TY - JOUR
T1 - Phase I Study of the Investigational Aurora A Kinase Inhibitor Alisertib plus Rituximab or Rituximab/Vincristine in Relapsed/Refractory Aggressive B-cell Lymphoma
AU - Kelly, Kevin R.
AU - Friedberg, Jonathan W.
AU - Park, Steven I.
AU - McDonagh, Kevin
AU - Hayslip, John
AU - Persky, Daniel
AU - Ruan, Jia
AU - Puvvada, Soham
AU - Rosen, Peter
AU - Iyer, Swaminathan Padmanabhan
AU - Stefanovic, Alexandra
AU - Bernstein, Steven H.
AU - Weitman, Steven
AU - Karnad, Anand
AU - Monohan, Gregory
AU - VanderWalde, Ari
AU - Mena, Raul
AU - Schmelz, Monika
AU - Spier, Catherine
AU - Groshen, Susan
AU - Venkatakrishnan, Karthik
AU - Zhou, Xiaofei
AU - Sheldon-Waniga, Emily
AU - Jane Leonard, E.
AU - Mahadevan, Daruka
N1 - Funding Information: K.R. Kelly reports receiving commercial research grants from Takeda. J.W. Friedberg is a consultant/advisory board member for Bayer and Astellas. S.I. Park reports receiving commercial research grants from Bristol, Myers, Squibb; Seattle Genetics; Teva; and Takeda; reports receiving speakers bureau honoraria from Seattle Genetics; and is a consultant/advisory board member for Bristol, Myers, Squibb; Rafael Pharma; G1 Therapeutics; Teva; and Gilead. J. Hayslip is an employee of AbbVie. D. Persky is a consultant/advisory board member for Genentech, Sandoz and Morphosys. S. Puvvada reports receiving commercial research grants to their institution from Spectrum, AbbVie, Genentech, Seattle Genetics, Takeda, and Janssen; reports receiving speakers bureau honoraria from Gilead Sciences; and is a consultant/advisory board member for AbbVie, Gen-entech, Pharmacyclics, and Seattle Genetics. G. Monohan holds ownership interest (including patents) in Johnson & Johnson, Novartis, and Pfizer. X. Zhou Funding Information: The authors would like to acknowledge all of the patients who participated in this study. The authors also acknowledge Yosef Mansour of FireKite, an Ashfield company, part of UDG Healthcare plc, for writing support during the development of this manuscript, which was funded by Millennium Pharmaceuticals, Inc. in compliance with Good Publication Practice 3 ethical guidelines (Battisti and colleagues, Ann Intern Med 2015;163:461–4). Publisher Copyright: © 2018 American Association for Cancer Research.
PY - 2018/12/15
Y1 - 2018/12/15
N2 - Purpose: The aurora A kinase inhibitor alisertib demonstrated single-agent clinical activity and preclinical synergy with vincristine/rituximab in B-cell non-Hodgkin lymphoma (B-NHL). This phase I study aimed to determine the safety and recommended phase II dose (RP2D) of alisertib in combination with rituximab vincristine in patients with relapsed/ refractory aggressive B-NHL. Patients and Methods: Patients with relapsed/refractory, diffuse, large, or other aggressive B-NHL received oral alisertib 50 mg b.i.d. days 1 to 7, plus i.v. rituximab 375 mg/m2 on day 1, for up to eight 21-day cycles (MR). Patients in subsequent cohorts (3 þ 3 design) received increasing doses of alisertib (30 mg starting dose; 10 mg increments) b.i.d. days 1 to 7 plus rituximab and vincristine [1.4 mg/m2 (maximum 2 mg) days 1, 8] for 8 cycles (MRV). Patients benefiting could continue single-agent alisertib beyond 8 cycles. Cell-of-origin and MYC/ BCL2 IHC was performed on available archival tissue. Results: Forty-five patients participated. The alisertib RP2D for MR was 50 mg b.i.d. For MRV (n ¼ 32), the RP2D was determined as 40 mg b.i.d. [1 dose-limiting toxicity (DLT) at 40 mg; 2 DLTs at 50 mg]. Drug-related adverse events were reported in 89% of patients, the most common was neutropenia (47%). Seven patients had complete responses (CR), 7 had partial responses (PRs); 9 of 20 (45%) patients at the MRV RP2D responded (4 CRs, 5 PRs), all with non–germinal center B-cell (GCB) diffuse large B-cell lymphoma (DLBCL). Conclusions: The combination of alisertib 50 mg b.i.d. plus rituximab or alisertib 40 mg b.i.d. plus rituximab and vincristine was well tolerated and demonstrated activity in non-GCB DLBCL.
AB - Purpose: The aurora A kinase inhibitor alisertib demonstrated single-agent clinical activity and preclinical synergy with vincristine/rituximab in B-cell non-Hodgkin lymphoma (B-NHL). This phase I study aimed to determine the safety and recommended phase II dose (RP2D) of alisertib in combination with rituximab vincristine in patients with relapsed/ refractory aggressive B-NHL. Patients and Methods: Patients with relapsed/refractory, diffuse, large, or other aggressive B-NHL received oral alisertib 50 mg b.i.d. days 1 to 7, plus i.v. rituximab 375 mg/m2 on day 1, for up to eight 21-day cycles (MR). Patients in subsequent cohorts (3 þ 3 design) received increasing doses of alisertib (30 mg starting dose; 10 mg increments) b.i.d. days 1 to 7 plus rituximab and vincristine [1.4 mg/m2 (maximum 2 mg) days 1, 8] for 8 cycles (MRV). Patients benefiting could continue single-agent alisertib beyond 8 cycles. Cell-of-origin and MYC/ BCL2 IHC was performed on available archival tissue. Results: Forty-five patients participated. The alisertib RP2D for MR was 50 mg b.i.d. For MRV (n ¼ 32), the RP2D was determined as 40 mg b.i.d. [1 dose-limiting toxicity (DLT) at 40 mg; 2 DLTs at 50 mg]. Drug-related adverse events were reported in 89% of patients, the most common was neutropenia (47%). Seven patients had complete responses (CR), 7 had partial responses (PRs); 9 of 20 (45%) patients at the MRV RP2D responded (4 CRs, 5 PRs), all with non–germinal center B-cell (GCB) diffuse large B-cell lymphoma (DLBCL). Conclusions: The combination of alisertib 50 mg b.i.d. plus rituximab or alisertib 40 mg b.i.d. plus rituximab and vincristine was well tolerated and demonstrated activity in non-GCB DLBCL.
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U2 - 10.1158/1078-0432.CCR-18-0286
DO - 10.1158/1078-0432.CCR-18-0286
M3 - Article
C2 - 30082475
SN - 1078-0432
VL - 24
SP - 6150
EP - 6159
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 24
ER -