A phase I trial of imetelstat in children with refractory or recurrent solid tumors: A children's oncology group phase I consortium study (ADVL1112)

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, Susan M. Blaney

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)6578-6584
Number of pages7
JournalClinical Cancer Research
Volume19
Issue number23
DOIs
StatePublished - Dec 1 2013

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Telomerase
Neoplasms
Pharmacokinetics
Lymphopenia
Ewing's Sarcoma
Osteosarcoma
Neutropenia
Oligonucleotides
Thrombocytopenia
Blood Cells
Research Design
imetelstat

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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A phase I trial of imetelstat in children with refractory or recurrent solid tumors : A children's oncology group phase I consortium study (ADVL1112). / Thompson, Patrick A.; Drissi, Rachid; Muscal, Jodi A.; Panditharatna, Eshini; Fouladi, Maryam; Ingle, Ashish M.; Ahern, Charlotte H.; Reid, Joel M; Lin, Tong; Weigel, Brenda J.; Blaney, Susan M.

In: Clinical Cancer Research, Vol. 19, No. 23, 01.12.2013, p. 6578-6584.

Research output: Contribution to journalArticle

Thompson, PA, Drissi, R, Muscal, JA, Panditharatna, E, Fouladi, M, Ingle, AM, Ahern, CH, Reid, JM, Lin, T, Weigel, BJ & Blaney, SM 2013, 'A phase I trial of imetelstat in children with refractory or recurrent solid tumors: A children's oncology group phase I consortium study (ADVL1112)', Clinical Cancer Research, vol. 19, no. 23, pp. 6578-6584. https://doi.org/10.1158/1078-0432.CCR-13-1117
Thompson, Patrick A. ; Drissi, Rachid ; Muscal, Jodi A. ; Panditharatna, Eshini ; Fouladi, Maryam ; Ingle, Ashish M. ; Ahern, Charlotte H. ; Reid, Joel M ; Lin, Tong ; Weigel, Brenda J. ; Blaney, Susan M. / A phase I trial of imetelstat in children with refractory or recurrent solid tumors : A children's oncology group phase I consortium study (ADVL1112). In: Clinical Cancer Research. 2013 ; Vol. 19, No. 23. pp. 6578-6584.
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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.

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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.

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