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In this work, we demonstrate a mathematical technique for optimizing combination regimens with constraints. We apply the technique to a mathematical model for treatment of patients with chronic myeloid leukemia. The in-host model includes leukemic cell and immune system dynamics during treatment with tyrosine kinase inhibitors and immunomodulatory compounds. The model is minimal (semi-mechanistic) with just enough detail that all relevant therapeutic effects can be represented. The regimens are optimized to yield the highest possible reduction in disease burden, taking into account dosing constraints and side effect risks due to drug exposure. We compare the following three types of regimens: (1) regimens that are restricted to certain discrete dose levels, which can only change every three months; (2) optimal regimens determined using optimal control; and (3) regimens that are piecewise-constant like the first type of regimen, but are obtained as approximations to the optimal control regimens. All three types of regimens result in similar outcomes, but the last one is easy to compute in addition to being clinically feasible.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Modelos Biológicos , Antineoplásicos/administración & dosificación , Antineoplásicos Inmunológicos/administración & dosificación , Simulación por Computador , Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Humanos , Factores Inmunológicos/administración & dosificación , Inmunoterapia/métodos , Inmunoterapia/estadística & datos numéricos , Leucemia Mielógena Crónica BCR-ABL Positiva/terapia , Conceptos Matemáticos , Inhibidores de Proteínas Quinasas/administración & dosificaciónRESUMEN
Glioblastoma is an aggressive disease characterized by moderate initial response rates to first-line radiation-chemotherapy intervention followed by low poor response rates to second-line intervention. This article discusses novel strategic platforms for the development of radiation-investigational agent combination clinical trials for primary and recurrent glioblastoma in a NCI-NCTN settings with simultaneous analysis of challenges in the drug development process.
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Neoplasias Encefálicas/terapia , Quimioradioterapia , Glioblastoma/terapia , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/metabolismo , Neoplasias Encefálicas/metabolismo , Ensayos Clínicos como Asunto , Descubrimiento de Drogas , Glioblastoma/metabolismo , HumanosRESUMEN
PURPOSE: Dasatinib has been shown preclinically to overcome resistance to gemcitabine. We evaluated the safety and biological activity of the combination of dasatinib and gemcitabine in patients with advanced solid tumors. EXPERIMENTAL DESIGN: In a phase 1 study (3 + 3 design), patients received daily dasatinib with weekly gemcitabine on days 1, 8 and 15 of a 28-day cycle (except cycle 1 which was 8 weeks). Dose escalation began with dasatinib 70 mg orally (PO) daily and gemcitabine 800 mg/m(2) intravenously (IV) weekly. RESULTS: Forty-seven patients (15 men; median age = 55 years; median number of prior systemic treatments = 4) were enrolled. Dose-limiting toxicities were grade 3 fatigue and dehydration, with the maximum tolerated dose being dasatinib 100 mg PO qd and gemcitabine 600 mg/m(2) IV weekly. The most common grade 3-4 toxicities were anemia (21.5 %), thrombocytopenia (26.2 %), leukopenia (26.2 %), and pleural effusion (10.7 %). Six of 47 patients attained stable disease (SD) ≥ 6 months or partial response including 2 of 8 patients with pancreatic cancer (SD ≥ 6 months; both gemcitabine-refractory), 2 of 3 patients with thymoma (SD for 9.8 and 15 months), 1 of 1 patient with anal squamous cancer (SD 15 months) and 1 of 5 patients with inflammatory breast cancer. No significant changes in circulating tumor cells or interleukin-8 levels were observed. CONCLUSIONS: The combination was well tolerated at doses of dasatinib 100 mg PO daily and gemcitabine 600 mg/m(2) IV weekly. SD ≥ 6 months/ PR was observed in gemcitabine-refractory pancreatic cancer, thymoma, anal cancer and inflammatory breast cancer.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Desoxicitidina/análogos & derivados , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Pirimidinas/uso terapéutico , Tiazoles/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Recuento de Células , Dasatinib , Demografía , Desoxicitidina/efectos adversos , Desoxicitidina/farmacología , Desoxicitidina/uso terapéutico , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Interleucina-8/sangre , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias/sangre , Células Neoplásicas Circulantes/efectos de los fármacos , Células Neoplásicas Circulantes/patología , Pirimidinas/efectos adversos , Pirimidinas/farmacología , Tiazoles/efectos adversos , Tiazoles/farmacología , Adulto Joven , GemcitabinaRESUMEN
