Pilot phase II study of Selinexor in combination with Ifosfamide, Etoposide and Dexamethasone (SIDE) in patients with relapsed or refractory Peripheral T-cell Lymphomas.

The standard treatment for peripheral T-cell lymphoma (PTCL) is CHOP/CHOEP chemotherapy followed by high-dose chemotherapy in patients eligible for autologous stem cell transplantation (SCT), but only 40% of patients can be cured. The prognosis of relapsed/refractory PTCL is poor, with an overall response rate (ORR) of 30–40% and a median progression-free survival (PFS) and overall survival (OS) of 3 and 5.5 months, respectively. 

Selinexor is an oral, first-in-class, selective inhibitor of nuclear export (SINE) that binds to exportin-1 (XPO1/CRM1), resulting in nuclear retention of tumor suppressor proteins (TSPs), growth regulatory proteins (GRPs, such as TP53, p21, p27, FOXO3, NPM1), and the enzyme topoisomerase IIα, thereby restoring their function. XPO1 is overexpressed in many malignancies, including PTCL, and is associated with poor prognosis. 

Selinexor has been approved by the U.S. Food and Drug Administration (FDA) for relapsed or refractory multiple myeloma and diffuse large B-cell lymphoma (DLBCL), and has demonstrated notable anti-tumor activity in preclinical models, including T-cell acute lymphoblastic leukemia. 

In a phase I study, Selinexor showed an ORR of approximately 30% in relapsed/refractory non-Hodgkin lymphoma. In another phase I study combining Selinexor with high-dose dexamethasone, ifosfamide, carboplatin, and etoposide (DICE), 11 patients with relapsed/refractory T-cell and natural killer cell lymphoma were treated. The most significant toxicities were hematologic (particularly thrombocytopenia). The maximum tolerated dose (MTD) of Selinexor in combination with DICE was 40 mg. Among the 10 evaluable patients, the ORR was 91%, with 82% achieving complete remission (CR). 

These ORR and CR rates are very promising and superior to other combination therapies tested in relapsed/refractory PTCL (with the exception of results obtained with brentuximab vedotin in CD30+ ALK-positive anaplastic lymphomas). However, these results are preliminary and need to be confirmed in a larger study. For this reason, we have designed a phase II study of Selinexor in combination with standard chemotherapy including ifosfamide, etoposide, and dexamethasone. We decided to omit carboplatin to reduce nausea and hematologic toxicity, and because the role of carboplatin in PTCL is debatable.