An Investigator Initiated Study of RCHOP in Combination with Selinexor (KPT-330) in Diffuse Large B Cell Lymphoma and Richter Transformation

Background and Significance: Rituximab-containing chemoimmunotherapy remains standard front-line treatment for newly diagnosed diffuse large B cell lymphoma (DLBCL) including Richter transformation (RT). Approximately 70% of patients with DLBCL achieve durable remission with this approach. Patients with RT, however, frequently experience shorter remissions. Therefore, novel strategies are warranted to improve outcomes of these patients. Selinexor is a first in class, slowly reversible, potent and selective inhibitor of nuclear export (SINE) compound that specifically blocks exportin 1 (XPO1) and is approved for relapsed refractory DLBCL after ≥2 prior lines of therapy. We hypothesize that combination of Selinexor and RCHOP may improve outcomes of newly diagnosed DLBCL and RT. Study Design and Methods: This was a phase I/II investigator-initiated dose escalation/dose-expansion study to evaluate the safety and tolerability of selinexor when combined with RCHOP. Phase I cohort included B-non-Hodgkin lymphoma and the RP2D of selinexor was determined to be 60 mg weekly (Seymour et al, 2021). Currently phase II expansion cohorts are enrolling. Key eligibility criteria for phase II expansion include patients ≥18 years of age with newly diagnosed advanced stage III-IV DLBCL (Group A) or RT (Group B), ECOG PS £1, and FDG avid measurable disease by PET. Patients with RT could receive prior non-anthracycline-based CLL treatment. All patients will receive selinexor orally on days 1, 8, 15 during each 21-day cycle for a total of 6 cycles along with standard dosing of RCHOP. Patients with response (partial or complete remission) at the end of 6 cycles will receive optional maintenance selinexor for 1 year. Maintenance selinexor will be given once a week on days 1, 8, 15, 22 in a 4-week cycle (1 cycle=28 days). The primary objective of phase II expansion is to estimate 2-year progression-free survival (PFS) for group A, and overall response rate (ORR) for group B. Exploratory objective will evaluate association of baseline XPO-1 expression with response and outcomes after therapy. For group A, we expect to enroll 31 participants with DLBCL in the phase II expansion cohort. This design will provide 80% statistical power and a one-sided 5% type I error to assess a 2-year PFS greater than 55%. For group B, we will enroll 7 participants per the Simon's first stage of the study. If ³ 4 participants have an ORR by 12 weeks, an additional 13 participants will be enrolled for a total of 20. If at least 12 of 20 have an ORR by 12 weeks, it will be concluded that there is sufficient evidence of efficacy, that the ORR is at least 40%. The study is currently enrolling. The clinicalTrials.gov ID is NCT03147885.