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 Rituximab-Dose-Intensive Cyclophosphamide, Etoposide, Cisplatin (R-DICEP) Versus R-GDP

Introduction: The CCTG LY.12 trial established rituximab combined with gemcitabine, dexamethasone and cisplatin (R-GDP) as a standard salvage chemotherapy option prior to ASCT for patients (pts) with relapsed/refractory (RR) DLBCL (Crump JCO 2014). CCTG LY.17 is an ongoing multi-arm randomized phase II "pick a winner" trial evaluating novel salvage therapy compared with R-GDP in ASCT-eligible RR-DLBCL pts.

Methods: The primary endpoint of the study is overall response rate (ORR) using CT imaging. According to the protocol futility rule, any treatment arm with an ORR lower than the R-GDP control arm at the first interim analysis (n = 16), or less than 10% higher at the second interim analysis (n=32) would not continue to full target accrual of 64 pts per treatment arm. Encouraging results could then be pursued in a larger phase III trial designed to detect differences in progression-free survival (PFS). This report involves the component of the trial that randomly allocated pts to either 1 cycle of inpatient R-DICEP (Rituximab 375mg/m² IV or 1400mg sc days 1 and 5 plus dose-intensive Cyclophosphamide 5.25g/m², Etoposide 1050mg/m², Cisplatin 105mg/m² divided over days 2-4, with daily filgrastim starting day 15 until apheresis of blood stem cells approximately between days 20-22) or to 3 cycles of outpatient R-GDP. This report is the result of the protocol-specified second interim analysis.

Results: A total of 67 pts were randomized to R-DICEP (n=32) or to R-GDP (n=35) between April 2016 and April 2021. Table 1 lists baseline pt characteristics. Four pts (R-DICEP=2, R-GDP=2) were not evaluable for response. The ORR was 65.6% for R-DICEP (70.0% for evaluable pts), which was 17% greater than the ORR of 48.6% for R-GDP (51.5% for evaluable pts). Additionally, only 1 (3.1%) R-DICEP pts versus (vs) 11 (31.4%) R-GDP pts experienced progressive disease as best response to salvage therapy. Of interest, the ORR to salvage was 40% (14/35) for pts primary refractory to RCHOP (no response to RCHOP or progressive disease during or <3mo post RCHOP) vs 75% (24/32) for those who relapsed >3mo post RCHOP (p=0.006), with ORR to R-DICEP of 50% vs 81.3% and ORR to R-GDP of 31.6% vs 68.8% for primary refractory vs relapse >3mo, respectively. The ORR based on PET-CT scan was 50.0% vs 31.4% for the R-DICEP (n=26) vs R-GDP (n=25) arms, respectively. Overall, 23 (71.9%) R-DICEP pts and 19 (54.3%) R-GDP pts underwent ASCT. In total, 26 out of 27 (96.3%) R-DICEP, and 18 out of 20 (90%) R-GDP pts underwent successful autologous blood stem cell collection (requiring >1 attempt in 0 R-DICEP and 2 R-GDP pts). The median time to neutrophil engraftment post-ASCT was 13 (1-32) and 12 (1-22) days, and to platelet engraftment was 12 (1-50) and 16 (7-22) days for R-DICEP and R-GDP pts, respectively. Regarding adverse events (AEs) of salvage therapy and subsequent ASCT, R-DICEP pts had higher rates of culture positive infection (84% vs 40%), platelet (96.6% vs 60.0%) and red cell (75.0% vs 42.9%) transfusions, diarrhea (44% vs 14%), serious adverse events (50% vs 34.3%), and treatment-related mortality (3.1% vs 0%) but similar rates of other AEs including arrhythmia (6% vs 9%), bleeding (0 vs 0), fungal infections (0 vs 0) and pneumonitis (0 vs 0). At a median duration of follow-up of 26.9 months (R-DICEP 26.4 months and R-GDP 27.4 months), the 1-year PFS rate was 42% for R-DICEP and 32% for R-GDP (HR 0.59, 95%CI: 0.32-1.09, logrank p=0.09), and 1-year OS rate was 65% for R-DICEP and 55% for R-GDP (HR 0.675, 95%CI: 0.333-1.369, logrank p=0.27).

Conclusions: Although the 17% improvement in ORR for R-DICEP vs R-GDP in the second interim analysis exceeded the pre-specified 10% threshold required proceed to full accrual of 64 pts in the R-DICEP arm, we decided to stop accrual to the R-DICEP arm of the LY.17 trial due to slow accrual, higher AE rates, and greater utilization of healthcare resources including hospitalization needed to administer treatment, which limits feasibility of R-DICEP at several Canadian centres. The LY.17 trial continues testing other salvage regimens.

Stewart:Seagen: Honoraria; Roche: Honoraria; Janssen: Honoraria; Beigene: Honoraria; Novartis: Honoraria; Gilead: Honoraria; Apobiologix: Honoraria. Chua:Seagen: Honoraria; Abbvie: Honoraria; Incyte: Honoraria; Amgen: Honoraria; Merck: Honoraria; Gilead: Honoraria; Bayer: Honoraria; Pfizer: Honoraria. Baetz:Servier: Honoraria; Roche: Honoraria; Gilead: Honoraria; Astrazeneca: Honoraria; BeiGene: Honoraria. Crump:Kyte-Gilead, Novartis: Honoraria; Roche: Research Funding. Shafey:BeiGene: Honoraria; Janssen: Honoraria; Astrazeneca: Honoraria; Novartis: Honoraria; BMS: Honoraria; Kite/Gilead: Honoraria; Incyte: Honoraria. Robinson:Roche: Honoraria; Janssen: Honoraria; Astrazeneca: Honoraria; BeiGene: Honoraria; AbbVie: Honoraria; Novartis: Honoraria. Fleury:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite-Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seagen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Grant during the conduct of the study , Research Funding, Speakers Bureau. Hay:Merck: Research Funding; Seagen: Research Funding; Karyopharm: Research Funding; Roche: Research Funding; AbbVie: Research Funding. Kuruvilla:Gilead: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria, Other: DSMB; Merck: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Medison Ventures: Consultancy; Antengene: Consultancy; Novartis: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Astra Zeneca: Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Inctye: Honoraria; Seattle Genetics: Consultancy, Honoraria; Pfizer: Honoraria; Lymphoma Canada: Membership on an entity's Board of Directors or advisory committees.