BACKGROUND:Enzastaurin and bevacizumab have demonstrated synergistic antitumor effects and, in phase 1 studies, the combination was well tolerated. This phase 2 study assessed enzastaurin with 5-fluorouracil/leucovorin plus bevacizumab as maintenance therapy for metastatic colorectal cancer (MCRC). METHODS:Patients with locally advanced or MCRC and stable or responding disease after completing 6 cycles of first-line chemotherapy randomly received a loading dose of enzastaurin 1125 mg, followed by 500 mg/d subsequent doses or placebo. Both arms received 5-fluorouracil/leucovorin (leucovorin 400 mg/m(2) intravenously [IV], 5-fluorouracil 400-mg/m(2) bolus, 5-fluorouracil 2400 mg/m(2) IV) plus bevacizumab 5 mg/kg IV, every 2 weeks. The primary endpoint was progression-free survival (PFS), from randomization. Overall survival (OS) and PFS were also assessed from start of first-line therapy. Enrollment was stopped, and the final analysis was conducted after 73 PFS events. RESULTS:Fifty-eight patients were randomized to enzastaurin and 59 to placebo. For the enzastaurin and placebo arms, respectively, the median cycles received were 9 and 10, and the median PFS was 5.8 and 8.1 months (hazard ratio [HR], 1.35; 95% confidence interval [CI], 0.84-2.16; P = .896). Median OS was not calculable because of high censoring (77.6% enzastaurin; 91.5% placebo). The median PFS from start of first-line therapy was 8.9 months for enzastaurin and 11.3 months for placebo (HR, 1.39; 95% CI, 0.86-2.23; P = .913). More enzastaurin patients developed thrombosis or embolism compared with placebo (15.8% and 1.7%; P = .008). One possibly enzastaurin-related death occurred because of arrhythmia. CONCLUSIONS:Enzastaurin combined with bevacizumab-based therapy is tolerable, but does not improve PFS during maintenance therapy in patients with MCRC compared with bevacizumab-based therapy alone.
RCT Entities:
BACKGROUND:Enzastaurin and bevacizumab have demonstrated synergistic antitumor effects and, in phase 1 studies, the combination was well tolerated. This phase 2 study assessed enzastaurin with 5-fluorouracil/leucovorin plus bevacizumab as maintenance therapy for metastatic colorectal cancer (MCRC). METHODS:Patients with locally advanced or MCRC and stable or responding disease after completing 6 cycles of first-line chemotherapy randomly received a loading dose of enzastaurin 1125 mg, followed by 500 mg/d subsequent doses or placebo. Both arms received 5-fluorouracil/leucovorin (leucovorin 400 mg/m(2) intravenously [IV], 5-fluorouracil 400-mg/m(2) bolus, 5-fluorouracil 2400 mg/m(2) IV) plus bevacizumab 5 mg/kg IV, every 2 weeks. The primary endpoint was progression-free survival (PFS), from randomization. Overall survival (OS) and PFS were also assessed from start of first-line therapy. Enrollment was stopped, and the final analysis was conducted after 73 PFS events. RESULTS: Fifty-eight patients were randomized to enzastaurin and 59 to placebo. For the enzastaurin and placebo arms, respectively, the median cycles received were 9 and 10, and the median PFS was 5.8 and 8.1 months (hazard ratio [HR], 1.35; 95% confidence interval [CI], 0.84-2.16; P = .896). Median OS was not calculable because of high censoring (77.6% enzastaurin; 91.5% placebo). The median PFS from start of first-line therapy was 8.9 months for enzastaurin and 11.3 months for placebo (HR, 1.39; 95% CI, 0.86-2.23; P = .913). More enzastaurinpatients developed thrombosis or embolism compared with placebo (15.8% and 1.7%; P = .008). One possibly enzastaurin-related death occurred because of arrhythmia. CONCLUSIONS:Enzastaurin combined with bevacizumab-based therapy is tolerable, but does not improve PFS during maintenance therapy in patients with MCRC compared with bevacizumab-based therapy alone.
Authors: James A McCubrey; Linda S Steelman; William H Chappell; Stephen L Abrams; Richard A Franklin; Giuseppe Montalto; Melchiorre Cervello; Massimo Libra; Saverio Candido; Grazia Malaponte; Maria C Mazzarino; Paolo Fagone; Ferdinando Nicoletti; Jörg Bäsecke; Sanja Mijatovic; Danijela Maksimovic-Ivanic; Michele Milella; Agostino Tafuri; Francesca Chiarini; Camilla Evangelisti; Lucio Cocco; Alberto M Martelli Journal: Oncotarget Date: 2012-10