RESUMEN
AIM: Phase II multi-disease randomized discontinuation trial to assess the safety and efficacy of sorafenib including patients with advanced soft tissue sarcoma (STS). METHODS: Sorafenib (400 mg twice daily) was initially administered for 12 weeks. Patients with: ≥25% tumour shrinkage continued sorafenib; ≥25% tumour growth discontinued; other patients were randomized and received sorafenib or placebo. RESULTS: Twenty-six patients (median age 55 years) were enrolled. Common drug-related adverse events, including fatigue, hand-foot skin reaction, rash or gastrointestinal disturbances, were manageable, reversible and generally low grade. Fatigue, skin toxicity, nausea, diarrhoea and hypertension occurred at grade ≥3 in 19% of patients. After 12 weeks eight (31%) patients had not progressed. Three patients who experienced tumour shrinkage and continued on sorafenib, and five (19%) were randomized either to continue sorafenib or to receive placebo. Of the three patients randomized to sorafenib, one achieved a partial response and two had SD. Overall one patient achieved a partial response and three further patients achieved minor responses. CONCLUSIONS: There was evidence of disease activity in STS as defined by tumor regressions including one objective partial response. Further investigation in STS is warranted.
Asunto(s)
Bencenosulfonatos/uso terapéutico , Piridinas/uso terapéutico , Sarcoma/tratamiento farmacológico , Neoplasias de los Tejidos Blandos/tratamiento farmacológico , Adulto , Anciano , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Bencenosulfonatos/efectos adversos , Demografía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Niacinamida/análogos & derivados , Compuestos de Fenilurea , Piridinas/efectos adversos , Sarcoma/diagnóstico por imagen , Neoplasias de los Tejidos Blandos/diagnóstico por imagen , Sorafenib , Tomografía Computarizada por Rayos X , Resultado del Tratamiento , Adulto JovenRESUMEN
PURPOSE: This phase I study evaluated the effect of folate supplementation on the toxicity, tolerability, and pharmacokinetics of pemetrexed in patients with locally advanced or metastatic cancer. It also examined two different types of vitamin supplementation and whether the extent of prior myelosuppressive therapy affected pemetrexed tolerability. PATIENTS AND METHODS: Patients received a 10-min infusion of 600 to 14,00 mg/m(2) pemetrexed every 3 weeks. Patients were stratified into cohorts by pretreatment status [lightly pretreated (LPT) or heavily pretreated (HPT)] and were supplemented with intermittent high-dose folic acid (HDFA) or with continuous daily multivitamins (MVI) containing nutritional doses of folic acid. Pemetrexed plasma pharmacokinetics were evaluated for cycle 1. RESULTS: Sixty-two HDFA patients (28 HPT and 34 LPT) were treated with 204 cycles of pemetrexed, and 43 MVI patients (20 HPT and 23 LPT) were treated with 182 cycles. Hematologic dose-limiting toxicities included grade 4 neutropenia (5 of 105 patients), grade 4 thrombocytopenia (4 of 105 patients), and febrile neutropenia (3 of 105 patients). Nonhematologic toxicities included fatigue, vomiting, diarrhea, and nausea. Pemetrexed doses of 800 and 1,050 mg/m(2) were well tolerated when administered with vitamin supplementation to HPT and LPT patients, respectively. There were no clinically relevant differences in toxicities or pemetrexed pharmacokinetics for LPT versus HPT patients or for patients receiving HDFA versus daily MVI supplementation. CONCLUSIONS: The pemetrexed doses tolerated in this study with vitamin supplementation were significantly higher than those tolerated in earlier studies without supplementation, and toxicities were independent of the type of vitamin supplementation or prior myelosuppressive treatment. The recommended dose of pemetrexed is 1,050 mg/m(2) in LPT patients and 800 mg/m(2) in HPT patients, irrespective of the type of vitamin supplementation.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Suplementos Dietéticos , Ácido Fólico/administración & dosificación , Glutamatos/efectos adversos , Glutamatos/farmacocinética , Guanina/análogos & derivados , Complejo Vitamínico B/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Femenino , Ácido Fólico/uso terapéutico , Glutamatos/administración & dosificación , Guanina/administración & dosificación , Guanina/efectos adversos , Guanina/farmacocinética , Humanos , Infusiones Parenterales , Masculino , Metástasis de la Neoplasia , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Pemetrexed , Complejo Vitamínico B/uso terapéuticoRESUMEN
