TY - JOUR
T1 - A phase 1 clinical trial of single-agent selinexor in acute myeloid leukemia
AU - Garzon, Ramiro
AU - Savona, Michael
AU - Baz, Rachid
AU - Andreeff, Michael
AU - Gabrail, Nashat
AU - Gutierrez, Martin
AU - Savoie, Lynn
AU - Mau-Sorensen, Paul Morten
AU - Wagner-Johnston, Nina
AU - Yee, Karen
AU - Unger, Thaddeus J.
AU - Saint-Martin, Jean Richard
AU - Carlson, Robert
AU - Rashal, Tami
AU - Kashyap, Trinayan
AU - Klebanov, Boris
AU - Shacham, Sharon
AU - Kauffman, Michael
AU - Stone, Richard
N1 - Publisher Copyright:
© 2017 by The American Society of Hematology.
PY - 2017/6/15
Y1 - 2017/6/15
N2 - Selinexor is a novel, first-in-class, selective inhibitor of nuclear export compound, which blocks exportin 1 (XPO1) function, leads to nuclear accumulation of tumor suppressor proteins, and induces cancer cell death. A phase 1 dose-escalation study was initiated to examine the safety and efficacy of selinexor in patients with advanced hematological malignancies. Ninety-five patients with relapsed or refractory acute myeloid leukemia (AML) were enrolled between January 2013 and June 2014 to receive 4, 8, or 10 doses of selinexor in a 21- or 28-day cycle. The most frequently reported adverse events (AEs) in patients with AML were grade 1 or 2 constitutional and gastrointestinal toxicities, which were generally manageable with supportive care. The only nonhematological grade 3/4 AE, occurring in >5%of the patient population, was fatigue (14%). There were no reported dose-limiting toxicities or evidence of cumulative toxicity. The recommended phase 2 dose was established at 60 mg (∼35 mg/m2) given twice weekly in a 4-week cycle based on the totality of safety and efficacy data. Overall, 14% of the 81 evaluable patients achieved an objective response (OR) and 31% percent showed ≥50% decrease in bone marrow blasts from baseline. Patients achieving an OR had a significant improvement in median progression-free survival (PFS) (5.1 vs 1.3 months; P=.008; hazard ratio [HR], 3.1) and overall survival (9.7 vs 2.7 months; P=.01; HR, 3.1) compared with nonresponders. These findings suggest that selinexor is safe as a monotherapy in patients with relapsed or refractory AML and have informed subsequent phase 2 clinical development.
AB - Selinexor is a novel, first-in-class, selective inhibitor of nuclear export compound, which blocks exportin 1 (XPO1) function, leads to nuclear accumulation of tumor suppressor proteins, and induces cancer cell death. A phase 1 dose-escalation study was initiated to examine the safety and efficacy of selinexor in patients with advanced hematological malignancies. Ninety-five patients with relapsed or refractory acute myeloid leukemia (AML) were enrolled between January 2013 and June 2014 to receive 4, 8, or 10 doses of selinexor in a 21- or 28-day cycle. The most frequently reported adverse events (AEs) in patients with AML were grade 1 or 2 constitutional and gastrointestinal toxicities, which were generally manageable with supportive care. The only nonhematological grade 3/4 AE, occurring in >5%of the patient population, was fatigue (14%). There were no reported dose-limiting toxicities or evidence of cumulative toxicity. The recommended phase 2 dose was established at 60 mg (∼35 mg/m2) given twice weekly in a 4-week cycle based on the totality of safety and efficacy data. Overall, 14% of the 81 evaluable patients achieved an objective response (OR) and 31% percent showed ≥50% decrease in bone marrow blasts from baseline. Patients achieving an OR had a significant improvement in median progression-free survival (PFS) (5.1 vs 1.3 months; P=.008; hazard ratio [HR], 3.1) and overall survival (9.7 vs 2.7 months; P=.01; HR, 3.1) compared with nonresponders. These findings suggest that selinexor is safe as a monotherapy in patients with relapsed or refractory AML and have informed subsequent phase 2 clinical development.
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U2 - 10.1182/blood-2016-11-750158
DO - 10.1182/blood-2016-11-750158
M3 - Article
C2 - 28336527
AN - SCOPUS:85021161080
SN - 0006-4971
VL - 129
SP - 3165
EP - 3174
JO - Blood
JF - Blood
IS - 24
ER -