The non-receptor tyrosine kinase Src activation plays a role in the malignant progression of breast cancer, including development of endocrine therapy resistance and survival of bone metastases. This study investigated whether adding Src kinase inhibitor dasatinib to aromatase inhibitor (AI) therapy improved outcomes in estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer (MBC). Postmenopausal patients with ER-positive, HER2-negative MBC (0-1 prior chemotherapies and no prior AI for MBC) were eligible for this non-comparative, parallel group, phase-II study. Patients were randomized to letrozole (2.5 mg/day PO) alone or with dasatinib (100 mg/day PO). Patients with disease progression on letrozole alone could crossover to dasatinib plus continued letrozole. The primary endpoint was clinical-benefit-rate (CBR; complete response + partial response + stable disease ≥6 months). A total of 120 patients were randomized. The CBR of 71% (95% CI 58-83%) was observed with letrozole + dasatinib versus the projected CBR of the combination of 56%. The CBR of 66% (95% CI 52-77%) with letrozole alone also exceeded the projected CBR of 39% with letrozole alone. The CBR was 23% in the crossover arm of letrozole plus dasatinib in patients progressing on letrozole alone. Median progression-free survival with the combination was 20.1 months and 9.9 months with letrozole alone. Letrozole plus dasatinib was well tolerated, although 26% of patients required dasatinib dose reductions. In this non-comparative phase-II trial, the CBR of 71% and the median PFS of 20.1 months with letrozole + dasatinib are encouraging and suggest that dasatinib may inhibit the emergence of acquired resistance to AI therapy.
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BACKGROUND: Retinoblastoma is the most common intraocular tumor of childhood. Vision salvage rates in advanced cases are less than ideal, and the optimal treatment for intraocular retinoblastoma has not been established. We report the results of an institutional retinoblastoma treatment trial to determine the vision salvage rates and toxicity of a regimen combining carboplatin and etoposide with focal retinal therapy. PROCEDURE: Twenty-nine patients diagnosed with retinoblastoma in 48 eyes were treated between 1992 and 2004 with at least six cycles of carboplatin and etoposide combined with focal retinal therapy. RESULTS: The response rate of eyes after six cycles of chemotherapy was 85.4%. Twenty-two eyes were enucleated, but only seven eyes received EBRT. The vision salvage rate without EBRT was 82.6% for eyes with Reese-Ellsworth (R-E) groups I-IV tumors and 20% for eyes with R-E group V tumors. The vision salvage rate without EBRT for eyes with Murphree groups A and B tumors was 77.3% but was only 26.9% for eyes with groups C and D tumors. Acute side effects were minimal. CONCLUSIONS: The combination of carboplatin and etoposide with focal therapy is a well-tolerated regimen that has acceptable vision salvage rates for R-E groups I-IV and Murphree groups A and B retinoblastoma. This combination avoids the use of EBRT and the toxicity of additional chemotherapy agents. However, patients with R-E group V and Murphree groups C and D retinoblastoma have poorer outcomes and require more intensive therapy.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Crioterapia , Hipertermia Inducida , Terapia por Láser , Neoplasias Primarias Múltiples/tratamiento farmacológico , Neoplasias de la Retina/tratamiento farmacológico , Retinoblastoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Ceguera/prevención & control , Carboplatino/administración & dosificación , Carboplatino/efectos adversos , Preescolar , Terapia Combinada , Progresión de la Enfermedad , Etopósido/administración & dosificación , Etopósido/efectos adversos , Enucleación del Ojo , Humanos , Lactante , Recién Nacido , Recurrencia Local de Neoplasia , Neoplasias Primarias Múltiples/cirugía , Estudios Prospectivos , Neoplasias de la Retina/patología , Neoplasias de la Retina/cirugía , Retinoblastoma/patología , Retinoblastoma/cirugía , Resultado del Tratamiento , Agudeza VisualRESUMEN
Background: Immunotherapies have demonstrated efficacy across a diverse set of tumors supporting further evaluation in glioblastoma. The objective of this study was to evaluate the safety/tolerability and describe immune-mediated effects of nivolumab ± ipilimumab in patients with recurrent glioblastoma. Exploratory efficacy outcomes are also reported. Methods: Patients were randomized to receive nivolumab 3 mg/kg every 2 weeks (Q2W; NIVO3) or nivolumab 1 mg/kg + ipilimumab 3 mg/kg every 3 weeks (Q3W) for 4 doses, then nivolumab 3 mg/kg Q2W (NIVO1+IPI3). An alternative regimen of nivolumab 3 mg/kg + ipilimumab 1 mg/kg Q3W for 4 doses, then nivolumab 3 mg/kg Q2W (NIVO3+IPI1) was investigated in a nonrandomized arm. Results: Forty patients were enrolled (NIVO3, n = 10; NIVO1+IPI3, n = 10; NIVO3+IPI1, n = 20). The most common treatment-related adverse events (AEs) were fatigue (NIVO3, 30%; NIVO1+IPI3, 80%; NIVO3+IPI1, 55%) and diarrhea (10%, 70%, 