CRC-403: A Phase 1/2 Study of bbT369, a Dual CD79a and CD20 Targeting CAR T Cell Drug Product with a Gene Edit, in Relapsed and/or Refractory B Cell Non-Hodgkin's Lymphoma (NHL)

BACKGROUND: Currently approved CD19 directed CAR T cell therapies have improved outcomes for non-Hodgkin lymphoma (NHL) patients, however only 30-40% of patients treated at 2^nd relapse or later obtain long term remission after this treatment (Neelapu et al. 2017; Schuster et al. 2019). A next generation autologous CAR T cell, bbT369, has been devised specifically to address and overcome hypothesized mechanisms of CD19 CAR T cell treatment failure including loss/downregulation of target antigen, loss of co-stimulation pathways on tumor cells, exhaustion of CAR T cells, and CAR T cell dysfunction due to an immunosuppressive microenvironment (Shah and Fry 2019). bbT369 is a dual targeting (CD79a/CD20) CAR T cell that uses an OR gated design (encounter with either antigen activates the CAR T cell) to limit antigen escape. The construct contains split costimulatory domains (CD28 and 41BB) to enhance T cell activation and a gene edit knocking-out CBLB function intended to enhance potency and reduce T cell exhaustion. Studies have demonstrated CD79a and CD20 may be ideal targets in B cell lymphoma, with high tissue restricted expression. In Daudi cell and mouse models, bbT369 outperformed CD19 directed CAR T cells demonstrating increased IL-2 secretion and longer durations of tumor control (Certo et al, 2022).

METHODS: CRC-403 (NCT05169489) is a non-randomized, open label, multi-site Phase 1/2 study enrolling relapsed and/or refractory B Cell Non-Hodgkin's Lymphoma (NHL), including diffuse large B cell lymphoma (DLBCL), high-grade B cell lymphoma (HGBCL), primary mediastinal (thymic) large B cell lymphoma (PMBCL), follicular lymphoma (FL) 3b, and DLBCL transformed from FL (tFL). Patients must have relapsed after ASCT or after at least 2 prior lines of therapy, including an anti-CD20 monoclonal antibody and an anthracycline containing chemotherapy regimen. Patients with tFL must be relapsed after receipt of ASCT or at least 2 prior therapies after documentation of transformation. In addition to patients naïve to CAR T cell therapy, patients with prior exposure to non-investigational CD19 CAR T cell therapy are eligible for enrollment if they did not experience disease progression within 6 weeks of initial CAR T cell infusion.

Approximately 50 patients will be enrolled during the dose escalation phase to ensure a maximum of 36 subjects will be treated with bbT369. The primary endpoint of the phase 1 portion of this study is incidence of safety events, including adverse event, adverse events of special interest and dose limiting toxicities. Secondary endpoints include investigator assessed overall response rate including complete response rate, time to response, time to complete response and time to next therapy for B-NHL. Exploratory endpoints include OS, DOR, PFS, bbT369 expansion kinetics including expansion and persistence, immunophenotype in peripheral blood and tumor biopsy tissue with the objective of correlating findings with clinical response. The starting dose of bbT369 is 50x10⁶ CAR+ T cells and a BOIN design is being used for dose escalation/de-escalation decisions during the study. Upon establishment of the RP2D, the phase 2 portion will begin enrollment.

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