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Selective inhibition of nuclear export with selinexor in patients with non-Hodgkin lymphoma

2017; Elsevier BV; Volume: 129; Issue: 24 Linguagem: Inglês

10.1182/blood-2016-11-750174

1528-0020

John Kuruvilla, Michael R. Savona, Rachid Baz, Morten Mau‐Sørensen, Nashat Gabrail, Ramiro Garzon, Richard M. Stone, Michael Wang, Lynn Savoie, Peter Martin, Ian W. Flinn, Meagan A. Jacoby, Thaddeus J. Unger, Jean-Richard Saint-Martin, Tami Rashal, Sharon Friedlander, Robert Carlson, Michael Kauffman, Sharon Shacham, Martin Gutierrez,

Cancer-related Molecular Pathways

Abstract Patients with relapsed or refractory (R/R) non-Hodgkin 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, Richter’s transformation, mantle cell lymphoma, follicular lymphoma, and chronic lymphocytic leukemia, were enrolled. In the dose-escalation phase, patients received 3 to 80 mg/m2 of selinexor in 3- or 4-week cycles and were assessed for toxicities, pharmacokinetics, and antitumor activity. In the dose-expansion phase, patients were treated with selinexor at 35 or 60 mg/m2. The most common grade 3 to 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 responses, including 4 complete responses and 18 partial responses, which were observed across a spectrum of NHL subtypes. A dose of 35 mg/m2 (60 mg) 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 anticancer activity in patients with R/R NHL. The trial was registered at www.clinicaltrials.gov as #NCT01607892.