RESUMEN
BACKGROUND: Polo-like kinases (Plks) control multiple steps during the cell cycle, and Plk1 is overexpressed in urothelial cancer (UC). Volasertib (BI 6727), a Plk inhibitor, has demonstrated antitumor activity in several malignancies, including UC. In this phase 2 trial, the authors investigated volasertib as a second-line treatment in advanced/metastatic UC. METHODS: Patients who progressed within 2 years of 1 prior chemotherapy regimen received 300 mg volasertib on day 1 every 3 weeks. The dose was escalated to 350 mg in cycle 2 if volasertib was tolerated in cycle 1. The primary endpoint was tumor response, which was assessed every 6 weeks; secondary endpoints were progression-free survival, overall survival, duration of response, safety, and pharmacokinetics. RESULTS: Fifty patients were enrolled, and the median patient age was 68.5 years (range, 52-83 years). All patients had received prior platinum, 94% of patients had relapsed ≤2 years after prior therapy, 36% had liver metastases, and 54% had lung metastases. The median number of treatment cycles was 2 (range, 1-27 treatment cycles), and 23 patients were dose escalated at cycle 2. Seven patients (14%) had a partial response, 13 (26%) had stable disease, and 30 (60%) progressed within 6 weeks. The median response duration was 41 weeks (range, 29.1-77.3 weeks). The median progression-free survival was 1.4 months, and the median overall survival was 8.5 months. The most frequent grade 3 and 4 adverse events were neutropenia (28%), thrombocytopenia (20%), and anemia (16%). No cumulative toxicity was observed. CONCLUSIONS: Volasertib as second-line treatment for advanced/metastatic UC had an acceptable safety profile but demonstrated insufficient antitumor activity for further evaluation as a monotherapy.
Asunto(s)
Pteridinas/uso terapéutico , Neoplasias Urológicas/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Pteridinas/farmacocinética , Resultado del Tratamiento , Neoplasias Urológicas/enzimología , Neoplasias Urológicas/metabolismo , Neoplasias Urológicas/patologíaRESUMEN
BACKGROUND: Treatment options for metastatic colorectal cancer (CRC) are limited after a fluoropyrimidine, oxaliplatin and irinotecan; novel agents need to be explored in this setting. Dasatinib, an oral inhibitor of Src family kinases, inhibits proliferation in CRC cell lines and has antitumor activity in CRC xenograft models. PATIENTS AND METHODS: We conducted a multi-center phase II trial of dasatinib in unresectable, previously-treated metastatic CRC patients. No more than 2 prior chemotherapy regimens were permitted, which must have contained a fluoropyrimidine, oxaliplatin and irinotecan. The primary endpoint was progression-free survival (PFS) at 4 months. The Simon two-stage design required that at least 5 of the first 19 patients be progression-free at 4 months to expand to a second stage. RESULTS: Nineteen patients enrolled at 9 centers. The study was terminated after the first stage due to lack of efficacy. There were no objective responses; 1 patient (5%) had stable disease for 7.3 months. The PFS rate at 4 months was 5.3% (90% CI: 0.3, 22.6). Median PFS was 1.6 months (90% CI: 1.4, 1.8). Median overall survival was 5.1 months (90% CI: 2.4, 6.3). Grade 3/4 toxicities included fatigue in 16% of patients, and anemia, anorexia, nausea/vomiting and dyspnea in 11%. CONCLUSION: Dasatinib is inactive as a single agent in previously treated metastatic CRC patients.
