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1.
Invest New Drugs ; 33(3): 710-9, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-25902900

RESUMEN

The primary objective of this phase I study of LY2780301, a dual p70 S6 kinase and Akt inhibitor, was to determine the recommended phase II dose as a single agent in patients with advanced cancer. Secondary objectives included safety, pharmacokinetic, and pharmacodynamic analyses, and co-clinical analyses in Avatar models. Eligible patients received total daily doses of LY2780301 100-500 mg, given orally as a single dose or divided into 2 doses for 28-day cycles. Dose escalation followed 3 + 3 design. The primary pharmacodynamic endpoint was inhibition of S6 assessed by skin and tumor biopsy. Thirty-two patients were treated. Common toxicities possibly related to treatment included constipation (19 %), fatigue (13 %), nausea (9 %), and diarrhea (9 %). Grade 3/4 toxicities potentially related to treatment were anemia (n = 2), increased alanine aminotransferase/aspartate aminotransferase (ALT) (n = 1), and increased gamma-glutamyl transpeptidase (GGT) (n = 1). One patient experienced best overall response of prolonged stable disease for 6 cycles. Plasma exposures of LY2780301 exceeded predicted efficacious exposures, but were not dose proportional. Among patients receiving 500 mg daily >50 % exhibited reduced S6 in skin biopsies at Day 8 of treatment, but the effect was not maintained. Plasma concentrations of LY2780301 and/or its metabolites were not correlated with S6 expression in the epidermis. There was minimal antitumor activity against the model, CRC 019. Avatar models showed minimal pharmacodynamic effects consistent with the observed antitumor effects. This study suggests a dose of LY2780301 500 mg QD for future studies.


Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas Quinasas S6 Ribosómicas 70-kDa/antagonistas & inhibidores , Adulto , Anciano , Animales , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Femenino , Humanos , Masculino , Ratones Desnudos , Persona de Mediana Edad , Metástasis de la Neoplasia , Estadificación de Neoplasias , Neoplasias/enzimología , Neoplasias/patología , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/farmacocinética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Quinasas S6 Ribosómicas 70-kDa/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , Adulto Joven
2.
Invest New Drugs ; 32(5): 955-68, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-24942404

RESUMEN

LY2603618 is an inhibitor of checkpoint kinase 1 (CHK1), an important regulator of the DNA damage checkpoints. Preclinical experiments analyzed NCI-H2122 and NCI-H441 NSCLC cell lines and in vitro/in vivo models treated with pemetrexed and LY2603618 to provide rationale for evaluating this combination in a clinical setting. Combination treatment of LY2603618 with pemetrexed arrested DNA synthesis following initiation of S-phase in cells. Experiments with tumor-bearing mice administered the combination of LY2603618 and pemetrexed demonstrated a significant increase of growth inhibition of NCI-H2122 (H2122) and NCI-H441 (H441) xenograft tumors. These data informed the clinical assessment of LY2603618 in a seamless phase I/II study, which administered pemetrexed (500 mg/m(2)) and cisplatin (75 mg/m(2)) and escalating doses of LY2603618: 130-275 mg. Patients were assessed for safety, toxicity, and pharmacokinetics. In phase I, 14 patients were enrolled, and the most frequently reported adverse events included fatigue, nausea, pyrexia, neutropenia, and vomiting. No DLTs were reported at the tested doses. The systemic exposure of LY2603618 increased in a dose-dependent manner. Pharmacokinetic parameters that correlate with the maximal pharmacodynamic effect in nonclinical xenograft models were achieved at doses ≥240 mg. The pharmacokinetics of LY2603618, pemetrexed, and cisplatin were not altered when used in combination. Two patients achieved a confirmed partial response (both non-small cell lung cancer), and 8 patients had stable disease. LY2603618 administered in combination with pemetrexed and cisplatin demonstrated an acceptable safety profile. The recommended phase II dose of LY2603618 was 275 mg.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias/tratamiento farmacológico , Adulto , Anciano , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/sangre , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Línea Celular Tumoral , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Cisplatino/sangre , Cisplatino/farmacocinética , ADN/metabolismo , Femenino , Glutamatos/administración & dosificación , Glutamatos/efectos adversos , Glutamatos/sangre , Glutamatos/farmacocinética , Guanina/administración & dosificación , Guanina/efectos adversos , Guanina/análogos & derivados , Guanina/sangre , Guanina/farmacocinética , Humanos , Masculino , Ratones Desnudos , Persona de Mediana Edad , Neoplasias/sangre , Neoplasias/patología , Pemetrexed , Compuestos de Fenilurea/administración & dosificación , Compuestos de Fenilurea/efectos adversos , Compuestos de Fenilurea/sangre , Compuestos de Fenilurea/farmacocinética , Pirazinas/administración & dosificación , Pirazinas/efectos adversos , Pirazinas/sangre , Pirazinas/farmacocinética , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
3.
Chemotherapy ; 54(4): 268-73, 2008.
Artículo en Inglés | MEDLINE | ID: mdl-18667816