30%, respectively). AEs leading to discontinuation occurred in 10% (NIVO3), 30% (NIVO1+IPI3), and 20% (NIVO3+IPI1) of patients. Three patients achieved a partial response (NIVO3, n = 1; NIVO3+IPI1, n = 2) and 8 had stable disease for ≥12 weeks (NIVO3, n = 2; NIVO1+IPI3, n = 2; NIVO3+IPI1, n = 4 [Response Assessment in Neuro-Oncology criteria]). Most patients (68%) had tumor-cell programmed death ligand-1 expression ≥1%. Immune-mediated effects mimicking radiographic progression occurred in 2 patients. Conclusions: Nivolumab monotherapy was better tolerated than nivolumab + ipilimumab; the tolerability of the combination was influenced by ipilimumab dose. These safety and exploratory findings merit further investigation of immunotherapies in glioblastoma.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Glioblastoma/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Adulto , Anciano , Neoplasias Encefálicas/patología , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Glioblastoma/patología , Humanos , Ipilimumab/administración & dosificación , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Nivolumab/administración & dosificación , PronósticoRESUMEN
INTRODUCTION: The Network Genomic Medicine Lung Cancer was set up to rapidly translate scientific advances into early clinical trials of targeted therapies in lung cancer performing molecular analyses of more than 3500 patients annually. Because sequential analysis of the relevant driver mutations on fixated samples is challenging in terms of workload, tissue availability, and cost, we established multiplex parallel sequencing in routine diagnostics. The aim was to analyze all therapeutically relevant mutations in lung cancer samples in a high-throughput fashion while significantly reducing turnaround time and amount of input DNA compared with conventional dideoxy sequencing of single polymerase chain reaction amplicons. METHODS: In this study, we demonstrate the feasibility of a 102 amplicon multiplex polymerase chain reaction followed by sequencing on an Illumina sequencer on formalin-fixed paraffin-embedded tissue in routine diagnostics. Analysis of a validation cohort of 180 samples showed this approach to require significantly less input material and to be more reliable, robust, and cost-effective than conventional dideoxy sequencing. Subsequently, 2657 lung cancer patients were analyzed. RESULTS: We observed that comprehensive biomarker testing provided novel information in addition to histological diagnosis and clinical staging. In 2657 consecutively analyzed lung cancer samples, we identified driver mutations at the expected prevalence. Furthermore we found potentially targetable DDR2 mutations at a frequency of 3% in both adenocarcinomas and squamous cell carcinomas. CONCLUSION: Overall, our data demonstrate the utility of systematic sequencing analysis in a clinical routine setting and highlight the dramatic impact of such an approach on the availability of therapeutic strategies for the targeted treatment of individual cancer patients.
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Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/terapia , Neoplasias Pulmonares/genética , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Estudios de Cohortes , ADN de Neoplasias/análisis , ADN de Neoplasias/genética , ADN de Neoplasias/aislamiento & purificación , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/terapia , Reacción en Cadena de la Polimerasa/métodos , Análisis de Secuencia de ADN/métodosRESUMEN
PURPOSE: Dasatinib has limited single-agent activity in unselected patients with metastatic breast cancer. Several gene signatures predictive of dasatinib response in vitro have been reported. The purpose of this three-arm, phase II study was to prospectively assess the utility of three previously published gene signatures to select patients with clinical benefit from dasatinib. EXPERIMENTAL DESIGN: Patients with metastatic breast cancer underwent biopsy for gene expression profiling in an academic CLIA laboratory; those who were positive for any one of three predictive gene signatures (dasatinib sensitivity signature, SRC pathway activity signature, and dasatinib target index) received dasatinib 100 mg orally daily. The three marker-defined cohorts were analyzed separately, using early stopping rules for futility. RESULTS: Ninety-seven patients were enrolled, 93 underwent biopsy, and 80% of the biopsies were sufficient for molecular testing. Thirty patients were positive for at least one signature and received treatment. Only 1 patient experienced clinical benefit and had stable disease over 300 days. All three arms were closed early for futility. There was one serious biopsy-related adverse event (hematoma and pain following a liver biopsy). There were no unexpected toxicities from dasatinib. CONCLUSION: None of the three predictive gene signatures, although supported by preclinical evidence, defined tumors clinically sensitive to dasatinib as a single agent.
