RESUMEN
BACKGROUND: Molecular alterations of the PI3K and Ras pathways often occur in human cancer. In this trial, the pharmacokinetics, toxicity, and activity of two drugs inhibiting these pathways-everolimus and sorafenib-were investigated. METHODS: Thirteen patients with progressing solid tumors were treated with everolimus and sorafenib, according to a 3+3 scheme. Patients were selected on the basis of immunohistochemical expression of tumor molecular targets, including phospho-AKT, -p70S6K, and -ERK1/2. RESULTS: The daily recommended dose identified was 2.5 mg of everolimus and 600 mg of sorafenib. Dose-limiting toxicities included grade 3 asthenia and hand-foot skin reaction. No grade 4 adverse events were observed. The most frequent grade 3 toxicities were hypophosphatemia (30.8%), alanine aminotransferase level increase, asthenia, and anorexia (14%). No pharmacokinetic interactions were identified between everolimus and sorafenib. Of 12 evaluable patients, we observed 2 partial responses, with greater than 10% shrinkage in an additional 5 patients. Objective responses were observed in one patient with a thymoma and in one patient with a lung adenocarcinoma. Tumor shrinkage that did not qualify as a partial response was seen in an abdominal leiomyosarcoma and in adenoid cystic carcinomas. CONCLUSION: The combination of everolimus and sorafenib is safe. The tumor activity observed in different tumor types could be the result of the combined action of these drugs as well as the molecular selection of the treated population. Further research is warranted to better investigate drugs simultaneously blocking the PI3K and the Ras pathways and to refine patient selection.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Niacinamida/análogos & derivados , Compuestos de Fenilurea/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Sirolimus/análogos & derivados , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Everolimus , Quinasas MAP Reguladas por Señal Extracelular/antagonistas & inhibidores , Humanos , Niacinamida/efectos adversos , Niacinamida/farmacocinética , Niacinamida/uso terapéutico , Compuestos de Fenilurea/efectos adversos , Compuestos de Fenilurea/farmacocinética , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/farmacocinética , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Sirolimus/efectos adversos , Sirolimus/farmacocinética , Sirolimus/uso terapéutico , Sorafenib , Proteínas ras/antagonistas & inhibidoresRESUMEN
This study: (i) investigated the in vitro cytotoxicity and mode of action of lurbinectedin (PM01183) and Zalypsis® (PM00104) compared with trabectedin in cell lines deficient in specific mechanisms of repair, (ii) evaluated their in vivo antitumor activity against a series of murine tumors and human xenografts. The antiproliferative activity, the DNA damage and the cell cycle perturbations induced by the three compounds on tumor lines were very similar. Nucleotide Excision Repair (NER) deficient cells were approximately fourfold more resistant to trabectedin, lurbinectedin and Zalypsis®. Cells deficient in non-homologous end joining (NHEJ), MRN complex and translesion synthesis (TLS) were slightly more sensitive to the three compounds (approximately fivefold) while cells deficient in homologous recombination (HR) were markedly more sensitive (150-200-fold). All three compounds showed a good antitumor activity in several in vivo models. Lurbinectedin and trabectedin had a similar pattern of antitumor activity in murine tumors and in xenografts, whereas Zalypsis® appeared to have a distinct spectrum of activity. The fact that no relationship whatsoever was found between the in vitro cytotoxic potency and the in vivo antitumor activity, suggests that in addition to direct cytotoxic mechanisms other host-mediated effects are involved in the in vivo pharmacological effects.