Asunto(s)
Neoplasias Colorrectales/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Tiazoles/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Colorrectales/patología , Dasatinib , Femenino , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/secundario , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/secundario , Masculino , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/efectos adversos , Pirimidinas/efectos adversos , Tiazoles/efectos adversos , Familia-src Quinasas/antagonistas & inhibidoresRESUMEN
PURPOSE: Despite high initial remission rates, most lymphomas relapse and require further therapy. The mammalian target of rapamycin (mTOR) pathway is a validated target in mantle cell lymphoma, but has not been extensively evaluated in other lymphomas. PATIENTS AND METHODS: We performed a phase II trial of single-agent temsirolimus 25-mg weekly in patients with relapsed aggressive and indolent lymphomas. The primary objective was overall and complete response rate. Patients were stratified by histology: group A (diffuse large B-cell lymphoma, transformed follicular lymphoma), group B (follicular lymphoma), and group C (chronic lymphocytic leukemia/small lymphocytic lymphoma, and other indolent lymphomas). RESULTS: Eighty-nine patients were treated, with outcome strongly dependent on histology. Group A had an overall and complete response rate of 28.1% and 12.5%, respectively, and median progression-free survival (PFS) of 2.6 months and median overall survival (OS) of 7.2 months. Group B had overall and complete response rates of 53.8% and 25.6%, respectively, and median PFS of 12.7 months; median OS has not yet been reached. Group C had a partial response rate of 11% with no complete responders. Toxicity was mainly mild and/or reversible myelosuppression and mucositis; however, four patients developed pneumonitis. CONCLUSIONS: Single-agent temsirolimus has significant activity in both diffuse large B-cell lymphoma and follicular lymphoma, although the durability of responses and PFS are longer for patients with follicular lymphoma. This is the first report of substantial activity of temsirolimus in lymphomas other than mantle cell lymphoma, and supports further evaluation of mTOR as a target in these diseases.
Asunto(s)
Antineoplásicos/uso terapéutico , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Linfoma no Hodgkin/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Serina-Treonina Quinasas/metabolismo , Sirolimus/análogos & derivados , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Médula Ósea/efectos de los fármacos , Chicago , Supervivencia sin Enfermedad , Femenino , Humanos , Péptidos y Proteínas de Señalización Intracelular/efectos de los fármacos , Estimación de Kaplan-Meier , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Linfoma Folicular/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células del Manto/tratamiento farmacológico , Linfoma no Hodgkin/metabolismo , Masculino , Persona de Mediana Edad , Mucositis/inducido químicamente , Neumonía/inducido químicamente , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Proteínas Serina-Treonina Quinasas/efectos de los fármacos , Inducción de Remisión , Sirolimus/administración & dosificación , Sirolimus/efectos adversos , Sirolimus/uso terapéutico , Serina-Treonina Quinasas TOR , Resultado del TratamientoRESUMEN
PURPOSE: Azacitidine (AZA) is effective treatment for myelodysplastic syndromes (MDS) at a dosing schedule of 75 mg/m(2)/d subcutaneously for 7 days every 4 weeks. The initial phase of this ongoing multicenter, community-based, open-label study evaluated three alternative AZA dosing schedules without weekend dosing. PATIENTS AND METHODS: MDS patients were randomly assigned to one of three regimens every 4 weeks for six cycles: AZA 5-2-2 (75 mg/m(2)/d subcutaneously for 5 days, followed by 2 days no treatment, then 75 mg/m(2)/d for 2 days); AZA 5-2-5 (50 mg/m(2)/d subcutaneously for 5 days, followed by 2 days no treatment, then 50 mg/m(2)/d for 5 days); or AZA 5 (75 mg/m(2)/d subcutaneously for 5 days). RESULTS: Of patients randomly assigned to AZA 5-2-2 (n = 50), AZA 5-2-5 (n = 51), or AZA 5 (n = 50), most were French-American-British (FAB) lower risk (refractory anemia [RA]/RA with ringed sideroblasts/chronic myelomonocytic leukemia with < 5% bone marrow blasts, 63%) or RA with excess blasts (30%), and 79 (52%) completed > or = six treatment cycles. Hematologic improvement (HI) was achieved by 44% (22 of 50), 45% (23 of 51), and 56% (28 of 50) of AZA 5-2-2, AZA 5-2-5, and AZA 5 arms, respectively. Proportions of RBC transfusion-dependent patients who achieved transfusion independence were 50% (12 of 24), 55% (12 of 22), and 64% (16 of 25), and of FAB lower-risk transfusion-dependent patients were 53% (nine of 17), 50% (six of 12), and 61% (11 of 18), respectively. In the AZA 5-2-2, AZA 5-2-5, and AZA 5 groups, 84%, 77%, and 58%, respectively, experienced > or = 1 grade 3 to 4 adverse events. CONCLUSION: All three alternative dosing regimens produced HI, RBC transfusion independence, and safety responses consistent with the currently approved AZA regimen. These results support AZA benefits in transfusion-dependent lower-risk MDS patients.