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Phase I Study of the Investigational Aurora A Kinase Inhibitor Alisertib plus Rituximab or Rituximab/Vincristine in Relapsed/Refractory Aggressive B-cell Lymphoma.

Publication ,  Journal Article
Kelly, KR; Friedberg, JW; Park, SI; McDonagh, K; Hayslip, J; Persky, D; Ruan, J; Puvvada, S; Rosen, P; Iyer, SP; Stefanovic, A; Bernstein, SH ...
Published in: Clinical cancer research : an official journal of the American Association for Cancer Research
December 2018

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 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.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).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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Published In

Clinical cancer research : an official journal of the American Association for Cancer Research

DOI

EISSN

1557-3265

ISSN

1078-0432

Publication Date

December 2018

Volume

24

Issue

24

Start / End Page

6150 / 6159

Related Subject Headings

  • Vincristine
  • Treatment Outcome
  • Rituximab
  • Retreatment
  • Recurrence
  • Pyrimidines
  • Oncology & Carcinogenesis
  • Neoplasm Staging
  • Neoplasm Metastasis
  • Molecular Targeted Therapy
 

Citation

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Kelly, K. R., Friedberg, J. W., Park, S. I., McDonagh, K., Hayslip, J., Persky, D., … Mahadevan, D. (2018). Phase I Study of the Investigational Aurora A Kinase Inhibitor Alisertib plus Rituximab or Rituximab/Vincristine in Relapsed/Refractory Aggressive B-cell Lymphoma. Clinical Cancer Research : An Official Journal of the American Association for Cancer Research, 24(24), 6150–6159. https://doi.org/10.1158/1078-0432.ccr-18-0286
Kelly, Kevin R., Jonathan W. Friedberg, Steven I. Park, Kevin McDonagh, John Hayslip, Daniel Persky, Jia Ruan, et al. “Phase I Study of the Investigational Aurora A Kinase Inhibitor Alisertib plus Rituximab or Rituximab/Vincristine in Relapsed/Refractory Aggressive B-cell Lymphoma.Clinical Cancer Research : An Official Journal of the American Association for Cancer Research 24, no. 24 (December 2018): 6150–59. https://doi.org/10.1158/1078-0432.ccr-18-0286.
Kelly KR, Friedberg JW, Park SI, McDonagh K, Hayslip J, Persky D, et al. Phase I Study of the Investigational Aurora A Kinase Inhibitor Alisertib plus Rituximab or Rituximab/Vincristine in Relapsed/Refractory Aggressive B-cell Lymphoma. Clinical cancer research : an official journal of the American Association for Cancer Research. 2018 Dec;24(24):6150–9.
Kelly, Kevin R., et al. “Phase I Study of the Investigational Aurora A Kinase Inhibitor Alisertib plus Rituximab or Rituximab/Vincristine in Relapsed/Refractory Aggressive B-cell Lymphoma.Clinical Cancer Research : An Official Journal of the American Association for Cancer Research, vol. 24, no. 24, Dec. 2018, pp. 6150–59. Epmc, doi:10.1158/1078-0432.ccr-18-0286.
Kelly KR, Friedberg JW, Park SI, McDonagh K, Hayslip J, Persky D, Ruan J, Puvvada S, Rosen P, Iyer SP, Stefanovic A, Bernstein SH, Weitman S, Karnad A, Monohan G, VanderWalde A, Mena R, Schmelz M, Spier C, Groshen S, Venkatakrishnan K, Zhou X, Sheldon-Waniga E, Leonard EJ, Mahadevan D. Phase I Study of the Investigational Aurora A Kinase Inhibitor Alisertib plus Rituximab or Rituximab/Vincristine in Relapsed/Refractory Aggressive B-cell Lymphoma. Clinical cancer research : an official journal of the American Association for Cancer Research. 2018 Dec;24(24):6150–6159.

Published In

Clinical cancer research : an official journal of the American Association for Cancer Research

DOI

EISSN

1557-3265

ISSN

1078-0432

Publication Date

December 2018

Volume

24

Issue

24

Start / End Page

6150 / 6159

Related Subject Headings

  • Vincristine
  • Treatment Outcome
  • Rituximab
  • Retreatment
  • Recurrence
  • Pyrimidines
  • Oncology & Carcinogenesis
  • Neoplasm Staging
  • Neoplasm Metastasis
  • Molecular Targeted Therapy