• Patrick A Thompson, Rachid Drissi, Jodi A Muscal, Eshini Panditharatna, Maryam Fouladi, Ashish M Ingle, Charlotte H Ahern, Joel M Reid, Tong Lin, Brenda J Weigel, and Susan M Blaney.
• Authors' Affiliations: Texas Children's Cancer Center and Department of Pediatrics; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas; Division of Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Children's Oncology Group, Arcadia; Geron Corporation, Menlo Park, California; Department of Oncology, Mayo Clinic, Rochester; and Department of Pediatrics, Hematology-Oncology, University of Minnesota, Minneapolis, Minnesota.
• Clin Cancer Res. 2013 Dec 1;19(23):6578-84.

PurposeImetelstat is a covalently-lipidated 13-mer thiophosphoramidate oligonucleotide that acts as a potent specific inhibitor of telomerase. It binds with high affinity to the template region of the RNA component of human telomerase (hTERC) and is a competitive inhibitor of telomerase enzymatic activity. The purpose of this study was to determine the recommended phase II dose of imetelstat in children with recurrent or refractory solid tumors.Experimental DesignImetelstat was administered intravenously more than two hours on days 1 and 8, every 21 days. Dose levels of 225, 285, and 360 mg/m(2) were evaluated, using the rolling-six design. Imetelstat pharmacokinetic and correlative biology studies were also performed during the first cycle.ResultsTwenty subjects were enrolled (median age, 14 years; range, 3-21). Seventeen were evaluable for toxicity. The most common toxicities were neutropenia, thrombocytopenia, and lymphopenia, with dose-limiting myelosuppression in 2 of 6 patients at 360 mg/m(2). Pharmacokinetics is dose dependent with a lower clearance at the highest dose level. Telomerase inhibition was observed in peripheral blood mononuclear cells at 285 and 360 mg/m(2). Two confirmed partial responses, osteosarcoma (n = 1) and Ewing sarcoma (n = 1), were observed.ConclusionsThe recommended phase II dose of imetelstat given on days 1 and 8 of a 21-day cycle is 285 mg/m(2).©2013 AACR.

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