Phase I study of cladribine, cytarabine, granulocyte colony stimulating factor (CLAG regimen) and midostaurin and all-trans retinoic acid in relapsed/refractory AML

Abstract

We conducted a phase I study using midostaurin (25 or 50 mg orally twice daily), all-trans retinoic acid (ATRA) and CLAG chemotherapy to target multiple pathways in relapsed/refractory AML. 10 patients received the combination and no dose-limiting toxicities were observed. Two patients (22 %) achieved complete remission and 1 patient (11 %) achieved complete remission with incomplete count recovery. Pharmacokinetic data showed that the 25 mg dosing of midostaurin achieved therapeutic levels with no significant interaction between midostaurin and ATRA. With evidence of activity of ATRA in NPM1-mutated AML and midostaurin in FLT3-ITD AML, this combination warrants further investigation.

Trial registration: ClinicalTrials.gov NCT01161550.

Figures

Figure 1

Schematic representation of the treatment protocol

Figure 2. Pharmacokinetic studies of midostaurin and ATRA

A. Mean concentration (+/− standard deviation) of midostaurin and midostaurin metabolite (CGP52421 and CGP62221) at base line and 2, 4, 6 and 12 hours post ingestion after a single dose (Cycle 1, day 7). B. Mean concentration (+/− standard deviation) of ATRA levels at on day 7 Cycle 1 at base line and 2, 4, 6 and 12 hours post ingestion when administrated with midostaurin at 25mg (●) and at 50mg (▲)