Phase IB Study of Selinexor, a First-in-Class Inhibitor of Nuclear Export, in Patients With Advanced Refractory Bone or Soft Tissue Sarcoma

Abstract

Purpose We evaluated the pharmacokinetics (PKs), pharmacodynamics, safety, and efficacy of selinexor, an oral selective inhibitor of nuclear export compound, in patients with advanced soft tissue or bone sarcoma with progressive disease. Patients and Methods Fifty-four patients were treated with oral selinexor twice per week (on days 1 and 3) at one of three doses (30 mg/m2, 50 mg/m2, or flat dose of 60 mg) either continuously or on a schedule of 3 weeks on, 1 week off. PK analysis was performed under fasting and fed states (low v high fat content) and using various formulations of selinexor (tablet, capsule, or suspension). Tumor biopsies before and during treatment were evaluated for pharmacodynamic changes. Results The most commonly reported drug-related adverse events (grade 1 or 2) were nausea, vomiting, anorexia, and fatigue, which were well managed with supportive care. Commonly reported grade 3 or 4 toxicities were fatigue, thrombocytopenia, anemia, lymphopenia, and leukopenia. Selinexor was significantly better tolerated when administered as a flat dose on an intermittent schedule. PK analysis of selinexor revealed a clinically insignificant increase (approximately 15% to 20%) in drug exposure when taken with food. Immunohistochemical analysis of paired tumor biopsies revealed increased nuclear accumulation of tumor suppressor proteins, decreased cell proliferation, increased apoptosis, and stromal deposition. Of the 52 patients evaluable for response, none experienced an objective response by RECIST (version 1.1); however, 17 (33%) showed durable (≥ 4 months) stable disease, including seven (47%) of 15 evaluable patients with dedifferentiated liposarcoma. Conclusion Selinexor was well tolerated at a 60-mg flat dose on a 3-weeks-on, 1-week-off schedule. There was no clinically meaningful impact of food on PKs. Preliminary evidence of anticancer activity in sarcoma was demonstrated.

Selective inhibition of nuclear export with selinexor in patients with non-Hodgkin lymphoma

“…It is without doubt that treatment with selinexor in this phase 1 study, and other studies in solid tumors, does lead to an unfamiliar toxicity paradigm and constellation of symptoms for most oncologists. 37,38 Experience with managing patients treated with selinexor and aggressive use of supportive care tools can mitigate most nonhematologic toxicities. Grade 3 or 4 AEs were largely hematologic in nature, including thrombocytopenia, neutropenia, and anemia, and could be managed through drug holidays, dose reductions, and/or growth factor support, such as eltrombopag for thrombocytopenia and filgrastim for neutropenia.…”

Molecular mechanism and therapeutic implications of selinexor (KPT-330) in liposarcoma

“…Recently, a phase 1 clinical trial of selinexor in patients with advanced solid tumors including liposarcoma [36, 37] showed a favorable anti-tumor effect of selinexor in 78% (14 of 18) of the liposarcoma patients, with a well-tolerated dose of 35 mg/m 2 (approximately 60 mg flat dose) [37]. Taken together, these results strongly indicate that inhibition of XPO1 might be a valuable treatment approach for this disease.…”

Selinexor (KPT-330) Induces Tumor Suppression through Nuclear Sequestration of IκB and Downregulation of Survivin

“…Among the sarcoma cell lines we tested, liposarcoma (LS141) shows the greatest sensitivity to selinexor and this appears to be due to the induction of apoptosis as well as the downregulation of survivin protein expression, both in vitro and in vivo. Selinexor has completed phase I and phase 1b studies (41,42) and antitumor activity was noted in patients, among them patients with dedifferentiated liposarcoma (DDLPS), with 40% of the 15 patients showing reduction in target lesions and 47% showing stable disease for 4 months or longer (41). Based on these clinical results, a phase II randomized study of selinexor versus placebo in patients with advanced liposarcoma is under way (NCT02606461).…”