title: First-in-Class, First-in-Human Phase I Study of Selinexor, a Selective Inhibitor of Nuclear Export, in Patients With Advanced Solid Tumors.
abstract: Purpose This trial evaluated the safety, pharmacokinetics, pharmacodynamics, and efficacy of selinexor (KPT-330), a novel, oral small-molecule inhibitor of exportin 1 (XPO1/CRM1), and determined the recommended phase II dose. Patients and Methods In total, 189 patients with advanced solid tumors received selinexor (3 to 85 mg/m2) in 21- or 28-day cycles. Pre- and post-treatment levels of XPO1 mRNA in patient-derived leukocytes were determined by reverse transcriptase quantitative polymerase chain reaction, and tumor biopsies were examined by immunohistochemistry for changes in markers consistent with XPO1 inhibition. Antitumor response was assessed according Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 guidelines. Results The most common treatment-related adverse events included fatigue (70%), nausea (70%), anorexia (66%), and vomiting (49%), which were generally grade 1 or 2. Most commonly reported grade 3 or 4 toxicities were thrombocytopenia (16%), fatigue (15%), and hyponatremia (13%). Clinically significant major organ or cumulative toxicities were rare. The maximum-tolerated dose was defined at 65 mg/m2using a twice-a-week (days 1 and 3) dosing schedule. The recommended phase II dose of 35 mg/m2given twice a week was chosen based on better patient tolerability and no demonstrable improvement in radiologic response or disease stabilization compared with higher doses. Pharmacokinetics were dose proportional, with no evidence of drug accumulation. Dose-dependent elevations in XPO1 mRNA in leukocytes were demonstrated up to a dose level of 28 mg/m2before plateauing, and paired tumor biopsies showed nuclear accumulation of key tumor-suppressor proteins, reduction of cell proliferation, and induction of apoptosis. Among 157 patients evaluable for response, one complete and six partial responses were observed (n = 7, 4%), with 27 patients (17%) achieving stable disease for ≥ 4 months. Conclusion Selinexor is a novel and safe therapeutic with broad antitumor activity. Further interrogation into this class of therapy is warranted.
authors.affiliation: Albiruni R. Abdul Razak and Lee-Anne Stayner, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Morten Mau-Soerensen and Ulrik Lassen, Rigshospitalet, Copenhagen, Denmark; Nashat Y. Gabrail, Gabrail Cancer Institute, Canton, OH; John F. Gerecitano, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College, New York, NY; Anthony F. Shields, Karmanos Cancer Institute, Wayne State University, Detroit, MI; Thaddeus J. Unger, Jean R. Saint-Martin, Robert Carlson, Yosef Landesman, Dilara McCauley, Tami Rashal, Mansoor R. Mirza, Michael Kauffman, and Sharon Shacham, Karyopharm Therapeutics, Newton, MA; and Richard Kim and Amit Mahipal, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.
authors.forename: Albiruni R
authors.initials: AR
authors.lastname: Abdul Razak
authors.affiliation: Albiruni R. Abdul Razak and Lee-Anne Stayner, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Morten Mau-Soerensen and Ulrik Lassen, Rigshospitalet, Copenhagen, Denmark; Nashat Y. Gabrail, Gabrail Cancer Institute, Canton, OH; John F. Gerecitano, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College, New York, NY; Anthony F. Shields, Karmanos Cancer Institute, Wayne State University, Detroit, MI; Thaddeus J. Unger, Jean R. Saint-Martin, Robert Carlson, Yosef Landesman, Dilara McCauley, Tami Rashal, Mansoor R. Mirza, Michael Kauffman, and Sharon Shacham, Karyopharm Therapeutics, Newton, MA; and Richard Kim and Amit Mahipal, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.
authors.forename: Morten
authors.initials: M
authors.lastname: Mau-Soerensen
authors.affiliation: Albiruni R. Abdul Razak and Lee-Anne Stayner, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Morten Mau-Soerensen and Ulrik Lassen, Rigshospitalet, Copenhagen, Denmark; Nashat Y. Gabrail, Gabrail Cancer Institute, Canton, OH; John F. Gerecitano, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College, New York, NY; Anthony F. Shields, Karmanos Cancer Institute, Wayne State University, Detroit, MI; Thaddeus J. Unger, Jean R. Saint-Martin, Robert Carlson, Yosef Landesman, Dilara McCauley, Tami Rashal, Mansoor R. Mirza, Michael Kauffman, and Sharon Shacham, Karyopharm Therapeutics, Newton, MA; and Richard Kim and Amit Mahipal, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.
