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1.
Am J Hematol ; 94(1): 118-132, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-30264861

RESUMEN

Immune thrombocytopenia (ITP) is a rare platelet disorder that is often persistent or chronic in adults. Patient management is dependent upon physician judgment and patient preference, given both the rarity of the condition and a paucity of high-quality clinical trial evidence to inform practice guidelines. A systematic literature review was conducted to provide an up-to-date summary of studies evaluating the safety and efficacy/effectiveness of therapies used to treat adults with primary ITP in the second-line setting. Using comprehensive search strings, several medical research databases were queried. Final abstraction was performed on 186 articles. Most (75%) studies were observational in nature; nearly half were conducted in Europe. Splenectomy was the most commonly studied (n = 83, 47%), followed by rituximab (n = 49, 26%) and the thrombopoietin-receptor agonists (TPO-RAs) romiplostim (n = 34, 18%) and eltrombopag (n = 24, 13%). Twelve prospective, randomized controlled trials (RCTs) with a placebo or standard-of-care arm evaluating the safety and efficacy of either rituximab or a TPO-RA were identified and described in detail. These trials provide important information on the safety and efficacy of these treatments, and in the absence of head-to-head data, offer insights on how these therapies compare with one another in treating adult ITP in the second-line setting. This review confirms that for most second-line ITP treatment options, there remains a lack of rigorous evidence derived from RCTs, and for many treatments, there is limited evidence of any kind. The need for additional research to guide treatment choices in this setting and greater use of standardized ITP terminology are highlighted.


Asunto(s)
Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Adulto , Benzoatos/uso terapéutico , Estudios de Casos y Controles , Estudios de Cohortes , Terapia Combinada , Método Doble Ciego , Quimioterapia Combinada , Humanos , Hidrazinas/uso terapéutico , Inmunosupresores/uso terapéutico , Estudios Multicéntricos como Asunto/estadística & datos numéricos , Estudios Observacionales como Asunto/estadística & datos numéricos , Púrpura Trombocitopénica Idiopática/cirugía , Pirazoles/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto/estadística & datos numéricos , Receptores Fc/uso terapéutico , Proteínas Recombinantes de Fusión/uso terapéutico , Rituximab/uso terapéutico , Esplenectomía , Trombopoyetina/uso terapéutico
2.
Cancer Immunol Immunother ; 67(4): 605-613, 2018 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-29327109

RESUMEN

Combination immunotherapies utilizing complementary modalities that target distinct tumor attributes or immunosuppressive mechanisms, or engage different arms of the antitumor immune response, can elicit greater therapeutic efficacy than the component monotherapies. Increasing the number of agents included in a therapeutic cocktail can further increase efficacy, however, this approach poses numerous challenges for clinical translation. Here, a novel platform to simplify combination immunotherapy by covalently linking immunotherapeutic agonists to the costimulatory receptors CD134 and CD137 into a single heterodimeric drug, "OrthomAb", is shown. This reagent not only retains costimulatory T cell activity, but also elicits unique T cell functions that are not programmed by either individual agonist, and preferentially expands effector T cells over Tregs. Finally, in an aggressive melanoma model OrthomAb elicits better therapeutic efficacy compared to the unlinked agonists. This demonstration that two drugs can be combined into one provides a framework for distilling complex combination drug cocktails into simpler delivery platforms.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Inmunoterapia , Melanoma Experimental/tratamiento farmacológico , Receptores OX40/inmunología , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/inmunología , Animales , Diferenciación Celular , Femenino , Activación de Linfocitos , Melanoma Experimental/inmunología , Melanoma Experimental/metabolismo , Ratones , Ratones Endogámicos C57BL , Receptores OX40/antagonistas & inhibidores , Células Tumorales Cultivadas , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/antagonistas & inhibidores
3.
J Immunol ; 195(12): 5816-26, 2015 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-26561553

