Dose Escalation of HLA-A2-WT1 CD3 T-Cell Bispecific Antibody in a Phase I Study in Patients with Relapsed/Refractory Acute Myeloid Leukemia (AML)

Background: RO7283420 (RG6007) is a 2+1 TCR-like (TCR-L) T-cell bispecific (TCB) antibody targeting CD3 and the RMFPNAPYL peptide of Wilms Tumor 1 (WT1) protein presented by the major histocompatibility complex-I HLA-A*02 on acute myeloid leukemia (AML) blasts and other antigen presenting cells. The...

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Published in:Blood 2023-11, Vol.142 (Supplement 1), p.1537-1537
Main Authors: Hutchings, Martin, Montesinos, Pau, Santoro, Armando, Hou, Hsin-An, Martinez-Sanchez, Maria Pilar, Vives, Susana, Galimberti, Sara, Chen, Tsai-Yun, Frigeni, Marco, Garciaz, Sylvain, Salamero, Olga, Yeh, Su-Peng, Yee, Karen, Schnetzler, Gabriel, Barata, Teresa, Simon, Silke, Hinton, Heather, Korfi, Koorosh, Richard, Muriel, Keshelava, Nino, Subklewe, Marion
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Language:English
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Summary:Background: RO7283420 (RG6007) is a 2+1 TCR-like (TCR-L) T-cell bispecific (TCB) antibody targeting CD3 and the RMFPNAPYL peptide of Wilms Tumor 1 (WT1) protein presented by the major histocompatibility complex-I HLA-A*02 on acute myeloid leukemia (AML) blasts and other antigen presenting cells. The pre-clinical evaluation of RO7283420 in our in vivo humanized AML xenografts and ex vivo AML co-culture models showed strong T-cell mediated AML cell killing (Augsberger C, et al. Blood 2021). A Phase 1 dose-escalation (DE) study (NCT04580121) evaluated the safety, tolerability, pharmacokinetics, anti-drug antibodies (ADAs), and anti-leukemic activity of RO7283420 in patients with relapsed/refractory (R/R) AML. Methods: In this open-label, multi-center study, DE was performed using a 3+3 design. Patients received RO7283420 every 3 weeks (Q3W, n=46), or every week (QW, n=4) as intravenous (IV) infusions. Preliminary anti-leukemic activity included response assessment according to European Leukemia Net (ELN) response categories (adapted from Döhner H, et al. Blood 2017). Results: As of 13 April 2023, 50 HLA-A2+ R/R AML patients received at least one dose of RO7283420. Patients had a median age of 65.5 years (range 35-84), presented with ECOG of 0 (56%) or 1 (38%) or 2 (6%), and 58% were male. Median prior line of therapy was 2 (range 1-5). Overall, 58% of patients had relapsed and 42% had primary refractory disease. According to the ELN 2017 risk stratification, patients were of adverse (48%), intermediate (38%) or favorable (8%) risk category, for 6% of patients the risk category missing. The most common genetic abnormalities reported were RUNX1 (21%), ASXL1 (17%), TP53 (10.6%), FLT3-ITD (6.4%) and NPM1 (6.4%) of the 47 patients tested. Median bone marrow blast percentage at baseline was 35% (range 3-90%), while the median of circulating blast was 17% (range 0-88%). Study patients received RO7283420 IV at 13 different dose levels, ranging from a Minimum Anticipated Biological Effect Level (MABEL) of 0.15 mg (flat) to 18 mg Q3W (with a preceding weekly 1/3 mg ‘double step-up’ during Cycle 1) and one QW dose level with 9 mg preceded by a 1/3 mg step-up. Maximum tolerated dose was reached at 1/3/12 mg double step-up Q3W. Explored alternative QW schedule was not tolerable at 1/3/9 mg. The most common (≥20%) adverse events (AEs) were cytokine release syndrome (CRS) occurring in 34 (68%), pneumonia 14 (28%), pyrexia 13 (26%), febrile neutropenia 13 (26%), hyperglycemi
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2023-173302