Karyopharm Therapeutics Inc. has announced the dosing of the first patient in a Phase 1/2 clinical study (XPORT-GBM-029/NCT04421378) evaluating oral selinexor in combination with standard of care therapy for patients with newly diagnosed or recurrent glioblastoma (GBM). The global study is expected to enroll approximately 400 patients at clinical sites in the U.S., Europe, and Israel.
Selinexor's Mechanism and Rationale
Selinexor is an oral Selective Inhibitor of Nuclear Export (SINE) compound that blocks the cellular protein XPO1. XPO1 plays a crucial role in regulating tumor suppressor proteins and oncoproteins relevant in cancer cell biology. Overexpression of XPO1 is frequently observed in GBM and high-grade gliomas, correlating with higher tumor grade and poor overall patient survival. Preclinical studies suggest selinexor has potent anti-GBM activity as a monotherapy and demonstrates synergy when combined with radiation, temozolomide, and lomustine. Prior clinical studies, such as the KING study (NCT01986348), have shown that selinexor crosses the blood-brain barrier, achieving adequate intra-tumoral penetration and single-agent efficacy with durable responses and disease stabilization in heavily pretreated GBM patients.
Trial Design and Endpoints
The randomized, multi-center, Phase 1/2 study will be conducted in two phases: a Phase 1 dose-finding study followed by a Phase 2 randomized efficacy exploration study. The trial is designed to independently evaluate three different combination regimens in three treatment arms in patients with newly diagnosed GBM (Arms A and B) or with recurrent GBM (Arm C). Arms A and B will investigate selinexor in combination with radiation therapy with or without the addition of temozolomide, while Arm C will evaluate the combination of selinexor and lomustine. The primary endpoints in the study are progression-free survival in patients with newly diagnosed GBM and overall survival (OS) in patients with recurrent GBM.
Expert Commentary
Yazmín Odia, M.D., Chief of Neuro-Oncology at Miami Cancer Institute, Baptist Health South Florida (BHSF), an investigator in the study, stated, “We are very excited about the launch of this innovative clinical trial on behalf of our patients who desperately need new treatment options for what is typically an incurable disease and given the few meaningful therapeutic advances in recent years.”
Minesh Mehta, M.D., Chief of Radiation Oncology at Miami Cancer Institute, BHSF, also an investigator in the study, commented, “We are hopeful that this study evaluating the activity of selinexor in combination with currently used standard treatments will help us further identify promising novel approaches for the treatment of patients with both newly diagnosed and recurrent GBM.”
Selinexor's Broader Applications
Sharon Shacham, PhD, MBA, President and Chief Scientific Officer of Karyopharm, noted, “While selinexor has been most extensively studied in patients with hematologic malignancies, there is increasing evidence that selinexor may also play an important role in the treatment of a variety of solid tumors, including patients with GBM. We were highly encouraged by the results from our previous Phase 2 KING study, which evaluated selinexor as a single agent in patients with recurrent GBM and demonstrated clear anti-cancer activity. We now look forward to assessing selinexor’s activity in combination with currently used standard of care treatments where we hope it will prove to be synergistic and even more effective.”
About Glioblastoma
Glioblastoma Multiforme (GBM) is one of the most common and aggressive forms of brain tumors, originating primarily from glial cells. It is typically diagnosed in patients around the median age of 64 but can occur at any age. GBM is an incurable disease with a poor prognosis, largely due to its aggressive infiltration of surrounding central nervous system tissue and frequent inaccessibility for surgical resection. The blood-brain barrier also poses a significant obstacle for many chemotherapeutic agents, limiting the access of many drugs to the tumor site. Median survival for patients with newly diagnosed GBM is approximately 15 months, and approximately five to seven months for those with recurrent disease.