Asunto(s)
Carbolinas/farmacología , Daño del ADN/efectos de los fármacos , Reparación del ADN/efectos de los fármacos , Dioxoles/farmacología , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Neoplasias/tratamiento farmacológico , Tetrahidroisoquinolinas/farmacología , Alcaloides/farmacología , Animales , Antineoplásicos Alquilantes/farmacología , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Pollos , Citometría de Flujo , Humanos , Técnicas In Vitro , Ratones , Ratones Endogámicos C57BL , Ratones Desnudos , Estructura Molecular , Neoplasias/patología , Trabectedina , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
OBJECTIVE: Malignant peripheral nerve sheath tumors (MPNST) are aggressive sarcomas characterized by high recurrence rates and early metastases. These tumors arise more frequently within neurofibromatosis type 1 (NF1) and present with resistance during standard chemotherapy leading to increased mortality and morbidity in those patients. In vitro all-trans retinoic acid (ATRA) and MEK inhibitors (MEKi) were shown to inhibit tumor proliferation, especially when applied in combination. Therefore, we established a nude mouse model to investigate if treatment of xenografts derived from NF1 associated S462 and T265 MPNST cells respond to ATRA and the MEKi PD0325901. RESULTS: We demonstrated that human NF1 associated MPNST derived from S462 but not T265 cells form solid subcutaneous tumors in Foxn1 nude mice but not in Balb/c, SHO or Shorn mice. We verified a characteristic staining pattern of human MPNST xenografts by immunohistochemistry. Therapeutic effects of ATRA and/or MEKi PD0325901 on growth of S462 MPNST xenografts in Foxn1 nude mice were not demonstrated in vitro, as we did not observe significant suppression of MPNST growth compared with placebo treatment.
Asunto(s)
Antineoplásicos/farmacología , Benzamidas/farmacología , Difenilamina/análogos & derivados , Neoplasias de la Vaina del Nervio/tratamiento farmacológico , Sarcoma/tratamiento farmacológico , Animales , Difenilamina/farmacología , Xenoinjertos , Humanos , Ratones , Ratones Desnudos , NeurilemomaRESUMEN
Importance: There are no medical interventions for the orphan disease CYLD cutaneous syndrome (CCS). Transcriptomic profiling of CCS skin tumors previously highlighted tropomyosin receptor kinases (TRKs) as candidate therapeutic targets. Objective: To investigate if topical targeting of TRK with an existing topical TRK inhibitor, pegcantratinib, 0.5% (wt/wt), is safe and efficacious in CCS. Design, Setting, and Participants: A phase 1b open-label safety study, followed by a phase 2a within-patient randomized (by tumor), double-blind, placebo-controlled trial (the Tropomyosin Receptor Antagonism in Cylindromatosis [TRAC] trial). The setting was a single-center trial based at a tertiary dermatogenetics referral center for CCS (Royal Victoria Infirmary, Newcastle, United Kingdom). Patients who had germline mutations in CYLD or who satisfied clinical diagnostic criteria for CCS were recruited between March 1, 2015, and July 1, 2016. Interventions: In phase 1b, patients with CCS applied pegcantratinib for 4 weeks to a single skin tumor. In phase 2a, allocation of tumors was to either receive active treatment on the right side and placebo on the left side (arm A) or active treatment on the left side and placebo on the right side (arm B). Patients were eligible if they had 10 small skin tumors, with 5 matched lesions on each body side; patients were randomized to receive active treatment (pegcantratinib) to one body side and placebo to the other side once daily for 12 weeks. Main Outcomes and Measures: The primary outcome measure was the number of tumors meeting the criteria for response in a prespecified critical number of pegcantratinib-treated tumors. Secondary clinical outcome measures included an assessment for safety of application, pain in early tumors, and compliance with the trial protocol. Results: In phase 1b, 8 female patients with a median age of 60 years (age range, 41-80 years) were recruited and completed the study. None of the participants experienced any adverse treatment site reactions. Three patients reported reduced pain in treated tumors. In phase 2a (15 patients [13 female; median age, 51 years], with 150 tumors), 2 tumors treated with pegcantratinib achieved the primary outcome measure of response compared with 6 tumors treated with placebo. The primary prespecified number of responses was not met. The incidence of adverse events was low. Conclusions and Relevance: In this study, pegcantratinib, 0.5% (wt/wt), applied once daily appeared to be well tolerated and to penetrate the tumor tissue; however, the low tumor drug concentrations demonstrated are likely to account for the lack of response. Dose-escalation studies to assess the maximal tolerated dose may be beneficial in future studies of CCS. Trial Registration: isrctn.org Identifier: ISRCTN75715723.
