Phase IB study of selinexor, a first-in-class inhibitor of nuclear export, in patients with advanced refractory bone or soft tissue sarcoma

Mrinal M. Gounder*, Alona Zer, William D. Tap, Samer Salah, Mark A. Dickson, Abha A. Gupta, Mary Louise Keohan, Herbert H. Loong, Sandra P. D'Angelo, Stephanie Baker, Mercedes Condy, Kjirsten Nyquist-Schultz, Lanier Tanner, Joseph P. Erinjeri, Francis H. Jasmine, Sharon Friedlander, Robert Carlson, Thaddeus J. Unger, Jean Richard Saint-Martin, Tami RashalJoel Ellis, Michael Kauffman, Sharon Shacham, Gary K. Schwartz, Albiruni Ryan Abdul Razak

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)3166-3174
Number of pages9
JournalJournal of Clinical Oncology
Volume34
Issue number26
DOIs
StatePublished - 10 Sep 2016
Externally publishedYes

Funding

FundersFunder number
Sharon Shacham Merck
National Cancer InstituteP30CA008748
Novartis
Karyopharm Therapeutics

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