RESUMEN

The ability of immune-based cancer therapies to elicit beneficial CD8(+) CTLs is limited by tolerance pathways that inactivate tumor-specific CD4 Th cells. A strategy to bypass this problem is to engage tumor-unrelated CD4 Th cells. Thus, CD4 T cells, regardless of their specificity per se, can boost CD8(+) CTL priming as long as the cognate epitopes are linked via presentation on the same dendritic cell. In this study, we assessed the therapeutic impact of engaging tumor-unrelated CD4 T cells during dual costimulation with CD134 plus CD137 that provide help via the above-mentioned classical linked pathway, as well as provide nonlinked help that facilitates CTL function in T cells not directly responding to cognate Ag. We found that engagement of tumor-unrelated CD4 Th cells dramatically boosted the ability of dual costimulation to control the growth of established B16 melanomas. Surprisingly, this effect depended upon a CD134-dependent component that was extrinsic to the tumor-unrelated CD4 T cells, suggesting that the dual costimulated helper cells are themselves helped by a CD134(+) cell(s). Nevertheless, the delivery of therapeutic help tracked with an increased frequency of tumor-infiltrating granzyme B(+) effector CD8 T cells and a reciprocal decrease in Foxp3(+)CD4(+) cell frequency. Notably, the tumor-unrelated CD4 Th cells also infiltrated the tumors, and their deletion several days following initial T cell priming negated their therapeutic impact. Taken together, dual costimulation programs tumor-unrelated CD4 T cells to deliver therapeutic help during both the priming and effector stages of the antitumor response.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Células Dendríticas/inmunología , Inmunoterapia , Melanoma Experimental/inmunología , Receptores OX40/metabolismo , Neoplasias Cutáneas/inmunología , Linfocitos T Citotóxicos/inmunología , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/metabolismo , Animales , Presentación de Antígeno , Linfocitos T CD4-Positivos/inmunología , Diferenciación Celular , Línea Celular , Citocinas/metabolismo , Epítopos de Linfocito T/metabolismo , Activación de Linfocitos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Transgénicos , Receptor Cross-Talk , Escape del Tumor
4.
J Immunother Cancer ; 10(10)2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-36302562

RESUMEN

BACKGROUND: Ivuxolimab (PF-04518600) and utomilumab (PF-05082566) are humanized agonistic IgG2 monoclonal antibodies against OX40 and 4-1BB, respectively. This first-in-human, multicenter, open-label, phase I, dose-escalation/dose-expansion study explored safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of ivuxolimab+utomilumab in patients with advanced solid tumors. METHODS: Dose-escalation: patients with advanced bladder, gastric, or cervical cancer, melanoma, head and neck squamous cell carcinoma, or non-small cell lung cancer (NSCLC) who were unresponsive to available therapies, had no standard therapy available or declined standard therapy were enrolled into five dose cohorts: ivuxolimab (0.1-3 mg/kg every 2 weeks (Q2W)) intravenously plus utomilumab (20 or 100 mg every 4 weeks (Q4W)) intravenously. Dose-expansion: patients with melanoma (n=10) and NSCLC (n=20) who progressed on prior anti-programmed death receptor 1/programmed death ligand-1 and/or anti-cytotoxic T-lymphocyte-associated antigen 4 (melanoma) received ivuxolimab 30 mg Q2W intravenously plus utomilumab 20 mg Q4W intravenously. Adverse events (AEs) were graded per National Cancer Institute Common Terminology Criteria for Adverse Events V.4.03 and efficacy was assessed using Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1 and immune-related RECIST (irRECIST). Paired tumor biopsies and whole blood were collected to assess pharmacodynamic effects and immunophenotyping. Whole blood samples were collected longitudinally for immunophenotyping. RESULTS: Dose-escalation: 57 patients were enrolled; 2 (3.5%) patients with melanoma (0.3 mg/kg+20 mg and 0.3 mg/kg+100 mg) achieved partial response (PR), 18 (31.6%) patients achieved stable disease (SD); the disease control rate (DCR) was 35.1% across all dose levels. Dose-expansion: 30 patients were enrolled; 1 patient with NSCLC achieved PR lasting >77 weeks. Seven of 10 patients with melanoma (70%) and 7 of 20 patients with NSCLC (35%) achieved SD: median (range) duration of SD was 18.9 (13.9-49.0) weeks for the melanoma cohort versus 24.1 (14.3-77.9+) weeks for the NSCLC cohort; DCR (NSCLC) was 40%. Grade 3-4 treatment-emergent AEs were reported in 28 (49.1%) patients versus 11 (36.7%) patients in dose-escalation and dose-expansion, respectively. There were no grade 5 AEs deemed attributable to treatment. Ivuxolimab area under the concentration-time curve increased in a dose-dependent manner at 0.3-3 mg/kg doses. CONCLUSIONS: Ivuxolimab+utomilumab was found to be well tolerated and demonstrated preliminary antitumor activity in selected groups of patients. TRIAL REGISTRATION NUMBER: NCT02315066.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias , Humanos , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Inmunoglobulina G , Neoplasias Pulmonares/tratamiento farmacológico , Melanoma/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos
5.
Res Pract Thromb Haemost ; 5(1): 69-80, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33537531

