A phase I study of selinexor in combination with high-dose cytarabine and mitoxantrone for remission induction in patients with acute myeloid leukemia.

Abstract

BACKGROUND:

Novel therapies for patients with acute myeloid leukemia (AML) are imperative, particularly for those with high-risk features. Selinexor, an exportin 1 (XPO1/CRM1) inhibitor, has demonstrated anti-leukemia activity as a single agent, as well as in combination with anthracyclines and/or DNA-damaging agents.

METHODS:

We report the findings of a phase I dose escalation trial with cohort expansion in 20 patients with newly diagnosed or relapsed/refractory AML that combined selinexor with age-adjusted high-dose cytarabine and mitoxantrone (HiDAC/Mito).

RESULTS:

Three (15%) patients received the initial dose of 60 mg of selinexor (~ 35 mg/m2), and 17 (85%) received the target level of 80 mg (~ 50 mg/m2). No dose-limiting toxicities were observed. Common adverse events included febrile neutropenia (70%), diarrhea (40%), anorexia (30%), electrolyte abnormalities (30%), bacteremia (25%), cardiac toxicities (25%), fatigue (25%), and nausea/vomiting (25%). None were unexpected given the HiDAC/Mito regimen. Serious adverse events occurred in 6 (30%) patients; one was fatal. Ten (50%) patients achieved a complete remission (CR), 3 (15%) achieved CR with incomplete recovery (CRi), 1 (5%) achieved partial remission (PR), and 6 (30%) had progressive disease for an overall response rate (ORR) of 70%. Eight of 14 (57%) responders proceeded to allogeneic stem cell transplantation. Correlative studies of WT1 levels showed persistently detectable levels in patients who either did not respond or relapsed quickly after induction.

CONCLUSION:

The selinexor/HiDAC/Mito regimen is feasible and tolerable at selinexor doses of 80 mg/day (~ 50 mg/m2/day) twice weekly. The recommended phase II dose is 80 mg and warrants further study in this combination.

TRIAL REGISTRATION:

ClinicalTrials.gov , NCT02573363 . Registered October 5, 2015.

• Authors: Amy Y Wang, Howard Weiner, Margaret Green, Hua Chang, Noreen Fulton, Richard A Larson, Olatoyosi Odenike, Andrew S Artz, Michael R Bishop, Lucy A Godley, Michael J Thirman, Satyajit Kosuri, Jane E Churpek, Emily Curran, Kristen Pettit, Wendy Stock, Hongtao Liu
• Journal: Journal of hematology & oncology (J Hematol Oncol) Vol. 11 Issue 1 Pg. 4 (01 05 2018) ISSN: 1756-8722 [Electronic] England
• PMID: 29304833 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Cytarabine
• Mitoxantrone

Topics

• Adult
• Aged
• Antineoplastic Agents (administration & dosage, adverse effects, therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, adverse effects, therapeutic use)
• Cytarabine (administration & dosage, adverse effects, therapeutic use)
• Female
• Humans
• Leukemia, Myeloid, Acute (drug therapy, pathology)
• Male
• Middle Aged
• Mitoxantrone (administration & dosage, adverse effects, therapeutic use)
• Remission Induction (methods)