TY - JOUR
T1 - Phase i study of enzastaurin and bevacizumab in patients with advanced cancer
T2 - Safety, efficacy and pharmacokinetics
AU - Nwankwo, Nwabundo
AU - Zhang, Zhe
AU - Wang, Ting
AU - Collins, Connie
AU - Resta, Lee
AU - Ermisch, Sabine
AU - Day, Jeannette
AU - Decker, Rodney
AU - Kornberg, Lori
AU - Nicol, Steven
AU - Thornton, Donald
AU - Armstrong, Deborah K.
AU - Carducci, Michael A.
N1 - Funding Information:
Conflicts of interest M. Carducci received research funding from Eli Lilly and Company. D. Armstrong served on advisory boards for Genen-tech, supplier of bevacizumab. S. Ermisch, R. Decker, S. Nicol, and D. Thornton are employees of Eli Lilly and Company and own stock. J. Day and L. Kornberg are employees of PharmaNet/i3, which performs services for Eli Lilly and Company; J. Day owns Eli Lilly and Company stock.
PY - 2013/6
Y1 - 2013/6
N2 - Purpose Given distinct mechanism of actions of enzastaurin and bevacizumab, preclinical studies suggest enhanced antitumor activity in combination. This phase I study assessed the combination's safety and efficacy. Patients and methods Six advanced cancer patients could be enrolled in each of 11 cohorts. Patients received an enzastaurin loading dose. Oral enzastaurin (500 mg once daily [QD], 250 mg twice daily [BID], 375 mg BID, 500 mg BID, and 750 mg BID) was escalated in each cohort in combination with bevacizumab dosed at 5 mg/kg every 2 weeks, 10 mg/kg every 2 weeks, or 15 mg/kg every 3 weeks until a dose-limiting toxicity (DLT) occurred in 2 of 6 patients in any cohort. Results Sixty-seven patients (31, ovarian cancer [ovcar]) were evaluable for safety and efficacy. Six treatment-related DLTs occurred: grade 3 fatigue (n = 4), grade 4 cerebral hemorrhage, and grade 3 elevated aspartate transaminase. Common drug-related toxicities included change in color of urine and stool, fatigue, pain, diarrhea, and nausea. The maximum tolerated dose of enzastaurin was 750 mg BID in combination with any tested bevacizumab dose/schedule. Overall response rate was 19.4 % (32.3 % ovcar). Median time to progression was 3.7 months (95 % confidence interval [CI], 2.7-5.5), with 8.3 months (95 % CI, 3.7-11.1) in ovcar. Overall, 35.9 % (50.4 % ovcar) of patients remained without disease progression after 6 months. Conclusion The recommended phase II doses of enzastaurin were 500 mg QD up to 500 mg BID with any tested dose/schedule of bevacizumab. This combination demonstrated encouraging clinical activity, particularly in ovcar.
AB - Purpose Given distinct mechanism of actions of enzastaurin and bevacizumab, preclinical studies suggest enhanced antitumor activity in combination. This phase I study assessed the combination's safety and efficacy. Patients and methods Six advanced cancer patients could be enrolled in each of 11 cohorts. Patients received an enzastaurin loading dose. Oral enzastaurin (500 mg once daily [QD], 250 mg twice daily [BID], 375 mg BID, 500 mg BID, and 750 mg BID) was escalated in each cohort in combination with bevacizumab dosed at 5 mg/kg every 2 weeks, 10 mg/kg every 2 weeks, or 15 mg/kg every 3 weeks until a dose-limiting toxicity (DLT) occurred in 2 of 6 patients in any cohort. Results Sixty-seven patients (31, ovarian cancer [ovcar]) were evaluable for safety and efficacy. Six treatment-related DLTs occurred: grade 3 fatigue (n = 4), grade 4 cerebral hemorrhage, and grade 3 elevated aspartate transaminase. Common drug-related toxicities included change in color of urine and stool, fatigue, pain, diarrhea, and nausea. The maximum tolerated dose of enzastaurin was 750 mg BID in combination with any tested bevacizumab dose/schedule. Overall response rate was 19.4 % (32.3 % ovcar). Median time to progression was 3.7 months (95 % confidence interval [CI], 2.7-5.5), with 8.3 months (95 % CI, 3.7-11.1) in ovcar. Overall, 35.9 % (50.4 % ovcar) of patients remained without disease progression after 6 months. Conclusion The recommended phase II doses of enzastaurin were 500 mg QD up to 500 mg BID with any tested dose/schedule of bevacizumab. This combination demonstrated encouraging clinical activity, particularly in ovcar.
KW - Advanced cancer
KW - Bevacizumab
KW - Enzastaurin
KW - Ovarian cancer
KW - Phase I
UR - http://www.scopus.com/inward/record.url?scp=84879106474&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84879106474&partnerID=8YFLogxK
U2 - 10.1007/s10637-012-9850-6
DO - 10.1007/s10637-012-9850-6
M3 - Article
C2 - 22766773
AN - SCOPUS:84879106474
SN - 0167-6997
VL - 31
SP - 653
EP - 660
JO - Investigational New Drugs
JF - Investigational New Drugs
IS - 3
ER -