authors.forename: Nashat Y
authors.initials: NY
authors.lastname: Gabrail
authors.affiliation: Albiruni R. Abdul Razak and Lee-Anne Stayner, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Morten Mau-Soerensen and Ulrik Lassen, Rigshospitalet, Copenhagen, Denmark; Nashat Y. Gabrail, Gabrail Cancer Institute, Canton, OH; John F. Gerecitano, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College, New York, NY; Anthony F. Shields, Karmanos Cancer Institute, Wayne State University, Detroit, MI; Thaddeus J. Unger, Jean R. Saint-Martin, Robert Carlson, Yosef Landesman, Dilara McCauley, Tami Rashal, Mansoor R. Mirza, Michael Kauffman, and Sharon Shacham, Karyopharm Therapeutics, Newton, MA; and Richard Kim and Amit Mahipal, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.
authors.forename: John F
authors.initials: JF
authors.lastname: Gerecitano
authors.affiliation: Albiruni R. Abdul Razak and Lee-Anne Stayner, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Morten Mau-Soerensen and Ulrik Lassen, Rigshospitalet, Copenhagen, Denmark; Nashat Y. Gabrail, Gabrail Cancer Institute, Canton, OH; John F. Gerecitano, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College, New York, NY; Anthony F. Shields, Karmanos Cancer Institute, Wayne State University, Detroit, MI; Thaddeus J. Unger, Jean R. Saint-Martin, Robert Carlson, Yosef Landesman, Dilara McCauley, Tami Rashal, Mansoor R. Mirza, Michael Kauffman, and Sharon Shacham, Karyopharm Therapeutics, Newton, MA; and Richard Kim and Amit Mahipal, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.
authors.forename: Anthony F
authors.initials: AF
authors.lastname: Shields
authors.affiliation: Albiruni R. Abdul Razak and Lee-Anne Stayner, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Morten Mau-Soerensen and Ulrik Lassen, Rigshospitalet, Copenhagen, Denmark; Nashat Y. Gabrail, Gabrail Cancer Institute, Canton, OH; John F. Gerecitano, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College, New York, NY; Anthony F. Shields, Karmanos Cancer Institute, Wayne State University, Detroit, MI; Thaddeus J. Unger, Jean R. Saint-Martin, Robert Carlson, Yosef Landesman, Dilara McCauley, Tami Rashal, Mansoor R. Mirza, Michael Kauffman, and Sharon Shacham, Karyopharm Therapeutics, Newton, MA; and Richard Kim and Amit Mahipal, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.
authors.forename: Thaddeus J
authors.initials: TJ
authors.lastname: Unger
authors.affiliation: Albiruni R. Abdul Razak and Lee-Anne Stayner, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Morten Mau-Soerensen and Ulrik Lassen, Rigshospitalet, Copenhagen, Denmark; Nashat Y. Gabrail, Gabrail Cancer Institute, Canton, OH; John F. Gerecitano, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College, New York, NY; Anthony F. Shields, Karmanos Cancer Institute, Wayne State University, Detroit, MI; Thaddeus J. Unger, Jean R. Saint-Martin, Robert Carlson, Yosef Landesman, Dilara McCauley, Tami Rashal, Mansoor R. Mirza, Michael Kauffman, and Sharon Shacham, Karyopharm Therapeutics, Newton, MA; and Richard Kim and Amit Mahipal, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.
authors.forename: Jean R
authors.initials: JR
authors.lastname: Saint-Martin
authors.affiliation: Albiruni R. Abdul Razak and Lee-Anne Stayner, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Morten Mau-Soerensen and Ulrik Lassen, Rigshospitalet, Copenhagen, Denmark; Nashat Y. Gabrail, Gabrail Cancer Institute, Canton, OH; John F. Gerecitano, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College, New York, NY; Anthony F. Shields, Karmanos Cancer Institute, Wayne State University, Detroit, MI; Thaddeus J. Unger, Jean R. Saint-Martin, Robert Carlson, Yosef Landesman, Dilara McCauley, Tami Rashal, Mansoor R. Mirza, Michael Kauffman, and Sharon Shacham, Karyopharm Therapeutics, Newton, MA; and Richard Kim and Amit Mahipal, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.
