Trial-in-Progress: A Phase 1/2 Multi-Center Study of Onct-808, a ROR1-Specific CAR T, in Adult Patients with Relapsed/Refractory Aggressive B Cell Lymphoma

BACKGROUND: The therapeutic landscape for B-cell lymphomas (BCL) leverages several modalities, including chemotherapy, targeted agents, adoptive cell therapy, and immunotherapy. While these approaches have shown clinical benefit, challenges remain, such as variable response rates, treatment resistance, and toxicities. ROR1-specific CAR T-cell therapy represents a promising potential advancement in the treatment of aggressive BCL in patients (pts) who have failed previous CD19 CAR T therapy. ROR1-targeted CAR T therapy offers several advantages that could address these challenges. By directing CAR T cells to specifically recognize and eliminate ROR1-expressing tumor cells, it offers a highly targeted approach with the potential for enhanced efficacy. Moreover, ROR1 is often highly expressed on aggressive BCL, making it a suitable therapeutic target. This focused approach may help overcome the limitations associated with current treatments and improve response rates. After birth ROR1 is predominantly expressed on malignant cells; therefore, this selective expression pattern may reduce the risk of toxicities, including off-tumor target elimination and non-specific activation of immune cells. The development of ROR1-specific CAR T holds promise in enhancing the treatment outcomes for patients with aggressive BCL. With targeted action and potential to reduce toxicity, ROR1-specific CAR T cell therapy offers an innovative and novel strategy for improving patient outcomes in BCL. The ROR1 binding moiety for ONCT-808 is derived from zilovertamab. Zilovertamab vedotin showed preliminary evidence of efficacy and no evidence of on-target off-tumor toxicity in patients with advanced B cell malignancies (Wang 2022). METHODS: This is a Phase 1/2, single-arm, open-label, multi-center trial to evaluate the safety and efficacy of ONCT-808 in pts with aggressive BCL, including large B-cell lymphoma (LBCL) and mantle cell lymphoma (MCL) with no approved therapy available. The study comprises two distinct phases: Phase 1 for dose escalation followed by Phase 2 for dose expansion. In Phase 1, a standard 3+3 dose escalation design will be used with 3 provisional dose levels and expected sample size of up to 18 patients. Subjects will receive a conditioning regimen of intravenous (IV) cyclophosphamide and fludarabine, followed by ONCT-808 IV infusion. The dose of ONCT-808 will be sequentially escalated to determine the recommended Phase 2 dose (RP2D) for LBCL and MCL cohorts. Br