Phase I Trial, Pharmacokinetics, and Pharmacodynamics of Vandetanib and Dasatinib in Children with Newly Diagnosed Diffuse Intrinsic Pontine Glioma

Abstract

Purpose Testing of promising drug combinations is crucial in the treatment of diffuse intrinsic pontine glioma (DIPG). Since the VEGF and PDGF pathways are critical in gliomas, we evaluated the safety, maximum tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of vandetanib, a VEGFR-2 inhibitor, combined with dasatinib, a potent PDGFR inhibitor, during and after radiotherapy in children with newly diagnosed DIPG. Experimental Design Dasatinib was started concurrently with radiotherapy. Vandetanib was started 8 days later. We tested increasing doses of vandetanib (65 and 85 mg/m2 once daily) and dasatinib (65 and 85 mg/m2 twice daily). Dose-limiting toxicities were evaluated during the first six weeks of therapy. Plasma pharmacokinetics was obtained on days 8 and 42±3 in all patients and concomitantly with cerebrospinal fluid (CSF) when possible. Inhibition of targets of dasatinib in peripheral blood mononuclear cells (PBMCs) was evaluated. Results Twenty-five patients were treated. Treatment was well tolerated. The median duration of treatment was 184 days. Diarrhea was the most significant toxicity. Three patients experienced substantial myelosuppression. The steady-state plasma pharmacokinetics of vandetanib was comparable to previous studies. Although the plasma exposure to dasatinib decreased from days 8 to 42, it remained similar to adult studies. CSF to plasma exposure of vandetanib and dasatinib were approximately 2% in 2 patients. Phosphorylated 70S6K decreased during therapy in PBMCs. Conclusions The MTD of vandetanib and dasatinib in combination was 65 mg/m2 for each drug. Other studies are underway to test dasatinib and other PDGFR inhibitors alone or in combination for this deadly cancer.

Incidence, Diagnosis, and Management of QT Prolongation Induced by Cancer Therapies: A Systematic Review

“…A meta‐analysis of 9 randomized trials with 4813 patients estimated a risk ratio for QTc prolongation versus control of 7.90 (95% confidence interval, 4.03–15.50) 154. In our review, the weighted incidence of any vandetanib‐related QTc prolongation was 8.6%, with QTc >500 ms in 2.6% 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70155, 156, 157 Because of its long half‐life (19 days), special care is needed when monitoring patients with QTc prolongation.…”

The Genetic Signatures of Pediatric High-Grade Glioma: No Longer a One-Act Play

“…PDGFRα mutants drive glioma formation in vivo 27,28 , with murine-derived HGGs recapitulating critical features of the human disease such as histopathologic characteristics and expression profiles 27 . In an effort to target PDGFR therapeutically, pediatric trials using dasatinib, crenolanib or imatinib have been launched 29-31 . Unfortunately, the benefit derived from selective RTK inhibitors may be marginal at best.…”

Potential role of tyrosine kinase inhibitors during primary HIV-1 infection

“…The PK of dasatinib in body compartments, and particularly the CNS, is poorly studied. In the limited number of available cases, cerebrospinal fluid (CSF) concentrations of dasatinib seem to be low (around 2% of plasma AUC) [16], but the same drug has also been successfully used to treat acute lymphoblastic leukemia with meningeal involvement [17] and is also under evaluation for other CNS neoplasms, such as malignant gliomas [16], suggesting that the antineoplastic effect could be achieved even with low CSF concentrations. Whether this could be extrapolated to HIV is unknown.…”