Asunto(s)
Carcinoma Adenoide Quístico/tratamiento farmacológico , Enzima Desubiquitinante CYLD/genética , Compuestos Heterocíclicos de 4 o más Anillos/administración & dosificación , Inhibidores de Proteínas Quinasas/administración & dosificación , Neoplasias Cutáneas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Adenoide Quístico/genética , Carcinoma Adenoide Quístico/patología , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Mutación de Línea Germinal , Compuestos Heterocíclicos de 4 o más Anillos/efectos adversos , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Humanos , Masculino , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/farmacología , Receptor trkA/antagonistas & inhibidores , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Resultado del Tratamiento , Reino UnidoRESUMEN
AIM: SRA737 is an orally active small-molecule inhibitor of checkpoint kinase 1 being investigated in an oncology setting. A HPLC-MS/MS method for quantifying plasma concentrations of SRA737 was validated. METHODS & RESULTS: Sample preparation involved protein precipitation with acetonitrile following addition of 13C15N-deuterated SRA737 as internal standard. A rapid and selective method was fully validated across a range of 5-20,000 ng/ml, exhibiting good sensitivity, overall precision (expressed as coefficient of variation) ≤8.0% and accuracy 96-102%. Consistently high recovery was observed, with no matrix effect and a lower limit of quantitation of 5 ng/ml. CONCLUSION: A novel method for analyzing SRA737 in human plasma has been validated and is now being utilized for quantification of SRA737 in a Phase I trial.
Asunto(s)
Análisis Químico de la Sangre/métodos , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/antagonistas & inhibidores , Cromatografía Líquida de Alta Presión/métodos , Compuestos Heterocíclicos de 4 o más Anillos/sangre , Inhibidores de Proteínas Quinasas/sangre , Espectrometría de Masas en Tándem/métodos , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Humanos , Límite de Detección , Modelos Lineales , Inhibidores de Proteínas Quinasas/farmacologíaRESUMEN
AIM: Pegcantratinib is a mini-PEGylated K252a derivative, under clinical evaluation as an anticancer agent acting through inhibition of the tropomyosin receptor kinase. A method for quantifying pegcantratinib in skin tumor biopsies of patients was required to determine tumor drug penetration. METHODS & RESULTS: A sensitive and PEGylated molecule specific HPLC-MS/MS method coupled with in-source collision-induced dissociation was developed. The method exhibited excellent precision (coefficient of variation ≤8.5%), accuracy in the range 95-102%, high and consistent recovery and no matrix effect. The assay was linear across a range of 1-500 ng/ml, with a limit of quantitation of 2.5 ng/ml. CONCLUSION: We have developed and validated a method for analyzing pegcantratinib in human tumor biopsies, with the approach successfully applied to clinical trial samples.
Asunto(s)
Carbazoles/análisis , Cromatografía Liquida/métodos , Inhibidores Enzimáticos/análisis , Alcaloides Indólicos/análisis , Polietilenglicoles/química , Neoplasias Cutáneas/tratamiento farmacológico , Espectrometría de Masa por Ionización de Electrospray/métodos , Espectrometría de Masas en Tándem/métodos , Carbazoles/farmacología , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , Inhibidores Enzimáticos/farmacología , Humanos , Alcaloides Indólicos/farmacología , Neoplasias Cutáneas/metabolismoRESUMEN
The fibroblast growth factor receptor (FGFR) pathway has been implicated both as an escape mechanism from anti-angiogenic therapy and as a driver oncogene in different tumor types. Lucitanib is a small molecule inhibitor of vascular endothelial growth factor (VEGF) receptors 1 to 3 (VEGFR1 to 3), platelet derived growth factor α/ß (PDGFRα/ß) and FGFR1-3 tyrosine kinases and has demonstrated activity in a phase I/II clinical study, with objective RECIST responses in breast cancer patients with FGFR1 or FGF3/4/19 gene amplification, as well as in patients anticipated to benefit from anti-angiogenic agents. We report here the in vitro and in vivo antitumor activity of lucitanib in experimental models with or without FGFR1/2 amplification or mutations. In cell assays, lucitanib potently inhibited the growth of tumor cell lines with amplified FGFR1 or mutated/amplified FGFR2. In all xenograft models studied, lucitanib demonstrated marked tumor growth inhibition due to potent inhibition of angiogenesis. Notably, in two lung cancer models with FGFR1 amplification, the antitumor efficacy was higher, suggesting that the simultaneous inhibition of VEGF and FGF receptors in FGFR1 dependent tumors can be therapeutically advantageous. Similar antitumor activity was observed in FGFR2 wild-type and amplified or mutated xenograft models. Pharmacokinetic studies showed lucitanib plasma concentrations in the micro/sub-micromolar range demonstrated drug accumulation following repeated lucitanib administration.
