrometría de Masas en Tándem/métodos , Administración Oral , Antineoplásicos/administración & dosificación , Antineoplásicos/aislamiento & purificación , Farnesol/administración & dosificación , Farnesol/sangre , Farnesol/aislamiento & purificación , Humanos , Salicilatos/administración & dosificación , Salicilatos/aislamiento & purificaciónRESUMEN
PURPOSE: To determine the maximum tolerated dose (MTD) of trabectedin plus gemcitabine administered on a weekly schedule in patients with advanced solid tumors. METHODS: Patients with ECOG performance status 0-1 and adequate organ function were enrolled. On days 1, 8, and 15 of a 28-day cycle, patients received gemcitabine (starting dose, 800 mg/m(2)) followed by trabectedin (starting dose, 0.3 mg/m(2)). Strict liver function test treatment criteria were employed to avoid hepatic toxicity seen in previous trabectedin studies. Plasma samples were collected during cycles 1 and 2 for pharmacokinetic analyses. RESULTS: Fifteen patients received >or=1 dose, with a median of two treatment cycles (range 1-10). The most common drug-related toxicity was hepatic. Dose reductions were required for trabectedin in four (27%) patients and gemcitabine in six (40%) patients. Cycle delays/dose holds were required in 11 (73%) patients and doses above trabectedin 0.4 mg/m(2) and gemcitabine 1,000 mg/m(2), which is the recommended phase II dose, were not feasible. Seven patients maintained stable disease after two cycles. Gemcitabine and trabectedin pharmacokinetics were not altered substantially with concomitant administration. CONCLUSIONS: Given the lack of pharmacokinetic interaction and potential efficacy of trabectedin and gemcitabine combination therapy, further study is warranted with alternate schedules.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacocinética , Dioxoles/administración & dosificación , Dioxoles/efectos adversos , Dioxoles/farmacocinética , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Enfermedades Hematológicas/inducido químicamente , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Neoplasias/patología , Tetrahidroisoquinolinas/administración & dosificación , Tetrahidroisoquinolinas/efectos adversos , Tetrahidroisoquinolinas/farmacocinética , Trabectedina , GemcitabinaRESUMEN
PURPOSE: The combination of chemotherapy and immunotherapy has not been examined in patients with advanced pancreatic cancer. We conducted a study of two granulocyte macrophage colony-stimulating factor-secreting pancreatic cancer cell lines (CG8020/CG2505) as immunotherapy administered alone or in sequence with cyclophosphamide in patients with advanced pancreatic cancer. EXPERIMENTAL DESIGN: This was an open-label study with two cohorts: cohort A, 30 patients administered a maximum of six doses of CG8020/CG2505 at 21-day intervals; and cohort B, 20 patients administered 250 mg/m(2) of cyclophosphamide i.v. 1 day before the same immunotherapy given as in cohort A. The primary objective was to evaluate safety and duration of immunity. Secondary objectives included time to disease progression and median overall survival. RESULTS: The administration of CG8020/CG2505 alone or in sequence with cyclophosphamide showed minimal treatment-related toxicity. Median survival values in cohort A and cohort B were 2.3 and 4.3 months, respectively. CD8(+) T-cell responses to HLA class I-restricted mesothelin epitopes were identified predominantly in patients treated with cyclophosphamide + CG8020/CG2505 immunotherapy. CONCLUSION: Granulocyte macrophage colony-stimulating factor-secreting pancreatic cancer cell lines CG8020/CG2505 alone or in sequence with cyclophosphamide showed minimal treatment-related toxicity in patients with advanced pancreatic cancer. Also, mesothelin-specific T-cell responses were detected/enhanced in some patients treated with CG8020/CG2505 immunotherapy. In addition, cyclophosphamide-modulated immunotherapy resulted in median survival in a gemcitabine-resistant population similar to chemotherapy alone. These findings support additional investigation of cyclophosphamide with CG8020/CG2505 immunotherapy in patients with advanced pancreatic cancer.
Asunto(s)
Adenocarcinoma/terapia , Antineoplásicos Alquilantes/uso terapéutico , Ciclofosfamida/uso terapéutico , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Inmunoterapia , Neoplasias Pancreáticas/terapia , Adenocarcinoma/secundario , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Terapia Combinada , Estudios de Factibilidad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/patología , Proyectos Piloto , Tasa de Supervivencia , Distribución TisularRESUMEN
Recent advances in our understanding of the complex signaling pathways involved in immune system regulation, along with analyses of genetic differences between tumors and their normal cellular counterparts, have accelerated development of immune-based strategies for cancer treatment and prevention. More clinically relevant animal models have shown that successful immune-based strategies will require the integration of interventions that target specific tumor antigens with regulators of the antitumor immune response. Immunotherapy for cancer is at a critical crossroad, as therapeutics designed to target cancer-associated antigens and regulatory signaling molecules enter clinical trials. We outline here a paradigm for early-stage clinical development of immunotherapy combinations that use vaccines to drive tumor antigen-specific responses while simultaneously targeting immune regulatory pathways.
Asunto(s)
Inmunoterapia/métodos , Neoplasias/genética , Neoplasias/microbiología , Neoplasias/terapia , Antígenos de Neoplasias/metabolismo , Ensayos Clínicos como Asunto , Progresión de la Enfermedad , Humanos , Sistema Inmunológico , Biología Molecular , Transducción de SeñalAsunto(s)
Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/radioterapia , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/radioterapia , Antimetabolitos Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Vacunas contra el Cáncer/uso terapéutico , Quimioterapia Adyuvante , Fluorouracilo/uso terapéutico , Factor Estimulante de Colonias de Granulocitos y Macrófagos/uso terapéutico , Humanos , Inmunoterapia , Terapia Neoadyuvante , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/cirugía , Dosificación Radioterapéutica , Radioterapia AdyuvanteRESUMEN
Approximately 10% of pancreatic cancers are believed to have a familial basis. The familial aggregation of pancreatic cancers provides a unique opportunity to prevent the development of pancreatic cancer, to identify and treat precancerous lesions of the pancreas, and to advance our understanding of the genetic basis for the development of all forms of pancreatic cancer. After appropriate genetic counseling, individuals with a strong family history of pancreatic cancer can now be tested for inherited genetic alterations that are known to increase the risk of pancreatic cancer. These include germline BRCA2, STK11/LKB1, p16/CDKN2A and PRSS1 gene mutations. Individuals with one of these inherited genetic alterations and individuals with a strong family history of pancreatic cancer can be counseled on smoking cessation and possible dietary modifications. Selected individuals, even if they are asymptomatic, can be screened using a combination of endoscopic ultrasound and multidetector computed tomography. Patients found to have a mass lesion in the pancreas would then be candidates for surgical resection. The resection of noninvasive precancers will cure these lesions before they have the opportunity to spread and metastasize. Even with the best early detection efforts, some patients will still be diagnosed with an invasive cancer. Surgical resection of invasive pancreatic cancer is proven to be safe and can provide long-term survival in patients with small, node-negative, and margin-negative cancers. Chemotherapy and radiation therapy are effective in some patients with invasive pancreatic cancer, but these therapies do not usually result in long-term cures. Individuals with a family history of pancreatic cancer may also choose to join a research study such as the National Familial Pancreas Tumor Registry.
RESUMEN
The identification of key signalling pathways involved in immune-system regulation, along with the development of early pancreatic tumours in mouse models have provided new opportunities for pancreatic cancer treatment and prevention. Immunotherapy for pancreatic cancer is one approach that is at a crucial crossroads, as therapeutics that are designed to target pancreatic-cancer-associated antigens and regulatory signalling molecules are entering clinical trials.