Phase I Study of the Investigational Aurora A Kinase Inhibitor Alisertib plus Rituximab or Rituximab/Vincristine in Relapsed/Refractory Aggressive B-cell Lymphoma
Kevin R Kelly, Jonathan W Friedberg, Steven I Park, Kevin McDonagh, John Hayslip, Daniel Persky, Jia Ruan, Soham Puvvada, Peter Rosen, Swaminathan Padmanabhan Iyer, Alexandra Stefanovic, Steven H Bernstein, Steven Weitman, Anand Karnad, Gregory Monohan, Ari VanderWalde, Raul Mena, Monika Schmelz, Catherine Spier, Susan Groshen, Karthik Venkatakrishnan, Xiaofei Zhou, Emily Sheldon-Waniga, E Jane Leonard, Daruka Mahadevan, Kevin R Kelly, Jonathan W Friedberg, Steven I Park, Kevin McDonagh, John Hayslip, Daniel Persky, Jia Ruan, Soham Puvvada, Peter Rosen, Swaminathan Padmanabhan Iyer, Alexandra Stefanovic, Steven H Bernstein, Steven Weitman, Anand Karnad, Gregory Monohan, Ari VanderWalde, Raul Mena, Monika Schmelz, Catherine Spier, Susan Groshen, Karthik Venkatakrishnan, Xiaofei Zhou, Emily Sheldon-Waniga, E Jane Leonard, Daruka Mahadevan
Abstract
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 + 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 = 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.
Trial registration: ClinicalTrials.gov NCT01397825.
Conflict of interest statement
Disclosure of Potential Conflicts of Interest
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, Genentech, Pharmacyclics, and Seattle Genetics. G. Monohan holds ownership interest (including patents) in Johnson & Johnson, Novartis, and Pfizer. X. Zhou is an employee of Xiaofei Zhou. E. Sheldon-Waniga is an employee of Takeda. D. Mahadevan reports receiving speakers bureau honoraria from Pfizer. No potential conflicts of interest were disclosed by the other authors.
©2018 American Association for Cancer Research.
Source: PubMed