A phase I study of perifosine with temsirolimus for recurrent pediatric solid tumors Journal Article


Authors: Becher, O. J.; Gilheeney, S. W.; Khakoo, Y.; Lyden, D. C.; Haque, S.; De Braganca, K. C.; Kolesar, J. M.; Huse, J. T.; Modak, S.; Wexler, L. H.; Kramer, K.; Spasojevic, I.; Dunkel, I. J.
Article Title: A phase I study of perifosine with temsirolimus for recurrent pediatric solid tumors
Abstract: Background: The PI3K/AKT/mTOR pathway is aberrantly activated in many pediatric solid tumors including gliomas and medulloblastomas. Preclinical data in a pediatric glioma model demonstrated that the combination of perifosine (AKT inhibitor) and temsirolimus (mTOR inhibitor) is more potent at inhibiting the axis than either agent alone. We conducted this study to assess pharmacokinetics and identify the maximum tolerated dose for the combination. Procedure: We performed a standard 3+3 phase I, open-label, dose-escalation study in patients with recurrent/refractory pediatric solid tumors. Four dose levels of perifosine (25–75 mg/m2/day) and temsirolimus (25–75 mg/m2 IV weekly) were investigated. Results: Twenty-three patients (median age 8.5 years) with brain tumors (diffuse intrinsic pontine glioma [DIPG] n = 8, high-grade glioma n = 6, medulloblastoma n = 2, ependymoma n = 1), neuroblastoma (n = 4), or rhabdomyosarcoma (n = 2) were treated. The combination was generally well tolerated and no dose-limiting toxicity was encountered. The most common grade 3 or 4 toxicities (at least possibly related) were thrombocytopenia (38.1%), neutropenia (23.8%), lymphopenia (23.8%), and hypercholesterolemia (19.0%). Pharmacokinetic findings for temsirolimus were similar to those observed in the temsirolimus single-agent phase II pediatric study and pharmacokinetic findings for perifosine were similar to those in adults. Stable disease was seen in 9 of 11 subjects with DIPG or high-grade glioma; no partial or complete responses were achieved. Conclusions: The combination of these AKT and mTOR inhibitors was safe and feasible in patients with recurrent/refractory pediatric solid tumors. © 2016 Wiley Periodicals, Inc.
Keywords: temsirolimus; akt; phase i clinical trials; perifosine; mtor
Journal Title: Pediatric Blood and Cancer
Volume: 64
Issue: 7
ISSN: 1545-5009
Publisher: Wiley Periodicals, Inc  
Date Published: 2017-07-01
Start Page: e26409
Language: English
DOI: 10.1002/pbc.26409
PROVIDER: scopus
PUBMED: 28035748
DOI/URL:
Notes: Article -- Export Date: 3 July 2017 -- Source: Scopus
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MSK Authors
  1. Ira J Dunkel
    321 Dunkel
  2. David C Lyden
    85 Lyden
  3. Kim Kramer
    206 Kramer
  4. Shakeel Modak
    211 Modak
  5. Yasmin Khakoo
    130 Khakoo
  6. Leonard H Wexler
    163 Wexler
  7. Sofia S Haque
    122 Haque
  8. Jason T Huse
    133 Huse
  9. Oren Josh Becher
    25 Becher