RESUMEN

BACKGROUND: Thrombopoietin receptor agonists (TPO-RAs) are used to treat primary immune thrombocytopenia (ITP). Some patients have discontinued treatment while maintaining a hemostatic platelet count. OBJECTIVES: To develop expert consensus on when it is appropriate to consider tapering TPO-RAs in ITP, how to taper patients off therapy, how to monitor patients after discontinuation, and how to restart therapy. METHODS: We used a RAND/UCLA modified Delphi panel method. Ratings were completed independently by each expert before and after a meeting. Second-round ratings were used to develop the panel's guidance. The panel was double-blinded: The sponsor and nonchair experts did not know each other's identities. RESULTS: Guidance on when it is appropriate to taper TPO-RAs in children and adults was developed based on patient platelet count, history of bleeding, intensification of treatment, trauma risk, and use of anticoagulants/platelet inhibitors. For example, it is appropriate to taper TPO-RAs in patients who have normal/above-normal platelet counts, have no history of major bleeding, and have not required an intensification of treatment in the past 6 months; it is inappropriate to taper TPO-RAs in patients with low platelet counts. Duration of ITP, months on TPO-RA, or timing of platelet response to TPO-RA did not have an impact on the panel's guidance on appropriateness to taper. Guidance on how to taper patients off therapy, how to monitor patients after discontinuation, and how to restart therapy is also provided. CONCLUSION: This guidance could support clinical decision making and the development of clinical trials that prospectively test the safety of tapering TPO-RAs.

6.
Clin Cancer Res ; 26(10): 2354-2361, 2020 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-32102950

RESUMEN

PURPOSE: The role of plasma-based tumor mutation burden (pTMB) in predicting response to pembrolizumab-based first-line standard-of-care therapy for metastatic non-small cell lung cancer (mNSCLC) has not been explored. EXPERIMENTAL DESIGN: A 500-gene next-generation sequencing panel was used to assess pTMB. Sixty-six patients with newly diagnosed mNSCLC starting first-line pembrolizumab-based therapy, either alone or in combination with chemotherapy, were enrolled (Clinicaltrial.gov identifier: NCT03047616). Response was assessed using RECIST 1.1. Associations were made for patient characteristics, 6-month durable clinical benefit (DCB), progression-free survival (PFS), and overall survival (OS). RESULTS: Of 66 patients, 52 (78.8%) were pTMB-evaluable. Median pTMB was 16.8 mutations per megabase (mut/Mb; range, 1.9-52.5) and was significantly higher for patients achieving DCB compared with no durable benefit (21.3 mut/Mb vs. 12.4 mut/Mb, P = 0.003). For patients with pTMB ≥ 16 mut/Mb, median PFS was 14.1 versus 4.7 months for patients with pTMB < 16 mut/Mb [HR, 0.30 (0.16-0.60); P < 0.001]. Median OS for patients with pTMB ≥ 16 was not reached versus 8.8 months for patients with pTMB < 16 mut/Mb [HR, 0.48 (0.22-1.03); P = 0.061]. Mutations in ERBB2 exon 20, STK11, KEAP1, or PTEN were more common in patients with no DCB. A combination of pTMB ≥ 16 and absence of negative predictor mutations was associated with PFS [HR, 0.24 (0.11-0.49); P < 0.001] and OS [HR, 0.31 (0.13-0.74); P = 0.009]. CONCLUSIONS: pTMB ≥ 16 mut/Mb is associated with improved PFS after first-line standard-of-care pembrolizumab-based therapy in mNSCLC. STK11/KEAP1/PTEN and ERBB2 mutations may help identify pTMB-high patients unlikely to respond. These results should be validated in larger prospective studies.


