PMID- 21690471 OWN - NLM STAT- MEDLINE DCOM- 20110916 LR - 20211203 IS - 1527-7755 (Electronic) IS - 0732-183X (Print) IS - 0732-183X (Linking) VI - 29 IP - 21 DP - 2011 Jul 20 TI - Phase I study of temsirolimus in pediatric patients with recurrent/refractory solid tumors. PG - 2933-40 LID - 10.1200/JCO.2010.33.4649 [doi] AB - 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/m(2). 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/m(2) 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 concentration-time 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. FAU - Spunt, Sheri L AU - Spunt SL AD - Department of Oncology, St Jude Children's Research Hospital, Memphis, TN 38105-3678, USA. sheri.spunt@stjude.org FAU - Grupp, Stephan A AU - Grupp SA FAU - Vik, Terry A AU - Vik TA FAU - Santana, Victor M AU - Santana VM FAU - Greenblatt, David J AU - Greenblatt DJ FAU - Clancy, Jill AU - Clancy J FAU - Berkenblit, Anna AU - Berkenblit A FAU - Krygowski, Mizue AU - Krygowski M FAU - Ananthakrishnan, Revathi AU - Ananthakrishnan R FAU - Boni, Joseph P AU - Boni JP FAU - Gilbertson, Richard J AU - Gilbertson RJ LA - eng GR - P01 CA023099/CA/NCI NIH HHS/United States GR - P30 CA021765/CA/NCI NIH HHS/United States GR - CA23099/CA/NCI NIH HHS/United States GR - P30 CA 21765/CA/NCI NIH HHS/United States PT - Clinical Trial, Phase I PT - Journal Article PT - Multicenter Study PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20110620 PL - United States TA - J Clin Oncol JT - Journal of clinical oncology : official journal of the American Society of Clinical Oncology JID - 8309333 RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (Antineoplastic Agents) RN - 0 (Cell Cycle Proteins) RN - 0 (EIF4EBP1 protein, human) RN - 0 (Phosphoproteins) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Ribosomal Protein S6) RN - 624KN6GM2T (temsirolimus) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Adaptor Proteins, Signal Transducing/metabolism MH - Adolescent MH - Antineoplastic Agents/administration & dosage/adverse effects/pharmacokinetics/*therapeutic use MH - Cell Cycle Proteins MH - Child MH - Child, Preschool MH - Drug Administration Schedule MH - Female MH - Humans MH - Infant MH - Infusions, Intravenous MH - Male MH - Maximum Tolerated Dose MH - Neoplasms/*drug therapy/enzymology/pathology MH - Phosphoproteins/metabolism MH - Phosphorylation MH - Protein Kinase Inhibitors/administration & dosage/adverse effects/pharmacokinetics/*therapeutic use MH - Proto-Oncogene Proteins c-akt/metabolism MH - Ribosomal Protein S6/metabolism MH - Signal Transduction/drug effects MH - Sirolimus/administration & dosage/adverse effects/*analogs & derivatives/pharmacokinetics/therapeutic use MH - TOR Serine-Threonine Kinases/antagonists & inhibitors/metabolism MH - Treatment Outcome MH - United States MH - Young Adult PMC - PMC3138720 COIS- Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article. EDAT- 2011/06/22 06:00 MHDA- 2011/09/17 06:00 PMCR- 2012/07/20 CRDT- 2011/06/22 06:00 PHST- 2011/06/22 06:00 [entrez] PHST- 2011/06/22 06:00 [pubmed] PHST- 2011/09/17 06:00 [medline] PHST- 2012/07/20 00:00 [pmc-release] AID - JCO.2010.33.4649 [pii] AID - 34649 [pii] AID - 10.1200/JCO.2010.33.4649 [doi] PST - ppublish SO - J Clin Oncol. 2011 Jul 20;29(21):2933-40. doi: 10.1200/JCO.2010.33.4649. Epub 2011 Jun 20.