Phase I trial of dasatinib, lenalidomide, and temozolomide in children with relapsed or refractory central nervous system tumors

  • Nathan J. Robison
  • Kee Kiat Yeo
  • Adrian P. Berliner
  • Jemily Malvar
  • Michael A. Sheard
  • Ashley S. Margol
  • Robert C. Seeger
  • Teresa Rushing
  • Jonathan L. Finlay
  • Richard Sposto
  • Girish Dhall
Clinical Study

Abstract

Single agent studies targeting the tumor microenvironment in central nervous system (CNS) tumors have largely been disappointing. Combination therapies targeting various pathways and cell types may be a more effective strategy. In this phase I study, we evaluated the combination of dasatinib, lenalidomide, and temozolomide in children with relapsed or refractory primary CNS tumors. Patients 1–21 years old with relapsed or refractory CNS tumors were eligible. Starting doses of dasatinib and lenalidomide were 65 mg/m2/dose twice daily and 55 mg/m2 once daily, respectively, while temozolomide was constant at 75 mg/m2 daily. The study followed a 3 + 3 phase I design, with a 4-week dose-limiting toxicity (DLT) evaluation period. Serial peripheral blood lymphocyte subsets were evaluated in consenting patients. Fifteen patients were enrolled and thirteen were DLT-evaluable. DLTs occurred in 5 patients, including somnolence and confusion (1 patient), hypokalemia (1 patient) and thrombocytopenia (3 patients). The maximum tolerated dose for the combination was dasatinib 65 mg/m2 twice daily, lenalidomide 40 mg/m2 daily, and temozolomide 75 mg/m2 daily, for 21 days followed by 7 days rest in repeating 28-day cycles. Transient increases in natural killer effector cells and cytotoxic T-cells were seen after 1 week of treatment. One out of six response-evaluable patients showed a partial response. The combination was feasible and relatively well tolerated in this heavily pre-treated population. The most common toxicities were hematologic. Preliminary evidence of clinical benefit was seen.

Keywords

Child Brain neoplasms Central nervous system neoplasms Tumor microenvironment Antiangiogenic agents Clinical trial Phase I 

Notes

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

11060_2018_2791_MOESM1_ESM.pdf (42 kb)
Supplementary material 1 (PDF 41 KB)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Nathan J. Robison
    • 1
    • 2
  • Kee Kiat Yeo
    • 1
    • 2
  • Adrian P. Berliner
    • 3
  • Jemily Malvar
    • 1
    • 2
  • Michael A. Sheard
    • 1
    • 2
  • Ashley S. Margol
    • 1
    • 2
  • Robert C. Seeger
    • 1
    • 2
  • Teresa Rushing
    • 1
    • 2
  • Jonathan L. Finlay
    • 4
  • Richard Sposto
    • 1
    • 2
  • Girish Dhall
    • 1
    • 2
  1. 1.Division of Hematology, Oncology and Blood & Marrow Transplantation, Children’s Center for Cancer and Blood DiseasesChildren’s Hospital Los AngelesLos AngelesUSA
  2. 2.University of Southern California Keck School of MedicineLos AngelesUSA
  3. 3.Department of Chemistry and Chemical BiologyHarvard UniversityCambridgeUSA
  4. 4.Nationwide Children’s Hospital and The Ohio State UniversityColumbusUSA

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