The US Food and Drug Administration (FDA) has granted selinexor (KPT-330) orphan designation for the treatment of acute myeloid leukemia (AML).
Selinexor is a selective inhibitor of nuclear transport that functions by binding to the nuclear export protein XPO1 (also called CRM1).
This leads to the accumulation of tumor suppressor proteins in the cell nucleus, which is thought to cause apoptosis in cancer cells while largely sparing normal cells.
The FDA grants orphan designation to promote the development of drugs that target conditions affecting 200,000 or fewer US patients annually and are expected to provide significant therapeutic advantage over existing treatments.
Selinexor’s orphan designation qualifies the drug’s developer, Karyopharm Therapeutics, Inc., for benefits that apply across all stages of development, including an accelerated approval process, 7 years of market exclusivity following marketing approval, tax credits on US clinical trials, eligibility for orphan drug grants, and a waiver of certain administrative fees.
Promising early results
Selinexor has shown promising results in a phase 1 trial of older patients with relapsed or refractory AML. The study, which was sponsored by Karyopharm, was published in Blood.
Researchers enrolled 16 patients with relapsed or refractory AML. The median age was 71 years, and the median number of prior therapeutic regimens was 2.
Patients received 8 to 10 doses of selinexor on a 4-week cycle across 2 dose levels, 16.8 mg/m2 to 23 mg/m2 (with additional cohorts ongoing).
The researchers reported no dose-limiting toxicity, no clinically significant cumulative toxicities, and no major organ dysfunction.
However, 4 patients experienced drug-related grade 3/4 adverse events, including hypotension (n=1), increased AST (n=1), hypokalemia (n=1), nausea (n=1), headache (n=1), and fatigue (n=1).
The most common grade 1/2 toxicities were nausea (9/17; 53%), anorexia (8/17; 47%), vomiting (6/17; 35%), fatigue (5/17; 29%), weight loss (5/17; 29%), and diarrhea (3/17; 18%). But these events were manageable.
Fourteen of the patients were evaluable for response. Two (14%) achieved a complete response with full hematologic recovery, and 2 (14%) achieved a complete response without hematologic recovery. Four patients (29%) had stable disease for more than 30 days, and 6 (43%) experienced progression.
Other trials of selinexor in AML
Karyopharm’s development plans for selinexor in AML include a number of additional studies.
In a phase 2 trial, researchers will evaluate selinexor monotherapy in older patients with AML. The study will enroll patients 60 years of age or older with relapsed or refractory AML who are ineligible for intensive chemotherapy and/or transplant.
In another study, researchers will evaluate selinexor in combination with decitabine for patients with relapsed, refractory, or newly diagnosed AML. The study will enroll up to 42 patients aged 60 or older who are ineligible for intensive chemotherapy.
Lastly, researchers are planning a study of selinexor in pediatric leukemia patients. The goal of this study is to determine the oral dosing, toxicity, and preliminary clinical activity of selinexor in pediatric patients. It will enroll up to 28 children with relapsed or refractory AML or acute lymphoblastic leukemia.
