CANADIAN CANCER TRIALS GROUP (CCTG) LY.17: A RANDOMIZED PHASE II STUDY EVALUATING NOVEL SALVAGE THERAPY PRE‐AUTOLOGOUS STEM CELL TRANSPLANT (ASCT) IN RELAPSED/REFRACTORY DIFFUSE LARGE B CELL LYMPHOMA (RR‐DLBCL) ‐ OUTCOME OF IBRUTINIB + R‐GDP

Introduction: Salvage chemotherapy and ASCT remains the standard of care in patients (pts) with relapsed/refractory (RR) DLBCL. CCTG trial LY.12 established rituximab combined with gemcitabine, dexamethasone and cisplatin (R-GDP) as a standard of care in this population (Crump JCO 2014), with a low incidence of febrile neutropenia (12%) and infection. Methods: CCTG LY.17 is an ongoing multi-arm randomized phase II “pick a winner” trial evaluating novel salvage therapy and R-GDP in RR-DLBCL pts post rituximab and anthracycline based chemotherapy failure. The first experimental arm evaluated ibrutinib 560 mg PO daily d1-21 with R-GDP (IR-GDP) q3W. Primary endpoint of the study is overall response rate (ORR) after 3 cycles of therapy using CT imaging (FDG-PET response is an exploratory endpoint). According to the protocol futility rule, any treatment arm with an ORR lower than the control arm at the first interim analysis (n = 16) is not considered worthy of further testing and enrolment in that arm will cease. After the run-in cohort of the first 5 IR-GDP pts suggested an increased risk of infection, twice weekly blood count monitoring and antimicrobial prophylaxis for opportunistic infection was recommended along with consideration of G-CSF support. This report is the result of the first interim analysis reporting on 30 pts. Results: Baseline pt characteristics are reported in Table 1. In the IR-GDP arm 11/14 pts received an ibrutinib dose intensity of >90%. The ORR to IR-GDP was 28.6% (CR 0, PR 28.6%, SD 28.6%, PD 14.3%, inevaluable 28.6%). 8 SAEs including 2 grade 5 events (1 sepsis, 1 pneumonia) and 3 grade 3 infectious events were reported in the IR-GDP arm. Median neutrophil and lymphocyte counts were 1.75 (0.9-20.7) and 0.23 (0.15-0.3) at time of onset of infection. The ORR to R-GDP was 50.1% (CR 6.3%, PR 43.8%, SD 12.5%, PD 37.5%, inevaluable 0). Among patients assigned to R-GDP there were no infections grade 3 or higher; there were 4 SAEs and no grade 5 events. At the time of database lock (median f/u 3.5 months, range 0.7-9.2), all patients were off protocol treatment (IR-GDP:R-GDP; death 2:0;, AE 1:0, PD prior to completion of protocol therapy 1:4; patient choice 0:1 and treatment complete 10:11) with 19 pts having a progression event (IR-GDP:R-GDP; on treatment 3:3; during follow-up 5:5; death without PD 2:1) and 11 alive without PD (IR-GDP 4, R-GDP 7). Conclusions: Addition of ibrutinib did not improve the activity of R-GDP and appeared to be associated with increased risk of infection; accrual to this arm has ceased and additional combinations are being explored. Keywords: diffuse large B-cell lymphoma (DLBCL); ibrutinib; salvage treatment.