TY - JOUR
T1 - A phase I trial of imetelstat in children with refractory or recurrent solid tumors
T2 - A children's oncology group phase I consortium study (ADVL1112)
AU - Thompson, Patrick A.
AU - Drissi, Rachid
AU - Muscal, Jodi A.
AU - Panditharatna, Eshini
AU - Fouladi, Maryam
AU - Ingle, Ashish M.
AU - Ahern, Charlotte H.
AU - Reid, Joel M.
AU - Lin, Tong
AU - Weigel, Brenda J.
AU - Blaney, Susan M.
PY - 2013/12/1
Y1 - 2013/12/1
N2 - Purpose: Imetelstat 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 Design: Imetelstat 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. Results: Twenty 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 doselimiting myelosuppression in 2 of 6 patients at 360 mg/m2. 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/m2. Two confirmed partial responses, osteosarcoma (n = 1) and Ewing sarcoma (n = 1), were observed. Conclusions: The recommended phase IIdoseof imetelstat given on days 1and 8of a 21-day cycle is285 mg/m2.
AB - Purpose: Imetelstat 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 Design: Imetelstat 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. Results: Twenty 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 doselimiting myelosuppression in 2 of 6 patients at 360 mg/m2. 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/m2. Two confirmed partial responses, osteosarcoma (n = 1) and Ewing sarcoma (n = 1), were observed. Conclusions: The recommended phase IIdoseof imetelstat given on days 1and 8of a 21-day cycle is285 mg/m2.
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U2 - 10.1158/1078-0432.CCR-13-1117
DO - 10.1158/1078-0432.CCR-13-1117
M3 - Article
C2 - 24097866
AN - SCOPUS:84890293036
SN - 1078-0432
VL - 19
SP - 6578
EP - 6584
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 23
ER -
