First-in-Class, First-in-Human Phase I Study of Selinexor, a Selective Inhibitor of Nuclear Export, in Patients With Advanced Solid Tumors

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.

Fig 1.

Pharmacodynamics of selinexor treatment: immunohistochemistry (IHC) of paired tumor biopsies. Patient tumor biopsies were analyzed by IHC for morphologic and biochemical changes in response to selinexor treatment. (A and B) Hematoxylin and eosin (H&E) staining of tumor samples taken from a patient with colorectal cancer (CRC) at baseline and 5 weeks after treatment with selinexor 23 mg/m². IHC staining (brown) for apoptosis markers (C and D) Apoptag (Millipore, Billerica, MA) and (E and F) cleaved caspase 3 in a patient with CRC at baseline and after treatment with selinexor 12 mg/m². (G and H) Decreased staining intensity for the proliferation marker Ki-67 in a patient with melanoma treated with selinexor 16.8 mg/m². Nuclear accumulation of XPO1 cargos (I and J) p53 and (K and L) FOXO3A in a patient with lung adenosquamous cell carcinoma treated with selinexor 35 mg/m². Images are × 10 magnification with smaller inserts magnified to × 40.

Fig 2.

Waterfall plot of change in target lesion volume after selinexor treatment. Best response in target lesions for 129 evaluable patients. Quantitative target lesion assessment was not available for the remaining 28 evaluable patients. These included 22 patients with progressive disease based solely on clinical symptoms and six patients with stable disease (SD), two of whom were patients with prostate cancer who had bone scans and remained on study for 325 and 72 days before showing disease progression. One patient with ovarian cancer had SD and remained on study for 365 days despite not having quantifiable baseline scans. The remaining three patients (two with prostate cancer and one with nasopharyngeal cancer) remained on study for 117, 71, and 44 days, respectively, without evidence of disease progression before withdrawing consent.