Asunto(s)
Amplificación de Genes , Mutación , Naftalenos/farmacología , Quinolinas/farmacología , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genética , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/genética , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Modelos Animales de Enfermedad , Resistencia a Antineoplásicos/genética , Femenino , Dosificación de Gen , Humanos , Concentración 50 Inhibidora , Ratones , Inhibidores de Proteínas Quinasas/farmacología , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Trabectedin is an anticancer agent registered for the second-line treatment of soft tissue sarcoma and ovarian cancer. No preclinical data are available on its tumor distribution, so a method for quantification in neoplastic tissues is required. METHODS/RESULTS: We validated an LC-MS/MS assay determining the recovery, sensitivity, linearity, precision and accuracy in mouse tumor and liver samples. The limit of quantification was 0.10 ng/ml with a curve range of 0.10-3.00 ng/ml (accuracy 96.1-102.1%). Inter-day precision and accuracy of QCs were 6.0-8.2 and 97.0-102.6% respectively. The method was applied in mesothelioma xenografts treated with therapeutic doses. CONCLUSION: The method was validated for measuring trabectedin in tissues. In a mesothelioma xenograft model, trabectedin distributed preferentially in tumor compared with liver.
Asunto(s)
Antineoplásicos Alquilantes/metabolismo , Dioxoles/metabolismo , Mesotelioma/tratamiento farmacológico , Espectrometría de Masa por Ionización de Electrospray/métodos , Tetrahidroisoquinolinas/metabolismo , Animales , Antineoplásicos Alquilantes/análisis , Cromatografía Líquida de Alta Presión/métodos , Dioxoles/análisis , Femenino , Humanos , Ratones , Ratones Desnudos , Espectrometría de Masas en Tándem/métodos , Tetrahidroisoquinolinas/análisis , Trabectedina , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
We developed and validated a high-performance liquid chromatography-tandem mass spectrometry analytical method to measure E-3810, a novel dual inhibitor of fibroblast growth factor receptor 1 and vascular endothelial growth factor receptor 1-3 in tissues and determined the drug concentration in a biopsy of human breast cancer for the first time. The method is a modification of our previous one in plasma to study the clinical pharmacokinetics of the drug during the phase I/II trial. In view of the changes in matrix, we applied a partial validation protocol to determine recovery, sensitivity, range of linearity, precision, accuracy and stability of the method over three runs in a mouse tumor tissue and liver. The recovery of E-3810 from liver or tumor homogenate was >69%, and the lower limit of quantification was 5 ng/ml. The method was linear in the concentration range 5.0-500.0 ng/ml, as demonstrated by a determination coefficient R(2) ≥ 0.9955. The range of the calibration curve was appropriate for the analysis, as demonstrated by the accuracy, which was between 91.4% and 106.7%. Interday precision and accuracy on quality control samples at 9, 30 and 300 ng/ml were 3.1-11.2% and 98.3-111.4%, respectively. The assay was applied successfully to determine the intratumor concentration of E-3810 in different mouse xenograft tumor models and in a biopsy of a patient with breast cancer included in the phase I/II trial of the drug. In mouse tumors, the concentrations of E-3810 were higher than necessary to exert antitumor activity in vitro (1 µM). Even more of interest was the result obtained in a human biopsy of few milligrams, where E-3810 reached 4.9 µg/g (11 µM).
