Phospholipases to treatment groups was determined by a computer generated random sequence

Taurine were to compare OS from the time of randomization, tocompare PFS and OS from the start of first line therapy, and to assess safety and adverse event profiles. Assignment to treatment groups was determined by a computer generated random sequence using an Interactive Voice Response System. Randomization was stratified for the following prognostic factors at baseline using the blocked randomization method: prior adjuvant therapy and response to first line treatment. In the enzastaurin arm, a loading dose of enzastaurin 1125 mg/d was given orally followed by subsequent doses of 500 mg/d orally. In the placebo arm, placebo was given orally 3 daily on day 1 of cycle 1 followed by subsequent doses given orally 2 times daily. Both arms received LV5FU2 plus bevacizumab on day 1 of each cycle : leucovorin 400 mg/m2 intravenously, then 5 fluorouracil 400 mg/m2 bolus followed by 2400 mg/m2 IV over 46 hours, and bevacizumab 5 mg/kg IV. Maintenance treatment phospholipases continued until the occurrence of progressive disease or unacceptable toxicity. Enzastaurin doses were not reduced or omitted for laboratory hematologic toxicity that was clearly attributable to 5 fluorouracil/leucovorin or bevacizumab therapy, with the exception of elevated liver transaminases and febrile neutropenia.
Any unusual or unexpected AEs that occurred that were above and berberine beyond the expected safety profile of 5 fluorouracil/leucovorin plus bevacizumab combination therapy required omission of enzastaurin until the event resolved. After the event resolved to grade 1 or baseline, patients were restarted on enzastaurin 250 mg daily. Baseline and Treatment Assessments Efficacy analyses were conducted on all randomized patients, safety analyses were conducted on all randomized patients who received at least 1 dose of enzastaurin/ placebo, 5 fluorouracil, leucovorin, or bevacizumab. Disease assessment was made every 6 weeks using a modified version of Response Evaluation Criteria in Solid Tumors.16 PFS was defined as the time from the date of randomization or from the start of first line therapy to the first date of objectively determined PD, clinical progression, or death. OS was defined as the time from the date of randomization or from the start of first line therapy to the everolimus date of death. Toxicity was assessed at each cycle using the National Cancer Institutes Common Terminology Criteria for Adverse Events, version 3.0.
Statistical Considerations The purpose of this phase 2 study was to detect an improvement in PFS with the addition of enzastaurin to 5 fluorouracil/leucovorin plus bevacizumab, not to rigorously demonstrate superiority. Originally, enrollment of approximately 150 patients was planned, with the expectation of 118 PFS events for the primary efficacy analysis. However, a decision was made to perform an earlier evaluation of the primary endpoint to assess the regimen relevance of outcomes from additional CRC studies, and the study was amended to perform the primary efficacy analysis after at least 50 events of clinical progression, objective progression, or death. At this point, enrollment was stopped, the study treatment assignment was unblinded, and the final analysis was performed. The study was thus powered to detect a 36% improvement in PFS by showing a median PFS of 7.5 months.

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