A phase 1 clinical trial of single-agent selinexor in acute myeloid leukemia.
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. This trial was registered at www.clinicaltrials.gov as #NCT01607892.
Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH.
Ramiro
R
Garzon
Division of Hematology and Oncology, Vanderbilt-Ingram Cancer Center/Vanderbilt University Medical Center, Nashville, TN.
Michael
0000-0003-3763-5504
M
Savona
Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.
Rachid
0000-0003-4538-4733
R
Baz
Division of Cancer Medicine, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX.
Michael
0000-0002-1144-1958
M
Andreeff
Gabrail Cancer Institute, Canton, OH.
Nashat
N
Gabrail
Department of Hematology, John Theurer Cancer Center, Hackensack, NJ.
Martin
M
Gutierrez
Division of Hematology, University of Calgary, Calgary, AB, Canada.
Lynn
L
Savoie
Department of Oncology, Rigshospitalet, Copenhagen, Denmark.
Paul Morten
PM
Mau-Sorensen
Siteman Cancer Center, St. Louis, MO.
Nina
N
Wagner-Johnston
Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre and The University of Toronto, Toronto, ON, Canada.
Karen
K
Yee
Karyopharm Therapeutics Inc, Newton, MA; and.
Thaddeus J
TJ
Unger
Karyopharm Therapeutics Inc, Newton, MA; and.
Jean-Richard
JR
Saint-Martin
Karyopharm Therapeutics Inc, Newton, MA; and.
Robert
R
Carlson
Karyopharm Therapeutics Inc, Newton, MA; and.
Tami
T
Rashal
Karyopharm Therapeutics Inc, Newton, MA; and.
Trinayan
T
Kashyap
Karyopharm Therapeutics Inc, Newton, MA; and.
Boris
B
Klebanov
Karyopharm Therapeutics Inc, Newton, MA; and.
Sharon
S
Shacham
Karyopharm Therapeutics Inc, Newton, MA; and.
Michael
M
Kauffman
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.
Richard
R
Stone
D000328:Adult; D001752:Blast Crisis / Q000097:blood / Q000188:drug therapy* / Q000401:mortality*; D001854:Bone Marrow Cells / Q000378:metabolism; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D006834:Hydrazines / Q000008:administration & dosage* / Q000009:adverse effects; D015470:Leukemia, Myeloid, Acute / Q000097:blood / Q000188:drug therapy* / Q000401:mortality*; D008297:Male; D008875:Middle Aged; D015996:Survival Rate; D014230:Triazoles / Q000008:administration & dosage* / Q000009:adverse effects
D006834:Hydrazines; D014230:Triazoles; C585161:selinexor