Chemical compound library developed thrombosis or embolism in the enzastaurin arm than in the placebo arm: 15.8% and 1.7%, respectively. Three patients, all in the enzastaurin arm, received transfusions while on study: 2 patients received packed red blood cells, and 1 patient received leukoreduced packed RBCs. Six patients in the enzastaurin arm discontinued treatment because of drug related serious AEs of diarrhea and fatigue and nausea and pulmonary embolism. Two patients in the placebo arm discontinued treatment because of drug related AEs of atrial fibrillation and chapped skin. One patient in the enzastaurin arm died during the study because of possibly drug related arrhythmia. DISCUSSION The role and timing of maintenance therapy remain uncertain in the management of metastatic CRC. Previously, patients were administered high throughput screening standard first line therapy of FOLFOX or FOLFIRI until progression, however, because of cumulative toxicities, first line induction therapy is now often given followed by complete treatment cessation or by maintenance therapy with LV5FU2.
In the current phase 2 study, patients received 6 cycles of rhein 478-43-3 induction FOLFOX or FOLFIRI followed by maintenance treatment with the 5 fluorouracil/leucovorin portion of the induction regimen combined with the targeted agent bevacizumab and either enzastaurin or placebo. Enrollment in the trial was stopped, the study results were unblinded, and the final analysis was conducted after 73 PFS events. The addition of enzastaurin to bevacizumab and LV5FU2 failed to improve PFS compared with placebo as maintenance therapy. On the basis of the observed data, the post hoc power analysis showed that even if the study was analyzed after achieving the originally planned 118 events, the probability of the study being successful would be very low. It is noteworthy that the study has limited power and a high type I error rate, thus the results of the study should be interpreted with caution. Nevertheless, the clinically meaningful results in favor of the placebo arm suggest that the termination of further development of maintenance therapy with enzastaurin plus 5 fluorouracil/leucovorin and bevacizumab was in the best interest of the patients. Consistent with the pazopanib current study, recent results of other phase 2 studies have shown that enzastaurin does not improve efficacy when combined with chemotherapy and bevacizumab in nonsmall cell lung cancer.
Activity was insufficient in epithelial ovarian or primary peritonealcarcinoma, and no PFS benefit was demonstrated with the combination of enzastaurin and capecitabine in metastatic breast cancer that progressed after anthracycline treatment.22,23 The reasons for poor PFS in the enzastaurin arm compared with placebo are uncertain. Because preclinical studies had demonstrated synergistic antitumor effects when enzastaurin was combined with bevacizumab, it seems unlikely that this combination had a negative impact on tumor biology. It is possible that there was a negative interaction between 5 fluorouracil and enzastaurin, which may have compromised the antitumor effect of leucovorin, 5 fluorouracil, and bevacizumab, although no findings currently support that hypothesis. Alternatively, the dual inhibition of the VEGF pathway achieved by combining bevacizumab with enzasta.