Phase ii study of alisertib, a selective aurora a kinase inhibitor, in relapsed and refractory aggressive B- And T-cell non-Hodgkin lymphomas

Jonathan W. Friedberg, Daruka Mahadevan, Erin Cebula, Daniel Persky, Izidore Lossos, Amit B. Agarwal, JungAh Jung, Richard Burack, Xiaofei Zhou, E. Jane Leonard, Howard Fingert, Hadi Danaee, Steven H. Bernstein

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Abstract

Purpose: Aurora A kinase (AAK) is overexpressed in aggressive lymphomas and can correlate with more histologically aggressive forms of disease. We therefore designed a phase II study of alisertib, a selective AAK inhibitor, in patients with relapsed and refractory aggressive non-Hodgkin lymphomas. Patients and Methods: Patients age ≥ 18 years were eligible if they had relapsed or refractory diffuse large B-cell lymphoma (DLBCL), mantle-cell lymphoma (MCL), transformed follicular lymphoma, Burkitt's lymphoma, or noncutaneous T-cell lymphoma. Alisertib was administered orally at 50 mg twice daily for 7 days in 21-day cycles. Results: We enrolled 48 patients. Histologies included DLBCL (n = 21), MCL (n = 13), peripheral T-cell lymphoma (n = 8), transformed follicular lymphoma (n = 5), and Burkitt's (n = 1). Most common grade 3 to 4 adverse events were neutropenia (63%), leukopenia (54%), anemia (35%), thrombocytopenia (33%), stomatitis (15%), febrile neutropenia (13%), and fatigue (6%). Four deaths during the study were attributed to progressive non-Hodgkin lymphoma (n = 2), treatment-related sepsis (n = 1), and unknown cause (n = 1). The overall response rate was 27%, including responses in three of 21 patients with DLBCL, three of 13 with MCL, one of one with Burkitt's lymphoma, two of five with transformed follicular lymphoma, and four of eight with noncutaneous T-cell lymphoma. The alisertib steady-state trough concentration (n = 25) revealed the expected pharmacokinetic variability, with a trend for higher incidence of adverse event-related dose reductions at higher trough concentrations. Analysis for AAK gene amplification and total AAK protein revealed no differences between histologies or correlation with clinical response. Conclusion: The novel AAK inhibitor alisertib seems clinically active in both B- and T-cell aggressive lymphomas. On the basis of these results, confirmatory single-agent and combination studies have been initiated.

Original languageEnglish
Pages (from-to)44-50
Number of pages7
JournalJournal of Clinical Oncology
Volume32
Issue number1
DOIs
StatePublished - Jan 1 2014

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Aurora Kinases
Aurora Kinase A
T-Cell Lymphoma
Non-Hodgkin's Lymphoma
Mantle-Cell Lymphoma
Follicular Lymphoma
Burkitt Lymphoma
Lymphoma, Large B-Cell, Diffuse
Histology
Peripheral T-Cell Lymphoma
Febrile Neutropenia
Stomatitis
Gene Amplification
Leukopenia
Neutropenia
Thrombocytopenia
Fatigue
Anemia
Lymphoma
Sepsis

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

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Phase ii study of alisertib, a selective aurora a kinase inhibitor, in relapsed and refractory aggressive B- And T-cell non-Hodgkin lymphomas. / Friedberg, Jonathan W.; Mahadevan, Daruka; Cebula, Erin; Persky, Daniel; Lossos, Izidore; Agarwal, Amit B.; Jung, JungAh; Burack, Richard; Zhou, Xiaofei; Leonard, E. Jane; Fingert, Howard; Danaee, Hadi; Bernstein, Steven H.

In: Journal of Clinical Oncology, Vol. 32, No. 1, 01.01.2014, p. 44-50.

