Abstract B48: A phase 1 study of an antisense oligonucleotide against survivin (LY2181308) in Japanese patients with solid tumors
Authors: Nokihara Hiroshi , Yamamoto Noboru , Yamada Yasuhide , Yamada Kazuhiko , Goto Yasushi , Tanioka Maki , Nambu Yoshihiro , Uenaka Kazunori , Sekiguchi Risa , Tamura Tomohide 
Published: June 2012

Abstract
Background: Survivin is a protein known to regulate apoptosis and cell division and highly expressed in various types of cancers. The inhibition of survivin is expected to normalize the cell cycle and selectively eradicate tumor cells. LY2181308 is a second generation antisense oligonucleotide (ASO) designed to complementarily bind to human survivin mRNA and to inhibit the gene/protein expression, which in turn should restore the normal apoptotic pathway in cancer cells. To evaluate the tolerability, pharmacokinetics (PK), and anti-tumor effect of LY2181308 in Japanese patients (pts) with solid tumors, a phase 1 dose-escalation study was conducted.
Methods: The primary objective of this study was to evaluate the tolerability of LY2181308 up to 750 mg. The secondary objectives included evaluation of PK and anti-tumor response. Dose-escalation cohorts include 3–6 pts starting at 400 mg with sequential escalations to 600 and 750 mg. The treatment schedule consisted in a loading dose of 3 consecutive daily intravenous infusions over 3 hours, followed by a maintenance weekly intravenous infusion over 3 hours.
Results: A total of 14 pts (11 male /3 female) were enrolled into 3 cohorts (4 at 400 mg; 4 at 600 mg; 6 at 750 mg): median age = 60 (44–73). The median treatment period was 2.0 cycle (1–4).
Of the 14 pts, 12 pts were evaluable for dose limiting toxicities (DLTs, 3 at 400 mg; 3 at 600 mg; 6 at 750 mg); 2 pts each at 400 mg and 600 mg were excluded due to early disease progression. Only 1 pt at 750 mg reported DLTs; Grade 3 elevations in ALT/AST/ -GTP. All 14 pts were evaluable for safety and PK. The most frequent adverse events (AEs) were hyperhidrosis, prothrombin time ratio increased, and pyrexia. Most AEs were CTCAE Grade 1 or 2. No deaths or study discontinuations due to any adverse events were reported. One serious AE (Grade 3 blood bilirubin increased) was observed in 1 pt with pancreatic cancer (600 mg); this toxicity was not judged to be causally related to the study drug due to disease progression. Abnormalities of blood coagulation values, commonly observed with second generation ASOs, were reported in most pts; they were all Grade 1.
The plasma PK profile primarily illustrated tissue distribution, and only a small percentage of the plasma exposure (∼7%) was eliminated under the terminal elimination t½. The terminal elimination t½ was ∼21 days. The geometric mean AUC0-∞ and Cmax following 750-mg dose on Day3 were 324000 ng*h/mL and 66700 ng/mL, which were comparable with those of non-Japanese pts. The terminal t½ was derived from a 4-compartment model which was found to fit adequately the data. Consistent with the long terminal t½, the PK analyses showed that the clearance to tissue and elimination clearance were low to moderate (i.e ∼2 L/h and ∼30 L/h, respectively) and that the volume of distribution was high (&gt;10000 L).
Of the 14 pts, 12 pts who had target lesions were evaluable for anti-tumor response. Eleven pts were Progressive Disease, and 1 pt was Stable Disease.
Conclusions: LY2181308 monotherapy in doses of up to 750 mg was confirmed to be tolerable for Japanese pts with solid tumors. LY2181308 showed very long half-life and was considered to be extensively distributed into tissues based on the rapid decrease of plasma LY2181308 concentration after the administration. Further investigations in combination with other anti-tumor drugs are ongoing.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B48.