Format

Send to

Choose Destination
J Clin Oncol. 2016 Sep 10;34(26):3166-74. doi: 10.1200/JCO.2016.67.6346. Epub 2016 Jul 25.

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

Author information

1
Mrinal M. Gounder, William D. Tap, Mark A. Dickson, Mary Louise Keohan, Sandra P. D'Angelo, Mercedes Condy, Lanier Tanner, Joseph P. Erinjeri, and Francis H. Jasmine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College; Gary K. Schwartz, Columbia University Medical Center, New York, NY; Alona Zer, Samer Salah, Abha A. Gupta, Herbert H. Loong, Stephanie Baker, Kjirsten Nyquist-Schultz, and Albiruni Ryan Abdul Razak, Princess Margaret Cancer Center, Toronto, Ontario, Canada; and Sharon Friedlander, Robert Carlson, Thaddeus J. Unger, Jean-Richard Saint-Martin, Tami Rashal, Joel Ellis, Michael Kauffman, and Sharon Shacham, Karyopharm Therapeutics, Newton, MA. gounderm@mskcc.org.
2
Mrinal M. Gounder, William D. Tap, Mark A. Dickson, Mary Louise Keohan, Sandra P. D'Angelo, Mercedes Condy, Lanier Tanner, Joseph P. Erinjeri, and Francis H. Jasmine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College; Gary K. Schwartz, Columbia University Medical Center, New York, NY; Alona Zer, Samer Salah, Abha A. Gupta, Herbert H. Loong, Stephanie Baker, Kjirsten Nyquist-Schultz, and Albiruni Ryan Abdul Razak, Princess Margaret Cancer Center, Toronto, Ontario, Canada; and Sharon Friedlander, Robert Carlson, Thaddeus J. Unger, Jean-Richard Saint-Martin, Tami Rashal, Joel Ellis, Michael Kauffman, and Sharon Shacham, Karyopharm Therapeutics, Newton, MA.

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.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT01896505.

PMID:
27458288
PMCID:
PMC5321073
DOI:
10.1200/JCO.2016.67.6346
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Atypon Icon for PubMed Central
Loading ...
Support Center