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Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Tiazoles/uso terapéutico , Transcriptoma , Adulto , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Biopsia , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Dasatinib , Femenino , Perfilación de la Expresión Génica , Humanos , Persona de Mediana Edad , Metástasis de la Neoplasia , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Pirimidinas/administración & dosificación , Pirimidinas/efectos adversos , Factores de Riesgo , Tiazoles/administración & dosificación , Tiazoles/efectos adversos , Resultado del Tratamiento , Familia-src Quinasas/metabolismoAsunto(s)
Antineoplásicos/uso terapéutico , Dasatinib/uso terapéutico , Resistencia a Antineoplásicos , Leucemia Mieloide de Fase Acelerada/tratamiento farmacológico , Leucemia Mieloide de Fase Acelerada/patología , Inhibidores de Proteínas Quinasas/uso terapéutico , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Dasatinib/administración & dosificación , Dasatinib/efectos adversos , Humanos , Mesilato de Imatinib/farmacología , Mesilato de Imatinib/uso terapéutico , Leucemia Mieloide de Fase Acelerada/mortalidad , Estadificación de Neoplasias , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto , Retratamiento , Resultado del TratamientoRESUMEN
PURPOSE: Dasatinib is an Src family kinase inhibitor with modest activity in advanced breast cancer. We aimed to assess toxicity and maximum tolerated dose (MTD) for dasatinib plus capecitabine, estimate efficacy, and explore effects on angiogenesis. EXPERIMENTAL DESIGN: Dose levels (DL) were dasatinib 50 mg twice daily (DL1), 70 mg twice daily (DL2 and DL3), or 100 mg daily (DL3a); plus capecitabine on days 1 to 14 of a 21-day cycle, at 825 mg/m(2) twice daily (DL1 and DL2) or 1,000 mg/m(2) twice daily [DL3 and DL3a (MTD)]. DL3a was expanded to evaluate safety/efficacy. Plasma samples were collected for biomarker analysis. RESULTS: Thirty-one and 21 patients were treated in the escalation and expansion phases. Sixty percent of tumors were hormone receptor-positive. Most common adverse events (AE) were any grade nausea (58%), hand-foot syndrome (44%), diarrhea (33%), fatigue (33%), vomiting (31%), and asthenia (31%). Most common grade 3/4 AEs were hand-foot syndrome (12%), diarrhea (8%), fatigue (8%), pleural effusion (8%), and vomiting (6%). The MTD was defined at DL3a (capecitabine 1,000 mg/m(2) twice daily and dasatinib 100 mg daily). Of 25 response-evaluable patients treated at DL3a, confirmed partial response was noted in 24% and stable disease in an additional 32%; median progression-free survival was 14.4 weeks. Significant decreases in plasma VEGF-A and increases in VEGFR-2 and collagen-IV were observed. CONCLUSIONS: Dasatinib 100 mg once daily plus capecitabine 1,000 mg/m(2) twice daily were tolerable and were associated with clinical benefit in 56% of response-evaluable patients. Biomarker changes were consistent with an antiangiogenic effect.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Biomarcadores/sangre , Neoplasias de la Mama/sangre , Capecitabina , Dasatinib , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/análogos & derivados , Humanos , Dosis Máxima Tolerada , Persona de Mediana Edad , Estadificación de Neoplasias , Pirimidinas/administración & dosificación , Tiazoles/administración & dosificación , Resultado del TratamientoRESUMEN
PURPOSE: Dasatinib is a potent BCR-ABL inhibitor with proven efficacy in adults with newly diagnosed chronic myeloid leukemia (CML) in chronic phase (CP) and in imatinib-resistant/intolerant disease. This phase I study of the Innovative Therapies for Children with Cancer Consortium assessed dasatinib safety and efficacy in pediatric patients. PATIENTS AND METHODS: Escalating once-daily dasatinib doses (60 to 120 mg/m(2)) were administered to children (n = 58) with (i) imatinib-pretreated CML or Philadelphia chromosome (Ph)-positive acute lymhoblastic leukemia (ALL) and (ii) treatment-refractory