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-Sørensen; 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

doi:10.1200/JCO.2015.65.3949

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-Sørensen, 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

Department of Clinical Medicine

109 Citations (Scopus)

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/m(2)) 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/m(2) using a twice-a-week (days 1 and 3) dosing schedule. The recommended phase II dose of 35 mg/m(2) 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/m(2) 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 language	English
Journal	Journal of Clinical Oncology
Volume	34
Issue number	34
Pages (from-to)	4142-4150
Number of pages	9
ISSN	0732-183X
DOIs	https://doi.org/10.1200/JCO.2015.65.3949
Publication status	Published - 1 Dec 2016

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Abdul Razak, A. R., Mau-Sørensen, M., Gabrail, N. Y., Gerecitano, J. F., Shields, A. F., Unger, T. J., Saint-Martin, J. R., Carlson, R., Landesman, Y., McCauley, D., Rashal, T., Lassen, U., Kim, R., Stayner, L.-A., Mirza, M. R., 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, 34(34), 4142-4150. https://doi.org/10.1200/JCO.2015.65.3949

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-Sørensen, Morten; Gabrail, Nashat Y et al.
In: Journal of Clinical Oncology, Vol. 34, No. 34, 01.12.2016, p. 4142-4150.

Research output: Contribution to journal › Journal article › Research › peer-review

Abdul Razak, AR, Mau-Sørensen, 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, L-A, 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

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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/m(2)) 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/m(2) using a twice-a-week (days 1 and 3) dosing schedule. The recommended phase II dose of 35 mg/m(2) 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/m(2) 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.",

author = "{Abdul Razak}, {Albiruni R} and Morten Mau-S{\o}rensen and Gabrail, {Nashat Y} and Gerecitano, {John F} and Shields, {Anthony F} and Unger, {Thaddeus J} and Saint-Martin, {Jean R} and Robert Carlson and Yosef Landesman and Dilara McCauley and Tami Rashal and Ulrik Lassen and Richard Kim and Lee-Anne Stayner and Mirza, {Mansoor R} and Michael Kauffman and Sharon Shacham and Amit Mahipal",

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language = "English",

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TY - JOUR

T1 - First-in-Class, First-in-Human Phase I Study of Selinexor, a Selective Inhibitor of Nuclear Export, in Patients With Advanced Solid Tumors

AU - Abdul Razak, Albiruni R

AU - Mau-Sørensen, 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

PY - 2016/12/1

Y1 - 2016/12/1

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/m(2)) 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/m(2) using a twice-a-week (days 1 and 3) dosing schedule. The recommended phase II dose of 35 mg/m(2) 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/m(2) 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.

AB - 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/m(2)) 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/m(2) using a twice-a-week (days 1 and 3) dosing schedule. The recommended phase II dose of 35 mg/m(2) 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/m(2) 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.

U2 - 10.1200/JCO.2015.65.3949

DO - 10.1200/JCO.2015.65.3949

M3 - Journal article

C2 - 26926685

SN - 0732-183X

VL - 34

SP - 4142

EP - 4150

JO - Journal of Clinical Oncology

JF - Journal of Clinical Oncology

IS - 34

ER -

First-in-Class, First-in-Human Phase I Study of Selinexor, a Selective Inhibitor of Nuclear Export, in Patients With Advanced Solid Tumors

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