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In 2021, the Food and Drug Administration Oncology Center of Excellence announced Project Optimus focusing on dose optimization for oncology drugs. The Methodology for the Development of Innovative Cancer Therapies (MDICT) Taskforce met to review and discuss the optimization of dosage for oncology trials and to develop a practical guide for oncology phase I trials. Defining a single recommended phase II dose based on toxicity may define doses that are neither the most effective nor the best tolerated. MDICT recommendations address the need for robust non-clinical data which are needed to inform trial design, as well as an expert team including statisticians and pharmacologists. The protocol must be flexible and adaptive, with clear definition of all endpoints. Health authorities should be consulted early and regularly. Strategies such as randomization, intrapatient dose escalation, and real-world eligibility criteria are encouraged whereas serial tumor sampling is discouraged in the absence of a strong rationale and appropriately validated assay. Endpoints should include consideration of all longitudinal toxicity. The phase I dose escalation trial should define the recommended dose range for later testing in randomized phase II trials, rather than a single recommended phase II dose, and consider scenarios where different populations may require different dosages. The adoption of these recommendations will improve dosage selection in early clinical trials of new anticancer treatments and ultimately, outcomes for patients.
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Antineoplásicos , Neoplasias , Humanos , Antineoplásicos/efectos adversos , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , Relación Dosis-Respuesta a Droga , Oncología Médica , Neoplasias/tratamiento farmacológico , Ensayos Clínicos Controlados Aleatorios como Asunto , Proyectos de Investigación , Terapias en Investigación/métodosRESUMEN
Introduction Selumetinib (AZD6244, ARRY-142886) is a potent inhibitor of MEK1/2, thereby inhibiting phosphorylation of ERK2. We investigated the toxicity and the recommended phase II dose of the combination of selumetinib with two platinum based first line chemotherapy combinations in non-small cell lung cancer. Methods This was a phase I trial of escalating doses of selumetinib with carboplatin (AUC 6), paclitaxel (200 mg/m2) (cohort 1) or pemetrexed (500 mg/m2) and cisplatin (75 mg/m2) (cohort 2) in patients with chemotherapy naïve, advanced or metastatic NSCLC. Patients enrolled on cohort 2 had non-squamous histology. Dose escalation of selumetinib proceeded using a 3 + 3 design: 50 mg b.i.d. days 2-19 (dose level 1); 75 mg b.i.d. days 2-19 (dose level 2); and 75 mg b.i.d. continuously. Adverse events were evaluated using CTC AE v4 and response by RECIST 1.1. Results Thirty-nine patients were enrolled (cohort 1 n = 16; cohort 2, n = 23). There were no dose limiting toxicities in either cohort and the recommended phase II dose for both regimens was standard doses of carboplatin, paclitaxel or pemetrexed and cisplatin with continuous selumetinib at a dose of 75 mg b.i.d. Most adverse events were grade 1 or 2 and were predominantly diarrhea, nausea, stomatitis, peripheral edema, neutropenia, and skin rash. Response rate was 37.5% for cohort 1 and 30.4% for cohort 2. Conclusion Selumetinib at a dose of 75 mg b.i.d continuously can be safely combined with paclitaxel and carboplatin or pemetrexed and cisplatin in patients with advanced or metastatic NSCLC. This trial provided the dose for the regimens used in a randomized phase II trial in NSCLC (CCTG IND.219).
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Bencimidazoles/administración & dosificación , Carboplatino/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/secundario , Cisplatino/administración & dosificación , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Pulmonares/patología , Metástasis Linfática , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Paclitaxel/administración & dosificación , Pemetrexed/administración & dosificación , Pronóstico , Distribución TisularRESUMEN
The Methodology for the Development of Innovative Cancer Therapies task force considered aspects of the design and conduct of early studies of combinations of immunotherapy agents during their 2018 meeting. The task force defined the relevant data to justify combination clinical trials, which includes a robust hypothesis for the combination, pre-clinical data with evidence of efficacy and an understanding of the pharmacodynamics effects of each agent, and ideally evidence of single agent activity. Evaluation of pharmacodynamic biomarkers is critical in early phase combination trials, and should be incorporated into trial objectives and go/no-go decisions. The task force also identified the need to develop assessment tools and end points that capture the unique patterns of tumour responses to immunotherapy, including pseudoprogression and hyperprogression. At least one additional tumour measurement before baseline and an early CT scan (at 4 weeks for example) would help define the incidence of hyperprogression, although a common definition is needed. Finally, the task force highlighted substantial redundancy and inefficiency in the combination immunotherapy space, and recommended the adoption of innovative trial designs.