Asunto(s)
Antineoplásicos Alquilantes/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Mutación , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/administración & dosificación , Antineoplásicos Inmunológicos/administración & dosificación , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/sangre , Carcinoma de Pulmón de Células no Pequeñas/patología , Femenino , Humanos , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Valor Predictivo de las Pruebas , Estudios Prospectivos , Tasa de Supervivencia , Resultado del Tratamiento
7.
Lancet ; 371(9610): 395-403, 2008 Feb 02.
Artículo en Inglés | MEDLINE | ID: mdl-18242413

RESUMEN

BACKGROUND: Chronic immune thrombocytopenic purpura (ITP) is characterised by accelerated platelet destruction and decreased platelet production. Short-term administration of the thrombopoiesis-stimulating protein, romiplostim, has been shown to increase platelet counts in most patients with chronic ITP. We assessed the long-term administration of romiplostim in splenectomised and non-splenectomised patients with ITP. METHODS: In two parallel trials, 63 splenectomised and 62 non-splenectomised patients with ITP and a mean of three platelet counts 30x10(9)/L or less were randomly assigned 2:1 to subcutaneous injections of romiplostim (n=42 in splenectomised study and n=41 in non-splenectomised study) or placebo (n=21 in both studies) every week for 24 weeks. Doses of study drug were adjusted to maintain platelet counts of 50x10(9)/L to 200x10(9)/L. The primary objectives were to assess the efficacy of romiplostim as measured by a durable platelet response (platelet count > or =50x10(9)/L during 6 or more of the last 8 weeks of treatment) and treatment safety. Analysis was per protocol. These studies are registered with ClinicalTrials.gov, numbers NCT00102323 and NCT00102336. FINDINGS: A durable platelet response was achieved by 16 of 42 splenectomised patients given romplostim versus none of 21 given placebo (difference in proportion of patients responding 38% [95% CI 23.4-52.8], p=0.0013), and by 25 of 41 non-splenectomised patients given romplostim versus one of 21 given placebo (56% [38.7-73.7], p<0.0001). The overall platelet response rate (either durable or transient platelet response) was noted in 88% (36/41) of non-splenectomised and 79% (33/42) of splenectomised patients given romiplostim compared with 14% (three of 21) of non-splenectomised and no splenectomised patients given placebo (p<0.0001). Patients given romiplostim achieved platelet counts of 50x10(9)/L or more on a mean of 13.8 (SE 0.9) weeks (mean 12.3 [1.2] weeks in splenectomised group vs 15.2 [1.2] weeks in non-splenectomised group) compared with 0.8 (0.4) weeks for those given placebo (0.2 [0.1] weeks vs 1.3 [0.8] weeks). 87% (20/23) of patients given romiplostim (12/12 splenectomised and eight of 11 non-splenectomised patients) reduced or discontinued concurrent therapy compared with 38% (six of 16) of those given placebo (one of six splenectomised and five of ten non-splenectomised patients). Adverse events were much the same in patients given romiplostim and placebo. No antibodies against romiplostim or thrombopoietin were detected. INTERPRETATION: Romiplostim was well tolerated, and increased and maintained platelet counts in splenectomised and non-splenectomised patients with ITP. Many patients were able to reduce or discontinue other ITP medications. Stimulation of platelet production by romiplostim may provide a new therapeutic option for patients with ITP.


