A PHASE 1 STUDY OF CARFILZOMIB WITH RITUXIMAB, IFOSFAMIDE, CARBOPLATIN AND ETOPOSIDE (C‐RICE) IN TRANSPLANT‐ELIGIBLE RELAPSED/REFRACTORY DIFFUSE LARGE B‐CELL LYMPHOMA

Background: The CORAL study highlighted the need to develop novel salvage regimens in R/R DLBCL previously treated with R-CHOP. Overall response rate (ORR) to second line therapy (either RICE or RDHAP) was 51% with a 3-year progression free survival (PFS) of only 30%. More recently, the SCHOLAR-1 study and the anti-CD19 CAR-T cell therapy trials have highlighted the dismal outcomes of pts with chemo-refractory disease. We previously demonstrated that 1) the ubiquitin-proteasome system (UPS) plays an important role in acquired rituximab-chemotherapy (R-C) resistance in DLBCL and that 2) carfilzomib (CFZ), a selective, irreversible proteasome inhibitor, overcomes R-C resistance in lymphoma pre-clinical models. We hypothesized that targeting the UPS with CFZ could result in improved outcomes with 2nd line therapy and high-dose chemotherapy with autologous stem cell transplant (HDC-ASCT) in R/R DLBCL pts. Methods: We conducted a single-center, open-label, prospective phase 1 study evaluating the safety, efficacy, and pharmacokinetics/pharmacodynamics (PK/PD) of CFZ in combination with R-ICE in HDC-ASCT eligible R/R DLBCL pts (NCT01959698). Classic 3+3 dose escalation schema was used to determine the MTD. Primary objectives were to determine the maximum tolerated dose (MTD) and examine the dose-limiting toxicities (DLT) of CFZ in combination with R-ICE. Secondary objectives include preliminary evaluation of activity, feasibility of successful mobilization of autologous stem cells and PK/PD analysis. Patients received CFZ (at 6 dose levels) on days 1, 2, 8, 9, and standard doses of rituximab-ICE on days 3-6. Cycles were repeated every 21 days for a maximum of 3 cycles before HDC-ASCT. Toxicity was assessed using NCI CTCAE version 4; responses were assessed after cycles 2 and 3 using revised Cheson criteria. Results: In the dose escalation phase, 18 pts were enrolled at 6 dose levels with no DLTs noted. CFZ 27 mg/m2 was selected as the MTD. 11 additional pts were enrolled in the dose expansion phase. Median age was 62 (29-75) yrs, 55% were male, 34% had germinal center B-cell like (GCB) subtype and 62% had non-GCB subtype DLBCL by Han's algorithm, data was missing for 1 pt. MYC and BCL2/BCL6 rearrangements were noted in 3 pts, an additional 2 pts had an isolated MYC rearrangement. Best ORR was 62% (45% CR, 15% PR), 52% pts underwent HDC-ASCT. Interestingly, an ORR of 100% was observed in pts with non-GCB DLBCL. Median PFS was 15.2 months (5.1 mo- not reached) and median OS was NR (10.2 mo- NR). Pts with non-GCB subtype had a significantly longer PFS (NR vs 7 mo, p = 0.02) and OS (NR vs 10.7 mo, p = 0.002) than those with GCB-subtype (Figure 1). Conclusion: C-RICE is well tolerated in pts with R/R DLBCL with toxicities comparable to RICE therapy. Improved outcomes observed in non-GCB DLBCL highlight the contribution of the UPS in acquiring rituximab- chemotherapy resistance. Our data shows that pts with non-GCB DLBCL benefit from incorporating CFZ into second line therapy. Improved PFS and OS was noted in pts with non-GCB DLBCL compared to GCB DLBCL with C-RICE therapy in the R/R setting. The research was funded by: Amgen Inc. Keywords: Aggressive B-cell non-Hodgkin lymphoma, Chemotherapy, Combination Therapies No conflicts of interests pertinent to the abstract.