Kuruvilla, John, Martin, Peter, Flinn, Ian, Jacoby, Meagan, Unger, Thaddeus J., Saint-Martin, Jean-Richard, Rashal, Tami, Friedlander, Sharon, Carlson, Robert, Kauffman, Michael, Shacham, Sharon, Gutierrez, Martin, Savona, Michael, Baz, Rachid, Mau-Sorensen, Paul Morten, Gabrail, Nashat, Garzon, Ramiro, Stone, Richard, Wang, Michael, and Savoie, Lynn
Patients with relapsed or refractory (R/R) non-Hodgkin's lymphoma (NHL) have a poor prognosis and limited treatment options. We evaluated selinexor, an orally bioavailable, first-in-class inhibitor of the nuclear export protein XPO1, in this phase 1 trial to assess safety and determine a recommended phase 2 dose (RP2D). Seventy-nine patients with various NHL histologies, including diffuse large B cell lymphoma (DLBCL), Richter's transformation, mantle cell lymphoma (MCL), follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL) were enrolled. In the dose escalation phase, patients received 3-80 mg/m2 of selinexor in 3- or 4-week cycles and were assessed for toxicities, pharmacokinetics and anti-tumor activity. In the dose expansion phase, patients were treated with selinexor at 35 or 60 mg/m2. The most common grade 3-4 drug-related adverse events were thrombocytopenia (47%), neutropenia (32%), anemia (27%), leukopenia (16%), fatigue (11%) and hyponatremia (10%). Tumor biopsies showed decreases in cell signaling pathways (Bcl-2, Bcl-6, c-Myc), reduced proliferation (Ki67), nuclear localization of XPO1 cargos (p53, PTEN) and increased apoptosis after treatment. Twenty-two (31%) of the 70 evaluable patients had an objective response (OR), including 4 complete responses (CR) and 18 partial responses (PR), which were observed across a spectrum of NHL subtypes. A dose of 35 mg/m2 (60mg) was identified as the RP2D. These findings suggest that inhibition of XPO1 with oral selinexor at 35 mg/m2 is a safe therapy with encouraging and durable anti-cancer activity in patients with R/R NHL. [ABSTRACT FROM AUTHOR]