Phase I study of temsirolimus in pediatric patients with recurrent/refractory solid tumors

Sheri L. Spunt, Stephan A. Grupp, Terry Vik, Victor M. Santana, David J. Greenblatt, Jill Clancy, Anna Berkenblit, Mizue Krygowski, Revathi Ananthakrishnan, Joseph P. Boni, Richard J. Gilbertson

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Abstract

Purpose: To determine dose-limiting toxicities, maximum-tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of weekly intravenous temsirolimus, a mammalian target of rapamycin (mTOR) signaling pathway inhibitor, in pediatric patients with recurrent or refractory solid tumors. Patients and Methods: Cohorts of three to six patients 1 to 21 years of age with recurrent or refractory solid tumors were treated with a 1-hour intravenous infusion of temsirolimus weekly for 3 weeks per course at one of four dose levels: 10, 25, 75, or 150 mg/m2. During the first two courses, pharmacokinetic and pharmacodynamic evaluations (phosphorylation of S6, AKT, and 4EBP1 in peripheral-blood mononuclear cells) were performed. Results: Dose-limiting toxicity (grade 3 anorexia) occurred in one of 18 evaluable patients at the 150 mg/m2 level, which was determined to be tolerable, and an MTD was not identified. In 13 patients evaluable for response after two courses of therapy, one had complete response (CR; neuroblastoma) and five had stable disease (SD). Four patients (three SDs + one CR) remained on treatment for more than 4 months. The sum of temsirolimus and sirolimus areas under the concentrationtime curve was comparable to values in adults. AKT and 4EBP1 phosphorylation were inhibited at all dose levels, particularly after two courses. Conclusion: Weekly intravenous temsirolimus is well tolerated in children with recurrent solid tumors, demonstrates antitumor activity, has pharmacokinetics similar to those in adults, and inhibits the mTOR signaling pathway in peripheral-blood mononuclear cells. Further studies are needed to define the optimal dose for use in combination with other antineoplastic agents in pediatric patients.

Original languageEnglish
Pages (from-to)2933-2940
Number of pages8
JournalJournal of Clinical Oncology
Volume29
Issue number21
DOIs
StatePublished - Jul 20 2011

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Pediatrics
Sirolimus
Neoplasms
Maximum Tolerated Dose
Pharmacokinetics
Blood Cells
Phosphorylation
S 6
Anorexia
temsirolimus
Neuroblastoma
Intravenous Infusions
Antineoplastic Agents
Area Under Curve
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Spunt, S. L., Grupp, S. A., Vik, T., Santana, V. M., Greenblatt, D. J., Clancy, J., ... Gilbertson, R. J. (2011). Phase I study of temsirolimus in pediatric patients with recurrent/refractory solid tumors. Journal of Clinical Oncology, 29(21), 2933-2940. https://doi.org/10.1200/JCO.2010.33.4649

Phase I study of temsirolimus in pediatric patients with recurrent/refractory solid tumors. / Spunt, Sheri L.; Grupp, Stephan A.; Vik, Terry; Santana, Victor M.; Greenblatt, David J.; Clancy, Jill; Berkenblit, Anna; Krygowski, Mizue; Ananthakrishnan, Revathi; Boni, Joseph P.; Gilbertson, Richard J.

In: Journal of Clinical Oncology, Vol. 29, No. 21, 20.07.2011, p. 2933-2940.

Research output: Contribution to journalArticle

Spunt, SL, Grupp, SA, Vik, T, Santana, VM, Greenblatt, DJ, Clancy, J, Berkenblit, A, Krygowski, M, Ananthakrishnan, R, Boni, JP & Gilbertson, RJ 2011, 'Phase I study of temsirolimus in pediatric patients with recurrent/refractory solid tumors', Journal of Clinical Oncology, vol. 29, no. 21, pp. 2933-2940. https://doi.org/10.1200/JCO.2010.33.4649
Spunt, Sheri L. ; Grupp, Stephan A. ; Vik, Terry ; Santana, Victor M. ; Greenblatt, David J. ; Clancy, Jill ; Berkenblit, Anna ; Krygowski, Mizue ; Ananthakrishnan, Revathi ; Boni, Joseph P. ; Gilbertson, Richard J. / Phase I study of temsirolimus in pediatric patients with recurrent/refractory solid tumors. In: Journal of Clinical Oncology. 2011 ; Vol. 29, No. 21. pp. 2933-2940.
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AU - Greenblatt, David J.

AU - Clancy, Jill

AU - Berkenblit, Anna

AU - Krygowski, Mizue

AU - Ananthakrishnan, Revathi

AU - Boni, Joseph P.

AU - Gilbertson, Richard J.

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N2 - Purpose: To determine dose-limiting toxicities, maximum-tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of weekly intravenous temsirolimus, a mammalian target of rapamycin (mTOR) signaling pathway inhibitor, in pediatric patients with recurrent or refractory solid tumors. Patients and Methods: Cohorts of three to six patients 1 to 21 years of age with recurrent or refractory solid tumors were treated with a 1-hour intravenous infusion of temsirolimus weekly for 3 weeks per course at one of four dose levels: 10, 25, 75, or 150 mg/m2. During the first two courses, pharmacokinetic and pharmacodynamic evaluations (phosphorylation of S6, AKT, and 4EBP1 in peripheral-blood mononuclear cells) were performed. Results: Dose-limiting toxicity (grade 3 anorexia) occurred in one of 18 evaluable patients at the 150 mg/m2 level, which was determined to be tolerable, and an MTD was not identified. In 13 patients evaluable for response after two courses of therapy, one had complete response (CR; neuroblastoma) and five had stable disease (SD). Four patients (three SDs + one CR) remained on treatment for more than 4 months. The sum of temsirolimus and sirolimus areas under the concentrationtime curve was comparable to values in adults. AKT and 4EBP1 phosphorylation were inhibited at all dose levels, particularly after two courses. Conclusion: Weekly intravenous temsirolimus is well tolerated in children with recurrent solid tumors, demonstrates antitumor activity, has pharmacokinetics similar to those in adults, and inhibits the mTOR signaling pathway in peripheral-blood mononuclear cells. Further studies are needed to define the optimal dose for use in combination with other antineoplastic agents in pediatric patients.

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