Asunto(s)
Proteínas Portadoras/uso terapéutico , Púrpura Trombocitopénica Trombótica/tratamiento farmacológico , Receptores Fc/uso terapéutico , Adulto , Anciano , Proteínas Portadoras/administración & dosificación , Proteínas Portadoras/efectos adversos , Enfermedad Crónica/tratamiento farmacológico , Método Doble Ciego , Esquema de Medicación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Recuento de Plaquetas , Púrpura Trombocitopénica Trombótica/sangre , Púrpura Trombocitopénica Trombótica/inmunología , Receptores Fc/administración & dosificación , Proteínas Recombinantes de Fusión , Esplenectomía , Trombopoyetina , Resultado del Tratamiento
8.
N Engl J Med ; 355(16): 1672-81, 2006 Oct 19.
Artículo en Inglés | MEDLINE | ID: mdl-17050891

RESUMEN

BACKGROUND: Most current treatments for chronic immune thrombocytopenic purpura (ITP) act by decreasing platelet destruction. In a phase 1-2 study, we administered a thrombopoiesis-stimulating protein, AMG 531, to patients with ITP. METHODS: In phase 1, 24 patients who had received at least one treatment for ITP were assigned to escalating-dose cohorts of 4 patients each and given two identical doses of AMG 531 (0.2 to 10 microg per kilogram of body weight). In phase 2, 21 patients were randomly assigned to receive six weekly subcutaneous injections of AMG 531 (1, 3, or 6 microg per kilogram) or placebo. The primary objective was to assess the safety of AMG 531; the secondary objective was to evaluate platelet counts during and after treatment. RESULTS: No major adverse events that could be attributed directly to AMG 531 occurred during the treatment period; 4 of 41 patients had transient post-treatment worsening of thrombocytopenia. In phase 1, a platelet count that was within the targeted range (50,000 to 450,000 per cubic millimeter) and at least twice the baseline count was achieved in 4 of 12 patients given 3, 6, or 10 mug of AMG 531 per kilogram. Overall, a platelet count of at least 50,000 per cubic millimeter was achieved in 7 of 12 patients, including 3 with counts exceeding 450,000 per cubic millimeter. Increases in the platelet count were dose-dependent; mean peak counts were 163,000, 309,000, and 746,000 per cubic millimeter with 3, 6, and 10 microg of AMG 531 per kilogram [corrected], respectively. In phase 2, the targeted platelet range was achieved in 10 of 16 patients treated with 1 or 3 mug of AMG 531 per kilogram per week for 6 weeks. Mean peak counts were 135,000, 241,000, and 81,000 per cubic millimeter in the groups that received the 1-mug dose, the 3-mug dose, and placebo, respectively. CONCLUSIONS: AMG 531 caused no major adverse events and increased platelet counts in patients with ITP. (ClinicalTrials.gov number, NCT00111475 [ClinicalTrials.gov].).


Asunto(s)
Proteínas Portadoras/administración & dosificación , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Receptores Fc/administración & dosificación , Trombopoyesis/efectos de los fármacos , Corticoesteroides/uso terapéutico , Adulto , Anciano , Anticuerpos/sangre , Proteínas Portadoras/efectos adversos , Proteínas Portadoras/inmunología , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Inyecciones Subcutáneas , Masculino , Persona de Mediana Edad , Recuento de Plaquetas , Púrpura Trombocitopénica Idiopática/sangre , Receptores Fc/inmunología , Proteínas Recombinantes de Fusión , Trombopoyetina/sangre , Trombopoyetina/inmunología
10.
Curr Med Res Opin ; 34(2): 209-216, 2018 02.
Artículo en Inglés | MEDLINE | ID: mdl-28748715