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Ensayos Clínicos como Asunto/normas , Inmunoterapia/métodos , Inmunoterapia/normas , Neoplasias/terapia , Guías de Práctica Clínica como Asunto/normas , Pautas de la Práctica en Medicina/normas , Proyectos de Investigación/normas , Investigación Biomédica , Humanos , Neoplasias/inmunología , Selección de Paciente , Microambiente TumoralRESUMEN
BACKGROUND: Pelareorep, a serotype 3 reovirus, has demonstrated preclinical and early clinical activity in breast cancer and synergistic cytotoxic activity with microtubule targeting agents. This multicentre, randomized, phase II trial was undertaken to evaluate the efficacy and safety of adding pelareorep to paclitaxel for patients with metastatic breast cancer (mBC). METHODS: Following a safety run-in of 7 patients, 74 women with previously treated mBC were randomized either to paclitaxel 80 mg/m2 intravenously on days 1, 8, and 15 every 4 weeks plus pelareorep 3 × 1010 TCID50 intravenously on days 1, 2, 8, 9, 15, and 16 every 4 weeks (Arm A) or to paclitaxel alone (Arm B). Primary endpoint was progression-free survival (PFS). Secondary endpoints were objective response rate, overall survival (OS), circulating tumour cell counts, safety, and exploratory correlative analyses. All comparisons used a two-sided test at an alpha level of 20%. Survival analyses were adjusted for prior paclitaxel. RESULTS: Final analysis was performed after a median follow-up of 29.5 months. Pelareorep was well tolerated. Patients in Arm A had more favourable baseline prognostic variables. Median adjusted PFS (Arm A vs B) was 3.78 mo vs 3.38 mo (HR 1.04, 80% CI 0.76-1.43, P = 0.87). There was no difference in response rate between arms (P = 0.87). Median OS (Arm A vs B) was 17.4 mo vs 10.4 mo (HR 0.65, 80% CI 0.46-0.91, P = 0.1). CONCLUSIONS: This first, phase II, randomized study of pelareorep and paclitaxel in previously treated mBC did not show a difference in PFS (the primary endpoint) or RR. However, there was a significantly longer OS for the combination. Further exploration of this regimen in mBC may be of interest.
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Neoplasias de la Mama/tratamiento farmacológico , Orthoreovirus Mamífero 3/genética , Viroterapia Oncolítica/métodos , Paclitaxel/administración & dosificación , Adulto , Anciano , Neoplasias de la Mama/patología , Neoplasias de la Mama/virología , Canadá , Terapia Combinada , Supervivencia sin Enfermedad , Femenino , Humanos , Persona de Mediana Edad , Metástasis de la Neoplasia , Pronóstico , Receptor ErbB-2RESUMEN
Background: The expression of programmed death (PD) ligand 1 (PD-L1) protein expression assessed by immunohistochemistry (IHC) has been correlated with response and survival benefit from anti-PD-1/PD-L1 immune checkpoint inhibitor therapies in advanced non-small cell lung carcinoma (NSCLC). The efficacy of several agents appears correlated with PD-L1 expression. It remains controversial whether PD-L1 is prognostic in NSCLC. We assessed the prognostic value of PD-L1 IHC and its predictive role for adjuvant chemotherapy in early stage NSCLC. Patients and methods: Tumor sections from three pivotal adjuvant chemotherapy trials (IALT, JBR.10, CALGB 9633) using the E1L3N antibody were studied in this pooled analysis. PD-L1 staining intensity and percentage in both tumor cells (TCs) and immune cells (ICs) were scored by two pathologists. The average or consensus PD-L1 expression levels across intensities and/or percent cells stained were correlated with clinicopathological and molecular features, patient survivals and potential benefit of adjuvant chemotherapy. Results: Results from 982 patients were available for analysis. Considering staining at any intensities for overall PD-L1 expression, 314 (32.0%), 204 (20.8%) and 141 (14.3%) tumor samples were positive for PD-L1 staining on TCs using cut-offs at ≥1%, ≥10% and ≥25%, respectively. For PD-L1 expressing ICs, 380 (38.7%), 308 (31.4%) and 148 (15.1%) were positive at ≥ 1%, ≥10% and 25% cut-offs, respectively. Positive PD-L1 was correlated with squamous histology, intense lymphocytic infiltrate, and KRAS but not with TP53 mutation. EGFR mutated tumors showed statistically non-significant lower PD-L1 expression. PD-L1 expression was neither prognostic with these cut-offs nor other exploratory cut-offs, nor were predictive for survival benefit from adjuvant chemotherapy. Conclusions: PD-L1 IHC is not a prognostic factor in early stage NSCLC patients. It is also not predictive for adjuvant chemotherapy benefit in these patients.