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Antineoplásicos/análisis , Cromatografía Líquida de Alta Presión/métodos , Receptores de Factores de Crecimiento de Fibroblastos/antagonistas & inhibidores , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Espectrometría de Masas en Tándem/métodos , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Neoplasias de la Mama/química , Femenino , Humanos , Hígado/química , Hígado/metabolismo , Ratones , Ratones Desnudos , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Distribución Tisular , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
A rapid, sensitive and specific HPLC-MS/MS method was developed and validated for the quantification of trabectedin in human plasma after using deuterated trabectedin as Internal Standard (IS). After the addition of ammonium sulphate, the analyte was extracted from human plasma with acidified methanol (0.1 M HCl). Chromatographic separation was done on an Accucore XL C18 column (4 µm; 50 mm × 2.1 mm) using a Mobile Phase (MP) consisting of CH3COONH4 10 mM, pH 6.8 (MP A) and CH3OH (MP B). The mass spectrometer worked with electrospray ionization in positive ion mode and Selected Reaction Monitoring (SRM), using target ions at [M-H2O+H]⺠m/z 744.4 for trabectedin and [M-H2O+H]âºm/z 747.5 for the IS. The standard curve was linear (R² ≥ 0.9955) over the concentration range 0.025-1.0 ng/ml and had good back-calculated accuracy and precision. The intra- and inter-day precision and accuracy determined on three quality control samples (0.04, 0.08 and 0.80 ng/ml) were <9.9% and between 98.3% and 105.3%, respectively. The extraction recovery was >81% and the lower limit of quantification 0.025 ng/ml. The method was successfully applied to study trabectedin pharmacokinetics in a patient with a liposarcoma who received 1.3 mg/m² as a 24 h continuous i.v. infusion.
Asunto(s)
Antineoplásicos Alquilantes/sangre , Cromatografía Líquida de Alta Presión/métodos , Dioxoles/sangre , Espectrometría de Masas en Tándem/métodos , Tetrahidroisoquinolinas/sangre , Dioxoles/farmacocinética , Humanos , Límite de Detección , Tetrahidroisoquinolinas/farmacocinética , TrabectedinaRESUMEN
PURPOSE: OTX008 is a galectin-1-targeting compound, currently undergoing a phase I clinical trial. This study aimed at investigating OTX008 pharmacokinetics (PK) and antineoplastic activity. METHODS: Pharmacokinetics and activity of OTX008 were analyzed in the human ovarian carcinoma A2780-1A9 and glioblastoma U87MG xenografted in nude mice. In vitro, OTX008 was tested on tumor and endothelial cells. RESULTS: After 5 mg/kg i.v., OTX008 achieved plasma Cmax of 14.39 µg/mL, distributed rapidly, and was eliminated with a half-life of 31.4 h. Tumor OTX008 Cmax (1.65 µg/g, 1.76 µM), achieved at 0.5 h, remained high at 24 h (0.516 µg/g, 0.55 µM) with AUC of 15.76 µg/g*h. OTX008 accumulated in the tumor after repeated administrations achieving a concentration of 2.3 µM, compatible with the concentrations active in vitro. OTX008 (5 mg/kg i.v., every other day for 3 weeks) inhibited the in vivo growth of A2780-1A9, whereas U87MG was not sensitive. In vitro, OTX008 affected endothelial cell proliferation, motility, invasiveness, and cord formation. Tumor cell proliferation was also inhibited, with differences in sensitivity among cell lines (IC50 from 1 to 190 µM). OTX008 potentiated the activity of the tyrosine kinase inhibitor sunitinib on A2780-1A9 in vivo and in vitro, where the combination showed synergistic (endothelial cells) and additive (A2780-1A9) antiproliferative activity, indicating that the combination targets both the tumor and vascular compartments. CONCLUSIONS: OTX008-alone or in combination with sunitinib-has a favorable PK and antineoplastic activity on selected tumor models through the effects on both endothelial and tumor cells.