Selinexor in combination with decitabine in patients with acute myeloid leukemia: results from a phase 1 study

Abstract

Current treatment options for older and relapsed or refractory (R/R) acute myeloid leukemia (AML) patients are limited and represent an unmet need. Based on preclinical studies showing strong anti-leukemic effects in vivo, this phase I dose-escalation study assessed the safety and preliminary clinical activity of the oral exportin-1 inhibitor, selinexor, in combination with the hypomethylating agent, decitabine 20 mg/m², in adults with R/R AML and in older (age ≥ 60) untreated AML patients. There were no protocol-defined dose limiting toxicities. The recommended phase 2 dose of selinexor was 60 mg (∼35 mg/m²) given twice-weekly. Notable grade ≥3 toxicities included asymptomatic hyponatremia (68%), febrile neutropenia (44%), sepsis (44%), hypophosphatemia (36%), and pneumonia (28%). In 25 patients, the overall response rate was 40%. Modification of selinexor to a flat dose of 60 mg, twice-weekly for two weeks after decitabine, improved tolerability of the regimen and demonstrated preliminary clinical activity in poor-risk patients with AML.

Keywords:

• Acute myeloid leukemia
• decitabine
• selinexor
• clinical trials

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Acknowledgments

The authors would like to thank the patients who participated in this trial and their families, the coinvestigators, nurses, and study coordinators. This trial was registered at www.clinicaltrials.gov as # NCT02093403.

Disclosure statement

B.B. received research support from Karyopharm Therapeutics. No potential conflict of interest was reported by all other authors.

Author contributions

B.B. and R.G. performed research, provided oversight for the conduct of this trial, analyzed the data and wrote the manuscript; Q.Z. and A.S.R. performed all statistical analyses and wrote the manuscript; A.S.M., S.V., G.K.B., K.L., J.S.B., W.B., R.B.K., J.C.B., and A.R.W. enrolled and treated patients on this trial and reviewed the manuscript; S.O., C.O., P.R., J.S.B., J.C.B., and R.G., performed laboratory and correlative analyses and reviewed the manuscript.

Additional information

Funding

This work was supported by R35 CA197734 (JCB), the D. Warren Brown Family Foundation (JCB), R01 CA188269 (RG) and the LLS scholar award (RG). Research support for BB was provided by Karyopharm Therapeutics.