RESUMEN
Pelareorep causes oncolysis in tumor cells with activated Ras. We hypothesized that pelareorep would have efficacy and immunomodulatory activity in metastatic pancreatic adenocarcinoma (MPA) when combined with carboplatin and paclitaxel. A randomized phase 2 study (NCT01280058) was conducted in treatment-naive patients with MPA randomized to two treatment arms: paclitaxel/carboplatin + pelareorep (Arm A, n = 36 evaluable patients) versus paclitaxel/carboplatin (Arm B, n = 37 evaluable patients). There was no difference in progression-free survival (PFS) between the arms (Arm A PFS = 4.9 months, Arm B PFS = 5.2 months, P = 0.6), and Kirsten rat sarcoma viral oncogene (KRAS) status did not impact outcome. Quality-adjusted Time without Symptoms or Toxicity analysis revealed that the majority of PFS time was without toxicity or progression (4.3 months). Patient immunophenotype appeared important, as soluble immune biomarkers were associated with treatment outcome (fractalkine, interleukin (IL)-6, IL-8, regulated on activation, normal T cell expressed and secreted (RANTES), and vascular endothelial growth factor (VEGF)). Increased circulating T and natural killer (NK)-cell subsets were also significantly associated with treatment outcome. Addition of pelareorep was associated with higher levels of 14 proinflammatory plasma cytokines/chemokines and cells with an immunosuppressive phenotype (Tregs, cytotoxic T lymphocyte associated protein 4 (CTLA4)(+) T cells). Overall, pelareorep was safe but does not improve PFS when administered with carboplatin/paclitaxel, regardless of KRAS mutational status. Immunologic studies suggest that chemotherapy backbone improves immune reconstitution and that targeting remaining immunosuppressive mediators may improve oncolytic virotherapy.
Asunto(s)
Carboplatino/administración & dosificación , Vectores Genéticos/administración & dosificación , Viroterapia Oncolítica/métodos , Paclitaxel/administración & dosificación , Neoplasias Pancreáticas/terapia , Adulto , Anciano , Anciano de 80 o más Años , Carboplatino/uso terapéutico , Supervivencia sin Enfermedad , Esquema de Medicación , Femenino , Vectores Genéticos/uso terapéutico , Humanos , Masculino , Orthoreovirus Mamífero 3/genética , Persona de Mediana Edad , Metástasis de la Neoplasia , Virus Oncolíticos/genética , Paclitaxel/uso terapéutico , Neoplasias Pancreáticas/inmunología , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a 5-year survival rate <7% and is ultimately refractory to most treatments. To date, an assessment of immunologic factors relevant to disease has not been comprehensively performed for treatment-naïve patients. We hypothesized that systemic immunologic biomarkers could predict overall survival (OS) in treatment-naïve PDAC patients. EXPERIMENTAL DESIGN: Peripheral blood was collected from 73 patients presenting with previously untreated metastatic PDAC. Extensive immunologic profiling was conducted to assess relationships between OS and the level of soluble plasma biomarkers or detailed immune cell phenotypes as measured by flow cytometry. RESULTS: Higher baseline levels of the immunosuppressive cytokines IL6 and IL10 were strongly associated with poorer OS (P = 0.008 and 0.026, respectively; HR = 1.16 and 1.28, respectively), whereas higher levels of the monocyte chemoattractant MCP-1 were associated with significantly longer OS (P = 0.045; HR = 0.69). Patients with a greater proportion of antigen-experienced T cells (CD45RO(+)) had longer OS (CD4 P = 0.032; CD8 P = 0.036; HR = 0.36 and 0.61, respectively). Although greater expression of the T-cell checkpoint molecule CTLA-4 on CD8(+) T cells was associated with significantly shorter OS (P = 0.020; HR = 1.53), the TIM3 molecule had a positive association with survival when expressed on CD4(+) T cells (P = 0.046; HR = 0.62). CONCLUSIONS: These data support the hypothesis that baseline immune status predicts PDAC disease course and overall patient survival. To our knowledge, this work represents the largest cohort and most comprehensive immune profiling of treatment-naïve metastatic PDAC patients to date. Clin Cancer Res; 22(10); 2565-74. ©2015 AACR.