Research output: Contribution to journalArticle

Friedberg, JW, Mahadevan, D, Cebula, E, Persky, D, Lossos, I, Agarwal, AB, Jung, J, Burack, R, Zhou, X, Leonard, EJ, Fingert, H, Danaee, H & Bernstein, SH 2014, 'Phase ii study of alisertib, a selective aurora a kinase inhibitor, in relapsed and refractory aggressive B- And T-cell non-Hodgkin lymphomas', Journal of Clinical Oncology, vol. 32, no. 1, pp. 44-50. https://doi.org/10.1200/JCO.2012.46.8793
Friedberg, Jonathan W. ; Mahadevan, Daruka ; Cebula, Erin ; Persky, Daniel ; Lossos, Izidore ; Agarwal, Amit B. ; Jung, JungAh ; Burack, Richard ; Zhou, Xiaofei ; Leonard, E. Jane ; Fingert, Howard ; Danaee, Hadi ; Bernstein, Steven H. / Phase ii study of alisertib, a selective aurora a kinase inhibitor, in relapsed and refractory aggressive B- And T-cell non-Hodgkin lymphomas. In: Journal of Clinical Oncology. 2014 ; Vol. 32, No. 1. pp. 44-50.
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abstract = "Purpose: Aurora A kinase (AAK) is overexpressed in aggressive lymphomas and can correlate with more histologically aggressive forms of disease. We therefore designed a phase II study of alisertib, a selective AAK inhibitor, in patients with relapsed and refractory aggressive non-Hodgkin lymphomas. Patients and Methods: Patients age ≥ 18 years were eligible if they had relapsed or refractory diffuse large B-cell lymphoma (DLBCL), mantle-cell lymphoma (MCL), transformed follicular lymphoma, Burkitt's lymphoma, or noncutaneous T-cell lymphoma. Alisertib was administered orally at 50 mg twice daily for 7 days in 21-day cycles. Results: We enrolled 48 patients. Histologies included DLBCL (n = 21), MCL (n = 13), peripheral T-cell lymphoma (n = 8), transformed follicular lymphoma (n = 5), and Burkitt's (n = 1). Most common grade 3 to 4 adverse events were neutropenia (63{\%}), leukopenia (54{\%}), anemia (35{\%}), thrombocytopenia (33{\%}), stomatitis (15{\%}), febrile neutropenia (13{\%}), and fatigue (6{\%}). Four deaths during the study were attributed to progressive non-Hodgkin lymphoma (n = 2), treatment-related sepsis (n = 1), and unknown cause (n = 1). The overall response rate was 27{\%}, including responses in three of 21 patients with DLBCL, three of 13 with MCL, one of one with Burkitt's lymphoma, two of five with transformed follicular lymphoma, and four of eight with noncutaneous T-cell lymphoma. The alisertib steady-state trough concentration (n = 25) revealed the expected pharmacokinetic variability, with a trend for higher incidence of adverse event-related dose reductions at higher trough concentrations. Analysis for AAK gene amplification and total AAK protein revealed no differences between histologies or correlation with clinical response. Conclusion: The novel AAK inhibitor alisertib seems clinically active in both B- and T-cell aggressive lymphomas. On the basis of these results, confirmatory single-agent and combination studies have been initiated.",
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T1 - Phase ii study of alisertib, a selective aurora a kinase inhibitor, in relapsed and refractory aggressive B- And T-cell non-Hodgkin lymphomas

AU - Friedberg, Jonathan W.

AU - Mahadevan, Daruka

AU - Cebula, Erin

AU - Persky, Daniel

AU - Lossos, Izidore

AU - Agarwal, Amit B.

AU - Jung, JungAh

AU - Burack, Richard

AU - Zhou, Xiaofei

AU - Leonard, E. Jane

AU - Fingert, Howard

AU - Danaee, Hadi

AU - Bernstein, Steven H.

PY - 2014/1/1

Y1 - 2014/1/1

N2 - Purpose: Aurora A kinase (AAK) is overexpressed in aggressive lymphomas and can correlate with more histologically aggressive forms of disease. We therefore designed a phase II study of alisertib, a selective AAK inhibitor, in patients with relapsed and refractory aggressive non-Hodgkin lymphomas. Patients and Methods: Patients age ≥ 18 years were eligible if they had relapsed or refractory diffuse large B-cell lymphoma (DLBCL), mantle-cell lymphoma (MCL), transformed follicular lymphoma, Burkitt's lymphoma, or noncutaneous T-cell lymphoma. Alisertib was administered orally at 50 mg twice daily for 7 days in 21-day cycles. Results: We enrolled 48 patients. Histologies included DLBCL (n = 21), MCL (n = 13), peripheral T-cell lymphoma (n = 8), transformed follicular lymphoma (n = 5), and Burkitt's (n = 1). Most common grade 3 to 4 adverse events were neutropenia (63%), leukopenia (54%), anemia (35%), thrombocytopenia (33%), stomatitis (15%), febrile neutropenia (13%), and fatigue (6%). Four deaths during the study were attributed to progressive non-Hodgkin lymphoma (n = 2), treatment-related sepsis (n = 1), and unknown cause (n = 1). The overall response rate was 27%, including responses in three of 21 patients with DLBCL, three of 13 with MCL, one of one with Burkitt's lymphoma, two of five with transformed follicular lymphoma, and four of eight with noncutaneous T-cell lymphoma. The alisertib steady-state trough concentration (n = 25) revealed the expected pharmacokinetic variability, with a trend for higher incidence of adverse event-related dose reductions at higher trough concentrations. Analysis for AAK gene amplification and total AAK protein revealed no differences between histologies or correlation with clinical response. Conclusion: The novel AAK inhibitor alisertib seems clinically active in both B- and T-cell aggressive lymphomas. On the basis of these results, confirmatory single-agent and combination studies have been initiated.

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