Karyopharm Modifies Primary Endpoint in Phase 3 SENTRY Trial of Selinexor for Myelofibrosis
核心洞察
Karyopharm (搜索) announced a change in the co-primary endpoint for its Phase 3 SENTRY trial evaluating selinexor plus ruxolitinib in JAKi-naïve myelofibrosis (搜索) patients.
The co-primary endpoint now includes absolute total symptom score (Abs-TSS), which is considered a more accurate assessment of symptom improvement.
Phase 1 data showed the combination of selinexor and ruxolitinib nearly doubled SVR35 to almost 80% and improved Abs-TSS by 18.5 points.
Karyopharm (搜索) Therapeutics has announced a favorable change in the co-primary endpoint for its pivotal Phase 3 SENTRY trial, which is evaluating the efficacy of selinexor in combination with ruxolitinib for the treatment of myelofibrosis (搜索) patients who are JAK (搜索) inhibitor (JAKi) naïve. The revised endpoint will now include the absolute total symptom score (Abs-TSS) alongside the spleen volume response rate (SVR35). This adjustment is supported by key investigators and patient advocacy organizations, who view Abs-TSS as a more accurate measure of symptom improvement in clinical trials.
The SENTRY trial (NCT04562389) is a Phase 3 study randomizing approximately 350 JAKi-naïve myelofibrosis (搜索) patients 2:1 to receive either once-weekly selinexor (60mg) in combination with twice-daily ruxolitinib or placebo plus ruxolitinib. The co-primary endpoints are SVR35 at week 24 and the change in Abs-TSS over 24 weeks relative to baseline.
Rationale for Endpoint Modification
The decision to include Abs-TSS as a co-primary endpoint is based on data from a Phase 1 trial of selinexor (60mg) plus ruxolitinib in JAKi-naïve myelofibrosis (搜索) patients. The Phase 1 trial demonstrated that 79% of patients (n=14) achieved SVR35, and the efficacy evaluable population (n=9) experienced an average Abs-TSS improvement of 18.5 points at week 24 compared to baseline. These results compare favorably to historical data with ruxolitinib monotherapy, where less than half of patients achieve SVR35, and Abs-TSS improvement ranges from 11 to 14 points.
Dr. Raajit Rampal, Director of the Center for Hematologic Malignancies at Memorial Sloan Kettering Cancer Center, noted, "There remains a tremendous unmet need in myelofibrosis (搜索), as less than half of patients achieve SVR35 with each of the approved JAK (搜索) inhibitors and many patients eventually stop responding to these treatments... I believe these data are meaningful and impressive and provide a strong rationale for the Phase 3 SENTRY trial."
Clinical Significance and Unmet Need
Myelofibrosis (搜索) is a rare and serious bone marrow disorder that disrupts the body's normal production of blood cells. It is characterized by bone marrow scarring, leading to anemia, fatigue, and an enlarged spleen. Current treatments, primarily JAK (搜索) inhibitors, can alleviate some symptoms but often fail to provide durable responses or address the underlying disease pathology. As Dr. Ruben Mesa, President of Atrium Health Levine Cancer, stated, "Improving symptomatic burden for patients with myelofibrosis is an important goal in therapy, directly linking to decreases in morbidity and likely mortality."
Selinexor: A Selective Inhibitor of Nuclear Export (SINE) Compound
Selinexor is a first-in-class, oral exportin 1 (XPO1 (搜索)) inhibitor. It functions by selectively binding to and inhibiting the nuclear export protein XPO1, which leads to the accumulation of tumor suppressor proteins in the nucleus, inducing apoptosis in cancer cells. Selinexor is already approved in the U.S. for multiple myeloma and diffuse large B-cell lymphoma (搜索) (DLBCL).
Trial Outlook
Karyopharm (搜索) anticipates reporting top-line results from the Phase 3 SENTRY trial in the second half of 2025. The company reports strong enrollment in the trial, reflecting the unmet need and interest in novel treatment approaches for myelofibrosis (搜索).