RESUMEN

OBJECTIVE: Immune thrombocytopenia (ITP) is characterized by low platelet counts and a tendency toward increased bleeding and bruising. We aimed to describe bleeding frequency and use of rescue ITP therapy to treat or prevent bleeding in elderly ITP patients in a real-world setting. METHODS: Using Medicare 20% sample data, 2007-2012, we identified elderly (ages ≥67 years) Medicare fee-for-service enrollees diagnosed with primary ITP between 1 January 2009 and 30 September 2012. Bleeding-related episodes (BREs) were defined as ≥1 bleeding event or use of ITP therapies commonly considered for rescue or emergency therapy. BRE rates were examined for the cohort overall, by time since ITP onset, and by splenectomy status. Patients were followed from ITP onset until the earliest of death, disenrollment from fee-for-service coverage, or 31 December 2012. RESULTS: We identified 3007 elderly patients diagnosed with primary ITP (mean [SD] age: 79.6 [7.5] years; 55% female); 2178 (72%) experienced at least one BRE (8867 BREs); 92 (3%) underwent splenectomy. Nearly half of BREs were defined by rescue therapy use alone. The overall rate was 1.72 BREs per patient-year (95% CI; 1.68-1.75); rates were higher during the first 3 months after ITP onset and after splenectomy. CONCLUSION: Elderly ITP patients experienced about two BREs per patient-year after ITP onset. Most patients experienced at least one BRE. These real-world results demonstrate the importance of examining both bleeding and use of rescue or emergency ITP therapy in the assessment of disease burden in elderly patients with ITP.


Asunto(s)
Hemorragia , Púrpura Trombocitopénica Idiopática , Esplenectomía , Anciano , Estudios de Cohortes , Femenino , Hemorragia/diagnóstico , Hemorragia/epidemiología , Hemorragia/etiología , Hemorragia/terapia , Humanos , Masculino , Medicare/estadística & datos numéricos , Recuento de Plaquetas/métodos , Púrpura Trombocitopénica Idiopática/complicaciones , Púrpura Trombocitopénica Idiopática/epidemiología , Estudios Retrospectivos , Esplenectomía/métodos , Esplenectomía/estadística & datos numéricos , Estados Unidos/epidemiología
11.
J Clin Oncol ; 36(32): 3223-3230, 2018 Nov 10.
Artículo en Inglés | MEDLINE | ID: mdl-30265610

RESUMEN

PURPOSE: Tumors may evade immunosurveillance through upregulation of the indoleamine 2,3-dioxygenase 1 (IDO1) enzyme. Epacadostat is a potent and highly selective IDO1 enzyme inhibitor. The open-label phase I/II ECHO-202/KEYNOTE-037 trial evaluated epacadostat plus pembrolizumab, a programmed death protein 1 inhibitor, in patients with advanced solid tumors. Phase I results on maximum tolerated dose, safety, tolerability, preliminary antitumor activity, and pharmacokinetics are reported. PATIENTS AND METHODS: Patients received escalating doses of oral epacadostat (25, 50, 100, or 300 mg) twice per day plus intravenous pembrolizumab 2 mg/kg or 200 mg every 3 weeks. During the safety expansion, patients received epacadostat (50, 100, or 300 mg) twice per day plus pembrolizumab 200 mg every 3 weeks. RESULTS: Sixty-two patients were enrolled and received one or more doses of study treatment. The maximum tolerated dose of epacadostat in combination with pembrolizumab was not reached. Fifty-two patients (84%) experienced treatment-related adverse events (TRAEs), with fatigue (36%), rash (36%), arthralgia (24%), pruritus (23%), and nausea (21%) occurring in ≥ 20%. Grade 3/4 TRAEs were reported in 24% of patients. Seven patients (11%) discontinued study treatment because of TRAEs. No TRAEs led to death. Epacadostat 100 mg twice per day plus pembrolizumab 200 mg every 3 weeks was recommended for phase II evaluation. Objective responses (per Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) occurred in 12 (55%) of 22 patients with melanoma and in patients with non-small-cell lung cancer, renal cell carcinoma, endometrial adenocarcinoma, urothelial carcinoma, and squamous cell carcinoma of the head and neck. The pharmacokinetics of epacadostat and pembrolizumab and antidrug antibody rate were comparable to historical controls for monotherapies. CONCLUSION: Epacadostat in combination with pembrolizumab generally was well tolerated and had encouraging antitumor activity in multiple advanced solid tumors.