Ph-negative ALL or acute myeloid leukemia (AML). RESULTS: Dasatinib safety and efficacy profiles compared favorably with those in adults. The most common drug-related nonhematologic adverse events were nausea (31%, all grades; 2%, grade 3 to 4), headache (22%, 3%), diarrhea (21%, 0%), and vomiting (17%, 2%). Of 17 patients with CML-CP, 14 (82%) achieved complete cytogenetic response (CCyR) and eight (47%) achieved major molecular response. After ≥ 24 months of follow-up, median complete hematologic response (CHR) and major cytogenetic response (MCyR) durations were not reached. Of 17 patients with advanced-phase CML or Ph-positive ALL, six (35%) achieved confirmed CHR and 11 (65%) achieved CCyR. Median MCyR duration was 4.6 months (95% CI, 2.1 to 17.4 months). No patient with Ph-negative ALL or AML responded. Dasatinib pediatric pharmacokinetic parameters were comparable with those in adult studies, showing rapid absorption (time to reach maximum concentration, 0.5 to 6.0 hours) and elimination (mean half-life, 3.0 to 4.4 hours). CONCLUSION: Dasatinib 60 mg/m(2) and 80 mg/m(2) once-daily dosing were selected for phase II studies in children with Ph-positive leukemias.
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Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Pirimidinas/administración & dosificación , Pirimidinas/efectos adversos , Tiazoles/administración & dosificación , Tiazoles/efectos adversos , Adolescente , Antineoplásicos/farmacocinética , Benzamidas/administración & dosificación , Benzamidas/efectos adversos , Niño , Preescolar , Dasatinib , Diarrea/inducido químicamente , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Cefalea/inducido químicamente , Humanos , Mesilato de Imatinib , Lactante , Estimación de Kaplan-Meier , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patología , Masculino , Náusea/inducido químicamente , Piperazinas/administración & dosificación , Piperazinas/efectos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Pirimidinas/farmacocinética , Tamaño de la Muestra , Terapias en Investigación , Tiazoles/farmacocinética , Resultado del Tratamiento , Vómitos/inducido químicamente , Adulto JovenRESUMEN
The treatment of patients with recurrent glioblastoma remains a major oncologic problem, with median survival after progression of 7-9 months. To determine the maximum tolerated dose and dose-limiting toxicity (DLT), the combination of dasatinib and cyclonexyl-chloroethyl-nitrosourea (CCNU) was investigated in this setting. The study was designed as multicenter, randomized phase II trial, preceded by a lead-in safety phase. The safety component reported here, which also investigated pharmacokinetics and preliminary clinical activity, required expansion and is therefore considered a phase I part to establish a recommended dosing regimen of the combination of CCNU (90-110 mg/m(2)) and dasatinib (100-200 mg daily). Overall, 28 patients were screened, and 26 patients were enrolled. Five dose levels were explored. DLTs, mainly myelosuppression, occurred in 10 patients. Grade 3 or 4 neutropenia was recorded in 7 patients (26.9%) and thrombocytopenia in 11 patients (42.3%). No significant effect of CCNU coadministration on dasatinib pharmacokinetics was found. Median progression-free survival (PFS) was 1.35 months (95% confidence interval: 1.2-1.4) and 6-month PFS was 7.7%. In this phase I study of recurrent glioblastoma patients, the combination of CCNU and dasatinib showed significant hematological toxicities and led to suboptimal exposure to both agents.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Glioblastoma/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/patología , Dasatinib , Supervivencia sin Enfermedad , Femenino , Glioblastoma/mortalidad , Glioblastoma/patología , Humanos , Lomustina/administración & dosificación , Lomustina/efectos adversos , Lomustina/farmacocinética , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Pirimidinas/administración & dosificación , Pirimidinas/efectos adversos , Pirimidinas/farmacocinética , Tiazoles/administración & dosificación , Tiazoles/efectos adversos , Tiazoles/farmacocinéticaRESUMEN
