Phase II Trial of Axicabagene Ciloleucel and Glofitamab As Second-Line Therapy for Patients with Relapsed or Refractory Large B-Cell Lymphoma

Background and Significance: Diffuse large B-cell lymphoma (DLBCL) treatment has evolved, with CAR (chimeric antigen receptor) T-cell therapy becoming the preferred second-line approach in patients with R/R (refractory/early relapsed) disease. Despite improvements with CAR T-cell therapy compared to chemotherapy-based approaches, overall survival at 2 years is only 60%, suggesting that additional approaches are needed to optimize treatment options.

Axicabagene Ciloleucel (Axi-cel) is an autologous CAR T-cell therapy which targets CD19, FDA approved as a second-line therapy for R/R LBCL within 12 months after first-line immunotherapy. Glofitamab is a bispecific antibody which targets CD20 and CD3, FDA approved for R/R LBCL patients after two or more lines of therapies. Both agents have demonstrated impressive single agent clinical efficacy, but have yet to be studied as a combined regimen.

We present the design of our investigator-initiated study where we assess the safety and efficacy of the combined use of axi-cel and glofitamab in second-line therapy in R/R LBCL (Glo-Axi-Glo, NCT06213311). hypothesizing that the combination will demonstrate an enhanced immune response against LBCL compared to the use of axi-cel alone. The strategy of targeting two different antigens on tumor cells reduces the probability of antigen escape, which in turn increases the probability of tumor cell death.

Study design and methods: The study is a phase 2, single-center, investigator-initiated, open-label study of the combination of Axi-cel and Glofitamab as second-line therapies in relapsed refractory DLBCL. The primary endpoints are to evaluate the safety of the combination and the efficacy by the best complete response rate. The secondary endpoints are the overall response rate, overall survival, and progression-free survival.

The major eligibility criteria are histologically proven CD19- and CD20- positive large-B cell lymphoma, refractory to or relapsed within 12 months after the completion of first-line chemoimmunotherapy, age 18 or older, ECOG 2 or less, adequate organ function, no suspicion of CNS involvement of lymphoma, and autoimmune disease under control. The study is planned to enroll 40 patients.

The treatment consists of 6 cycles of glofitamab (21 days each cycle) with Axi-cel administration between cycles 2 and 3. Patients will undergo apheresis, followed by obinutuzumab pretreatment of 1000mg on D1 (day), followed by Glofitamab step up dosing of 2.5 and 10mg on D8 and D15 of Cycle 1, respectively, and 30mg on Cycle 2 D1. Standard lymphodepleting chemotherapy with fludarabine 30mg/m2 and cyclophosphamide 500mg/m2 will be given, followed by Axi-cel infusion. Glofitamab step-up dosing will be repeated in cycle 3 without re-treatment with obinutuzumab. During cycles 4-6, glofitamab will be administered at 30mg on D1.

The sample size of 40 patients will allow for 80% power at the significance level of 0.05 to determine if the historical response rate of 0.65 is different from the projected experimental response rate of 0.825. Exploratory analyses are planned to evaluate the tumor profile and antigen density, single cell multiome sequencing and whole exome sequencing, ctDNA kinetics, and immune cell fitness.