PURPOSE: The main objectives of this phase I and pharmacokinetic, open-label study were to characterize the principal toxicities and determine the maximum tolerated dose of the multitargeted antifolate pemetrexed administered in combination with irinotecan. The study also sought to detect major pharmacokinetic drug-drug interactions between these agents and preliminary evidence of antitumor activity in patients with advanced solid malignancies. EXPERIMENTAL DESIGN: Pemetrexed was administered as a 10-min i.v. infusion followed by irinotecan given i.v. over 90 min every 3 weeks to patients with advanced solid malignancies. The study objectives were first pursued in heavily pretreated patients and then in lightly pretreated patients who also received vitamin supplementation. RESULTS: Twenty-three heavily pretreated patients enrolled in the first stage of the study, and the maximum tolerated dose level of pemetrexed/irinotecan without vitamin supplementation was 400/250 mg/m(2); further dose escalation was precluded by severe neutropenia that was protracted and/or associated with fever. In the second stage of the study, 28 lightly pretreated patients were administered pemetrexed/irinotecan with vitamin supplementation; these patients tolerated pemetrexed/irinotecan at a dose level of 500/350 mg/m(2), which reflected clinically relevant single-agent doses of both agents. No major pharmacokinetic interactions between the agents were evident. Four patients, two patients each with colorectal cancer refractory to fluoropyrimidines and advanced mesothelioma, had partial responses. CONCLUSIONS: The pemetrexed/irinotecan regimen is well tolerated in patients with advanced solid malignancies at clinically relevant single-agent doses. The recommended dose level of pemetrexed/irinotecan for subsequent disease-directed evaluations involving lightly pretreated patients is 500/350 mg/m(2) every 3 weeks with vitamin supplementation.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Camptotecina/análogos & derivados , Glutamatos/administración & dosificación , Guanina/análogos & derivados , Neoplasias/tratamiento farmacológico , Adulto , Anciano , Antineoplásicos/farmacología , Camptotecina/administración & dosificación , Camptotecina/farmacocinética , Estudios de Cohortes , Suplementos Dietéticos , Interacciones Farmacológicas , Femenino , Glutamatos/farmacocinética , Guanina/administración & dosificación , Guanina/farmacocinética , Humanos , Irinotecán , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Pemetrexed , Vitaminas/farmacologíaRESUMEN
PURPOSE: Pemetrexed is an antimetabolite that is structurally similar to methotrexate. Because nonsteroidal anti-inflammatory drugs (NSAID) impair methotrexate clearance and increase its toxicity, we evaluated the pharmacokinetics and toxicity of pemetrexed when coadministered with aspirin or ibuprofen in advanced cancer patients. EXPERIMENTAL DESIGN: In two independent, randomized, crossover drug interaction studies, cancer patients with a creatinine clearance (CrCl) > or =60 mL/min received an NSAID (aspirin or ibuprofen) with either the first or the second dose of pemetrexed (cycle 1 or 2). Pemetrexed (500 mg/m(2)) was infused i.v. on day 1 of a 21-day cycle, and all patients were supplemented with oral folic acid and i.m. vitamin B(12). Aspirin (325 mg) or ibuprofen (400 mg; 2 x 200 mg) was given orally every 6 hours, starting 2 days before pemetrexed administration, with the ninth and final dose taken 1 hour before infusion. Pemetrexed pharmacokinetics with and without concomitant NSAID treatment were compared for cycles 1 and 2. RESULTS: Data from 27 patients in each study were evaluable for the analysis of pemetrexed pharmacokinetics. Coadministration of aspirin did not alter pemetrexed pharmacokinetics; however, ibuprofen coadministration was associated with a 16% reduction in clearance, a 15% increase in maximum plasma concentration, and a 20% increase in area under the plasma concentration versus time curve but no significant change in V(ss) compared with pemetrexed alone. No febrile neutropenia occurred in any patient, and no increase in pemetrexed-related toxicity was associated with NSAID administration. CONCLUSIONS: Pemetrexed (500 mg/m(2)) with vitamin supplementation is well tolerated and requires no dosage adjustment when coadministered with aspirin (in patients with CrCl > or =60 mL/min) or ibuprofen (in patients with CrCl > or =80 mL/min).
