PMID- 28336527 OWN - NLM STAT- MEDLINE DCOM- 20170817 LR - 20210217 IS - 1528-0020 (Electronic) IS - 0006-4971 (Print) IS - 0006-4971 (Linking) VI - 129 IP - 24 DP - 2017 Jun 15 TI - A phase 1 clinical trial of single-agent selinexor in acute myeloid leukemia. PG - 3165-3174 LID - 10.1182/blood-2016-11-750158 [doi] 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 ( approximately 35 mg/m(2)) 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. CI - (c) 2017 by The American Society of Hematology. FAU - Garzon, Ramiro AU - Garzon R AD - Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH. FAU - Savona, Michael AU - Savona M AUID- ORCID: 0000-0003-3763-5504 AD - Division of Hematology and Oncology, Vanderbilt-Ingram Cancer Center/Vanderbilt University Medical Center, Nashville, TN. FAU - Baz, Rachid AU - Baz R AUID- ORCID: 0000-0003-4538-4733 AD - Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL. FAU - Andreeff, Michael AU - Andreeff M AUID- ORCID: 0000-0002-1144-1958 AD - Division of Cancer Medicine, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX. FAU - Gabrail, Nashat AU - Gabrail N AD - Gabrail Cancer Institute, Canton, OH. FAU - Gutierrez, Martin AU - Gutierrez M AD - Department of Hematology, John Theurer Cancer Center, Hackensack, NJ. FAU - Savoie, Lynn AU - Savoie L AD - Division of Hematology, University of Calgary, Calgary, AB, Canada. FAU - Mau-Sorensen, Paul Morten AU - Mau-Sorensen PM AD - Department of Oncology, Rigshospitalet, Copenhagen, Denmark. FAU - Wagner-Johnston, Nina AU - Wagner-Johnston N AD - Siteman Cancer Center, St. Louis, MO. FAU - Yee, Karen AU - Yee K AD - Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre and The University of Toronto, Toronto, ON, Canada. FAU - Unger, Thaddeus J AU - Unger TJ AD - Karyopharm Therapeutics Inc, Newton, MA; and. FAU - Saint-Martin, Jean-Richard AU - Saint-Martin JR AD - Karyopharm Therapeutics Inc, Newton, MA; and. FAU - Carlson, Robert AU - Carlson R AD - Karyopharm Therapeutics Inc, Newton, MA; and. FAU - Rashal, Tami AU - Rashal T AD - Karyopharm Therapeutics Inc, Newton, MA; and. FAU - Kashyap, Trinayan AU - Kashyap T AD - Karyopharm Therapeutics Inc, Newton, MA; and. FAU - Klebanov, Boris AU - Klebanov B AD - Karyopharm Therapeutics Inc, Newton, MA; and. FAU - Shacham, Sharon AU - Shacham S AD - Karyopharm Therapeutics Inc, Newton, MA; and. FAU - Kauffman, Michael AU - Kauffman M AD - Karyopharm Therapeutics Inc, Newton, MA; and. FAU - Stone, Richard AU - Stone R AD - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA. LA - eng SI - ClinicalTrials.gov/NCT01607892 GR - P50 CA100632/CA/NCI NIH HHS/United States GR - R01 CA188269/CA/NCI NIH HHS/United States PT - Clinical Trial, Phase I PT - Journal Article PT - Multicenter Study PT - Research Support, Non-U.S. Gov't DEP - 20170323 PL - United States TA - Blood JT - Blood JID - 7603509 RN - 0 (Hydrazines) RN - 0 (Triazoles) RN - 31TZ62FO8F (selinexor) SB - IM CIN - Blood. 2017 Jun 15;129(24):3137-3138. PMID: 28620100 EIN - Blood. 2020 Jul 9;136(2):259. PMID: 32645169 MH - Adult MH - Blast Crisis/blood/*drug therapy/*mortality MH - Bone Marrow Cells/metabolism MH - Disease-Free Survival MH - Female MH - Humans MH - Hydrazines/*administration & dosage/adverse effects MH - Leukemia, Myeloid, Acute/blood/*drug therapy/*mortality MH - Male MH - Middle Aged MH - Survival Rate MH - Triazoles/*administration & dosage/adverse effects PMC - PMC5524530 COIS- Conflict-of-interest disclosure: R.G. received a travel stipend from Karyopharm Therapeutics. M.S. owns stock in Karyopharm Therapeutics, has a consulting/advisory role at Amgen, CTI, Karyopharm Therapeutics, ARIAD, Gilead, and Celgene, and receives research funding from Astex, Sunesis, Takeda, and TG Therapeutics. R.B. has a consulting/advisory role at Celgene and receives research funding from Celgene, Karyopharm Therapeutics, Merck, Bristol-Myers Squibb, and Millennium/Takeda. N.G. receives honoraria from Heron, Sanofi, and Taiho and is a consultant/advisor at Heron. L.S. has a consulting/advisory role at Novartis, Bristol-Myers Squibb, Pfizer, Celgene, and JAZZ. P.M.M.-S. receives honorarium and a travel stipend from Karyopharm Therapeutics. T.J.U., J.-R.S.-M., R.C., T.R., T.K., B.K., S.S., and M.K. are employees and stockholders at Karyopharm Therapeutics. R.S. receives honoraria from Amgen, Arog, Agios, Celfor, Celgene, Sunesis, Bristol-Myers Squibb, Pfizer, Novartis, Karyopharm Therapeutics, Fujifilm, AbbVie, Roche, Genentech, and Merck, and receives research funding from Novartis. The remaining authors declare no competing financial interests. EDAT- 2017/03/25 06:00 MHDA- 2017/08/18 06:00 PMCR- 2017/06/15 CRDT- 2017/03/25 06:00 PHST- 2016/11/07 00:00 [received] PHST- 2017/03/06 00:00 [accepted] PHST- 2017/03/25 06:00 [pubmed] PHST- 2017/08/18 06:00 [medline] PHST- 2017/03/25 06:00 [entrez] PHST- 2017/06/15 00:00 [pmc-release] AID - S0006-4971(20)33298-5 [pii] AID - 2016/750158-BLD_129_24 [pii] AID - 10.1182/blood-2016-11-750158 [doi] PST - ppublish SO - Blood. 2017 Jun 15;129(24):3165-3174. doi: 10.1182/blood-2016-11-750158. Epub 2017 Mar 23.