A Phase 1 Study of AUTX-703 in Participants With Relapsed/Refractory Acute Myeloid Leukemia and Myelodysplastic Syndromes
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 69
- 试验地点
- 29
- 主要终点
- Incidence of Adverse Events (AEs), Dose-Limiting Toxicities (DLTs), and Serious Adverse Events (SAEs)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Participant must be ≥18 years of age
- •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)
- •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 0-1
- •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.
排除标准
- •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
- •Have a history of interstitial lung disease or pneumonitis.
研究组 & 干预措施
Dose Escalation - Part A
Participants will receive escalating dosages of AUTX-703 orally in tablet form once, twice or three times weekly to determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D).
干预措施: AUTX-703 (Drug)
Dose Optimization - Part B, Dosage 2
Participants will receive AUTX-703 at the second selected dosage determined from Part A, administered orally in tablet form either once, twice or three times weekly to further evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary clinical activity at this specified dose.
干预措施: AUTX-703 (Drug)
Dose Optimization - Part B, Dosage 1
Participants will receive AUTX-703 at the first selected dosage determined from Part A, administered orally in tablet form either once, twice or three times weekly to further evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary clinical activity at this specified dose.
干预措施: AUTX-703 (Drug)
结局指标
主要结局
Incidence of Adverse Events (AEs), Dose-Limiting Toxicities (DLTs), and Serious Adverse Events (SAEs)
时间窗: 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.
次要结局
- 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.)
- 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)
- 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)