RESUMEN
PURPOSE: Sunitinib is an oral, multitargeted tyrosine kinase inhibitor that inhibits vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor, stem cell factor receptor (KIT), and colony-stimulating factor-1 receptor. This phase II, open-label, multicenter study evaluated sunitinib monotherapy in patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: Sixty-four patients previously treated with an anthracycline and a taxane received sunitinib 50 mg/d in 6-week cycles (4 weeks on, then 2 weeks off treatment). The primary end point was objective response rate. Plasma samples were obtained for pharmacokinetic and biomarker analysis. RESULTS: Seven patients achieved a partial response (median duration, 19 weeks), giving an overall response rate of 11%. Three additional patients (5%) maintained stable disease for >or= 6 months. Median time to progression and overall survival were 10 and 38 weeks, respectively. Notably, responses occurred in triple negative tumors and HER2-positive, trastuzumab-treated patients. Thirty-three patients (52%) required dose interruption during >or= 1 cycle, and 25 patients required dose reduction (39%). Thirty-six patients (56%) had dose modifications due to adverse events (AEs). Treatment was associated with increases in plasma VEGF and decreases in soluble VEGFRs and KIT. The most common AEs were fatigue, nausea, diarrhea, mucosal inflammation, and anorexia. Most AEs were mild to moderate (grade 1 to 2) in severity and were effectively managed with dose delays or reductions. CONCLUSION: Sunitinib is active in patients with heavily pretreated MBC. Most AEs were of mild-to-moderate severity and manageable with supportive treatment and/or dose modification. Further studies in breast cancer are warranted.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Carcinoma/tratamiento farmacológico , Carcinoma/secundario , Indoles/uso terapéutico , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Pirroles/uso terapéutico , Administración Oral , Adulto , Anciano , Antraciclinas/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/sangre , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/sangre , Neoplasias de la Mama/sangre , Neoplasias de la Mama/mortalidad , Hidrocarburos Aromáticos con Puentes/administración & dosificación , Carcinoma/clasificación , Esquema de Medicación , Fatiga/inducido químicamente , Femenino , Enfermedades Gastrointestinales/inducido químicamente , Enfermedades Hematológicas/inducido químicamente , Humanos , Indoles/efectos adversos , Indoles/sangre , Persona de Mediana Edad , Pirroles/efectos adversos , Pirroles/sangre , Sunitinib , Tasa de Supervivencia , Taxoides/administración & dosificaciónRESUMEN
A phase I study of a combination of the proteasome inhibitor bortezomib and pegylated liposomal doxorubicin showed significant anti-tumor activity against advanced multiple myeloma, with 36% of patients achieving a complete or near-complete response and 73% having a partial response or better. Given this encouraging efficacy, it was therefore of interest to update the prior experience and define parameters such as time to progression, time to retreatment, and overall survival. Additional follow-up was collected on all evaluable multiple myeloma patients and revealed a median time to progression of 9.3 months versus 3.8 months on whatever had been the patient's prior therapy. Time to retreatment was prolonged from 5.9 months after the patient's prior therapy to 24.2 months after bortezomib with pegylated liposomal doxorubicin. The median overall survival after therapy with bortezomib and pegylated liposomal doxorubicin was 38.3 months. These findings compare favorably with results reported for bortezomib alone and support the possibility that the bortezomib/pegylated liposomal doxorubicin regimen may provide superior efficacy against relapsed/refractory multiple myeloma.