RESUMEN

BACKGROUND: Cytotoxic anti-tumor agents like methotrexate or cyclophosphamide have been used in the treatment of autoimmune diseases although the exact mechanism of their immunomodulatory function is unclear. By contrast, molecularly targeted anti-tumor agents, such as the serine/threonine kinase inhibitor enzastaurin, have not been evaluated for treatments other than cancer. METHODS: Blood was sampled from patients with metastatic thyroid cancer treated with enzastaurin followed by the combination treatment of enzastaurin and the anti-folate pemetrexed. During this sequential treatment, blood was drawn every 14 days to monitor changes in the lymphocyte population. RESULTS: We observed that enzastaurin monotherapy reduced the number of HLA-DR-expressing lymphocytes. No signs of infection were observed in any patient. CONCLUSION: Our findings suggest an immunomodulatory effect of enzastaurin in addition to the anti-tumor effect.


Asunto(s)
Antineoplásicos/uso terapéutico , Antígenos HLA-DR/inmunología , Indoles/uso terapéutico , Linfocitos/efectos de los fármacos , Linfocitos/inmunología , Neoplasias de la Tiroides/tratamiento farmacológico , Neoplasias de la Tiroides/inmunología , Humanos , Inmunofenotipificación , Recuento de Linfocitos , Linfocitos/citología , Metástasis de la Neoplasia/tratamiento farmacológico , Metástasis de la Neoplasia/inmunología , Metástasis de la Neoplasia/patología , Neoplasias de la Tiroides/patología
4.
Eur J Cancer ; 103: 88-97, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-30218977

RESUMEN

BACKGROUND: LY3039478 is an orally bioavailable selective Notch inhibitor. This phase 1a/b trial evaluated the safety, pharmacokinetics and antitumour activity of LY3039478 in patients with soft tissue sarcoma (STS) and gastrointestinal stromal tumour (GIST). METHODS: This multipart, phase 1 trial enrolled patients with refractory advanced/metastatic STS and GIST, measurable disease, Eastern Cooperative Oncology Group ≤1 and baseline tumour tissue. Eligible patients received LY3039478 50mg/75 mg three times per week, for 28-day cycle until disease progression. Safety assessments were based on Common Terminology Criteria for Adverse Events, V4.0. Tumour responses were assessed using Response Evaluation Criteria in Solid Tumours (RECIST 1.1) and Choi criteria. Primary objectives were to confirm the recommended phase 2 dose of LY3039478 and document the antitumour activity. Secondary objectives were safety and toxicity, pharmacokinetics (PK), progression-free survival (PFS) and overall survival (OS). RESULTS: Sixty-nine patients were enrolled and received LY3039478 (27 males, 42 females; median age 58, range 31-78). 16/37 (43%) patients with evaluable samples were positive for Notch 1 immunohistochemistry. Per RECIST 1.1, in leiomyosarcoma (LMS) group (n = 29), ten (36%) had stable disease (SD) and one (4%) had unconfirmed partial response (PR). In GIST group (n = 13), four (31%) had SD. Among other STS subtypes (n = 27), one patient with angiosarcoma had unconfirmed PR, six (21%) had SD. Median PFS was 1.9 months (95% confidence interval:1.6-3.3) for LMS, 1.9 months (0.3-6.1) for GIST and 1.7 months (1.4-2.2) for other STS groups. Median OS was 7.4 months (4.3-non-evaluable [NE]) for LMS, 16.5 months (3.9-16.5) for GIST and 5.6 months (3.4-NE) for other STS groups. Most common adverse events were diarrhoea, nausea, vomiting and decreased appetite. CONCLUSION: LY3039478 suggested a modest clinical activity in patients with STS and GIST and had a manageable safety profile.


Asunto(s)
Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Tumores del Estroma Gastrointestinal/genética , Sarcoma/tratamiento farmacológico , Sarcoma/genética , Neoplasias de los Tejidos Blandos/tratamiento farmacológico , Neoplasias de los Tejidos Blandos/genética , Femenino , Tumores del Estroma Gastrointestinal/patología , Humanos , Masculino , Receptores Notch/antagonistas & inhibidores , Sarcoma/patología , Neoplasias de los Tejidos Blandos/patología , Resultado del Tratamiento
5.
Lung Cancer ; 56(1): 115-23, 2007 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-17196704

RESUMEN

The epigenetic inactivation of genes plays an important role in lung cancer. We have investigated the methylation status of the promoter region of seven genes (APC1A, DAPK, FHIT, p14(ARF), p16(INK4a), RARbeta, RASSF1A) in serum DNA of NSCLC patients. The objective of our study was to reveal the influence of such alterations on overall survival. Blood samples were drawn pretherapeutically. Genomic DNA was purified from serum, treated with sodium bisulfite and hypermethylation was detected by a nested methylation-specific PCR in a group of 92 patients with histologically confirmed stage IIIB and IV NSCLC. All patients received gemcitabine first-line alone or in combination with other drugs. The vast majority (n=87) showed at least one epigenetic alteration. The methylation frequencies of individual genes varied between 25.9 and 47.3%. The hypermethylation status of none of the genes had a significant influence on median overall survival of the total population. In contrast, patients with a methylated RASSF1A gene who showed a partial response survived significantly longer (33.6+/-10.4 month) compared to those with a wild-type allele (12.9+/-4.7 month, P=0.0045). This effect became even more pronounced in combination with p14(ARF) (P=0.0004). This difference was not seen in patients with stable or progressive disease. A multivariate analysis confirmed that RASSF1A methylation was an independent prognostic factor. Our results show that the hypermethylation frequency of single genes and the accumulation of epigenetic alterations in individual samples of NSCLC patients may vary considerably. Molecular parameters such as hypermethylation of RASSF1A or p14(ARF) may be useful prognostic markers in subpopulations.


