A Phase 1/2 Study of a ROR1-Targeting CAR T Cell Therapy (ONCT-808) in Adult Patients with Relapsed/Refractory (R/R) Aggressive B Cell Lymphomas (BCL)

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INTRODUCTION ROR1 is an oncoembryonic pseudo-tyrosine kinase receptor expressed on malignant cells across a variety of hematologic and solid malignancies. As such, ROR1 is an ideal therapeutic target with potential for maximizing on-target anti-tumor activity while minimizing off-target toxicity. ONCT-808 utilizes a ROR1-binding moiety derived from zilovertamab, which, in a prior study of zilovertamab vedotin, demonstrated antitumor activity and no evidence of off-tumor toxicity in a population of heavily pretreated patients (pts) with aggressive lymphoma (Wang 2022, Spurgeon 2023). ROR1-specific CAR T-cell therapy represents a promising modality for the treatment of aggressive BCL, particularly in pts who have previously failed or were ineligible for CD19 CAR T therapy. METHODS This is a multicenter, open label, phase 1/2 study of ONCT-808 in R/R BCL (mantle cell lymphoma [MCL] and large BCL [LBCL]). ONCT-808 is administered as a single infusion following lymphodepletion with fludarabine and cyclophosphamide. The primary objective of phase 1 is to identify dose-limiting toxicities (DLTs) and establish a recommended phase 2 dose. Phase 1 consists of escalation at three provisional doses (0.3, 0.6, and 1 x 106 viable ONCT-808 cells/kg). Phase 2 will test two dose levels with a primary endpoint of overall response rate (ORR). Adverse events (AEs) are graded using CTCAE v5.0, except for cytokine release syndrome (CRS) and IEC-associated neurotoxicity syndrome (ICANS) which are based on ASTCT grading. Secondary endpoints include efficacy and pharmacokinetics. RESULTS To date, 8 pts have been enrolled and underwent leukapheresis, with 100% success for cellular manufacturing; 2 pts withdrew consent prior to treatment. Of the 6 treated pts, 5 had relapsed following prior CD19 CAR T. During initial dose escalation, 3 pts with heavily pretreated R/R MCL (all males, median age 55 [range 50-57]), were treated at a dose of 1 x 106 viable ONCT-808 cells/kg; subsequently, one pt (80yo male, R/R diffuse LBCL [DLBCL] with high tumor burden), was treated at a higher dose of 3 x 106 cells/kg and died due to complications of shock. A modified dosing scheme starting at 0.3 x 106 cells/kg was subsequently incorporated, and 2 pts have been treated (R/R DLBCL, males, age 60, 62). No DLTs were reported during the 28-day evaluation window at 1 or 0.3 x 106 cells/kg doses. In these two dosing cohorts, AEs related to ONCT-808 included G1-2 CRS (4/5 pts), G2 ICANS (1/5), G3 pneumonia (1/5 pts), and G3-4 cytopenias (1/5 patients). Response assessments were evaluated in 5 pts; 3 treated with ONCT-808 at 1 x 106 and 2 treated with 0.3 x 106 viable ONCT-808 CAR T cells/kg. Of 5 patients, at the Month 1 (M1) timepoint, 2 patients had demonstrated complete metabolic response (CMR) and 2 had demonstrated partial metabolic response (PMR). One patient with CMR had a confirmatory bone marrow biopsy and sustained CMR at M3 and M6 timepoints. Notably, the pt treated at the 3 x 106 cells/kg dose did not have histologic evidence of lymphoma on autopsy despite bulky disease at baseline, or evidence of immune-mediated inflammation in the brain. Preliminary PK demonstrates successful expansion and persistence of ROR1-positive CAR T cells, including beyond 12 months post-infusion. CONCLUSIONS ONCT-808 is a novel ROR1-targeting CAR T therapy with promising early activity and appears to be well-tolerated at 0.3 x 106 and 1 x 106 viable cells/kg dose in patients with R/R BCL. Dose escalation continues towards optimizing activity and safety (NCT 05588440).

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