A phase II study of vibecotamab, a CD3-CD123 bispecific T-cell engaging antibody, for MRD-positive AML and MDS after hypomethylating agent failure.
Authors: Short Nicholas James , Bachireddy Pavan , Huang Xuelin , Hwang Hyunsoo , Leng Xiaohong , Lee Jaehyun , Nguyen Danielle , Garcia-Manero Guillermo , Dinardo Courtney Denton , Borthakur Gautam , Kadia Tapan M. , Daver Naval Guastad , Issa Ghayas C. , Maiti Abhishek , Ravandi Farhad 
Published: June 2023

TPS7076 Background: CD123 is a marker of leukemic stem cells that is differentially overexpressed in most patients with acute myeloid leukemia (AML), myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). In contrast, CD123 is expressed at negligibly low levels on normal hematopoietic progenitors, making it a potentially promising therapeutic target. Vibecotamab (formally XmAb14045) is a CD3-CD123 bispecific engaging antibody that has established clinical activity in relapsed/refractory AML. In a phase I study, the overall response rate was 14.8% in patients who received vibecotamab at a dose of ≥ 0.75 µg/kg (Ravandi F et al. ASH 2020 abstract #460). Response rates were notably higher in those with lower disease burden (bone marrow blasts ≤ 25%) where the overall response rate was 25.9%. In light of the activity of vibecotamab in relapsed/refractory low-blast AML, we designed this phase II study to evaluate vibecotamab in other low-blast states, including CD123-positive, MRD-positive AML and in MDS or CMML after failure of hypomethylating agents. Methods: This is a two-arm, open-label, phase II study of vibecotamab in patients with AML in first or second morphological remission with detectable MRD at a level of ≥0.1% by flow cytometry and in patients with MDS (intermediate or higher-risk by IPSS-R) or CMML (CMML-1 or CMML-2) after failure of hypomethylating agents. CD123 expression ≥20% on aberrant myeloid blasts is required for study eligibility. Vibecotamab is given IV in a ramp-up dose schedule on days 1, 3, 5 and 8 of cycle 1, followed by weekly doses of vibecotamab at a dose of 1.7 µg/kg. Patients may receive up to 4 cycles of vibecotamab in 28-day cycles. The primary objective of the AML MRD cohort is to determine the MRD negativity rate after 4 cycles; the primary objective of the MDS/CMML cohort is to determine the response rate (CR + mCR + PR + HI + clinical benefit) after 4 cycles. The target MRD response in the AML MRD cohort is 50%, and the target response rate in the MDS/CMML cohort is 30%. Secondary endpoints include remission duration, duration of MRD response (AML MRD arm), CR rate (MDS/CMML arm), relapse-free survival, overall survival, and safety. Exploratory endpoints include correlation of clinical outcomes with CD123 expression and the dynamics of CD123 expression at treatment initiation and at the time of relapse. Additional immunological correlatives will be performed, including 1.) determination of molecular immune states that predict response or resistance, 2.) functional interrogation of TCR-antigen interactions, and 3.) nomination of leukemic neo-antigens. The planned enrollment is 40 patients (20 in each of the two cohorts). To date, 13 patients have been enrolled (7 in the AML MRD cohort and 6 in the MDS/CMML cohort). The trial is actively accruing at MD Anderson Cancer Center. Clinical trial information: NCT05285813 .