Karyopharm Therapeutics (KPTI) Reports Successful Outcome from Phase 2 Portion of Phase 2/3 SEAL Study
Karyopharm Therapeutics Inc. (NASDAQ: KPTI) today reported a successful outcome from the Phase 2 portion of the SEAL study evaluating the activity of selinexor (KPT-330), the Company's lead, novel, oral Selective Inhibitor of Nuclear Export / SINE™ compound, in 57 patients with previously treated, advanced unresectable dedifferentiated liposarcoma. For the SEAL study’s primary endpoint of progression-free survival (PFS), oral selinexor showed superiority over placebo, achieving a hazard ratio (HR) of 0.60, representing a 40% reduction in the risk of progression or death. PFS was assessed by Independent Central Radiological Review (ICRR) based on RECIST v1.1.
In this randomized, blinded Phase 2 portion of the study, oral selinexor demonstrated an expected and manageable safety profile, primarily with nausea, anorexia and fatigue, low levels of Grade 3/4 cytopenias, and no new or unexpected safety signals identified. The majority of treatment-related adverse events (AEs) were low grade and reversible with dose modifications and/or standard supportive care. Importantly, the incidence of infections in the selinexor arm (overall 29%; Grades ≥3, 0%) was less than that reported in the placebo arm (overall 39%; Grade ≥3, 19%).
Additional efficacy assessments included PFS by World Health Organization (WHO) response criteria, effects on metabolic parameters via PET Scans, and PFS according to Choi Criteria. PFS per WHO criteria achieved a HR of 0.84; the WHO response criteria will not be included as part of the Phase 3 study objectives. Karyopharm intends to submit detailed results from the Phase 2 portion of the SEAL study for presentation at a future medical meeting.
“There are few effective treatment options for previously treated patients with recurrent dedifferentiated liposarcoma and extending PFS is an important clinical goal because the rapid progression of disease frequently results in early mortality,” said Mrinal M. Gounder, MD, Attending Physician, Sarcoma Service and Developmental Therapeutics Service, Memorial Sloan Kettering Cancer Center, and Lead Investigator of the SEAL trial. “These data are promising because they show that oral selinexor is active and has the potential to prolong PFS in this patient population, with an expected and manageable safety profile. As an orally administered agent, selinexor could be a welcome addition to the liposarcoma treatment landscape and we look forward to further elucidating selinexor’s efficacy and safety in the already ongoing Phase 3 portion of the SEAL study.”
The Phase 3 portion of the SEAL study, which was originally initiated in North America, is ongoing and has been expanded to include Europe. In this blinded, placebo-controlled Phase 3 study, up to 222 patients are expected to be enrolled and randomized 2:1 to receive either oral selinexor, (60mg fixed dose twice weekly) until disease progression or intolerability, or placebo. Patients whose disease progresses on placebo will be permitted to cross over to the selinexor arm. The primary endpoint of the Phase 3 portion of the study is PFS (RECIST v1.1) as assessed by the ICRR. The Phase 3 study design and primary endpoint of PFS were agreed to by the U.S. Food and Drug Administration (FDA). Top-line data from the Phase 3 portion of the SEAL study are anticipated by the end of 2019. Assuming a positive outcome, these data are expected to support a New Drug Application for oral selinexor as a potential new treatment for patients with advanced dedifferentiated liposarcoma.
“Liposarcomas are difficult to treat solid tumors that arise from the body’s fat tissue cells or their precursors,” said Sharon Shacham, PhD, MBA, President and Chief Scientific Officer of Karyopharm. “Dedifferentiated liposarcoma is an aggressive form of the disease that is resistant to both standard chemotherapy and radiation and has a particularly high rate of recurrence following surgery. Most patients who progress following surgery will ultimately succumb to their disease, highlighting the significant unmet need that exists for novel therapies. The FDA has confirmed their acceptance of the proposed Phase 3 SEAL study design, including the PFS primary endpoint, and agreed that positive results from this study could support regulatory approval in this patient population.”
Selinexor (KPT-330) is a first-in-class, oral Selective Inhibitor of Nuclear Export / SINE™ compound. Selinexor functions by binding with and inhibiting the nuclear export protein XPO1 (also called CRM1), leading to the accumulation of tumor suppressor proteins in the cell nucleus. This reinitiates and amplifies their tumor suppressor function and is believed to lead to the selective induction of apoptosis in cancer cells, while largely sparing normal cells. To date, over 2,100 patients have been treated with selinexor and it is currently being evaluated in several mid- and later-phase clinical trials across multiple cancer indications, including in multiple myeloma in a pivotal, randomized Phase 3 study in combination with Velcade® (bortezomib) and low-dose dexamethasone (BOSTON), in combination with low-dose dexamethasone (STORM) and backbone therapies (STOMP), and in diffuse large B-cell lymphoma (SADAL), and liposarcoma (SEAL), among others. Additional Phase 1, Phase 2 and Phase 3 studies are ongoing or currently planned, including multiple studies in combination with one or more approved therapies in a variety of tumor types to further inform the Company's clinical development priorities for selinexor. Additional clinical trial information for selinexor is available at www.clinicaltrials.gov.