Phase 1 study of selinexor in combination with salvage chemotherapy in Adults with relapsed or refractory Acute myeloid leukemia

Abstract

Selinexor, an oral inhibitor of the nuclear transport protein Exportin-1, shows promising single-agent activity in clinical trials of relapsed/refractory (R/R) acute myeloid leukemia (AML) and preclinical synergy with topoisomerase (topo) IIα inhibitors. We conducted a phase 1, dose-escalation study of selinexor with mitoxantrone, etoposide, and cytarabine (MEC) in 23 patients aged < 60 years with R/R AML. Due to dose-limiting hyponatremia in 2 patients on dose level 2 (selinexor 40 mg/m²), the maximum tolerated dose was 30 mg/m². The most common grade ≥ 3 treatment-related non-hematologic toxicities were febrile neutropenia, catheter-related infections, diarrhea, hyponatremia, and sepsis. The overall response rate was 43% with 6 patients (26%) achieving complete remission (CR), 2 (9%) with CR with incomplete count recovery, and 2 (9%) with a morphologic leukemia-free state. Seven of 10 responders proceeded to allogeneic stem cell transplantation. The combination of selinexor with MEC is a feasibile treatment option for patients with R/R AML.

Keywords:

• Acute myeloid leukemia
• selinexor
• relapsed
• refractory
• clinical trial
• mitoxantrone
• etoposide
• cytarabine

Acknowledgements

The authors wish to thank the patients and their families for participating in this study. We also express great appreciation to the nurses, pharmacists, research coordinators and other clinical staff members who took care of these patients.

Author contributions

BB and RG designed the study, provided study oversight and analyzed the data. QZ and ASR did statistical analysis. BB, ASM, SV, GKB, KL, JSB, WB, RBK, ARW and RG enrolled patients and directly participated in the care of patients. MAB, KLL, KRD and MAP performed the pharmacokinetic studies. PR and RG performed preclinical laboratory studies. BB, QZ, MAB, MAP and RG wrote the manuscript. All authors reviewed, edited and approved the manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This study was funded by Karyopharm Therapeutics. BB has received advisory board honoraria from Karyopharm Therapeutics.