Abstract
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 chemotherapy (either RICE or RDHAP) was 51% in patients previously treated with R-CHOP with a 3-year progression free survival (PFS) of only 30%. In the SCHOLAR-1 study, pts with chemo-refractory disease had a worse prognosis with ORR of approximately 26% and a median overall survival (OS) of 6-7 months. We previously demonstrated that 1) the ubiquitin-proteasome system (UPS) plays an important role in acquired rituximab-chemotherapy resistance in DLBCL and 2) that carfilzomib (CFZ), a selective, irreversible proteasome inhibitor, overcomes rituximab-chemotherapy in lymphoma pre-clinical models. We hypothesize that targeting the UPS with CFZ could result in higher response rates and improved outcomes following high-dose chemotherapy with autologous stem cell transplant (HDC-ASCT) in R/R DLBCL pts.
Methods: We are conducting a single-center, open-label, prospective Phase I/II clinical trial evaluating the safety, efficacy, and pharmacokinetics/pharmacodynamics (PK/PD) of CFZ in combination with R-ICE in HDC-ASCT eligible R/R DLBCL (NCT01959698). Here, we present the results of the Phase I part of the study. Classic 3+3 dose escalation of CFZ was utilized for the phase 1 portion. 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 feasibility of successful mobilization of autologous stem cells, preliminary evaluation of activity and PK/PD analysis. Patients received CFZ on days 1, 2, 8, 9, rituximab on day 3 followed by ICE (days 4-6) at standard doses. 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 2 and 3 cycles using revised Cheson criteria.
Results: As of July 20th, 2017, a total of 14 pts have been enrolled in the phase 1 portion at 10 mg/m2 (n=3) (dose level 1 [DL1]), 15 mg/m2 (n=3) (DL2), 20 mg/m2 (n=3)(DL3), 20 mg/m2 d1-2, 27 mg/m2 d8-9 (n=3)(DL4), and 20 mg/m2 d1-2, 36 mg/m2 d8-9 (n=2)(DL5). Median age 60 yrs, 64% males, median time from diagnosis 14.8 (4.1-77.3) mo, 6/14 (43%) were primary refractory, 5/14 pts have a germinal center B-cell like (GCB) subtype, 8/14 pts have a non-germinal center (non-GBC subtype) by Han's criteria, 1 pt has T cell/histiocyte rich large cell lymphoma. Two pts have double hit (DL) DLBCL by FISH studies and 2 have a sole MYC rearrangement. With one more dose-level to test (DL6), no DLTs have been recorded so far. The MTD is yet to be defined. Majority of the grade 3/4 drug-related adverse events (AEs) reported were hematological (thrombocytopenia- 71%, anemia- 50%, neutropenia- 43%, lymphopenia 7%, febrile neutropenia 14.3%). Grade 3 non-hematological AEs include gastrointestinal hemorrhage (1), device-related infection (1), abscess at biopsy site (1), dehydration (1), hyperglycemia (1), hypokalemia (1), hypophosphatemia (1), headache (1), dyspnea (1), pulmonary embolism (1). Grade 4 non-hematological AEs were hypocalcemia (1) and hypokalemia (1). Preliminary results demonstrate an ORR of 64% (50% CR, 14% PR) (Figure 1). Interestingly, an ORR of 100% was observed in pts with relapsed non-GCB DLBCL subtype (all CRs). In contrast, all patients with primary refractory DLBCL fared poorly (1- partial response, 3-stable disease, 2- progressive disease) and were unable to proceed to HDC-ASCT. All responding patients (N=8) underwent successful stem cell collection and received HDC-ASCT. The median TTP post HDC-ASCT, PFS and OS have not been reached. PK/PD/correlative data will be presented at the meeting.
Conclusion: C-RICE is well tolerated in pts with R/R DLBCL with toxicities comparable to RICE chemo-immunotherapy. The selective higher CR rate (100%) observed in non-GCB DLBCL highlights the effects of CFZ in NFκB activity and its contribution to chemotherapy resistance. Our data suggest that non-GCB DLBCL benefit significantly from incorporating CFZ into second line therapy and HDC-ASCT. The phase II of the study will commence shortly and tailoring enrollment to non-GCB R/R DLBCL may optimize treatment options to all subtypes of R/R DLBCL.
No relevant conflicts of interest to declare.
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