TY - JOUR
T1 - Phase i study of LY2181308, an antisense oligonucleotide against survivin, in patients with advanced solid tumors
AU - Tanioka, M.
AU - Nokihara, H.
AU - Yamamoto, N.
AU - Yamada, Y.
AU - Yamada, K.
AU - Goto, Y.
AU - Fujimoto, T.
AU - Sekiguchi, R.
AU - Uenaka, K.
AU - Callies, S.
AU - Tamura, T.
N1 - Funding Information:
Fig. 2 Mean plasma concentration–time proWles of LY2181308. Mean plasma concentration–time proWles of LY2181308 on day 1 (a) and day 3–7 (b). Cmax and AUC at 750 mg were comparable between Japanese and non-Japanese patients [21] Acknowledgments The study was sponsored and supported by Eli Lilly Japan K.K. We thank Dr. Michael Lahn, Dr. Hisashi Taniai and Dr. Sotaro Enatsu for their review of the manuscript, and Toshinori Mishina for editorial assistance.
PY - 2011/8
Y1 - 2011/8
N2 - Purpose: LY2181308 is an antisense oligonucleotide that complementarily binds to survivin mRNA and inhibits its expression in tumor tissue. This phase I dose escalation study evaluated the tolerability, pharmacokinetics, and anticancer activity of LY2181308 in Japanese. Methods: Patients with solid tumors refractory to standard therapy received LY2181308 (400, 600, or 750 mg) as a 3-h intravenous infusion for 3 consecutive days and thereafter once a week. Results: LY2181308 was administered to 14 patients, aged 44-73 (median 60) years. Flu-like syndrome, prolonged prothrombin time-international normalized ratio (PT-INR), thrombocytopenia, and fatigue were common reversible grade 1/2 toxicities. The dose-limiting toxicity was reversible grade 3 elevation of ALT/AST/γ-GTP in 1 patient treated at the 750-mg dose. Pharmacokinetic analysis showed a long terminal half-life of 21 days and an extensive tissue distribution of LY2181308. In 12 evaluable patients, one patient had stable disease, while the remaining 11 patients had progressive disease. Conclusions: LY2181308 monotherapy is well tolerated up to 750 mg with a manageable toxicity, the pharmacokinetic profile warrants further evaluation of LY2181308 in combination with cytotoxic agents or radiotherapy.
AB - Purpose: LY2181308 is an antisense oligonucleotide that complementarily binds to survivin mRNA and inhibits its expression in tumor tissue. This phase I dose escalation study evaluated the tolerability, pharmacokinetics, and anticancer activity of LY2181308 in Japanese. Methods: Patients with solid tumors refractory to standard therapy received LY2181308 (400, 600, or 750 mg) as a 3-h intravenous infusion for 3 consecutive days and thereafter once a week. Results: LY2181308 was administered to 14 patients, aged 44-73 (median 60) years. Flu-like syndrome, prolonged prothrombin time-international normalized ratio (PT-INR), thrombocytopenia, and fatigue were common reversible grade 1/2 toxicities. The dose-limiting toxicity was reversible grade 3 elevation of ALT/AST/γ-GTP in 1 patient treated at the 750-mg dose. Pharmacokinetic analysis showed a long terminal half-life of 21 days and an extensive tissue distribution of LY2181308. In 12 evaluable patients, one patient had stable disease, while the remaining 11 patients had progressive disease. Conclusions: LY2181308 monotherapy is well tolerated up to 750 mg with a manageable toxicity, the pharmacokinetic profile warrants further evaluation of LY2181308 in combination with cytotoxic agents or radiotherapy.
KW - Antisense oligonucleotide
KW - Pharmacokinetics
KW - Phase I
KW - Survivin
UR - http://www.scopus.com/inward/record.url?scp=79960918427&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79960918427&partnerID=8YFLogxK
U2 - 10.1007/s00280-010-1506-7
DO - 10.1007/s00280-010-1506-7
M3 - Article
C2 - 21079959
AN - SCOPUS:79960918427
SN - 0344-5704
VL - 68
SP - 505
EP - 511
JO - Cancer Chemotherapy and Pharmacology
JF - Cancer Chemotherapy and Pharmacology
IS - 2
ER -
