A phase I trial of selinexor, an inhibitor of the nuclear export compound exportin 1 (XPO1), found the drug was reasonably well tolerated and showed some activity in patients with advanced soft-tissue or bone sarcoma with progressive disease.
“For patients with metastatic disease, treatment options are limited, and the median overall survival is 10 to 18 months, highlighting the need for new therapies” in soft-tissue and bone sarcoma, wrote study authors led by Mrinal M. Gounder, MD, of Memorial Sloan Kettering Cancer Center in New York. Overexpression of XPO1 has been reported in several malignancies, and is one mechanism by which apoptosis and other processes are circumvented.
The new study included 54 sarcoma patients who received oral selinexor twice per week at one of three doses, either continuously or on a 3 weeks on, 1 week off schedule; the most common tumor types included liposarcoma in 19 patients and leiomyosarcoma in 12 patients. The results were published online ahead of print yesterday in the Journal of Clinical Oncology.
Among 52 patients evaluable for response, there were no complete or partial responses. However, 30 patients (58%) had stable disease; 17 patients (33%) had stable disease for at least 4 months. Among 43 evaluable patients, 13 (30%) had a reduction in the size of the target lesion from baseline. The best responses were noted in patients with dedifferentiated liposarcoma: 40% of those patients had a reduction in the target lesion size, and 47% had stable disease for at least 4 months.
The most common adverse events (AEs) included nausea, fatigue, and anorexia, though most were grade 1 or 2 and were well controlled. Grade 3/4 AEs included fatigue, diarrhea, thrombocytopenia, anemia, and neutropenia. A 60 mg flat dose (as opposed to dosing based on patient weight) delivered on an intermittent schedule was better tolerated in general, with less dizziness, nausea, vomiting, and other AEs.
Pharmacokinetic analysis showed that drug exposure increased by 15% to 20% when taken with food, and immunohistochemistry revealed an increase in nuclear accumulation of tumor suppressor proteins, increased apoptosis, and other potentially beneficial results.
“Selinexor is well tolerated in patients with advanced refractory sarcoma,” the authors concluded. “Prolonged disease control was noted in several tumor types, including liposarcoma and leiomyosarcoma.” A phase II/III trial comparing selinexor to placebo is now ongoing specifically in dedifferentiated liposarcoma patients.