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Clinical Trial
. 2018 Nov;59(11):2595-2601.
doi: 10.1080/10428194.2018.1443330. Epub 2018 Apr 4.

A phase-1 study of dasatinib plus all-trans retinoic acid in acute myeloid leukemia

Robert L Redner  1   2 , Jan H Beumer  1   2   3 , Patricia Kropf  2 , Mounzer Agha  1   2 , Michael Boyiadzis  1   2 , Kathleen Dorritie  1   2 , Rafic Farah  1   2 , Jing-Zhao Hou  1   2 , Annie Im  1   2 , Seah H Lim  2 , Anastasios Raptis  1   2 , Alison Sehgal  1   2 , Susan M Christner  1 , Daniel Normolle  4 , Daniel E Johnson  2
Affiliations
Clinical Trial

A phase-1 study of dasatinib plus all-trans retinoic acid in acute myeloid leukemia

Robert L Redner et al. Leuk Lymphoma. 2018 Nov.

Abstract

Src family kinases (SFKs) are hyperactivated in acute myeloid leukemia (AML). SFKs impede the retinoic acid receptor, and SFK inhibitors enhance all-trans retinoic acid (ATRA)-mediated cellular differentiation in AML cell lines and primary blasts. To translate these findings into the clinic, we undertook a phase-I dose-escalation study of the combination of the SFK inhibitor dasatinib and ATRA in patients with high-risk myeloid neoplasms. Nine subjects were enrolled: six received 70 mg dasatinib plus 45 mg/m2 ATRA daily, and three received 100 mg dasatinib plus 45 mg/m2 ATRA daily for 28 days. Headache and QTc prolongations were the only two grade 3 adverse events observed. No significant clinical responses were observed. We conclude that the combination of 70 mg dasatinib and 45 mg/m2 ATRA daily is safe with acceptable toxicity. Our results provide the safety profile for further investigations into the clinical efficacy of this combination therapy in myeloid malignancies.

Keywords: AML; ATRA; dasatinib; pharmacodynamics; pharmacokinetics; phase I.

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Conflict of interest statement

The authors report no conflicts of interest.

Figures

FIGURE 1.
FIGURE 1.
Peripheral blood absolute neutrophil and blast counts for subjects receving more than 14 days of study drug.
See this image and copyright information in PMC

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