A Phase I Study of Ibrutinib in Combination with R-ICE in Patients with Relapsed or Primary Refractory DLBCL

Craig S. Sauter, Matthew J. Matasar, Heiko Schoder, Sean M. Devlin, Pamela Drullinsky, John Gerecitano, Anita Kumar, Ariela Noy, Maria L. Palomba, Carol S. Portlock, David J. Straus, Andrew D. Zelenetz, Susan J. McCall, Shoshana T. Miller, Amanda I. Courtien, Anas Younes and Craig H. Moskowitz

Key points

  • Ibrutinib + R-ICE was safe, tolerable and was not prohibitive to mobilizing hematopoietic stem cells for autologous transplantation.

  • Favorable early signal in all evaluable rel/ref non-germinal center DLBCL achieving a complete metabolic remission was observed.


In the post-rituximab era, approximately half the patients with relapsed or refractory (rel/ref) diffuse large B-cell lymphoma (DLBCL) fail to achieve a chemosensitive response to standard salvage therapy, and are thus ineligible to proceed to autologous stem cell transplantation (ASCT) with curative intent. The Bruton's tyrosine kinase inhibitor ibrutinib demonstrates single-agent activity in rel/ref DLBCL, particularly of non-germinal center (non-GC) cell-of-origin (COO). We conducted a single center phase I study evaluating dose escalated ibrutinib, in a 3 by 3 design, in combination with rituximab, ifosfamide, carboplatin and etoposide (R-ICE) in physiologically transplant-eligible rel/ref DLBCL patients. Twenty-one patients have been treated and are evaluable for toxicity with no dose limiting toxicities observed through expansion with ibrutinib at 840 mg daily at dose level #3. Of the 20 patients evaluable for response, per modern ICML criteria, 11 patients achieved complete remission (CR) and 7 patients achieved partial remission (PR) for an overall response rate of 90%. All evaluable patients with non-GC DLBCL achieved a metabolic CR. Ibrutinib in combination with R-ICE demonstrates tolerability and efficacy in rel/ref DLBCL, particularly of non-GC phenotype. This treatment program warrants further investigation in later phase studies.

  • Submitted August 24, 2017.
  • Accepted January 15, 2018.