authors.forename: Robert
authors.initials: R
authors.lastname: Carlson
authors.affiliation: Albiruni R. Abdul Razak and Lee-Anne Stayner, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Morten Mau-Soerensen and Ulrik Lassen, Rigshospitalet, Copenhagen, Denmark; Nashat Y. Gabrail, Gabrail Cancer Institute, Canton, OH; John F. Gerecitano, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College, New York, NY; Anthony F. Shields, Karmanos Cancer Institute, Wayne State University, Detroit, MI; Thaddeus J. Unger, Jean R. Saint-Martin, Robert Carlson, Yosef Landesman, Dilara McCauley, Tami Rashal, Mansoor R. Mirza, Michael Kauffman, and Sharon Shacham, Karyopharm Therapeutics, Newton, MA; and Richard Kim and Amit Mahipal, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.
authors.forename: Yosef
authors.initials: Y
authors.lastname: Landesman
authors.affiliation: Albiruni R. Abdul Razak and Lee-Anne Stayner, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Morten Mau-Soerensen and Ulrik Lassen, Rigshospitalet, Copenhagen, Denmark; Nashat Y. Gabrail, Gabrail Cancer Institute, Canton, OH; John F. Gerecitano, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College, New York, NY; Anthony F. Shields, Karmanos Cancer Institute, Wayne State University, Detroit, MI; Thaddeus J. Unger, Jean R. Saint-Martin, Robert Carlson, Yosef Landesman, Dilara McCauley, Tami Rashal, Mansoor R. Mirza, Michael Kauffman, and Sharon Shacham, Karyopharm Therapeutics, Newton, MA; and Richard Kim and Amit Mahipal, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.
authors.forename: Dilara
authors.initials: D
authors.lastname: McCauley
authors.affiliation: Albiruni R. Abdul Razak and Lee-Anne Stayner, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Morten Mau-Soerensen and Ulrik Lassen, Rigshospitalet, Copenhagen, Denmark; Nashat Y. Gabrail, Gabrail Cancer Institute, Canton, OH; John F. Gerecitano, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College, New York, NY; Anthony F. Shields, Karmanos Cancer Institute, Wayne State University, Detroit, MI; Thaddeus J. Unger, Jean R. Saint-Martin, Robert Carlson, Yosef Landesman, Dilara McCauley, Tami Rashal, Mansoor R. Mirza, Michael Kauffman, and Sharon Shacham, Karyopharm Therapeutics, Newton, MA; and Richard Kim and Amit Mahipal, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.
authors.forename: Tami
authors.initials: T
authors.lastname: Rashal
authors.affiliation: Albiruni R. Abdul Razak and Lee-Anne Stayner, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Morten Mau-Soerensen and Ulrik Lassen, Rigshospitalet, Copenhagen, Denmark; Nashat Y. Gabrail, Gabrail Cancer Institute, Canton, OH; John F. Gerecitano, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College, New York, NY; Anthony F. Shields, Karmanos Cancer Institute, Wayne State University, Detroit, MI; Thaddeus J. Unger, Jean R. Saint-Martin, Robert Carlson, Yosef Landesman, Dilara McCauley, Tami Rashal, Mansoor R. Mirza, Michael Kauffman, and Sharon Shacham, Karyopharm Therapeutics, Newton, MA; and Richard Kim and Amit Mahipal, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.
authors.forename: Ulrik
authors.initials: U
authors.lastname: Lassen
authors.affiliation: Albiruni R. Abdul Razak and Lee-Anne Stayner, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Morten Mau-Soerensen and Ulrik Lassen, Rigshospitalet, Copenhagen, Denmark; Nashat Y. Gabrail, Gabrail Cancer Institute, Canton, OH; John F. Gerecitano, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College, New York, NY; Anthony F. Shields, Karmanos Cancer Institute, Wayne State University, Detroit, MI; Thaddeus J. Unger, Jean R. Saint-Martin, Robert Carlson, Yosef Landesman, Dilara McCauley, Tami Rashal, Mansoor R. Mirza, Michael Kauffman, and Sharon Shacham, Karyopharm Therapeutics, Newton, MA; and Richard Kim and Amit Mahipal, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.