Asunto(s)
Biomarcadores de Tumor/sangre , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Desoxicitidina/análogos & derivados , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Proteínas Supresoras de Tumor/sangre , Adulto , Anciano , Distribución de Chi-Cuadrado , Metilación de ADN , Cartilla de ADN , Desoxicitidina/uso terapéutico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Regiones Promotoras Genéticas , Modelos de Riesgos Proporcionales , Gemcitabina
6.
Lung Cancer ; 54(1): 109-16, 2006 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-16893590

RESUMEN

Hypermethylation occurs frequently in neoplastic cells and affects tumorigenesis. Malignant mesothelioma is an aggressive cancer developing in the thoracic cavity and patients have a rather bad prognosis. Our goal was to determine epigenetic alterations of a series of genes and to analyse the potential correlation of such changes with overall survival. We have analysed the methylation status of the promoter region of nine genes in serum DNA of mesothelioma patients by a nested methylation-specific PCR. Modest methylation frequencies were detected for APC1A (14.3%), RASSF1A (19.5%) and DAPK (20.0%) while hypermethylation of E-cadherin (71.4%) and FHIT (78.0%) occurred at a high incidence. Intermediate values were seen for p16(INK4a) (28.2%), APC1B (32.5%), p14(ARF) (44.2%) and RARbeta (55.8%). The methylation status of none of the single genes significantly influenced prognosis. In contrast, combining RARbeta with either DAPK or RASSF1A showed a significantly shorter overall survival of those patients who had both genes methylated compared to those with only one or no epigenetic alteration (P=0.025 and 0.040, respectively). Similarly, the combination of all three genes revealed a worse prognosis for patients with double or triple methylations compared to the group which had only one or no gene methylated (P=0.028). Our results support the idea that the prognostic value of a combination of epigenetic alterations is superior to the impact of an individual gene alone on overall survival.


Asunto(s)
Proteínas Reguladoras de la Apoptosis/genética , Proteínas Quinasas Dependientes de Calcio-Calmodulina/genética , Metilación de ADN , Mesotelioma/genética , Neoplasias Pleurales/genética , Receptores de Ácido Retinoico/genética , Proteínas Supresoras de Tumor/genética , Adulto , Anciano , Biomarcadores de Tumor/sangre , Proteínas Quinasas Asociadas a Muerte Celular , Epigénesis Genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Mesotelioma/patología , Persona de Mediana Edad , Neoplasias Pleurales/patología , Reacción en Cadena de la Polimerasa , Valor Predictivo de las Pruebas , Pronóstico , Regiones Promotoras Genéticas , Tasa de Supervivencia
7.
Eur J Cancer ; 44(16): 2444-52, 2008 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-18804996

RESUMEN

This non-randomised Phase-I-study determined recommended dose (RD) and dose-limiting toxicities (DLTs) of four different schedules combining pemetrexed (P), gemcitabine (G) and cisplatin (C). Patients 18 years with locally advanced/metastatic cancer were enrolled. Doses were escalated for one 21-d (q3w; PGC d1, G d8) and three 28-d schedules (q4wA: PG d1, GC d15; q4wB: GC d1, PC d15; q4wC: PGC d1+15). Starting doses were P 400/500 mg/m(2) (q3w/q4w), G 800 mg/m(2) and C 40 mg/m(2). Sixty patients were enroled (n=12/14/30/4 for q3w/q4wA/q4wB/q4wC). Common cancers included head and neck (n=19), prostate (n=7), sarcoma (n=5) and stomach (n=5). Thirteen patients experienced DLTs, most frequently fatigue (n=4) and neutropenia (n=3). Schedule q4wB reached the highest doses (P 600 mg/m(2) d15; G 1250 mg/m(2) d1; C 70 mg/m(2)d1+15). There were no CRs, 11 PRs and 25 SDs (n=47). The PGC-combination was feasible. The recommended schedule for subsequent studies would be 1250 mg/m(2) G and 60 mg/m(2) C on d1, followed by 500 mg/m(2) P and 60 mg/m(2) C on d15.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias/tratamiento farmacológico , Adolescente , Adulto , Anciano , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Desoxicitidina/análogos & derivados , Estudios de Factibilidad , Femenino , Glutamatos/administración & dosificación , Glutamatos/efectos adversos , Guanina/administración & dosificación , Guanina/efectos adversos , Guanina/análogos & derivados , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Pemetrexed , Resultado del Tratamiento , Adulto Joven , Gemcitabina
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