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Antígeno B7-H1/biosíntesis , Biomarcadores de Tumor/análisis , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Neoplasias Pulmonares/metabolismo , Antígeno B7-H1/análisis , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Quimioterapia Adyuvante , Humanos , Inmunohistoquímica , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/mortalidad , PronósticoRESUMEN
BACKGROUND: Chemotherapy (CT) combined with radiotherapy is the standard treatment of 'limited-stage' small-cell lung cancer. However, controversy persists over the optimal timing of thoracic radiotherapy and CT. MATERIALS AND METHODS: We carried out a meta-analysis of individual patient data in randomized trials comparing earlier versus later radiotherapy, or shorter versus longer radiotherapy duration, as defined in each trial. We combined the results from trials using the stratified log-rank test to calculate pooled hazard ratios (HRs). The primary outcome was overall survival. RESULTS: Twelve trials with 2668 patients were eligible. Data from nine trials comprising 2305 patients were available for analysis. The median follow-up was 10 years. When all trials were analysed together, 'earlier or shorter' versus 'later or longer' thoracic radiotherapy did not affect overall survival. However, the HR for overall survival was significantly in favour of 'earlier or shorter' radiotherapy among trials with a similar proportion of patients who were compliant with CT (defined as having received 100% or more of the planned CT cycles) in both arms (HR 0.79, 95% CI 0.69-0.91), and in favour of 'later or longer' radiotherapy among trials with different rates of CT compliance (HR 1.19, 1.05-1.34, interaction test, P < 0.0001). The absolute gain between 'earlier or shorter' versus 'later or longer' thoracic radiotherapy in 5-year overall survival for similar and for different CT compliance trials was 7.7% (95% CI 2.6-12.8%) and -2.2% (-5.8% to 1.4%), respectively. However, 'earlier or shorter' thoracic radiotherapy was associated with a higher incidence of severe acute oesophagitis than 'later or longer' radiotherapy. CONCLUSION: 'Earlier or shorter' delivery of thoracic radiotherapy with planned CT significantly improves 5-year overall survival at the expense of more acute toxicity, especially oesophagitis.
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Cisplatino/uso terapéutico , Quimioterapia , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/radioterapia , Terapia Combinada , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Modelos de Riesgos Proporcionales , Ensayos Clínicos Controlados Aleatorios como Asunto , Carcinoma Pulmonar de Células Pequeñas/patologíaRESUMEN
Efficient intravenous delivery is the greatest single hurdle, with most nanotherapeutics frequently found to be unstable in the harsh conditions of the bloodstream. In the case of nanotherapeutics for gene delivery, viral vectors are often avidly recognized by both the innate and the adaptive immune systems. So, most modern delivery systems have benefited from being coated with hydrophilic polymers. Self-assembling delivery systems can achieve both steric and lateral stabilization following surface coating, endowing them with much improved systemic circulation properties and better access to disseminated targets; similarly, gene delivery viral vectors can be 'stealthed' and their physical properties modulated by surface coating. Polymers that start degrading under acidic conditions are increasingly investigated as a pathway to trigger the release of drugs or genes once the carrier reaches a slightly acidic tumor environment or after the carrier has been taken up by cells, resulting in the localization of the polymer in acidic endosomes and lysosomes. Advances in the design of acid-degradable drug and gene delivery systems have been focused and discussed in this article with stress placed on HPMA-based copolymers. We designed a system that is able to "throw away" the polymer coat after successful transport of the vector into a target cell. Initial biological studies were performed and it was demonstrated that this principle is applicable for real adenoviral vectors. It was shown that the transfection ability of coated virus at pH 7.4 is 75 times lower then transfection at pH 5.4.
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Química Farmacéutica , Técnicas de Transferencia de Gen , Nanomedicina/métodos , Adenoviridae/genética , Endosomas , Vectores Genéticos , Humanos , Concentración de Iones de Hidrógeno , Lisosomas , Microesferas , Polímeros , TransfecciónRESUMEN
BACKGROUND: A subgroup of sarcomas is characterized by defining chromosomal translocations, creating fusion transcription factor oncogenes. Resultant fusion oncoproteins associate with chromatin-modifying complexes containing histone deacetylases (HDAC), and lead to epigenetic transcriptional dysregulation. HDAC inhibitors were shown to be effective in vitro, reversing gene repression by these complexes, restoring PTEN expression and apoptosis via the PI3K/Akt/mTOR pathway. PATIENTS AND METHODS: SB939 is an oral inhibitor of classes 1 and 2 HDAC. Eligible patients with recurrent or metastatic translocation-associated sarcoma (TAS) by local pathology were treated with 60 mg/day every other day for 3 of 4 weeks. Central pathology review was conducted with fusion oncogenes characterized, and HDAC2 expression correlated with efficacy in pre-specified methods. RESULTS: Twenty-two patients were treated with a median of 2 cycles. Fourteen patients were assessable for response with confirmed specific chromosomal translocations; 8 had a best response of stable disease (SD) (median duration 5.4 months) with no confirmed objective responses. The 3-month progression-free survival (PFS) rate was 49%. Among those with HDAC2 score ≥5, 7/10 had SD, versus 0/3 with HDAC2 score <5. SB939 was considered as well tolerated with <10% patients experienced ≥grade 3 toxicity. CONCLUSION: This study was stopped prematurely due to prolonged unavailability of SB939. No objective responses were seen. Although the observed SD in HDAC2 high patients was interesting, due to the small sample size, no definitive conclusion can be drawn about the efficacy of SB939 in this patient population. CLINICAL TRIAL: NCT01112384.
