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

• 发表时间: 11 2018
• 来源期刊: Leuk Lymphoma
• DOI: 10.1080/10428194.2018.1443330
• PMID: 29616864
• 文章类型: Clinical Trial, Phase I
• 作者列表: Redner RL,Beumer JH,Kropf P,Agha M,Boyiadzis M,Dorritie K,Farah R,Hou JZ,Im A,Lim SH,Raptis A,Sehgal A,Christner SM,Normolle D,Johnson DE

关键词: AML; ATRA; dasatinib; pharmacodynamics; pharmacokinetics; phase I

Mesh: Acute Disease; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols / adverse effects pharmacokinetics therapeutic use; Dasatinib / administration & dosage adverse effects pharmacokinetics; Drug Administration Schedule; Headache / chemically induced; Humans; Leukemia, Myeloid / drug therapy metabolism pathology; Long QT Syndrome / chemically induced; Middle Aged; Treatment Outcome; Tretinoin / administration & dosage adverse effects pharmacokinetics; src-Family Kinases / antagonists & inhibitors metabolism

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.