Asunto(s)
Ácidos Borónicos/uso terapéutico , Doxorrubicina/análogos & derivados , Mieloma Múltiple/tratamiento farmacológico , Polietilenglicoles/uso terapéutico , Pirazinas/uso terapéutico , Anciano , Ácidos Borónicos/administración & dosificación , Bortezomib , Doxorrubicina/uso terapéutico , Quimioterapia Combinada , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Persona de Mediana Edad , Pirazinas/administración & dosificación , Factores de Tiempo , Resultado del TratamientoRESUMEN
Proteasome inhibitors, a novel class of chemotherapeutic agents, enhance the antitumor efficacy of anthracyclines in vitro and in vivo. We therefore sought to determine the maximum tolerated dose (MTD) and dose-limiting toxicities of bortezomib and pegylated liposomal doxorubicin (PegLD). Bortezomib was given on days 1, 4, 8, and 11 from 0.90 to 1.50 mg/m2 and PegLD on day 4 at 30 mg/m2 to 42 patients with advanced hematologic malignancies. Grade 3 or 4 toxicities in at least 10% of patients included thrombocytopenia, lymphopenia, neutropenia, fatigue, pneumonia, peripheral neuropathy, febrile neutropenia, and diarrhea. The MTD based on cycle 1 was 1.50 and 30 mg/m2 of bortezomib and PegLD, respectively. However, due to frequent dose reductions and delays at this level, 1.30 and 30 mg/m2 are recommended for further study. Pharmacokinetic and pharmacodynamic studies did not find significant drug interactions between these agents. Antitumor activity was seen against multiple myeloma, with 8 of 22 evaluable patients having a complete response (CR) or near-CR, including several with anthracycline-refractory disease, and another 8 having partial responses (PRs). One patient with relapsed/refractory T-cell non-Hodgkin lymphoma (NHL) achieved a CR, whereas 2 patients each with acute myeloid leukemia and B-cell NHL had PRs. Bortezomib/PegLD was safely administered in this study with promising antitumor activity, supporting further testing of this regimen.
Asunto(s)
Antibióticos Antineoplásicos/administración & dosificación , Ácidos Borónicos/administración & dosificación , Doxorrubicina/administración & dosificación , Neoplasias Hematológicas/tratamiento farmacológico , Inhibidores de Proteasas/administración & dosificación , Pirazinas/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Antibióticos Antineoplásicos/efectos adversos , Antibióticos Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Ácidos Borónicos/efectos adversos , Ácidos Borónicos/farmacocinética , Bortezomib , Doxorrubicina/efectos adversos , Doxorrubicina/farmacocinética , Femenino , Humanos , Liposomas , Masculino , Persona de Mediana Edad , Polietilenglicoles , Inhibidores de Proteasas/efectos adversos , Inhibidores de Proteasas/farmacocinética , Inhibidores de Proteasoma , Pirazinas/efectos adversos , Pirazinas/farmacocinética , Resultado del TratamientoRESUMEN
PURPOSE: To determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacodynamics (PD) of the proteasome inhibitor bortezomib (previously known as PS-341) in patients with refractory hematologic malignancies. PATIENTS AND METHODS: Patients received PS-341 twice weekly for 4 weeks at either 0.40, 1.04, 1.20, or 1.38 mg/m(2), followed by a 2-week rest. The PD of PS-341 was evaluated by measurement of whole blood 20S proteasome activity. RESULTS: Twenty-seven patients received 293 doses of PS-341, including 24 complete cycles. DLTs at doses above the 1.04-mg/m(2) MTD attributed to PS-341 included thrombocytopenia, hyponatremia, hypokalemia, fatigue, and malaise. In three of 10 patients receiving additional therapy, serious reversible adverse events appeared during cycle 2, including one episode of postural hypotension, one systemic hypersensitivity reaction, and grade 4 transaminitis in a patient with hepatitis C and a substantial acetaminophen ingestion. PD studies revealed PS-341 induced 20S proteasome inhibition in a time-dependent manner, and this inhibition was also related to both the dose in milligrams per meter squared, and the absolute dose of PS-341. Among nine fully assessable patients with heavily pretreated plasma cell dyscrasias completing one cycle of therapy, there was one complete response and a reduction in paraprotein levels and/or marrow plasmacytosis in eight others. In addition, one patient with mantle cell lymphoma and another with follicular lymphoma had shrinkage of nodal disease. CONCLUSION: PS-341 was well tolerated at 1.04 mg/m(2) on this dose-intensive schedule, although patients need to be monitored for electrolyte abnormalities and late toxicities. Additional studies are indicated to determine whether incorporation of dose/body surface area yields a superior PD model to dosing without normalization. PS-341 showed activity against refractory multiple myeloma and possibly non-Hodgkin's lymphoma in this study, and merits further investigation in these populations.