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Antineoplásicos/uso terapéutico , Bencimidazoles/uso terapéutico , Biomarcadores de Tumor/genética , Histona Desacetilasa 2/antagonistas & inhibidores , Inhibidores de Histona Desacetilasas/uso terapéutico , Recurrencia Local de Neoplasia , Sarcoma/tratamiento farmacológico , Translocación Genética , Administración Oral , Adulto , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/provisión & distribución , Bencimidazoles/administración & dosificación , Bencimidazoles/efectos adversos , Bencimidazoles/provisión & distribución , Canadá , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Esquema de Medicación , Terminación Anticipada de los Ensayos Clínicos , Femenino , Histona Desacetilasa 2/metabolismo , Inhibidores de Histona Desacetilasas/administración & dosificación , Inhibidores de Histona Desacetilasas/efectos adversos , Inhibidores de Histona Desacetilasas/provisión & distribución , Humanos , Masculino , Persona de Mediana Edad , Sarcoma/enzimología , Sarcoma/secundario , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: AT7519 is a small-molecular inhibitor of multiple cyclin-dependent kinases (CDKs). It shows encouraging anti-cancer activity against multiple cell lines and in tumour xenografts. This phase I study was conducted to evaluate the safety and tolerability of AT7519 given as 1-h intravenous infusion on days 1, 4, 8 and 11 every 3 weeks. METHODS: Patients with advanced refractory solid tumours or non-Hodgkin's lymphoma were enroled. Dose escalation occurred in a 3+3 manner based on toxicity assessment. Pharmacokinetic samples were collected after first AT7519 infusion, whereas pharmacodynamics (PD) samples were obtained in selected patients. RESULTS: Thirty-four patients were enroled, and 32 received study treatments over 4 dose levels. Dose-limiting toxicities included mucositis, febrile neutropenia, rash, fatigue and hypokalemia. The recommended phase II dose (RP2D) was 27.0 mg m(-2). Ten of 19 patients evaluable for efficacy had stable disease as the best response (median duration: 3.3 months; range: 2.5 to 11.1 months). There was no clinically significant QTc prolongation. There was an apparent dose proportional increase in AT7519 exposure. The PD studies showed reduction in markers of CDK activity in selected patients' skin biopsies post treatment. CONCLUSIONS: AT7519, when administered as an intravenous infusion on days 1, 4, 8 and 11, was well tolerated. The RP2D is 27.0 mg m(-2). At this dose level, plasma AT7519 concentrations were above the biologically active concentrations, and preliminary anti-cancer activity was observed in patients. This dosing schedule is being further evaluated in multiple phase II studies.
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Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Piperidinas/administración & dosificación , Inhibidores de Proteínas Quinasas/administración & dosificación , Pirazoles/administración & dosificación , Adulto , Anciano , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/enzimología , Neoplasias/metabolismo , Piperidinas/efectos adversos , Piperidinas/farmacocinética , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/farmacocinética , Pirazoles/efectos adversos , Pirazoles/farmacocinéticaRESUMEN
Intravenous (i.v.) delivery of therapeutic viruses to human patients exposes virus particles to the potentially neutralising environment of the human bloodstream, where many components of the innate and adaptive immune system provide a formidable barrier to virus infection of target cells. Here we assess the haemocompatibility of ColoAd1, an oncolytic adenovirus currently undergoing clinical assessment for treatment of disseminated cancer by i.v. delivery. Compared with the commonly used serotype Ad5, ColoAd1 (which has a capsid derived from Ad11p) showed only minor inhibition of oncolytic activity by pooled human serum or washed human blood cells, with the amount of ColoAd1 required to kill cancer cells in vitro (the IC50) increasing <10-fold. However, some virus-blood interactions are concentration- and context-dependent, requiring study in whole, undiluted, human blood. ColoAd1 showed <50-fold increases in the IC50 in whole blood from most donors, whereas the activity of Ad5 was ablated. Extrapolating these findings to the clinical situation indicates that ColoAd1 would 'breakthrough' neutralisation in some patients receiving as few as 10(10) ColoAd1 particles i.v., and in most patients receiving doses of 10(12) or above, well within the achievable dose range.
