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Phase IB Study of Selinexor, a First-in-Class Inhibitor of Nuclear Export, in Patients With Advanced Refractory Bone
Mrinal M Gounder1, Alona Zer2, William D Tap2
1Mrinal 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.
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.
Insights
Selinexor, an oral inhibitor of nuclear export, showed preliminary anticancer activity in advanced sarcoma. It was well tolerated on an intermittent schedule with no significant food interactions, demonstrating potential for sarcoma treatment.
Area of Science:
- Pharmacology and Oncology
- Drug Development
- Sarcoma Research
Background:
- Advanced soft tissue and bone sarcomas represent a significant clinical challenge with limited treatment options.
- Selective inhibitors of nuclear export (SNxE) are a novel class of anticancer agents.
Purpose of the Study:
- To evaluate the pharmacokinetics (PKs), pharmacodynamics, safety, and efficacy of selinexor in patients with advanced sarcoma.
- To determine optimal dosing and administration schedules for selinexor in this patient population.
Main Methods:
- A phase I/II study involving 54 patients with advanced sarcoma treated with oral selinexor at various doses and schedules.
- Pharmacokinetic analysis under different feeding conditions and formulations.
- Tumor biopsy analysis for pharmacodynamic changes and correlation with treatment response.
Main Results:
- Selinexor was better tolerated on a flat 60-mg dose, intermittent schedule (3 weeks on, 1 week off).
- Food intake had a minimal impact on selinexor's pharmacokinetics.
- Preliminary evidence of anticancer activity was observed, with 33% of patients achieving durable stable disease (≥ 4 months), particularly in dedifferentiated liposarcoma.
Conclusions:
- A 60-mg flat dose of selinexor on an intermittent schedule is well-tolerated in sarcoma patients.
- Selinexor demonstrates preliminary anticancer activity in sarcoma, warranting further investigation.
- The drug's PK profile is not significantly affected by food, simplifying administration.
