1. Phase IB Study of Selinexor, a First-in-Class Inhibitor of Nuclear Export, in Patients With Advanced Refractory Bone or Soft Tissue Sarcoma.
- Author
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Gounder MM, Zer A, Tap WD, Salah S, Dickson MA, Gupta AA, Keohan ML, Loong HH, D'Angelo SP, Baker S, Condy M, Nyquist-Schultz K, Tanner L, Erinjeri JP, Jasmine FH, Friedlander S, Carlson R, Unger TJ, Saint-Martin JR, Rashal T, Ellis J, Kauffman M, Shacham S, Schwartz GK, and Abdul Razak AR
- Subjects
- Administration, Oral, Adolescent, Adult, Aged, Aged, 80 and over, Antineoplastic Agents adverse effects, Antineoplastic Agents pharmacokinetics, Biopsy, Canada, Capsules, Disease Progression, Drug Administration Schedule, Drug Compounding, Fasting blood, Female, Food-Drug Interactions, Humans, Hydrazines adverse effects, Hydrazines pharmacokinetics, Male, Middle Aged, New York City, Pharmaceutical Solutions, Postprandial Period, Sarcoma metabolism, Sarcoma pathology, Soft Tissue Neoplasms metabolism, Soft Tissue Neoplasms pathology, Tablets, Time Factors, Tomography, X-Ray Computed, Treatment Outcome, Triazoles adverse effects, Triazoles pharmacokinetics, Young Adult, Active Transport, Cell Nucleus drug effects, Antineoplastic Agents administration & dosage, Hydrazines administration & dosage, Sarcoma drug therapy, Soft Tissue Neoplasms drug therapy, Triazoles administration & dosage
- 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/m(2), 50 mg/m(2), 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.)
- Published
- 2016
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