First-in-class, first-in-human phase I study of selinexor, a selective inhibitor of nuclear export, in patients with advanced solid tumors

Albiruni R. Abdul Razak, Morten Mau-Soerensen, Nashat Y. Gabrail, John F. Gerecitano, Anthony F. Shields, Thaddeus J. Unger, Jean R. Saint-Martin, Robert Carlson, Yosef Landesman, Dilara McCauley, Tami Rashal, Ulrik Lassen, Richard Kim, Lee Anne Stayner, Mansoor R. Mirza, Michael Kauffman, Sharon Shacham, Amit Mahipal

Research output: Contribution to journalArticle

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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/m2 using a twice-a-week (days 1 and 3) dosing schedule. The recommended phase II dose of 35 mg/m2 given 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/m2 before 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.

Original languageEnglish (US)
Pages (from-to)4142-4150
Number of pages9
JournalJournal of Clinical Oncology
Volume34
Issue number34
DOIs
StatePublished - Dec 1 2016
Externally publishedYes

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Cell Nucleus Active Transport
Neoplasms
Fatigue
Leukocytes
Pharmacokinetics
Tumor Suppressor Proteins
Biopsy
Therapeutics
Messenger RNA
Maximum Tolerated Dose
Hyponatremia
Anorexia
Reverse Transcriptase Polymerase Chain Reaction
Thrombocytopenia
Nausea
Vomiting
KPT-330
Appointments and Schedules
Immunohistochemistry
Cell Proliferation

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

First-in-class, first-in-human phase I study of selinexor, a selective inhibitor of nuclear export, in patients with advanced solid tumors. / Abdul Razak, Albiruni R.; Mau-Soerensen, Morten; Gabrail, Nashat Y.; Gerecitano, John F.; Shields, Anthony F.; Unger, Thaddeus J.; Saint-Martin, Jean R.; Carlson, Robert; Landesman, Yosef; McCauley, Dilara; Rashal, Tami; Lassen, Ulrik; Kim, Richard; Stayner, Lee Anne; Mirza, Mansoor R.; Kauffman, Michael; Shacham, Sharon; Mahipal, Amit.

In: Journal of Clinical Oncology, Vol. 34, No. 34, 01.12.2016, p. 4142-4150.

Research output: Contribution to journalArticle

Abdul Razak, AR, Mau-Soerensen, M, Gabrail, NY, Gerecitano, JF, Shields, AF, Unger, TJ, Saint-Martin, JR, Carlson, R, Landesman, Y, McCauley, D, Rashal, T, Lassen, U, Kim, R, Stayner, LA, Mirza, MR, Kauffman, M, Shacham, S & Mahipal, A 2016, 'First-in-class, first-in-human phase I study of selinexor, a selective inhibitor of nuclear export, in patients with advanced solid tumors', Journal of Clinical Oncology, vol. 34, no. 34, pp. 4142-4150. https://doi.org/10.1200/JCO.2015.65.3949
Abdul Razak, Albiruni R. ; Mau-Soerensen, Morten ; Gabrail, Nashat Y. ; Gerecitano, John F. ; Shields, Anthony F. ; Unger, Thaddeus J. ; Saint-Martin, Jean R. ; Carlson, Robert ; Landesman, Yosef ; McCauley, Dilara ; Rashal, Tami ; Lassen, Ulrik ; Kim, Richard ; Stayner, Lee Anne ; Mirza, Mansoor R. ; Kauffman, Michael ; Shacham, Sharon ; Mahipal, Amit. / First-in-class, first-in-human phase I study of selinexor, a selective inhibitor of nuclear export, in patients with advanced solid tumors. In: Journal of Clinical Oncology. 2016 ; Vol. 34, No. 34. pp. 4142-4150.
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AU - Abdul Razak, Albiruni R.

AU - Mau-Soerensen, Morten

AU - Gabrail, Nashat Y.

AU - Gerecitano, John F.

AU - Shields, Anthony F.

AU - Unger, Thaddeus J.

AU - Saint-Martin, Jean R.

AU - Carlson, Robert

AU - Landesman, Yosef

AU - McCauley, Dilara

AU - Rashal, Tami

AU - Lassen, Ulrik

AU - Kim, Richard

AU - Stayner, Lee Anne

AU - Mirza, Mansoor R.

AU - Kauffman, Michael

AU - Shacham, Sharon

AU - Mahipal, Amit

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N2 - 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/m2 using a twice-a-week (days 1 and 3) dosing schedule. The recommended phase II dose of 35 mg/m2 given 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/m2 before 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.

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