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

Authors: Gounder, M. M.; Zer, A.; Tap, W. D.; Salah, S.; Dickson, M. A.; Gupta, A. A.; Keohan, M. L.; Loong, H. H.; D'Angelo, S. P.; Baker, S.; Condy, M.; Nyquist-Schultz, K.; Tanner, L.; Erinjeri, J. P.; Francis, J. H.; Friedlander, S.; Carlson, R.; Unger, T. J.; Saint-Martin, J. R.; Rashal, T.; Ellis, J.; Kauffman, M.; Shacham, S.; Schwartz, G. K.; Abdul Razak, A. R.
Article Title: 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. © 2016 by American Society of Clinical Oncology.
Journal Title: Journal of Clinical Oncology
Volume: 34
Issue: 26
ISSN: 0732-183X
Publisher: American Society of Clinical Oncology  
Date Published: 2016-09-10
Start Page: 3166
End Page: 3174
Language: English
DOI: 10.1200/jco.2016.67.6346
PROVIDER: scopus
PUBMED: 27458288
PMCID: PMC5321073
Notes: Article -- Export Date: 2 November 2016 -- Source: Scopus
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MSK Authors
  1. Jasmine Helen Francis
    95 Francis
  2. Mary Louise Keohan
    61 Keohan
  3. Mrinal M Gounder
    66 Gounder
  4. Mark Andrew Dickson
    75 Dickson
  5. Mercedes M Condy
    11 Condy
  6. William Douglas Tap
    118 Tap
  7. Lanier R Tanner
    3 Tanner