12.
Clin Ther ; 39(3): 603-609.e1, 2017 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-28190600

RESUMEN

PURPOSE: We estimated the real-world costs of bleeding-related episodes (BREs) in adults with primary immune thrombocytopenia (ITP). METHODS: This retrospective cohort study used the MarketScan Commercial Claims and Encounters and Medicare Supplemental and Coordination of Benefits databases. We identified adult patients diagnosed with primary ITP between 2007 and 2012, defined by at least 2 outpatient claims separated by ≥30 days or 1 inpatient claim (International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis code for primary ITP [287.31]). BRE was defined according to a combination of diagnosis codes and/or procedure codes indicating bleeding or use of rescue therapies. Costs were estimated using total reimbursed amount received by providers (including out-of-pocket costs and reimbursement from insurance, adjusted to 2015 US dollars). FINDINGS: In 6551 patients, 14,115 BREs were identified, mean (SD) age was 55 (18) years, and 62% of patients were women. Mean total reimbursement per BRE was $6022, with significantly higher mean inpatient ($45,114) versus outpatient ($2150) reimbursements (P < 0.0001). Mean BRE reimbursements were higher in splenectomized patients compared with nonsplenectomized patients ($8365 vs $5858); however, the difference was not statistically significant. Mean reimbursement for BREs associated with bleeding alone was $10,396, and with rescue therapy alone it was $2787. Reimbursement for BREs that included both bleeding and rescue therapy was $11,065. IMPLICATIONS: The real-world reimbursement rates of BREs in adult patients with primary ITP can be substantial, with significantly higher values among patients requiring hospitalization and for those with bleeding events. Additionally, there is a trend toward higher reimbursement rates among splenectomized patients.


Asunto(s)
Hemorragia/economía , Hospitalización/economía , Púrpura Trombocitopénica Idiopática/economía , Adulto , Anciano , Costos y Análisis de Costo , Bases de Datos Factuales , Femenino , Gastos en Salud , Humanos , Clasificación Internacional de Enfermedades , Masculino , Medicare , Persona de Mediana Edad , Estudios Retrospectivos , Estados Unidos
13.
Immunotherapy ; 9(1): 71-82, 2017 01.
Artículo en Inglés | MEDLINE | ID: mdl-28000531

RESUMEN

Recent advances in cancer biology and genetics have fostered precision therapies targeting tumor-specific attributes. Immune-based therapies that elicit cytolytic T cells (CTL) specific for tumor antigens can provide therapeutic benefit to cancer patients, however, cure rates are typically low. This largely results from immunosuppressive mechanisms operating within the tumor microenvironment, many of which inflict metabolic stresses upon CTL. Conversely, immunotherapies can mitigate specific metabolic stressors. For instance, dual costimulation immunotherapy with CD134 (OX40) plus CD137 (4-1BB) agonists appears to mediate tumor control in part by engaging cytokine networks that enable infiltrating CTL to compete for limiting supplies of glucose. Future efforts combining modalities that endow CTL with complimentary metabolic advantages should improve therapeutic efficacies.


Asunto(s)
Antineoplásicos/uso terapéutico , Inmunoterapia Adoptiva/métodos , Neoplasias/terapia , Linfocitos T Citotóxicos/inmunología , Animales , Movimiento Celular , Terapia Combinada , Citocinas/metabolismo , Citotoxicidad Inmunológica , Glucosa/metabolismo , Humanos , Neoplasias/inmunología , Receptores OX40/agonistas , Linfocitos T Citotóxicos/trasplante , Escape del Tumor , Microambiente Tumoral , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/agonistas
14.
Clin Epidemiol ; 8: 231-9, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27382333

