Refractory Acute Myeloid Leukemia (AML), Refractory Myelodysplastic Syndromes, Relapsed Acute Myeloid Leukemia (AML), Relapsed Myelodysplastic Syndromes, Relapsed/Refractory AML, Relapsed/Refractory (R/R) Acute Myeloid Leukemia (AML)
Conditions
Keywords
AUTX-703, Relapsed Acute Myeloid Leukemia, Refractory Acute Myeloid Leukemia, Relapsed/Refractory AML, Acute Myeloid Leukemia, Relapsed Myelodysplastic Syndromes, Refractory Myelodysplastic Syndromes, KAT2A/B degrader, Myelodysplastic Syndromes
Brief summary
This Phase 1, multicenter, open-label, dose escalation and dose optimization study is designed to assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary clinical activity of AUTX-703 administered orally in subjects with advanced hematologic malignancies.
Detailed description
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.
Interventions
DRUGAUTX-703
AUTX-703 administered orally
Sponsors
Auron Therapeutics, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This study consists of two parts: Part A (Dose Escalation) and Part B (Dose Optimization). In Part A, participants are assigned sequentially to escalating dosages of AUTX-703 to determine the maximum tolerated dose (MTD) and/or the recommended Phase 2 dose (RP2D). In Part B, participants are randomly assigned to receive one of two dosages of AUTX-703 for safety, pharmacokinetics, pharmacodynamics, and preliminary clinical activity.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: 1. Participant must be ≥18 years of age 2. Participant must have confirmed diagnosis as follows: R/R AML and has not achieved adequate response to, or cannot tolerate, 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) 3. Participant must be willing and able to comply with scheduled study visits and treatment plans. 4. Participant must be willing to undergo all study procedures unless contraindicated due to medical risk. 5. Participant must have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1 6. Participant must have adequate hepatic function 7. Participant must have adequate renal function 8. Participant must have adequate cardiovascular function 9. Participant must have a white blood cell (WBC) count ≤20 × 10⁹/L (with stable hydroxyurea use allowed) 10. Participant must meet timing requirements with respect to prior therapy and surgery 11. 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
1. Participant is unable to provide informed consent and/or to follow protocol requirements. 2. 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) 3. Participant has another malignancy that may interfere with diagnosis and treatment of R/R AML or R/R MDS. 4. 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. 5. Participant has a known sensitivity to AUTX-703 or any of its components. 6. Participant is taking systemic strong CYP3A4 inhibitors or inducers within 14 days of the first dose of study treatment. 7. Participant who are taking proton pump inhibitors should be switched to another acid-reducing agent such as an antacid or H2 blocker 8. Participant is taking P-gp and breast cancer resistance protein (BCRP) inhibitors or inducers within 14 days of first dose of study treatment. 9. Participant has active hepatitis B virus (HBV) or hepatitis C virus (HCV) infections with detectable viral load 10. Participant has experienced AIDS related illness within the past 6 months or have detectable HIV viral load. 11. Participant has an uncontrolled intercurrent illness 12. Participant has active Class III or IV cardiovascular disease within 6 months prior to the start of study treatment 13. 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 14. Participant is pregnant or breastfeeding or is planning to become pregnant within 1 year of the start of study treatment 15. Have a history of interstitial lung disease or pneumonitis.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Adverse Events (AEs), Dose-Limiting Toxicities (DLTs), and Serious Adverse Events (SAEs) | From the first dose through 28 days after the last dose of study drug. | To assess the safety and tolerability of AUTX-703 by evaluating the incidence and severity of AEs, DLTs, SAEs, and AEs leading to treatment discontinuation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| To Identify the Recommended Phase 2 Dose (RP2D) of AUTX-703 | From the first dose through 28 days after the last dose of study drug. | To determine the RP2D of AUTX-703 based on safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary clinical activity data. |
| Peak Plasma Concentration (Cmax) | From the first dose through the first treatment cycle (28 days) | — |
| Time to Maximum Concentration (Tmax) | From the first dose through the first treatment cycle (28 days) | — |
| Area Under the Plasma Concentration-Time Curve from Time Zero to Infinity (AUCinf) | From the first dose through the first treatment cycle (28 days) | — |
| Area Under the Plasma Concentration-Time Curve to the Last Measurable Concentration (AUClast) | From the first dose through the first treatment cycle (28 days) | — |
| Elimination Half-Life (t½) | From the first dose through the first treatment cycle (28 days) | — |
| Apparent Clearance (CL/F) | From the first dose through the first treatment cycle (28 days) | — |
| Apparent Volume of Distribution (Vd/F) | From the first dose through the first treatment cycle (28 days) | — |
| To characterize the PD of AUTX-703 | From the first dose through 28 days after the last dose of study drug | To evaluate changes in KAT2A and KAT2B levels in peripheral blood and bone marrow as markers of pharmacodynamic response |
| AML: Complete remission (CR) rate | Up to 18 months | — |
| AML: CR + CRh rate | Up to 18 months | — |
| AML: Duration of CR | Up to 18 months | — |
| AML: Duration of CR + CRh | Up to 18 months | — |
| Objective response rate (ORR) | Up to 24 months | — |
| AML: Duration of response (DOR) | Up to 18 months | — |
| AML: Transfusion independence (TI) rate | Up to 18 months | — |
| AML: Event free survival (EFS) | Up to 24 months | — |
| AML: Overall survival (OS) | Up to 24 months | — |
| MDS: Complete remission (CR) rate | Up to 18 months | — |
| MDS: PR rate | Up to 18 months | — |
| MDS: CR+PR rate | Up to 18 months | — |
| MDS: Duration of CR | Up to 18 months | — |
| MDS: Duration of PR | Up to 18 months | — |
| MDS: Duration of CR+PR | Up to 18 months | — |
| MDS: Event free survival (EFS) | Up to 24 months | — |
| MDS: Overall survival (OS) | Up to 24 months | — |
Countries
United States
Contacts
CONTACTAuron Clinical Trials
Outcome results
None listed