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

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:

• ATRA
• dasatinib
• phase I
• pharmacokinetics
• pharmacodynamics
• AML

Acknowledgments

The authors would like to thank Rita Johnson for valuable discussions. The authors would also like to thank the patients and nursing staff of the UPMC Hillman Cancer Center.

Potential conflict of interest

Disclosure forms provided by the authors are available with the full text of this article online at https://doi.org/10.1080/10428194.2018.1443330.

Additional information

Funding

This project was supported by grants from the Leukemia and Lymphoma Society TRP6028-10 and BMS CA180-333. This project used the UPMC Hillman Cancer Center Cancer Pharmacokinetics and Pharmacodynamics Facility (CPPF), Clinical Protocol and Data Management (CPDM) Facility, and Biostatistics Facility (BF) and was supported in part by an award from the National Cancer Institute, National Institutes of Health, USA P30-CA47904. The funding agencies had no role in the design or analysis of the trial.