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J Neurooncol. 2018 May;138(1):199-207. doi: 10.1007/s11060-018-2791-y. Epub 2018 Feb 9.

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

Author information

1
Division of Hematology, Oncology and Blood & Marrow Transplantation, Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, 4650 Sunset Boulevard, MS #54, Los Angeles, CA, 90027, USA. nrobison@chla.usc.edu.
2
University of Southern California Keck School of Medicine, Los Angeles, CA, USA. nrobison@chla.usc.edu.
3
Division of Hematology, Oncology and Blood & Marrow Transplantation, Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, 4650 Sunset Boulevard, MS #54, Los Angeles, CA, 90027, USA.
4
University of Southern California Keck School of Medicine, Los Angeles, CA, USA.
5
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA.
6
Nationwide Children's Hospital and The Ohio State University, Columbus, OH, USA.

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:

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

PMID:
29427149
PMCID:
PMC5930136
DOI:
10.1007/s11060-018-2791-y
[Indexed for MEDLINE]
Free PMC Article

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