Asunto(s)
Antiinflamatorios no Esteroideos/farmacocinética , Antimetabolitos Antineoplásicos/farmacocinética , Aspirina/farmacocinética , Glutamatos/farmacocinética , Guanina/análogos & derivados , Ibuprofeno/farmacocinética , Neoplasias/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Antiinflamatorios no Esteroideos/toxicidad , Antimetabolitos Antineoplásicos/toxicidad , Aspirina/toxicidad , Creatinina/sangre , Estudios Cruzados , Interacciones Farmacológicas , Quimioterapia Combinada , Femenino , Glutamatos/toxicidad , Guanina/farmacocinética , Guanina/toxicidad , Humanos , Ibuprofeno/toxicidad , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Neoplasias/tratamiento farmacológico , Pemetrexed , Timidilato Sintasa/antagonistas & inhibidores , Resultado del TratamientoRESUMEN
PURPOSE: This phase I study was conducted to determine the toxicities, pharmacokinetics, and recommended doses of pemetrexed in cancer patients with normal and impaired renal function. PATIENTS AND METHODS: Patients received a 10-minute infusion of 150 to 600 mg/m2 of pemetrexed every 3 weeks. Patients were stratified for independent dose escalation by measured glomerular filtration rate (GFR) into four cohorts ranging from > or = 80 to less than 20 mL/min. Pemetrexed plasma and urine pharmacokinetics were evaluated for the first cycle. Patients enrolled after December 1999 were supplemented with oral folic acid and intramuscular vitamin B12. RESULTS: Forty-seven patients were treated with 167 cycles of pemetrexed. Hematologic dose-limiting toxicities occurred in vitamin-supplemented patients (two; 15%) and non-supplemented patients (six; 18%), and included febrile neutropenia (four patients) and grade 4 thrombocytopenia (two patients). Nonhematologic toxicities included fatigue, diarrhea, and nausea, and did not correlate with renal function. Accrual was discontinued in patients with GFR less than 30 mL/min after one patient with a GFR of 19 mL/min died as a result of treatment-related toxicities. Pemetrexed plasma clearance positively correlated with GFR (r2 = 0.736), resulting in increased drug exposures in patients with impaired renal function. With vitamin supplementation, pemetrexed 600 mg/m2 was tolerated by patients with a GFR > or = 80 mL/min, whereas patients with a GFR of 40 to 79 mL/min tolerated a dose of 500 mg/m2. CONCLUSION: Pemetrexed was well tolerated at doses of 500 mg/m2 with vitamin supplementation in patients with GFR > or = 40 mL/min. Additional studies are needed to define appropriate dosing for renally impaired patients receiving higher dose pemetrexed with vitamin supplementation.
