https://orcid.org/0000-0003-3873-1741
Key points
RO7283420, a T-cell bispecific antibody engaging CD3 and Wilms Tumor Protein 1, demonstrated pharmacodynamic activity in this phase 1 study.
RO7283420 was discontinued due to the lack of exposure-response relationship and limited clinical efficacy in R/R AML patients.
Abstract
A novel T-cell bispecific antibody (TCB) RO7283420 engaging CD3 and HLA-A2-WT1 complex was evaluated in this open-label, multicenter, dose-escalation, phase 1 study (NCT04580121) which aimed to characterize safety/tolerability, determine the maximum tolerated dose (MTD), and recommend a phase 2 dose for relapsed/refractory acute myeloid leukemia patients in two groups: hematologic (Group I, n=57) and molecular (Group II, n=5) relapse. In Group I, 51 received RO7283420 intravenously (IV) and 6 subcutaneously. IV doses ranged 0.15–4 mg (flat, n=13) and 3–18 mg (step-up, n=34) administered every 3 weeks (Q3W), or 9 mg weekly (step-up, n=4). The MTD was 1/3/12 mg Q3W. The most frequent adverse event in the overall population was cytokine release syndrome (61.3%), with grade ≥3 in 9.7%. Twelve dose-limiting toxicities were reported in 11 patients and 12 (19.4%) experienced grade 5 adverse events, including one hemophagocytic lymphohistiocytosis case related to RO7283420. Among 42 efficacy-evaluable IV patients in Group I, 4.8% achieved complete remission (CR), and 2.4% achieved CR with incomplete hematologic recovery. RO7283420 induced pharmacodynamic changes in peripheral blood (PB) at doses ≥1 mg, including significant T-cell activation and expansion in PB and bone marrow (BM). Significant associations were found between blast reduction and baseline immunophenotype, including lower regulatory T cells and higher non-exhausted CD8+ T cells in BM. While dose escalation was discontinued due to limited efficacy and lack of exposure-BM response relationship, the observed pharmacodynamics underscore the promising potential of this class of TCBs targeting intracellular antigens.
Author notes
M.H. and K.K. are joint first authors.
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