PURPOSE: Dasatinib is a potent, oral SRC-family kinase inhibitor with preclinical antiproliferative, antimetastatic, and antiosteoclastic activity suggesting dasatinib sensitivity in triple-negative, or basal-like, breast cancer cell lines. This phase 2 trial assessed efficacy and safety of single-agent dasatinib in patients with advanced triple-negative breast cancer (TNBC). EXPERIMENTAL DESIGN: Female patients with measurable, locally advanced or metastatic TNBC initially received dasatinib 100 mg twice daily (BID); to improve tolerability, the protocol was amended and subsequent patients received 70 mg BID. Primary endpoint was Response Evaluation Criteria in Solid Tumors-defined objective response rate (ORR); secondary endpoints included progression-free survival (PFS), disease control rate (DCR), safety, and limited pharmacokinetics. RESULTS: Of the 44 treated patients, 43 were response evaluable. ORR was 4.7%: two patients had confirmed partial responses lasting 14 and 58 weeks, respectively. Of 11 patients with stable disease, two continued for more than 16 weeks, thus protocol-defined DCR was 9.3%. Median PFS was 8.3 weeks (95% CI: 7.3-15.3). Five patients discontinued before first tumor assessment. No grade 4 adverse events (AE) were reported; grade 3 AEs occurring in more than 5% of patients were fatigue (9.1%), diarrhea, pleural effusion, and dyspnea (all 6.8%). Laboratory abnormalities were uncommon. Dasatinib at 100 mg BID was not well tolerated; rates of treatment interruption, dose reduction, and serious AEs were lower with dasatinib 70 mg BID. CONCLUSIONS: Single-agent dasatinib has limited activity in unselected patients with TNBC. Dasatinib 70 mg BID was better tolerated than 100 mg BID. Future studies will investigate dasatinib in other breast cancer settings, including chemotherapy combinations.
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Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Tiazoles/uso terapéutico , Administración Oral , Adulto , Anciano , Dasatinib , Femenino , Humanos , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/efectos adversos , Pirimidinas/efectos adversos , Receptor ErbB-2/biosíntesis , Receptores de Estrógenos/biosíntesis , Receptores de Progesterona/biosíntesis , Tiazoles/efectos adversos , Familia-src Quinasas/antagonistas & inhibidores , Familia-src Quinasas/metabolismoRESUMEN
UNLABELLED: PURPOSE Dasatinib is an orally available tyrosine kinase inhibitor with low nanomolar activity against SRC family kinases, BCR-ABL, c-KIT, EPHA2, and the PDGF-ß receptor. Dasatinib was found to have selective activity in several tumor models in the Pediatric Preclinical Testing Program. PATIENTS AND METHODS A phase I study of dasatinib in pediatric patients with refractory solid tumors or imatinib-refractory, Philadelphia chromosome-positive leukemia was performed. Dose levels of 50, 65, 85, and 110 mg/m²/dose, administered orally twice daily for 28 days, with courses repeated without interruption, were studied. Pharmacokinetic studies were performed with the initial dose. RESULTS: A total of 39 patients (solid tumors, n = 28; chronic myeloid leukemia [CML], n = 9; acute lymphoblastic leukemia, n = 2) were enrolled. No dose-limiting toxicities (DLTs) were observed at the 50, 65, and 85 mg/m² dose levels. At 110 mg/m², two of six patients experienced DLT including grade 2 diarrhea and headache. In children with leukemia, grade 4 hypokalemia (50 mg/m²), grade 3 diarrhea (85 mg/m²), and grade 2 creatinine elevation (50 mg/m²) were observed. DLT in later courses included pleural effusions, hemangiomatosis, and GI hemorrhage. There were three complete cytogenetic responses, three partial cytogenetic responses, and two partial/minimal cytogenetic responses observed in evaluable patients with CML. CONCLUSION Overall, drug disposition and tolerability of dasatinib were similar to those observed in adult patients.
