RESUMEN
PURPOSE: Given distinct mechanism of actions of enzastaurin and bevacizumab, preclinical studies suggest enhanced antitumor activity in combination. This phase I study assessed the combination's safety and efficacy. PATIENTS AND METHODS: Six advanced cancer patients could be enrolled in each of 11 cohorts. Patients received an enzastaurin loading dose. Oral enzastaurin (500 mg once daily [QD], 250 mg twice daily [BID], 375 mg BID, 500 mg BID, and 750 mg BID) was escalated in each cohort in combination with bevacizumab dosed at 5 mg/kg every 2 weeks, 10 mg/kg every 2 weeks, or 15 mg/kg every 3 weeks until a dose-limiting toxicity (DLT) occurred in 2 of 6 patients in any cohort. RESULTS: Sixty-seven patients (31, ovarian cancer [ovcar]) were evaluable for safety and efficacy. Six treatment-related DLTs occurred: grade 3 fatigue (n=4), grade 4 cerebral hemorrhage, and grade 3 elevated aspartate transaminase. Common drug-related toxicities included change in color of urine and stool, fatigue, pain, diarrhea, and nausea. The maximum tolerated dose of enzastaurin was 750 mg BID in combination with any tested bevacizumab dose/schedule. Overall response rate was 19.4 % (32.3 % ovcar). Median time to progression was 3.7 months (95 % confidence interval [CI], 2.7-5.5), with 8.3 months (95 % CI, 3.7-11.1) in ovcar. Overall, 35.9 % (50.4 % ovcar) of patients remained without disease progression after 6 months. CONCLUSION: The recommended phase II doses of enzastaurin were 500 mg QD up to 500 mg BID with any tested dose/schedule of bevacizumab. This combination demonstrated encouraging clinical activity, particularly in ovcar.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Inhibidores de la Angiogénesis/administración & dosificación , Inhibidores de la Angiogénesis/efectos adversos , Inhibidores de la Angiogénesis/farmacocinética , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Bevacizumab , Femenino , Glucógeno Sintasa Quinasa 3/sangre , Glucógeno Sintasa Quinasa 3 beta , Humanos , Indoles/administración & dosificación , Indoles/efectos adversos , Indoles/farmacocinética , Masculino , Persona de Mediana Edad , Neoplasias/sangre , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/farmacocinética , Resultado del Tratamiento , Adulto JovenRESUMEN
PURPOSE: To find the maximum tolerated dose (MTD) of OSI-461 in combination with mitoxantrone in patients with advanced solid tumors. METHODS: This was a Phase I study using cohort dose escalation of OSI-461 dosed orally twice daily in combination with mitoxantrone 12 mg/m(2) given on Day 1 of each 21-day cycle. RESULTS: OSI-461 dose was escalated to 1,000 mg po bid. One patient experienced a dose-limiting toxicity (DLT). Three patients discontinued the study due to adverse events (AE). Two patients (10%) had a partial response, and ten patients (50%) had stable disease as best response. CONCLUSION: The combination of OSI-461 and mitoxantrone was well tolerated. Dose escalation was stopped because of toxicities in a concurrent Phase I trial. The response rate seen in patients with prostate cancer was comparable to response rates seen in trials of mitoxantrone and prednisone alone, and further studies of the combination of OSI-461 and mitoxantrone were not pursued.