Carfilzomib Combined with Rituximab, Ifosfamide, Carboplatin, and Etoposide for Relapsed or Refractory DLBCL.

The CORAL study highlighted the need to develop novel salvage regimens in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) previously treated with R-CHOP. Carfilzomib (CFZ) can overcome rituximab-chemotherapy resistance in lymphoma pre-clinical models by targeting the ubiquitin-proteasome system (UPS). We conducted an investigator initiated, single-center, open-label, prospective phase 1 study evaluating the safety and efficacy of CFZ in combination with R-ICE in high-dose chemotherapy with autologous stem cell transplant (HDC-ASCT) eligible R/R DLBCL pts (NCT01959698). In the dose-escalation phase, 18 pts were enrolled at six dose levels with no dose-limiting toxicities noted. CFZ 45 mg/m2 was selected as the recommended dose for expansion. Eleven additional pts were enrolled in the dose-expansion phase. Overall response rate (ORR) was 66% (48% CR, 17% PR), 52% pts underwent HDC-ASCT. An ORR of 85% was observed in pts with non-germinal center B-cell-like (non-GCB) DLBCL compared to only 13% in GCB-DLBCL. Median PFS was 15.2 months (5.1 mo- not reached), and median OS was 22.6 months (6.8 mo- NR). Pts with non-GCB subtype had a significantly longer PFS (NR vs. 6.6 mo, p= 0.0001) and OS (NR vs. 6.6 mo, p= 0.001) than those with GCB-subtype. C-R-ICE is well tolerated in pts with R/R DLBCL with toxicities comparable to R-ICE therapy. Our data show that pts with non-GCB DLBCL benefit significantly from incorporating CFZ into second-line therapy and HDC-ASCT.