authors.forename: Richard
authors.initials: R
authors.lastname: Kim
authors.affiliation: Albiruni R. Abdul Razak and Lee-Anne Stayner, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Morten Mau-Soerensen and Ulrik Lassen, Rigshospitalet, Copenhagen, Denmark; Nashat Y. Gabrail, Gabrail Cancer Institute, Canton, OH; John F. Gerecitano, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College, New York, NY; Anthony F. Shields, Karmanos Cancer Institute, Wayne State University, Detroit, MI; Thaddeus J. Unger, Jean R. Saint-Martin, Robert Carlson, Yosef Landesman, Dilara McCauley, Tami Rashal, Mansoor R. Mirza, Michael Kauffman, and Sharon Shacham, Karyopharm Therapeutics, Newton, MA; and Richard Kim and Amit Mahipal, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.
authors.forename: Lee-Anne
authors.initials: LA
authors.lastname: Stayner
authors.affiliation: Albiruni R. Abdul Razak and Lee-Anne Stayner, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Morten Mau-Soerensen and Ulrik Lassen, Rigshospitalet, Copenhagen, Denmark; Nashat Y. Gabrail, Gabrail Cancer Institute, Canton, OH; John F. Gerecitano, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College, New York, NY; Anthony F. Shields, Karmanos Cancer Institute, Wayne State University, Detroit, MI; Thaddeus J. Unger, Jean R. Saint-Martin, Robert Carlson, Yosef Landesman, Dilara McCauley, Tami Rashal, Mansoor R. Mirza, Michael Kauffman, and Sharon Shacham, Karyopharm Therapeutics, Newton, MA; and Richard Kim and Amit Mahipal, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.
authors.forename: Mansoor R
authors.initials: MR
authors.lastname: Mirza
authors.affiliation: Albiruni R. Abdul Razak and Lee-Anne Stayner, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Morten Mau-Soerensen and Ulrik Lassen, Rigshospitalet, Copenhagen, Denmark; Nashat Y. Gabrail, Gabrail Cancer Institute, Canton, OH; John F. Gerecitano, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College, New York, NY; Anthony F. Shields, Karmanos Cancer Institute, Wayne State University, Detroit, MI; Thaddeus J. Unger, Jean R. Saint-Martin, Robert Carlson, Yosef Landesman, Dilara McCauley, Tami Rashal, Mansoor R. Mirza, Michael Kauffman, and Sharon Shacham, Karyopharm Therapeutics, Newton, MA; and Richard Kim and Amit Mahipal, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.
authors.forename: Michael
authors.initials: M
authors.lastname: Kauffman
authors.affiliation: Albiruni R. Abdul Razak and Lee-Anne Stayner, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Morten Mau-Soerensen and Ulrik Lassen, Rigshospitalet, Copenhagen, Denmark; Nashat Y. Gabrail, Gabrail Cancer Institute, Canton, OH; John F. Gerecitano, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College, New York, NY; Anthony F. Shields, Karmanos Cancer Institute, Wayne State University, Detroit, MI; Thaddeus J. Unger, Jean R. Saint-Martin, Robert Carlson, Yosef Landesman, Dilara McCauley, Tami Rashal, Mansoor R. Mirza, Michael Kauffman, and Sharon Shacham, Karyopharm Therapeutics, Newton, MA; and Richard Kim and Amit Mahipal, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.
authors.forename: Sharon
authors.initials: S
authors.lastname: Shacham
authors.affiliation: Albiruni R. Abdul Razak and Lee-Anne Stayner, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Morten Mau-Soerensen and Ulrik Lassen, Rigshospitalet, Copenhagen, Denmark; Nashat Y. Gabrail, Gabrail Cancer Institute, Canton, OH; John F. Gerecitano, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College, New York, NY; Anthony F. Shields, Karmanos Cancer Institute, Wayne State University, Detroit, MI; Thaddeus J. Unger, Jean R. Saint-Martin, Robert Carlson, Yosef Landesman, Dilara McCauley, Tami Rashal, Mansoor R. Mirza, Michael Kauffman, and Sharon Shacham, Karyopharm Therapeutics, Newton, MA; and Richard Kim and Amit Mahipal, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.
authors.forename: Amit
authors.initials: A
authors.lastname: Mahipal
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001706:Biopsy; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D006834:Hydrazines / Q000008:administration & dosage / Q000494:pharmacology*; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D012107:Research Design; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016896:Treatment Outcome; D014230:Triazoles / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D006834:Hydrazines; D014230:Triazoles; C585161:selinexor