AML cells overexpress the nuclear exporter, Exportin 1 (XPO1/CRM1) and higher XPO1 levels correlate with poor outcome. The novel selective inhibitor of nuclear transport (SINE), Selinexor, antagonizes XPO1 and shows potent cytotoxicity for AML and ALL cells in vitro, independent of genotype. Mechanistic studies show that SINE induces nuclear localization and activation of multiple tumor suppressor proteins (TSPs), leading to rapid apoptosis of AML cells.


Relapsed and refractory AML patients (pts) were dosed with oral Selinexor (8-10 doses / 4-week cycle) in one arm of a Phase 1 trial in advanced hematological malignancies (NCT 01607892). Detailed pharmacokinetic (PK) and pharmacodynamic (PDn) analyses were done on serial marrow biopsies. Response evaluation was performed every cycle.


Sixteen AML pts with median age 71yrs; ECOG PS 0/1: 2/14; median number of prior regimens: 2 [range 0-7; Two patients had not received treatment specifically for AML, but had received hypomethylating agents and other therapy for myelodysplastic syndrome (MDS) prior to transformation to AML, and enrollment on the trial], received KPT-330 across 2 dose levels (16.8 to 23 mg/m2 (with additional cohorts ongoing). There has been no dose limiting toxicity. Four patients experienced drug-related grade 3/4 non-hematological Adverse Events (AEs) including hypotension (n=1), AST increased (n=1), hypokalemia (n=1), nausea (n=1), headache (n=1), fatigue (n=1)). The most common grade 1/2 toxicities were: nausea (9/17; 53%), anorexia (8/17pts; 47%), vomiting (6/17; 35%), fatigue (5/17; 29%), weight loss (5/17; 29%) and diarrhea (3/17; 18%). These adverse events were manageable with supportive care. There were no clinically significant cumulative toxicities or major organ dysfunction. PK analysis demonstrated a proportional increase in Cmax and AUC with increasing dose with no accumulation. Elimination half life was (6-7 hours) with rapid clearance of Selinexor. Of 14 pts who were evaluable for response, complete response (CR) with full hematological recovery was achieved in 2 patients (14%), and CR without hematological recovery (CRi) in 2 patients (14%). Four (29%) of the remaining patients have had stable disease for > 30 days, and 6 (43%) have had progressive disease.


Oral Selinexor treatment is generally well tolerated and has a favorable pharmacokinetic profile. Remissions have been observed at doses below the MTD, and dose escalation is ongoing with the current cohort being dosed at 40 mg/m2 twice weekly.


Garzon:Karyopharm : Research Funding. Yee:Karyopharm : Research Funding. Baz:Karyopharm : Research Funding. Kuruvilla:Karyopharm : Research Funding. Shacham:Karyopharm : Employment, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Patents & Royalties. Rashal:Karyopharm : Employment, Equity Ownership. Yau:Ozmosis Research Inc: Employment. McCauley:Karyopharm : Employment, Equity Ownership, Patents & Royalties. Saint-Martin:Karyopharm : Employment, Equity Ownership. McCartney:Karyopharm : Employment, Equity Ownership. Landesman:Karyopharm : Employment, Equity Ownership, Patents & Royalties. Klebanov:Karyopharm : Employment, Equity Ownership. Pond:Ozmosis Research: Consultancy. Oza:Ozmosis Research: Employment. Kauffman:Karyopharm : Employment, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Patents & Royalties. Mirza:Karyopharm : Consultancy, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees.

Author notes


Asterisk with author names denotes non-ASH members.