A phase 1 dose escalation and dose optimization study to evaluate the preliminary safety, tolerability, pharmacokinetic, pharmacodynamic, and clinical activity profile of AUTX703 in participants with relapsed/refractory acute myeloid leukemia and mye

Abstract Phenotypic cell state plasticity is a key hallmark of cancer and is an intrinsic vulnerability of tumor cells. Targeting drivers of cell state plasticity defines an emerging area of biology that is relatively underexplored in cancer therapies. Cell states and their associated transitions are regulated by chromatin modifications and cell state specific transcriptional programs. Lysine acetyltransferase 2A (KAT2A) and its paralog KAT2B are epigenetic enzymes involved in normal human development and have been shown to play a critical role in regulating somatic cell fate decisions. KAT2A expression has been shown to homogenize transcriptional programs to sustain stem cell phenotypes, while loss of KAT2A has been shown to promote differentiation. Alterations in KAT2A and/or KAT2B expression and activity have been noted in multiple cancers including acute myeloid leukemia (AML). AUTX-703 is a potent, selective, and orally bioavailable degrader of KAT2A/B. In preclinical studies, AUTX-703 potently inhibited cell growth and increased myeloid and monocytic differentiation in primary AML patient cells dosed ex vivo. Sensitivity to AUTX-703 was mutation agnostic and cell state dependent; response was positively correlated with granulocyte monocyte progenitor (GMP) cell state. In an AML patient-derived xenograft (PDX) model, dosing with AUTX-703 was demonstrated to prolong survival and increase monocytic differentiation in bone marrow. (Duparc et al. Blood, 2024) AUTX-703-001 is an open-label, multi-center, first-in-human Phase 1 study evaluating the preliminary safety, tolerability, pharmacokinetic (PK), pharmacodynamic (PD), and clinical activity profile of AUTX-703 in participants with relapsed/refractory (R/R) AML and myelodysplastic syndromes (MDS). The study consists of two phases, a dose escalation phase and dose optimization phase. The dose escalation portion is guided by the Bayesian optimal interval (BOIN) design to estimate the maximum tolerated dose (MTD) of AUTX-703. Successive cohorts of participants will receive AUTX-703 at increasing dosages (defined as dose and schedule) until the MTD or presumptive recommended Phase 2 dose(s) (RP2D[s]) is/are reached. In dose optimization, it is planned that participants will be randomized into two selected dosages of AUTX-703 in 1:1 ratio to characterize safety and tolerability, PK, PD, and clinical activity to support selection of the optimal dosage of AUTX-703 for future studies (i.e. RP2D). The primary objective is to assess safety and tolerability of AUTX-703; secondary objectives include identification of the RP2D, characterization of the PK, and assessment of PD by measurement of KAT2A and KAT2B levels in peripheral blood and bone marrow mononuclear cells. Additional secondary objectives include evaluation of preliminary clinical activity according to the European LeukemiaNet (ELN) 2022 criteria as well as overall survival and event-free survival. Eligible participants must be ≥ 18 years of age with a confirmed diagnosis of any of the following: 1) R/R AML and has not achieved adequate response to, cannot tolerate, or refused all approved therapies known to be active for treatment of their disease; 2) R/R MDS with over 10% blasts in the bone marrow and has not achieved an adequate response to at least 4 cycles of a hypomethylating agent (HMA)-containing regimen or other treatment known to be active for their disease; 3) R/R AML or R/R MDS that has relapsed after a hematopoietic stem cell transplant (HSCT). Participants must also have adequate organ function, an Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2 and a white blood cell count ≤ 20 × 109/L. Use of hydroxyurea is allowed to achieve an eligible white blood cell count. The first participants in the study were dosed in May 2025 and enrollment is ongoing. Nine study centers in the US will participate in dose escalation and additional sites in France are planned for dose optimization. Clinical Trial Information: NCT06846606