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Adenoviridae/inmunología , Inmunidad Innata , Neoplasias/terapia , Viroterapia Oncolítica , Virus Oncolíticos/inmunología , Adenoviridae/crecimiento & desarrollo , Administración Intravenosa , Humanos , Ensayo de Materiales , Neoplasias/sangre , Neoplasias/inmunología , Neoplasias/virología , Virus Oncolíticos/genéticaRESUMEN
Immune thrombocytopenia (ITP) is an autoimmune disorder of unknown aetiology, characterised by an isolated low platelet count in the absence of other identifiable causes. Genes influencing activation of the immune system have been identified as influencing predisposition. Killer cell immunoglobulin-like receptors (KIR) control T-cell and natural killer (NK) cell function via inhibitory and activating signalling pathways. The inhibitory KIR2DL3, KIR3DL2 and KIR3DL1 are up-regulated in the T-cells of patients with ITP in remission relative to those with active disease, and an association of KIR2DS2 and KIR2DL2 with ITP has also been reported. No comprehensive KIR analysis in ITP has been reported. We performed genotyping of all currently known KIR genes using sequence specific primer polymerase chain reaction (SSP-PCR) on a cohort of 83 adult patients with ITP (chronic/persistent or relapsed primary ITP identified by defined criteria) and 106 age matched healthy white volunteers. Non-white patients were not included in the analysis. There was an over-representation of KIR2DS3 (known to be in linkage disequilibrium with KIR2DS2 and 2DL2) and under-representation of KIR2DS5 (also protective against other immune mediated disorders) in adult ITP [odds ratio (OR) = 0.16, confidence interval (CI) 0.08-0.32, P < 0.001]. By multivariable binary logistic regression to adjust for age, sex and the effects of other KIR genes, the presence of KIR2DS2/2DL2 with KIR2DS5 abrogated the risk of KIR2DS2/2DL2 and the protective benefit of KIR2DS5. Further studies are required to establish the mechanistic basis for these observations and their potential impact on ITP therapy.
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Púrpura Trombocitopénica Idiopática/inmunología , Púrpura Trombocitopénica Idiopática/prevención & control , Receptores KIR/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Intervalos de Confianza , Femenino , Frecuencia de los Genes/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Antígenos HLA-C/genética , Haplotipos/genética , Humanos , Desequilibrio de Ligamiento/genética , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Púrpura Trombocitopénica Idiopática/genética , Receptores KIR/metabolismo , Adulto JovenRESUMEN
INTRODUCTION: This randomised double-blind placebo-controlled study evaluated the addition of cediranib, an inhibitor of vascular endothelial growth factor receptors 1-3, to standard carboplatin/paclitaxel chemotherapy in advanced non-small cell lung cancer. METHODS: Eligible patients received paclitaxel (200mg/m(2)) and carboplatin (area under the concentration time curve 6) intravenously every 3 weeks. Daily oral cediranib/placebo 20mg was commenced day 1 of cycle 1 and continued as monotherapy after completion of 4-6 cycles of chemotherapy. The primary end-point of the study was overall survival (OS). The trial would continue to full accrual if an interim analysis (IA) for progression-free survival (PFS), performed after 170 events of progression or death in the first 260 randomised patients, revealed a hazard ratio (HR) for PFS of ⩽ 0.70. RESULTS: The trial was halted for futility at the IA (HR for PFS 0.89, 95% confidence interval [CI] 0.66-1.20, p = 0.45). A final analysis was performed on all 306 enrolled patients. The addition of cediranib increased response rate ([RR] 52% versus 34%, p = 0.001) but did not significantly improve PFS (HR 0.91, 95% CI 0.71-1.18, p = 0.49) or OS (HR 0.94, 95% CI 0.69-1.30, p=0.72). Cediranib patients had more grade 3 hypertension, diarrhoea and anorexia. CONCLUSIONS: The addition of cediranib 20mg daily to carboplatin/paclitaxel chemotherapy increased RR and toxicity, but not survival.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Carboplatino/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Paclitaxel/administración & dosificación , Quinazolinas/administración & dosificación , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Progresión de la Enfermedad , Método Doble Ciego , Esquema de Medicación , Femenino , Humanos , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Placebos , Análisis de Supervivencia , Adulto JovenRESUMEN
PURPOSE: AT9283 is a potent inhibitor of the mitotic regulators, Aurora-kinases A and B, and has shown anti-tumor activity in patients with solid and haematological malignancies. This phase I study assessed safety, tolerability, pharmacokinetic and pharmacodynamic properties of AT9283. PATIENTS AND METHODS: Patients with advanced, incurable solid tumors or non-Hodgkin's lymphoma received AT9283 as a continuous 24-hour infusion on days 1, 8 of a 21-day cycle. A 3 + 3 dose escalation design was used with a starting dose of 1.5 mg/m(2)/day. Pharmacokinetic samples were collected from all patients on cycle one, and pharmacodynamic samples were collected from 4 patients at the recommended phase II dose (RP2D). RESULTS: 35 patients were evaluable for toxicity and 32 were evaluable for response. AT9283 was well tolerated, with main toxicities being reversible dose-related fatigue, gastrointestinal disturbance, anemia, lymphocytopenia and neutropenia. The dose limiting toxicities were febrile neutropenia (two patients) and neutropenia with grade 3 infection (1 patient) at 47 mg/m(2)/day (established as the maximum tolerated dose). The RP2D was 40 mg/m(2)/day. Pharmacokinetic analyses showed AT9283 appeared to follow linear kinetics, with a mean elimination half-life of 8.2 h. Pharmacodynamic analyses showed no consistent or significant changes, but trends suggested evidence of AT9283 inhibition and anti-proliferative activity. One patient had partial response and four patients experienced RECIST stable disease (median 2.6 months). CONCLUSION: In this study, AT9283 was well tolerated. The RP2D is 40 mg/m(2)/day on days 1, 8 of a 21-day cycle. Ongoing AT9283 trials will assess efficacy and safety in solid and haematological cancers.