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Neoplasias Hematológicas/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Pirimidinas/administración & dosificación , Pirimidinas/farmacocinética , Tiazoles/administración & dosificación , Tiazoles/farmacocinética , Administración Oral , Adolescente , Niño , Preescolar , Dasatinib , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Estudios de Seguimiento , Neoplasias Hematológicas/diagnóstico , Hospitales Pediátricos , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Masculino , Dosis Máxima Tolerada , Neoplasias/patología , Selección de Paciente , Pediatría , Philadelphia , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Pirimidinas/efectos adversos , Medición de Riesgo , Tiazoles/efectos adversos , Resultado del Tratamiento , Adulto JovenRESUMEN
PURPOSE: SRC-family kinases (SFK) are involved in numerous oncogenic signaling pathways. A phase 2 trial of dasatinib, a potent oral tyrosine kinase inhibitor of SFKs, was carried out in patients with human epidermal growth factor receptor 2-positive (HER2+) and/or hormone receptor-positive (HR+) advanced breast cancer. EXPERIMENTAL DESIGN: Patients with measurable tumors and progression after chemotherapy and HER2 and/or HR-targeted agents in adjuvant or metastatic settings (maximum of two prior metastatic setting regimens) received twice daily dasatinib. Primary endpoint was Response Evaluation Criteria in Solid Tumors-defined response rate. Secondary endpoints included toxicity and limited pharmacokinetics. RESULTS: Seventy patients (55 years median age) were treated, 83% of HER2+ patients had received prior HER2-directed therapy, and 61% of HR+ patients had received prior endocrine therapy in the advanced setting. Dasatinib starting dose was reduced from 100 to 70 mg twice daily to limit toxicity. Median therapy duration was 1.8 months in both dose groups and most discontinuations were due to progression. Of 69 evaluable patients, three had confirmed partial responses and six had stable disease for 16 weeks or more (disease control rate = 13.0%); all nine of these tumors were HR+ (two were also HER2+). The most common drug-related toxicities were gastrointestinal complaints, headache, asthenia, and pleural effusion. Grade 3-4 toxicity occurred in 37% of patients and was comparable between doses; drug-related serious adverse events were less frequent with 70 mg twice daily than 100 mg twice daily. CONCLUSION: Limited single-agent activity was observed with dasatinib in patients with advanced HR+ breast cancer.
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Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Tiazoles/uso terapéutico , Administración Oral , Adulto , Anciano , Dasatinib , Femenino , Humanos , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/efectos adversos , Pirimidinas/efectos adversos , Receptor ErbB-2/biosíntesis , Receptores de Estrógenos/biosíntesis , Receptores de Progesterona/biosíntesis , Tiazoles/efectos adversos , Familia-src Quinasas/antagonistas & inhibidores , Familia-src Quinasas/metabolismoRESUMEN
PURPOSE: Dasatinib is a BCR-ABL inhibitor, 325-fold more potent than imatinib against unmutated BCR-ABL in vitro. Phase II studies have demonstrated efficacy and safety with dasatinib 70 mg twice daily in chronic-phase (CP) chronic myelogenous leukemia (CML) after imatinib treatment failure. In phase I, responses occurred with once-daily administration despite only intermittent BCR-ABL inhibition. Once-daily treatment resulted in less toxicity, suggesting that toxicity results from continuous inhibition of unintended targets. Here, a dose- and schedule-optimization study is reported. PATIENTS AND METHODS: In this open-label phase III trial, 670 patients with imatinib-resistant or -intolerant CP-CML were randomly assigned 1:1:1:1 between four dasatinib treatment groups: 100 mg once daily, 50 mg twice daily, 140 mg once daily, or 70 mg twice daily. RESULTS: With minimum follow-up of 6 months (median treatment duration, 8 months; range, < 1 to 15 months), marked and comparable hematologic (complete, 86% to 92%) and cytogenetic (major, 54% to 59%; complete, 41% to 45%) response rates were observed across the four groups. Time to and duration of cytogenetic response were similar, as was progression-free survival (8% to 11% of patients experienced disease progression or died). Compared with the approved 70-mg twice-daily regimen, dasatinib 100 mg once daily resulted in significantly lower rates of pleural effusion (all grades, 7% v 16%; P = .024) and grade 3 to 4 thrombocytopenia (22% v 37%; P = .004), and fewer patients required dose interruption (51% v 68%), reduction (30% v 55%), or discontinuation (16% v 23%). CONCLUSION: Dasatinib 100 mg once daily retains the efficacy of 70 mg twice daily with less toxicity. Intermittent target inhibition with tyrosine kinase inhibitors may preserve efficacy and reduce adverse events.