RESUMEN

BACKGROUND: Immune thrombocytopenia (ITP) is a rare disorder characterized by low platelet counts and an increased tendency to bleed. The goal of ITP therapy is to treat or prevent bleeding. Actual rates of bleeding are unknown. Clinical trial data may not reflect real-world bleeding rates because of the inclusion of highly refractory patients and more frequent use of rescue therapy. METHODS: We used administrative medical claims data in the US to examine the occurrence of bleeding-related episodes (BREs) - a composite end point including bleeding and/or rescue therapy use - in adults diagnosed with primary ITP (2008-2012). BRE rates were calculated overall and by ITP phase and splenectomy status. Patients were followed from ITP diagnosis until death, disenrollment from the health plan, or June 30, 2013, whichever came first. RESULTS: We identified 6,651 adults diagnosed with primary ITP over the study period (median age: 53 years; 59% female). During 13,064 patient-years of follow-up, 3,768 patients (57%) experienced ≥1 BRE (1.08 BREs per patient-year; 95% confidence interval: 1.06-1.10). The majority (58%) of BREs consisted of rescue therapy use only. Common bleeding types were gastrointestinal hemorrhage, hematuria, ecchymosis, and epistaxis. Intracranial hemorrhage was reported in 74 patients (1%). Just over 7% of patients underwent splenectomy. Newly diagnosed and splenectomized patients had elevated BRE rates. CONCLUSION: We provide current real-world estimates of BRE rates in adults with primary ITP. The majority of ITP patients experienced ≥1 BRE, and over half were defined by rescue therapy use alone. This demonstrates the importance of examining both bleeding and rescue therapy use to fully assess disease burden.

15.
Expert Opin Biol Ther ; 16(5): 655-74, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-26855028

RESUMEN

INTRODUCTION: Monoclonal antibodies (mAbs) targeting checkpoint inhibitors have demonstrated clinical benefit in treating patients with cancer and have paved the way for additional immune-modulating mAbs such as those targeting costimulatory receptors. The full clinical utility of these agents, however, is hampered by immune-related adverse events (irAEs) that can occur during therapy. AREAS COVERED: We first provide a general overview of tumor immunity, followed by a review of the two major classes of immunomodulatory mAbs being developed as cancer therapeutics: checkpoint inhibitors and costimulatory receptor agonists. We then discuss therapy-associated adverse events. Finally, we describe in detail the mechanisms driving their therapeutic activity, with an emphasis on interactions between antibody fragment crystallizable (Fc) domains and Fc receptors (FcR). EXPERT OPINION: Given that Fc-FcR interactions appear critical in facilitating the ability of immunomodulatory mAbs to elicit both therapeutically useful as well as adverse effects, the engineering of mAbs that can effectively engage their targets while limiting interaction with FcRs might represent a promising future avenue for developing the next generation of immune-enhancing tumoricidal agents with increased safety and retention of efficacy.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Inmunomodulación , Neoplasias/terapia , Animales , Puntos de Control del Ciclo Celular/efectos de los fármacos , Receptores Coestimuladores e Inhibidores de Linfocitos T/metabolismo , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Humanos , Neoplasias/inmunología
16.
Lung Cancer ; 87(3): 220-5, 2015 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-25601485

RESUMEN

Oncogenic driver mutations have emerged as major treatment targets for molecular therapies in a variety of cancers. HER2 positivity has been well-studied in breast cancer, but its importance is still being explored in non-small cell lung cancer (NSCLC). Laboratory methods for assessment of HER2 positivity in NSCLC include immunohistochemistry (IHC) for protein overexpression, fluorescent in situ hybridization (FISH) for gene amplification, and next generation sequencing (NGS) for gene mutations. The prognostic and predictive significance of these tests remain to be validated, with an emerging association between HER2 gene mutations and response to HER2 targeted therapies. Despite the assay used to determine the HER2 status of lung tumors, all patients with advanced HER2 positive lung adenocarcinoma should be evaluated for treatment with targeted agents. Several clinical approaches for inclusion of these drugs into patient treatment plans exist, but there is no defined algorithm specific to NSCLC.


Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Terapia Molecular Dirigida , Receptor ErbB-2/antagonistas & inhibidores , Antineoplásicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Amplificación de Genes , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidad , Mutación , Pronóstico , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Transducción de Señal/efectos de los fármacos
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