Abstract C169: Intermittent dosing of Imetelstat Sodium, a telomerase inhibitor, induces drug exposure consistent with in vivo tumor growth inhibition
Authors: Ratain Mark J. , Heath Elisabeth , Weise Amy , Elias Laurence , Benedetti Fabio M. , Smith Jennifer A. , Lin Tong , Pirot Zhu , LoRusso Patricia 
Published: June 2012

Abstract
Background: Telomerase maintains telomere length (TL) of dividing cells, and is essential for cell immortalization. Telomerase is upregulated in tumors, particularly in cancer progenitor cells. Imetelstat (GRN163L), the first targeted telomerase inhibitor in clinical trials, is a 13-mer lipidated oligonucleotide that binds to the template RNA strand of telomerase. With weekly dosing, thrombocytopenia was dose limiting and MTD was 4.8 mg/kg. To increase drug exposure and maintain tolerability, we tested an intermittent dosing schedule of imetelstat.
Methods: Patients (pts) with advanced solid cancers were given imetelstat as a single agent by 2 hr. i.v. infusions on D1 and D8 of 21-Day cycles (Cy), starting at 4.8 mg/kg. A 3+3 dose escalation was used. Pre-treatment granulocyte TL (PMN TL), a surrogate of hematopoietic progenitor TL, was measured by Flow-FISH.
Results: 31 pts have been treated, with 4 currently on study. Mean number of prior cytotoxic regimens reported for 26 pts was 3.6 and 16 pts had prior irradiation.
Dose escalation proceeded to 11.7 mg/kg, which was judged to be in excess of the MTD due to cytopenias.
Three pts had been previously treated with 9.4 mg/kg without DLT, and the 9.4 mg/kg cohort was subsequently expanded to 12 pts, maintaining q21 D dosing. To date, severe myelosuppression has been observed in only 1 pt, and all 12 completed Cy 1. Three pts had doses held in Cy 2 for thrombocytopenia. Eight pts discontinued treatment after completing 1 to 4 Cy, 6 for PD, 1 for a hypersensitivity reaction and 1 for an unrelated SAE. Four pts are currently on treatment and have completed 2 to 3 Cy.
Hypersensitivity reactions were observed in 5 of 31 pts dosed to date and were associated with biochemical evidence of complement activation; one was managed with secondary prophylaxis with steroids and antihistamines, and routine primary prophylaxis was subsequently instituted for all patients. Transient (&lt;24hr) prolongation of aPTT occurs without clinical sequelae. Other AEs were non-specific, mild to moderate and of dubious causality. Mean ± SD (N) imetelstat AUC-inf from pts treated with 7.5, 9.4 and 11.7 mg/kg were 1036 ± 359 (3), 1219 ± 109 (2) and 1408 ± 812 (6), respectively. By comparison, antitumor effects were noted in xenograft models with AUC-inf of 819.
Preliminary analysis of pre- and post-treatment hair follicle samples for pharmacodynamic activity suggests a trend for telomerase inhibition. As previously noted*, thrombocytopenia correlated with short baseline PMN TL among 17 pts.
Conclusions: Intermittent dosing of imetelstat at 9.4 mg/kg was well tolerated for multiple cycles. Drug exposures were in a range associated with antitumor activity in preclinical models and preliminary evidence of a pharmacodynamic effect has been observed. Hematologic toxicity is doselimiting, and may be mechanism-based.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C169.