Asunto(s)
Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/farmacocinética , Glutamatos/administración & dosificación , Glutamatos/farmacocinética , Guanina/análogos & derivados , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/metabolismo , Neoplasias/complicaciones , Neoplasias/tratamiento farmacológico , Adulto , Anciano , Antimetabolitos Antineoplásicos/efectos adversos , Antimetabolitos Antineoplásicos/sangre , Antimetabolitos Antineoplásicos/orina , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Diarrea/inducido químicamente , Esquema de Medicación , Fatiga/inducido químicamente , Femenino , Ácido Fólico/administración & dosificación , Glutamatos/efectos adversos , Glutamatos/sangre , Glutamatos/orina , Guanina/administración & dosificación , Guanina/efectos adversos , Guanina/sangre , Guanina/farmacocinética , Guanina/orina , Humanos , Fallo Renal Crónico/sangre , Fallo Renal Crónico/orina , Masculino , Persona de Mediana Edad , Náusea/inducido químicamente , Neutropenia/inducido químicamente , Pemetrexed , Trombocitopenia/inducido químicamente , Vitamina B 12/administración & dosificaciónRESUMEN
The mitogen-activated protein kinase (MAPK) signaling pathway plays a critical role in transmitting proliferative signals generated by cell surface receptors and cytoplasmic signaling elements to the nucleus. Several important signaling elements of the MAPK pathway, particularly Ras and Raf, are encoded by oncogenes, and as such, their structures and functions can be modified, rendering them constitutively active. Because the MAPK pathway is dysregulated in a notable proportion of human malignancies, many of its aberrant and critical components represent strategic targets for therapeutic development against cancer. Raf, which is an essential serine/threonine kinase constituent of the MAPK pathway and a downstream effector of the central signal transduction mediator Ras, is activated in a wide range of human malignancies by aberrant signaling upstream of the protein (eg, growth factor receptors and mutant Ras) and activating mutations of the protein itself, both of which confer a proliferative advantage. Three isoforms of Raf have been identified, and therapeutics targeting Raf, including small-molecule inhibitors and antisense oligodeoxyribonucleotides (ASON), are undergoing clinical evaluation. The outcomes of these investigations may have far-reaching implications in the management of many types of human cancer. This review outlines the structure and diverse functions of Raf, the rationale for targeting Raf as a therapeutic strategy against cancer, and the present status of various therapeutic approaches including ASONs and small molecules, particularly sorafenib (BAY 43-9006).
Asunto(s)
Antineoplásicos/administración & dosificación , Sistemas de Liberación de Medicamentos , Sistema de Señalización de MAP Quinasas/fisiología , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Quinasas raf/metabolismo , Animales , Bencenosulfonatos/administración & dosificación , Regulación hacia Abajo , Humanos , MAP Quinasa Quinasa 1/genética , MAP Quinasa Quinasa 1/metabolismo , Biología Molecular , Mutación , Neoplasias/fisiopatología , Niacinamida/análogos & derivados , Compuestos de Fenilurea , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas A-raf/genética , Proteínas Proto-Oncogénicas A-raf/metabolismo , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/metabolismo , Proteínas Proto-Oncogénicas c-raf/genética , Proteínas Proto-Oncogénicas c-raf/metabolismo , Piridinas/administración & dosificación , Sensibilidad y Especificidad , Transducción de Señal , Sorafenib , Quinasas raf/genéticaRESUMEN
A greater understanding of cancer biology and major advances in biotechnology have resulted in the identification of a plethora of rationally designed, target-based anticancer therapeutics, particularly those that inhibit malignant-cell signal transduction, ushering in new therapeutic opportunities and extraordinary developmental challenges. Because these agents seem to principally target malignant cells, it is expected that they will produce less toxicity at clinically effective doses than nonspecific cytotoxic agents. The innate complexity of signaling networks, which have redundant relay systems that confer robustness, adaptability, and signaling diversity, also decreases the probability that any single therapeutic manipulation against any specific signaling element will be highly successful when used alone, particularly in patients with solid malignancies that have multiple relevant signaling aberrations. In addition, because the predominant therapeutic effect of inhibitors of signal transduction processes in preclinical studies is a decreased rate of tumor growth, it is anticipated that the predominant therapeutic outcome in the clinic will be similar; however, this end point is not readily detectable or quantifiable using traditional clinical evaluation methods. Furthermore, the results of preclinical and early clinical studies indicate that dose-toxicity relationships are not likely to be as steep as with nonspecific cytotoxic agents. Therefore, both regulatory and clinical practice end points, such as time to disease progression, disease-related symptoms, and quality of life, which are generally considered secondary for cytotoxic agents, may evolve into primary end points. The cumulative results of developmental evaluations to date indicate that the development, evaluation, and general clinical use of rationally designed, target-based anticancer therapeutics will require a radical departure from traditional paradigms to exploit the full potential of these new therapies.