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

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/m/dose twice daily and 55 mg/m once daily, respectively, while temozolomide was constant at 75 mg/m 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/m twice daily, lenalidomide 40 mg/m daily, and temozolomide 75 mg/m 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.

Italian Precision Medicine in Pediatric Oncology: Moving beyond Actionable Alterations

“…Additionally, lenalidomide can induce tumor cell apoptosis and act as an immune-modulator by stimulating T-cell proliferation, reducing the expression of immune-checkpoint inhibitors on both T and NK cells, inhibiting TNF-alpha and reducing T-regulatory cells. Some interesting reports have shown its efficacy in treating CNS relapse and its ability to cross the blood-brain barrier (BBB) [ 15 , 16 , 17 ]. Temozolomide, on the other hand, is an alkylating chemotherapy agent that is used in a variety of solid and CNS tumors, and which has excellent BBB penetration [ 15 ].…”

Phase 2 Study of Pomalidomide (CC-4047) Monotherapy for Children and Young Adults With Recurrent or Progressive Primary Brain Tumors

“…Identifying patients who could potentially benefit from combining POM with other anticancer agents may enhance the level of activity observed in clinical trials. A phase 1 trial examined the combination of dasatinib, lenalidomide, and temozolomide in pediatric patients with either relapsed or refractory CNS tumors ( 27 ). The trial established feasibility of the combination; however, any efficacy data were preliminary, and it remains to be determined whether an efficacy benefit exists.…”

Targeting Upstream Kinases of STAT3 in Human Medulloblastoma Cells

“…For Src inhibitors, KX2–391 has only proven to be a favorable pharmacokinetic profile and be well tolerated in patients with advanced malignancies in phase I trial [32] but not been reported in any brain tumors. Dasatinib has been reported to undertake phase I trial in children with relapsed or refractory central nervous system tumors and preliminary evidence of clinical benefit was seen [60].…”