Combination of Sulindac and Eflornithine Delays the Need for Lower Gastrointestinal Surgery in Patients With Familial Adenomatous Polyposis: Post Hoc Analysis of a Randomized Clinical Trial.

BACKGROUND: Colectomy and proctocolectomy are the initial standard of care for patients with familial adenomatous polyposis. Pharmacotherapy to prevent the progression of polyposis and surgeries in the lower GI tract would be beneficial to patients with this disease. OBJECTIVE: This analysis aimed to evaluate the impact of eflornithine-sulindac combination versus monotherapy in delaying time to disease progression in the lower GI tract of patients with familial adenomatous polyposis. DESIGN: This is a post hoc analysis of a randomized phase 3 trial. SETTING: This study was conducted in 21 hospitals in 7 countries treating patients with familial adenomatous polyposis. PATIENTS: Adults with familial adenomatous polyposis were randomly assigned 1:1:1 into 3 arms. INTERVENTIONS: Patients received either eflornithine (750 mg), sulindac (150 mg), or both once daily for up to 48 months. MAIN OUTCOME MEASURES: Efficacy was evaluated as the time from randomization to predefined primary disease progression end points. RESULTS: A total of 158 patients were included in the study. Disease progression was observed in 2 of 54 (3.7%), 9 of 53 (17.0%), and 10 of 51 (19.6%) patients with at least partial lower GI tract in the combination, sulindac, and eflornithine arms, corresponding to risk reductions of 80% (p = 0.02) and 83% (p = 0.01) between combination and sulindac or eflornithine. When endoscopic excision of adenomas ≥10 mm in size was censored, the need for major surgery was observed in 0 of 54, 7 of 53 (13.2%), and 8 of 51 (15.7%) patients in the combination, sulindac, and eflornithine arms, corresponding to risk reductions approaching 100% between combination and sulindac (p = 0.005) or combination and eflornithine (p = 0.003). LIMITATIONS: This was a post hoc analysis, the sample size was small, and there were fewer than expected events. CONCLUSIONS: Eflornithine-sulindac combination therapy was superior to either drug alone in delaying or preventing the need for lower GI tract surgery in patients with familial adenomatous polyposis. See Video Abstract at http://links.lww.com/DCR/B658. REGISTRATION: ClinicalTrials.gov, NCT01483144; EU Clinical Trials Register, EudraCT 2012-000427-41. LA COMBINACIN DE SULINDAC Y EFLORNITINA RETRASA LA NECESIDAD DE CIRUGA DEL TUBO DIGESTIVO BAJO EN PACIENTES CON PAF ANLISIS POSTHOC DE UN ENSAYO CLNICO ALEATORIZADO: ANTECEDENTES:La colectomía y la proctocolectomía son el estándar inicial de atención para los pacientes con poliposis adenomatosa familiar. La farmacoterapia para prevenir la progresión de la poliposis y las cirugías en el tracto gastrointestinal inferior sería beneficiosa para los pacientes con esta enfermedad.OBJETIVO:Este análisis tuvo como objetivo evaluar el impacto de la combinación de eflornitina-sulindac versus la monoterapia en el retraso del tiempo hasta la progresión de la enfermedad en el tracto gastrointestinal inferior de pacientes con poliposis adenomatosa familiar.DISEÑO:Este es un análisis posthoc de un ensayo de fase 3 aleatorizado.ENTORNO CLINICO:Veintiún hospitales en 7 países que tratan a pacientes con poliposis adenomatosa familiar.PACIENTES:Adultos con poliposis adenomatosa familiar fueron aleatorizados 1: 1: 1 en 3 brazos.INTERVENCIONES:Los pacientes recibieron eflornitina (750 mg), sulindac (150 mg) o ambos una vez al día durante un máximo de 48 meses.PRINCIPALES MEDIDAS DE VALORACION:La eficacia se evaluó como el tiempo desde la aleatorización hasta los criterios de valoración primarios predefinidos de progresión de la enfermedad.RESULTADOS:Los resultados se informan para la población de estudio excluyendo a los pacientes que se habían sometido a ileostomías permanentes (n = 158). Se observó progresión de la enfermedad en 2/54 (3,7%), 9/53 (17,0%) y 10/51 (19,6%) pacientes con al menos tracto gastrointestinal inferior parcial en los brazos de combinación, sulindac y eflornitina, respectivamente, correspondientes al riesgo de reducciones del 80% (p = 0,02) y del 83% (p = 0,01) entre la combinación y el sulindaco o la eflornitina, respectivamente. Cuando se censuró la escisión endoscópica de adenomas ≥10 mm de tamaño, se observó la necesidad de cirugía mayor en 0/54, 7/53 (13,2%) y 8/51 (15,7%) pacientes en la combinación, sulindac y eflornitina, respectivamente, correspondientes a reducciones de riesgo cercanas al 100% entre combinación y sulindac (p = 0,005) o combinación y eflornitina (p = 0,003).LIMITACIONES:Este fue un análisis posthoc, el tamaño de la muestra fue pequeño y hubo menos eventos de los esperados.CONCLUSIONES:La terapia de combinación de eflornitina-sulindac fue superior a cualquier fármaco solo para retrasar o prevenir la necesidad de cirugía del tracto gastrointestinal inferior en pacientes con poliposis adenomatosa familiar. Consulte Video Resumen en http://links.lww.com/DCR/B658.

A phase I study of imexon plus gemcitabine as first-line therapy for advanced pancreatic cancer.

PURPOSE: Imexon is an aziridine-derived iminopyrrolidone which has synergy with gemcitabine in pancreatic cancer cell lines. Gemcitabine is a standard therapy for pancreatic cancer. We performed a phase I trial of imexon and gemcitabine to evaluate safety, dose-limiting toxicity (DLT), and maximum tolerated dose (MTD) in patients with advanced pancreatic cancer. METHODS: Patients with untreated locally advanced or metastatic pancreatic adenocarcinoma received therapy in sequential cohorts on regimen A (n = 19; imexon 200 or 280 mg/m(2) intravenously (IV) over 30 min days 1-5, 15-19 and gemcitabine 800 or 1,000 mg/m(2) IV over 30 min on days 1,8,15 every 28 days) or regimen B (n = 86; imexon 280-1,300 mg/m(2) IV over 30-60 min days 1, 8, and 15 and gemcitabine 1,000 mg/m(2) IV over 30 min on days 1, 8, and 15 every 28 days). RESULTS: One hundred five patients received 340 treatment cycles (median 2, range 1-16). PATIENT CHARACTERISTICS: median age 63, 61% male, ECOG PS 0/1 50%/50%, 93% metastatic. DLT was abdominal cramping and pain, often with transient, acute diarrhea. Best response was confirmed partial response (PR) in 11.4%, 8.9% unconfirmed PR, and 48.1% with stable disease. There was a dose proportional increase in imexon AUC across the doses tested with terminal half life 69 min at the MTD and no alteration of gemcitabine pharmacokinetics. CONCLUSIONS: The recommended phase II dose of imexon is 875 mg/m(2) with gemcitabine 1,000 mg/m(2). DLT was acute abdominal pain and cramping. Encouraging antitumor responses support further evaluation of this combination in advanced pancreatic cancer.