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First-in-Class, First-in-Human Phase I Study of Selinexor, a Selective Inhibitor of Nuclear Export, in Patients With
Albiruni R Abdul Razak1, Morten Mau-Soerensen1, Nashat Y Gabrail1
1Albiruni R. Abdul Razak and Lee-Anne Stayner, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Morten Mau-Soerensen and Ulrik Lassen, Rigshospitalet, Copenhagen, Denmark; Nashat Y. Gabrail, Gabrail Cancer Institute, Canton, OH; John F. Gerecitano, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College, New York, NY; Anthony F. Shields, Karmanos Cancer Institute, Wayne State University, Detroit, MI; Thaddeus J. Unger, Jean R. Saint-Martin, Robert Carlson, Yosef Landesman, Dilara McCauley, Tami Rashal, Mansoor R. Mirza, Michael Kauffman, and Sharon Shacham, Karyopharm Therapeutics, Newton, MA; and Richard Kim and Amit Mahipal, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.
Abstract:
Purpose This trial evaluated the safety, pharmacokinetics, pharmacodynamics, and efficacy of selinexor (KPT-330), a novel, oral small-molecule inhibitor of exportin 1 (XPO1/CRM1), and determined the recommended phase II dose. Patients and Methods In total, 189 patients with advanced solid tumors received selinexor (3 to 85 mg/m2) in 21- or 28-day cycles. Pre- and post-treatment levels of XPO1 mRNA in patient-derived leukocytes were determined by reverse transcriptase quantitative polymerase chain reaction, and tumor biopsies were examined by immunohistochemistry for changes in markers consistent with XPO1 inhibition. Antitumor response was assessed according Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 guidelines. Results The most common treatment-related adverse events included fatigue (70%), nausea (70%), anorexia (66%), and vomiting (49%), which were generally grade 1 or 2. Most commonly reported grade 3 or 4 toxicities were thrombocytopenia (16%), fatigue (15%), and hyponatremia (13%). Clinically significant major organ or cumulative toxicities were rare. The maximum-tolerated dose was defined at 65 mg/m2 using a twice-a-week (days 1 and 3) dosing schedule. The recommended phase II dose of 35 mg/m2 given twice a week was chosen based on better patient tolerability and no demonstrable improvement in radiologic response or disease stabilization compared with higher doses. Pharmacokinetics were dose proportional, with no evidence of drug accumulation. Dose-dependent elevations in XPO1 mRNA in leukocytes were demonstrated up to a dose level of 28 mg/m2 before plateauing, and paired tumor biopsies showed nuclear accumulation of key tumor-suppressor proteins, reduction of cell proliferation, and induction of apoptosis. Among 157 patients evaluable for response, one complete and six partial responses were observed (n = 7, 4%), with 27 patients (17%) achieving stable disease for ≥ 4 months. Conclusion Selinexor is a novel and safe therapeutic with broad antitumor activity. Further interrogation into this class of therapy is warranted.
Insights
Selinexor, an oral exportin 1 inhibitor, demonstrated safety and antitumor activity in advanced solid tumors. The recommended Phase II dose was 35 mg/m² twice weekly, showing tolerability and efficacy.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Exportin 1 (XPO1/CRM1) is a key nuclear transport protein implicated in cancer.
- Inhibiting XPO1 may restore tumor suppressor function and induce cancer cell death.
Purpose of the Study:
- To evaluate the safety, pharmacokinetics, pharmacodynamics, and efficacy of selinexor, an oral XPO1 inhibitor.
- To determine the recommended Phase II dose for selinexor in patients with advanced solid tumors.
Main Methods:
- 189 patients with advanced solid tumors received oral selinexor in escalating doses.
- XPO1 mRNA levels, tumor marker changes, and antitumor responses (RECIST v1.1) were assessed.
- Pharmacokinetic and pharmacodynamic analyses were performed to understand drug behavior and target engagement.
Main Results:
- Common adverse events included fatigue, nausea, and anorexia; grade 3/4 toxicities were infrequent.
- The maximum tolerated dose was 65 mg/m² twice weekly; 35 mg/m² twice weekly was selected as the recommended Phase II dose.
- Selinexor demonstrated dose-dependent XPO1 inhibition, nuclear accumulation of tumor suppressors, reduced proliferation, and induced apoptosis.
- Objective response rate was 4% (complete/partial responses), with 17% achieving stable disease for ≥ 4 months.
Conclusions:
- Selinexor is a novel, safe oral therapeutic with broad antitumor activity in advanced solid tumors.
- The recommended Phase II dose offers a favorable tolerability profile.
- Further investigation of XPO1 inhibitors is warranted for cancer therapy.