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Antineoplásicos/administración & dosificación , Bencimidazoles/administración & dosificación , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/administración & dosificación , Urea/análogos & derivados , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Bencimidazoles/efectos adversos , Bencimidazoles/farmacocinética , Esquema de Medicación , Femenino , Histonas/metabolismo , Humanos , Infusiones Intravenosas , Antígeno Ki-67/metabolismo , Masculino , Persona de Mediana Edad , Neoplasias/metabolismo , Antígeno Nuclear de Célula en Proliferación/metabolismo , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/farmacocinética , Piel/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Urea/administración & dosificación , Urea/efectos adversos , Urea/farmacocinéticaRESUMEN
OBJECTIVES: As the bioavailability of erlotinib is dependent on gastric pH, an increase in gastric pH via the concurrent use of gastric acid suppressive medications (AS) may reduce its bioavailability and efficacy. We retrospectively analyzed the BR.21 trial database to pragmatically evaluate the impact of AS use on the median plasma drug levels of erlotinib, adverse events and outcome of participants. METHODS: Monthly median plasma levels of erlotinib were compared between participants utilizing AS and those who did not using a Wilcoxon test. Interaction p-value for AS users and AS non-users was performed using a multivariate Cox model with a time-dependent covariate for AS use. Grade 2 adverse events were compared using Fisher's Exact Test. RESULTS: The median plasma erlotinib level was not significantly different between AS users and AS non-users, and AS use did not appear to incur a negative impact on PFS or OS (Interaction p-values: PFS p = 0.16; OS p = 0.81). AS users receiving erlotinib had a similar frequency of rash (50.5% vs. 42.0%, p = 0.08) and a statistically higher rate of diarrhea (27.9% vs. 15.6%, p = 0.001) compared to AS non-users. In addition, AS users had higher rates of infections (erlotinib arm: 33.7% vs. 20.0%, p < 0.0001; placebo arm: 22.7% vs. 10.8%, p = 0.02). CONCLUSION: This retrospective analysis found that the co-administration of AS and erlotinib did not appear to have a significant impact on the median plasma drug levels or outcome.
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Antineoplásicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Omeprazol/farmacología , Inhibidores de la Bomba de Protones/farmacología , Quinazolinas/farmacología , Antiulcerosos/farmacología , Antiulcerosos/uso terapéutico , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Ensayos Clínicos Fase III como Asunto , Supervivencia sin Enfermedad , Método Doble Ciego , Interacciones Farmacológicas , Receptores ErbB/antagonistas & inhibidores , Clorhidrato de Erlotinib , Femenino , Humanos , Estimación de Kaplan-Meier , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Omeprazol/uso terapéutico , Inhibidores de la Bomba de Protones/uso terapéutico , Quinazolinas/farmacocinética , Quinazolinas/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Ranitidina/farmacología , Ranitidina/uso terapéutico , Estudios Retrospectivos , Úlcera Gástrica/tratamiento farmacológico , Resultado del TratamientoRESUMEN
A breast cancer-selective oncolytic adenovirus was engineered to express antagonists of vascular endothelial growth factor (VEGF) and Notch signaling to combine direct anticancer activity with disruption of tumor-associated angiogenesis. Replication of the parental virus, AdEHE2F, is stimulated by estrogen receptor (ER), E2F1 and hypoxia, and it mediates selective lysis of breast cancer cells in vitro and in vivo. Here, we encoded soluble Flt-1 (sFlt1) and soluble Dll4 (sDll4) under control of the E3 promoter. sFlt1 (the extra-cellular domain of VEGF receptor 1) binds VEGF-A and inhibits stimulation of VEGFR2, decreasing angiogenic stimulus. Conversely, sDll4 (the extracellular domain of Delta-like 4) antagonizes Notch signaling to prevent endothelial maturation. We hypothesized that these agents might show additive or synergistic activity. In vitro, sFlt1 inhibited endothelial cell proliferation and sprouting, whereas sDll4 increased the number of vascular branchpoints. In ER-positive ZR75.1 tumors in vivo AdEHE2F showed the potent direct virotherapy with no augmentation owing to sFlt1 or sDll4; however, in ER-negative MDA-231 tumors efficacy was enhanced by encoding sFlt1 or sDll4, with survival time extending to double that of controls. There was also a dramatic decrease in the total number of tumour blood vessels, as well as the number of perfused vessels, suggesting that improved efficacy reflects combined anti-tumour and anti-vascular effects.
