title: Phase II study of alisertib, a selective Aurora A kinase inhibitor, in relapsed and refractory aggressive B- and T-cell non-Hodgkin lymphomas.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Jonathan W. Friedberg, Erin Cebula, Richard Burack, and Steven H. Bernstein, University of Rochester Wilmot Cancer Center, Rochester, NY; Daruka Mahadevan, West Clinic and University of Tennessee Health Sciences Center, Memphis, TN; Daniel Persky, Yale University, New Haven, CT; Izidore Lossos, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL; Amit G. Agarwal, University of Arizona Cancer Center, Tucson, AZ; and JungAh Jung, Xiaofei Zhou, E. Jane Leonard, Howard Fingert, and Hadi Danaee, Millennium Pharmaceuticals, Cambridge, MA.
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Friedberg
authors.forename: Daruka
authors.initials: D
authors.lastname: Mahadevan
authors.forename: Erin
authors.initials: E
authors.lastname: Cebula
authors.forename: Daniel
authors.initials: D
authors.lastname: Persky
authors.forename: Izidore
authors.initials: I
authors.lastname: Lossos
authors.forename: Amit B
authors.initials: AB
authors.lastname: Agarwal
authors.forename: Jungah
authors.initials: J
authors.lastname: Jung
authors.forename: Richard
authors.initials: R
authors.lastname: Burack
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Zhou
authors.forename: E Jane
authors.initials: EJ
authors.lastname: Leonard
authors.forename: Howard
authors.initials: H
authors.lastname: Fingert
authors.forename: Hadi
authors.initials: H
authors.lastname: Danaee
authors.forename: Steven H
authors.initials: SH
authors.lastname: Bernstein
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors*; D001381:Azepines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002051:Burkitt Lymphoma / Q000188:drug therapy* / Q000201:enzymology; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008224:Lymphoma, Follicular / Q000188:drug therapy* / Q000201:enzymology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000201:enzymology; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy* / Q000201:enzymology; D016399:Lymphoma, T-Cell / Q000188:drug therapy* / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy / Q000379:methods; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012008:Recurrence; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D001381:Azepines; C550258:MLN 8237; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D064096:Aurora Kinase A
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