Phase 1 Study of AUTX-703 in Relapsed/Refractory AML and MDS

This is a first-in-human, Phase 1, multicenter study to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary clinical activity of AUTX-703, an orally bioavailable lysine acetyltransferase 2A (KAT2A) and lysine acetyltransferase 2B (KAT2B) degrader, in participants with relapsed/refractory acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS). The study consists of two parts: Part A (Dose Escalation) to determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D), and Part B (Dose Optimization) to further evaluate safety, PK, PD and efficacy at selected dosages.

Key Inclusion Criteria:

• Participant must be ≥18 years of age
• Participant must have confirmed diagnosis as follows:

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 OR 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 OR R/R AML or R/R MDS that has relapsed after a hematopoietic stem cell transplant (HSCT)

• Participant must be willing and able to comply with scheduled study visits and treatment plans.
• Participant must be willing to undergo all study procedures unless contraindicated due to medical risk.
• Participant must have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of ≤2
• Participant must have adequate hepatic function
• Participant must have adequate renal function
• Participant must have adequate cardiovascular function
• Participant must have a white blood cell (WBC) count ≤20 × 10⁹/L (with stable hydroxyurea use allowed)
• Participant must meet timing requirements with respect to prior therapy and surgery
• Participant must agree to use effective contraception during the study and for the required post-treatment period: Males: Use condoms (even if vasectomized) during the study and for 90 days post-treatment. Females of childbearing potential: Use a combination of 1 highly effective and 1 effective method of contraception during the study and for 180 days post-treatment.

Key Exclusion Criteria:

• Participant is unable to provide informed consent and/or to follow protocol requirements.
• Participant has undergone chimeric antigen receptor T cell therapy or HSCT within 60 days of the first dose of study treatment or has active clinically significant graft-versus-host disease (GVHD)
• Participant has another malignancy that may interfere with diagnosis and treatment of R/R AML or R/R MDS.
• Participant has an active severe infection that requires anti-infective therapy or has an unexplained temperature of >38.5°C during screening visits or on their first day of study treatment.
• Participant has a known sensitivity to AUTX-703 or any of its components.
• Participant is taking systemic strong CYP3A4 inhibitors or inducers within 14 days of the first dose of study treatment.
• Participant who are taking proton pump inhibitors should be switched to another acid-reducing agent such as an antacid or H2 blocker
• Participant is taking P-gp and breast cancer resistance protein (BCRP) inhibitors or inducers within 14 days of first dose of study treatment.
• Participant has active hepatitis B virus (HBV) or hepatitis C virus (HCV) infections with detectable viral load
• Participant has experienced AIDS related illness within the past 6 months or have detectable HIV viral load.
• Participant has an uncontrolled intercurrent illness
• Participant has active Class III or IV cardiovascular disease within 6 months prior to the start of study treatment
• Participant is unable to tolerate the administration of oral medication or has GI dysfunction that would preclude adequate absorption, distribution, metabolism, or excretion of an oral medication
• Participant is pregnant or breastfeeding or is planning to become pregnant within 1 year of the start of study treatment