Asunto(s)
Neoplasias de la Mama/terapia , Embolización Terapéutica/métodos , Viroterapia Oncolítica/métodos , Proteínas Adaptadoras Transductoras de Señales , Adenoviridae/genética , Adenoviridae/metabolismo , Adenoviridae/fisiología , Animales , Neoplasias de la Mama/irrigación sanguínea , Neoplasias de la Mama/patología , Neoplasias de la Mama/virología , Proteínas de Unión al Calcio , Procesos de Crecimiento Celular/fisiología , Terapia Combinada , Femenino , Expresión Génica , Células Endoteliales de la Vena Umbilical Humana , Humanos , Inmunohistoquímica , Péptidos y Proteínas de Señalización Intercelular/biosíntesis , Péptidos y Proteínas de Señalización Intercelular/genética , Ratones , Ratones Desnudos , Neovascularización Patológica/terapia , Receptores de Estrógenos/metabolismo , Transducción de Señal , Transgenes , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptor 1 de Factores de Crecimiento Endotelial Vascular/biosíntesis , Receptor 1 de Factores de Crecimiento Endotelial Vascular/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: BR.21 is a double-blind, placebo-controlled trial of second-/third-line erlotinib in stage IIIB/IV non-small cell lung cancer patients. Predictive and prognostic analyses of epidermal growth factor receptor (EGFR), ABCG2, and AKT1 genetic polymorphisms were performed. METHODS: Two hundred forty-two patients were genotyped for EGFR-216G>T (EGFR216), EGFR-191C>A (EGFR191), EGFR intron 1 CA-dinucleotide-repeat (CADR), ABCG2+421C>A (ABCG2), and AKT1-SNP4G>A (AKT1). Cox proportional hazard and logistic regression models compared genotypes with overall survival (OS), progression-free survival (PFS), and presence/absence of skin toxicity. RESULTS: Prognostic evaluation was based on the placebo arm: patients carrying at least one CADR long allele (>16 repeats) had a trend toward worse PFS: the adjusted hazard ratio was 1.7 (95% confidence interval [CI]: 1.0-3.0; p = 0.07). EGFR216, EGFR191, ABCG2, and AKT1 were not prognostic. Polymorphisms were not predictive for erlotinib effect (OS/PFS): no treatment-polymorphism interactions were demonstrated. Individuals carrying the rare T/T genotype of EGFR216 had an adjusted odds ratio of 8.8 (95% CI: 1.1-72; p = 0.04) of developing skin toxicity; no other significant polymorphic relationships with skin toxicity were found. CONCLUSIONS: In contrast to previous publications, carrying shorter alleles of the EGFR CADR polymorphism was not predictive of OS or PFS. EGFR216 homozygous variants were associated with greater skin toxicity from erlotinib.
