FDA Grants Selinexor Fast Track Designation for Relapsed/Refractory DLBCL

The FDA has granted a fast track designation to selinexor for the treatment of patients with previously treated diffuse large B-cell lymphoma (DLBCL) who are ineligible to receive high-dose chemotherapy with stem cell rescue or chimeric antigen receptor (CAR) T-cell therapy, according to Karyopharm Therapeutics, Inc., the manufacturer of the first-in-class SINE compound.¹

The designation is based on data from the multicenter, open-label, phase IIb SADAL trial evaluating oral selinexor in patients with relapsed/refractory DLBCL who previously received 2 to 5 lines of therapy and are not eligible for hematopoietic stem cell transplantation (NCT02227251). The company said that top-line results will be presented at the 2018 ASH Annual Meeting.

“The receipt of fast track designation from the FDA for selinexor in relapsed DLBCL underscores the great unmet medical need for this aggressive form of lymphoma,” Sharon Shacham, PhD, MBA, founder, president, and chief scientific officer of Karyopharm, said in a statement. “Pending positive results from the phase IIb SADAL study, we plan to submit a second [new drug application] to the FDA in the first half of 2019, with a request for accelerated approval, for oral selinexor as a potential new treatment for patients with relapsed or refractory DLBCL.”

The FDA's fast track program accelerates the development of drugs designed to treat serious conditions with the potential to address unmet medical needs.

In SADAL, approximately 125 patients are given 60 mg twice weekly in 4-week cycles. Fifty percent of patients must harbor the germinal center B-cell subtype. The primary endpoint of the trial is objective response rate (ORR); the secondary endpoint is duration of response. Patients will be followed until disease progression and/or death. Responses are assessed by an Independent Central Radiological Review committee using the Lugano Classification.

To be eligible for enrollment, patients must have an ECOG performance status of 0 to 2, have measurable disease, and a minimum lapse of 60 days for those whose most recent DLBCL treatment induced a partial or complete response. For all other patients, at least 14 weeks must have elapsed since their most recent systemic therapy. Patients cannot have primary mediastinal large B-cell lymphoma, known central nervous system lymphoma, hepatitis B or C infection, or HIV infection.

Selinexor binds to XPO1 (CRM1), a nuclear export protein, which leads to the accumulation of tumor suppressor proteins in the cell nucleus. In turn, this reinitiates and amplifies tumor suppressor function and potentially leads to the selective induction of apoptosis in cancer cells while sparing normal cells.

In October 2018, the FDA granted a priority review to a new drug application (NDA) for selinexor for the treatment of patients with penta-refractory multiple myeloma. Under the Prescription Drug User Fee Act, the FDA is scheduled to make a decision on the application by April 6, 2019.

The NDA is based on data from the phase IIb STORM study, which examined the combination of selinexor and dexamethasone. Updated findings presented at the 2018 SOHO Annual Meeting showed that the combination was associated with an ORR of 26.2% and a median overall survival of 8.6 months in patients with penta-refractory disease.²

Selinexor is also being investigated in clinical trials across malignancies, such as the randomized phase III BOSTON trial, which is looking at selinexor in combination with bortezomib (Velcade) and low-dose dexamethasone in patients with relapsed/refractory multiple myeloma (NCT03110562). Additionally, the phase Ib/II STOMP trial is evaluating selinexor with backbone treatments—pomalidomide (Pomalyst)/dexamethasone, bortezomib/dexamethasone, lenalidomide (Revlimid)/dexamethasone, pomalidomide/dexamethasone/bortezomib, daratumumab (Darzalex) /dexamethasone, and carfilzomib (Kyprolis)/dexamethasone.

References

1. Karyopharm. Karyopharm’s selinexor receives fast track designation from FDA for the treatment of patients with relapsed or refractory diffuse large b-cell lymphoma. Published November 7, 2018. https://bit.ly/2Qr2pmg. Accessed November 7, 2018.
2. Jagannath J, Vogl DT, Dimopoulos MA, et al. Phase 2b results of the STORM study: oral selinexor plus low dose dexamethasone (sd) in patients with penta-refractory myeloma (penta-MM). Clin Lymphoma Myeloma Leuk. 2018;18(suppl; Abstract MM-255). doi: 10.1016/j.clml.2018.07.149.