TY - JOUR
T1 - Phase IB study of selinexor, a first-in-class inhibitor of nuclear export, in patients with advanced refractory bone or soft tissue sarcoma
AU - Gounder, Mrinal M.
AU - Zer, Alona
AU - Tap, William D.
AU - Salah, Samer
AU - Dickson, Mark A.
AU - Gupta, Abha A.
AU - Keohan, Mary Louise
AU - Loong, Herbert H.
AU - D'Angelo, Sandra P.
AU - Baker, Stephanie
AU - Condy, Mercedes
AU - Nyquist-Schultz, Kjirsten
AU - Tanner, Lanier
AU - Erinjeri, Joseph P.
AU - Jasmine, Francis H.
AU - Friedlander, Sharon
AU - Carlson, Robert
AU - Unger, Thaddeus J.
AU - Saint-Martin, Jean Richard
AU - Rashal, Tami
AU - Ellis, Joel
AU - Kauffman, Michael
AU - Shacham, Sharon
AU - Schwartz, Gary K.
AU - Abdul Razak, Albiruni Ryan
N1 - Publisher Copyright:
© 2016 by American Society of Clinical Oncology.
PY - 2016/9/10
Y1 - 2016/9/10
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84989947743&partnerID=8YFLogxK
U2 - 10.1200/JCO.2016.67.6346
DO - 10.1200/JCO.2016.67.6346
M3 - Article
C2 - 27458288
AN - SCOPUS:84989947743
SN - 0732-183X
VL - 34
SP - 3166
EP - 3174
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 26
ER -