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.
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.
Authors: L Dudkin; M B Dilling; P J Cheshire; F C Harwood; M Hollingshead; S G Arbuck; R Travis; E A Sausville; P J Houghton Journal: Clin Cancer Res Date: 2001-06 Impact factor: 12.531
Authors: K Podsypanina; R T Lee; C Politis; I Hennessy; A Crane; J Puc; M Neshat; H Wang; L Yang; J Gibbons; P Frost; V Dreisbach; J Blenis; Z Gaciong; P Fisher; C Sawyers; L Hedrick-Ellenson; R Parsons Journal: Proc Natl Acad Sci U S A Date: 2001-08-14 Impact factor: 11.205
Authors: Yijiang Shi; Joseph Gera; Liping Hu; Jung-hsin Hsu; Robert Bookstein; Weiqun Li; Alan Lichtenstein Journal: Cancer Res Date: 2002-09-01 Impact factor: 12.701
Authors: Josep Maria Peralba; Linda DeGraffenried; William Friedrichs; Letitia Fulcher; Viktor Grünwald; Geoffrey Weiss; Manuel Hidalgo Journal: Clin Cancer Res Date: 2003-08-01 Impact factor: 12.531
Authors: G M Brodeur; J Pritchard; F Berthold; N L Carlsen; V Castel; R P Castelberry; B De Bernardi; A E Evans; M Favrot; F Hedborg Journal: J Clin Oncol Date: 1993-08 Impact factor: 44.544
Authors: Michael B Atkins; Manuel Hidalgo; Walter M Stadler; Theodore F Logan; Janice P Dutcher; Gary R Hudes; Young Park; Song-Heng Liou; Bonnie Marshall; Joseph P Boni; Gary Dukart; Matthew L Sherman Journal: J Clin Oncol Date: 2004-03-01 Impact factor: 44.544
Authors: Viswanath Reddy Belum; Courtney Washington; Christine A Pratilas; Vincent Sibaud; Franck Boralevi; Mario E Lacouture Journal: Pediatr Blood Cancer Date: 2015-02-12 Impact factor: 3.167
Authors: Myrthala Moreno-Smith; Anna Lakoma; Zaowen Chen; Ling Tao; Kathleen A Scorsone; Linda Schild; Kevin Aviles-Padilla; Rana Nikzad; Yankai Zhang; Rikhia Chakraborty; Jan J Molenaar; Sanjeev A Vasudevan; Vivien Sheehan; Eugene S Kim; Silke Paust; Jason M Shohet; Eveline Barbieri Journal: Clin Cancer Res Date: 2017-08-18 Impact factor: 12.531
Authors: Don W Coulter; Christine Walko; Jai Patel; Billie M Moats-Staats; Andrew McFadden; Scott V Smith; Wasiuddin A Khan; Arlene S Bridges; Allison M Deal; Javier Oesterheld; Ian J Davis; Julie Blatt Journal: Anticancer Drugs Date: 2013-04 Impact factor: 2.248