TY - JOUR
T1 - Selective inhibition of nuclear export with selinexor in patients with non-Hodgkin lymphoma
AU - Kuruvilla, John
AU - Savona, Michael
AU - Baz, Rachid
AU - Mau-Sorensen, Paul Morten
AU - Gabrail, Nashat
AU - Garzon, Ramiro
AU - Stone, Richard
AU - Wang, Michael
AU - Savoie, Lynn
AU - Martin, Peter
AU - Flinn, Ian
AU - Jacoby, Meagan
AU - Unger, Thaddeus J.
AU - Saint-Martin, Jean Richard
AU - Rashal, Tami
AU - Friedlander, Sharon
AU - Carlson, Robert
AU - Kauffman, Michael
AU - Shacham, Sharon
AU - Gutierrez, Martin
N1 - Publisher Copyright:
© 2017 by The American Society of Hematology.
PY - 2017/6/15
Y1 - 2017/6/15
N2 - 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%).Tumorbiopsies 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,whichwere observed across a spectrumofNHL subtypes.Adose of 35mg/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.
AB - 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%).Tumorbiopsies 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,whichwere observed across a spectrumofNHL subtypes.Adose of 35mg/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.
UR - https://www.scopus.com/pages/publications/85021167496
U2 - 10.1182/blood-2016-11-750174
DO - 10.1182/blood-2016-11-750174
M3 - Article
C2 - 28468797
AN - SCOPUS:85021167496
SN - 0006-4971
VL - 129
SP - 3175
EP - 3183
JO - Blood
JF - Blood
IS - 24
ER -