pharmacokinetic parameter estimates in the 250 mg dose group is due to a patient who had very high concentrations compared with the other two patients in the group. The mean steady state pharmacokinetic Imiquimod parameters for erlotinib 150 mg daily with 250 or 500 mg daily doses of enzastaurin are summarized in Table 5. The mean clearance of erlotinib was 6.07 L/h when given with 250 mg of enzastaurin and 5.75 L/h when given with 500 mg of enzastaurin. Data from one patient in dose level 2 were excluded from the analysis due to an error in the dose record. The mean steady state plasma concentration time profiles of erlotinib and total analyte are shown in Fig. 1.This patient was an Asian female non smoker, factors known to improve response to erlotinib , but her EGFR mutational status was not known.
Three patients had stable disease for . All four patients with prolonged SD or PR had NSCLC and were female; two were Asian and two were Caucasian. Seven patients progressed after just two cycles, three other patients Rifapentine clinical trial progressed before completing two cycles, and one progressed Rifapentine structure before completing one cycle. Of the seven patients who progressed by the first interim scan , the majority had tumors other than NSCLC and were smokers. Discussion To our knowledge, this phase I clinical trial was the first to combine enzastaurin with an EGFR inhibitor. The combination showed good tolerability, with no DLTs, and some evidence of activity. We were able to safely administer the maximum doses of both drugs without unexpected toxicity or pharmacokinetic interactions.
The recommended phase II dose of the combination is enzastaurin 500 mg orally daily, after a loading dose , and erlotinib 150 mg orally daily. In our study, there were no unexpected Rifapentine solubility AEs with the combination of erlotinib and enzastaurin, and those seen had been previously documented in single agent studies of erlotinib or enzastaurin . The most common AEs in this study, regardless of relationship to therapy, were diarrhea, chromaturia, rash, decreased appetite, feces discoloration, and nausea. The most common possibly drugrelated grade 3 4 toxicities included diarrhea, neurologic symptoms, and vomiting. In a phase II study of enzastaurin in advanced NSCLC, fatigue and nausea were the most common AEs . Grade 3 toxicities in that study included ataxia, pulmonary embolism, and anemia in one patient each, and there were two study discontinuations, one due to grade 3 fatigue and one due to grade 1 dizziness .
In advanced NSCLC, the welfare state most common AEs of erlotinib alone include rash, diarrhea, anorexia, nausea, and fatigue . In this trial, we did not see any additive toxicity and the regimen was well tolerated.The pharmacokinetic parameters of erlotinib appear similar when used in combination with 250 and 500 mg once daily doses of enzastaurin. The steady state clearance of erlotinib reported in a single agent erlotinib study ranged from 4.36 to 6.27 L/h for doses that ranged from 50 to 200 mg . In this study, steady state clearance of erlotinib was 6.07 and 5.75 L/h when given with 250 and 500 mg once daily enzastaurin, respectively, which is within the range of values reported in the historical data. The AUCs,ss of enzastaurin was 18,000 nmol 9 h/L in this study when enzastaurin 500 mg and erlotinib.