Asunto(s)
Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/mortalidad , Adenocarcinoma/inmunología , Adenocarcinoma/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Antígeno CTLA-4/inmunología , Carcinoma Ductal Pancreático/inmunología , Carcinoma Ductal Pancreático/mortalidad , Femenino , Humanos , Interleucina-10/inmunología , Interleucina-6/inmunología , Masculino , Persona de Mediana Edad , Monocitos/inmunología , Páncreas/inmunología , Tasa de SupervivenciaRESUMEN
PURPOSE: On the basis of preclinical evidence of synergistic activity between MEK and EGFR inhibitors in pancreatic ductal adenocarcinoma (PDAC), we evaluated the safety and efficacy of selumetinib, a MEK1/2 inhibitor, plus erlotinib in patients with previously treated advanced PDAC. EXPERIMENTAL DESIGN: In this single-arm phase II trial, eligible patients received the combination of erlotinib 100 mg plus selumetinib 100 mg daily in 3-week cycles. Study assessments included measurement of clinical outcomes, with a primary endpoint of overall survival, and exploration of potential molecular predictors of treatment benefit. RESULTS: Forty-six patients were enrolled and received a median of two cycles (range, 1-7). Although no objective responses were observed, 19 patients (41%) showed evidence of stable disease for ≥6 weeks, and 13 of 34 patients (38%) had a CA19-9 decline ≥50%. Median progression-free survival was 1.9 months [95% confidence interval (CI), 1.4-3.3 months], with a median overall survival of 7.3 months (95% CI, 5.2-8.0 months). Common adverse events included rash, diarrhea, and nausea/vomiting. Patients with tumors exhibiting an epithelial phenotype (demonstrated by a high level of E-cadherin expression) were more likely to be sensitive to study treatment. Tumor-derived DNA was detectable in plasma from the majority of patients using next-generation digital DNA sequencing, and its relative abundance correlated with tumor burden. CONCLUSIONS: A therapeutic strategy of dual targeted inhibition of the MEK and EGFR pathways shows modest antitumor activity in pancreatic cancer. Specific molecular subtypes may derive greatest benefit from this combination. Further exploration, both with more potent MEK inhibitors and in molecularly enriched patient subsets, is warranted.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/patología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Terapia Molecular Dirigida , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Adenocarcinoma/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bencimidazoles/administración & dosificación , Biomarcadores , ADN de Neoplasias/sangre , Resistencia a Antineoplásicos , Clorhidrato de Erlotinib/administración & dosificación , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Células Neoplásicas Circulantes , Neoplasias Pancreáticas/mortalidad , RetratamientoRESUMEN
This study was designed to evaluate the safety and feasibility of high-dose interleukin-2 (HD IL-2) followed by sorafenib in patients with metastatic melanoma (MM) and renal cell carcinoma (RCC). Biomarkers relevant to the antitumor effects of IL-2 that may be altered by sorafenib including the percentages of natural T-regulatory cells (Tregs), myeloid-derived suppressor cells (MDSC), and STAT5 phosphorylation (pSTAT5) in T cells were evaluated. We hypothesized that the proposed treatment schedule is feasible and safe and may lead to enhanced tumor response. A phase I dose escalation trial was conducted in patients with either metastatic RCC or MM. HD IL-2 (600,000 IU/kg IV q8h × 8-12 doses) was administered on days 1-5 and 15-19, followed by sorafenib on days 29-82. The sorafenib dose was escalated. The percentage of Tregs, MDSC, and pSTAT5 in T cells were evaluated in peripheral blood by flow cytometry. Twelve of the 18 patients were evaluable for dose-limiting toxicity. No dose-limiting toxicity was observed. The treatment-related toxicity was predictable and did not seem to be additive with this schedule of administration. Partial responses were seen in 3 patients. No significant changes in the percentage of circulating Treg and MDSC were observed, whereas sorafenib did not adversely affect the ability of IL-2 to induce pSTAT5 in T cells. HD IL-2 followed by sorafenib was safe and feasible in patients with MM and RCC and did not adversely affect T-cell signaling through STAT5 in response to IL-2.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Melanoma/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Células Renales/inmunología , Carcinoma de Células Renales/metabolismo , Femenino , Humanos , Interleucina-2/administración & dosificación , Interleucina-2/efectos adversos , Neoplasias Renales/inmunología , Neoplasias Renales/metabolismo , Masculino , Melanoma/inmunología , Melanoma/metabolismo , Persona de Mediana Edad , Niacinamida/administración & dosificación , Niacinamida/efectos adversos , Niacinamida/análogos & derivados , Compuestos de Fenilurea/administración & dosificación , Compuestos de Fenilurea/efectos adversos , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Factor de Transcripción STAT5/metabolismo , Sorafenib , Linfocitos T Reguladores/inmunologíaRESUMEN
PURPOSE: This study evaluated the tolerability, pharmacokinetics, and preliminary antitumor activity of EZN-2208, a water-soluble poly(ethylene) glycol conjugate of SN38. METHODS: Patients with advanced malignancies were enrolled in dose-escalating cohorts (3 + 3 design). EZN-2208 was administered as a 1-h intravenous infusion given weekly for 3 weeks per each 4-week cycle. Doses ranged from 1 to 12 mg/m(2). RESULTS: Forty-one patients received EZN-2208. All patients had received prior cancer therapy (median = 2, range = 1-11). Twenty patients (49 %) had received prior irinotecan, and one patient had received prior topotecan. One patient in the 9-mg/m(2) cohort had dose-limiting toxicity (grade 3 febrile neutropenia), and one patient in the 12-mg/m(2) cohort had grade 3 neutropenia that resulted in the inability to deliver the third dose of EZN-2208. The most commonly reported drug-related adverse events were nausea (51 %), diarrhea (46 %), fatigue (41 %), alopecia (29 %), neutropenia (24 %), and vomiting (22 %). Administration of EZN-2208 results in prolonged exposure to SN38. Stable disease, sometimes prolonged, was observed as best response. CONCLUSIONS: EZN-2208 has an acceptable safety profile in previously treated patients with advanced malignancies. The recommended phase II dose of EZN-2208 administered according to this schedule was 9 mg/m(2).