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Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Receptores ErbB/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Polimorfismo Genético/genética , Quinazolinas/uso terapéutico , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 , Transportadoras de Casetes de Unión a ATP/genética , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/genética , Antineoplásicos/uso terapéutico , ADN de Neoplasias/genética , Método Doble Ciego , Clorhidrato de Erlotinib , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/genética , Farmacogenética , Reacción en Cadena de la Polimerasa , Pronóstico , Proteínas Proto-Oncogénicas c-akt/genéticaRESUMEN
BACKGROUND: The IALT, JBR.10, ANITA and Cancer and Leukemia Group B 9633 trials compared adjuvant chemotherapy with observation for patients with resected non-small-cell lung cancer (R-NSCLC). Data from the metastatic setting suggest high tumor class III beta-tubulin (TUBB3) expression is a determinant of insensitivity to tubulin-targeting agents (e.g. vinorelbine, paclitaxel). In 265 patients from JBR.10 (vinorelbine-cisplatin versus observation), high TUBB3 was an adverse prognostic factor and was associated (nonsignificantly) with 'greater' survival benefit from chemotherapy. We explored this further in additional patients from JBR.10 and the other three trials. PATIENTS AND METHODS: TUBB3 immunohistochemical staining was scored for 1149 patients on the four trials. The original JBR.10 cut-off scores were used to classify tumors as TUBB3 high or low. The prognostic and predictive value of TUBB3 on disease-free survival (DFS) and overall survival (OS) was assessed by Cox models stratified by trial and adjusted for clinical factors. RESULTS: High TUBB3 expression was prognostic for OS [hazard ratio (HR)=1.27 (1.07-1.51), P=0.008) and DFS [HR=1.30 (1.11-1.53), P=0.001). TUBB3 was not predictive of a differential treatment effect [interaction P=0.20 (OS), P=0.23 (DFS)]. Subset analysis (n=420) on vinorelbine-cisplatin gave similar results. CONCLUSIONS: The prognostic effect of high TUBB3 expression in patients with R-NSCLC has been validated. We were unable to confirm a predictive effect for TUBB3.
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Biomarcadores de Tumor/análisis , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Tubulina (Proteína)/biosíntesis , Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Quimioterapia Adyuvante , Supervivencia sin Enfermedad , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidad , Pronóstico , Modelos de Riesgos Proporcionales , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
The development of novel strategies to enhance gene expression from therapeutic vectors may prove advantageous for complementation gene therapy. This applies to therapeutic expression of the low-density lipoprotein receptor (LDLR) gene to treat familial hypercholesterolaemia (FH), where appropriate gene regulation could enhance therapeutic effect. We have previously reported that LDLR genomic DNA expression vectors can be regulated in vivo by pravastatin. In the current study, we investigated whether targeted knockdown of the mevalonate pathway in conjunction with LDLR delivery would lead to enhanced LDLR transgene expression and improved phenotype recovery. We demonstrated here that knockdown of HMG CoA reductase (HMGCR) by up to 70% using small interfering RNAs (siRNAs) led to a significant increase in binding and internalisation of LDL particles in vitro in mouse and human cells. In vivo co-injection of LDLR promoter luciferase expression plasmids with siRNAs or microRNA (miRNA) expression vectors targeting mouse Hmgcr led to at least a 10-fold increase in luciferase expression. Injection of Ldlr(-/-) mice with pLDLR-LDLR expression plasmids led to a significant reduction in plasmid LDL cholesterol, which was further enhanced by co-injection with miRNA expression vectors targeted to mouse Hmgcr. Our data suggest that targeted knockdown of HMGCR may enhance gene therapy outcomes for FH.
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Hidroximetilglutaril-CoA Reductasas/genética , Hiperlipoproteinemia Tipo II/terapia , Interferencia de ARN , Receptores de LDL/genética , Animales , Línea Celular , LDL-Colesterol/metabolismo , Femenino , Técnicas de Silenciamiento del Gen , Terapia Genética/métodos , Humanos , Hígado/metabolismo , Ratones , MicroARNsRESUMEN
OBJECTIVE: : This study examines risk factors for persistent cervical intraepithelial neoplasia (CIN) and examines whether human papillomavirus (HPV) testing predicts persistent lesions. MATERIALS AND METHODS: : Women with histologically diagnosed CIN 1 or CIN 2 (n = 206) were followed up every 3 months without treatment. Human papillomavirus genotyping, plasma levels of ascorbic acid, and red blood cell folate levels were obtained. Cervical biopsy at 12 months determined the presence of CIN. Relative risk (RR) was estimated by log-linked binomial regression models. RESULTS: : At 12 months, 70% of CIN 1 versus 54% of CIN 2 lesions spontaneously regressed (p < .001). Levels of folate or ascorbic acid were not associated with persistent CIN at 12 months. Compared with HPV-negative women, those with multiple HPV types (RRs ranged from 1.68 to 2.17 at each follow-up visit) or high-risk types (RRs range = 1.74-2.09) were at increased risk for persistent CIN; women with HPV-16/18 had the highest risk (RRs range = 1.91-2.21). Persistent infection with a high-risk type was also associated with persistent CIN (RRs range = 1.50-2.35). Typing for high-risk HPVs at 6 months only had a sensitivity of 46% in predicting persistence of any lesions at 12 months. CONCLUSIONS: : Spontaneous regression of CIN 1 and 2 occurs frequently within 12 months. Human papillomavirus infection is the major risk factor for persistent CIN. However, HPV testing cannot reliably predict persistence of any lesion.