A Phase 1/2, Open-Label, Dose-Escalation and Expansion First-In-Human Study of ATX-559, an Oral Inhibitor of the Helicase DHX9, in Patients With Locally Advanced or Metastatic Solid Tumors and Molecularly Defined Cancers
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- 入组人数
- 17
- 试验地点
- 10
- 主要终点
- Recommended phase 2 dose (RP2D) and/or maximum tolerated dose (MTD) of ATX-559
研究概览
简要总结
The goal of this study is to identify a safe and tolerated dose of the orally administered DHX9 inhibitor ATX-559. In addition, this study will evaluate the pharmacokinetics, pharmacodynamics and preliminary antitumor activity of ATX-559 in patients with advanced solid tumors and molecularly defined cancers.
详细描述
ATX-559 is an oral drug that inhibits a protein called DHX9, a multi-functional RNA helicase that is involved in the maintenance of genomic stability by resolving DNA/RNA secondary structures that may lead to DNA replication stress and DNA damage in certain molecularly defined cancers. ATX-559 has been shown preclinically to induce robust anti-tumor activity of a variety of different solid tumors, including models with BRCA deficiency and microsatellite instability-high (MSI-H) and/or deficient mismatch repair (dMMR).
This is a first-in-human, Phase 1, open-label, single-arm, dose-escalation and expansion study to:
Evaluate the safety profile of ATX-559 and determine the recommended phase 2 dose (RP2D). In addition, the study aims to characterize the PK, PD, and preliminary anti-tumor activity of orally administered ATX-559. Exploratory objectives include examination of biomarker responses in relationship to ATX-559 exposure.
Patients with molecularly selected locally advanced or metastatic solid tumors (for example, BRCA1- or BRCA2-deficient breast cancer and solid tumors with microsatellite instability (MSI-H) and/or deficient mismatch repair (dMMR) will be enrolled to preliminarily assess the anti-tumor effect, and further examine the safety and PK of ATX-559 at the RP2D.
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
- •Patients with histologically confirmed solid tumors who have locally recurrent or metastatic disease
- •Refractory to or relapsed after all standard therapies with proven clinical benefit, unless as deemed by the Investigator, the subject is not a candidate for standard treatment, there is no standard treatment, or the subject refuses standard treatment after expressing an understanding of all available therapies with proven clinical benefit
- •For the expansion cohorts, participants must have histological confirmation of the specified tumor types:
- •BRCA1 or BRCA2 deficient, HER2 negative metastatic breast cancer
- •dMMR or MSI-H with unresectable or metastatic solid tumors
- •There is no limit to the number of prior treatment regimens
- •Have measurable or evaluable disease
- •Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
排除标准
- •Clinically unstable central nervous system (CNS) tumors or brain metastasis
- •Any other concurrent anti-cancer treatment
- •Has undergone a major surgery within 3 weeks of starting study treatment
- •Medical issue that limits oral ingestion or impairment of gastrointestinal function that is expected to significantly reduce the absorption of ATX-559
- •Clinically significant (ie, active) or uncontrolled cardiovascular disease
- •Unable to transition off strong or moderate CYP2C8 inhibitors or inducers
- •Pregnancy or intent to breastfeed or conceive a child within the projected duration of treatment
- •Other inclusion and exclusion criteria as defined in the study protocol
研究组 & 干预措施
Dose Expansion: MSI-H/dMMR solid tumors
干预措施: ATX-559 (Drug)
Dose escalation
Subjects will be enrolled at various doses or schedules of ATX-559 to identify the RP2D
干预措施: ATX-559 (Drug)
Dose Expansion: BRCA1- or BRCA2-deficient HER2-negative breast cancer
干预措施: ATX-559 (Drug)
结局指标
主要结局
Recommended phase 2 dose (RP2D) and/or maximum tolerated dose (MTD) of ATX-559
时间窗: 12 months
Identification of a tolerable and safe dose for expansion cohorts based on dose limiting toxicities
Safety and tolerability of ATX-559
时间窗: 12 months
Incidence of adverse events graded according to CTCAE v5.0
次要结局
- Preliminary evidence of antitumor activity(12 months)
- Pharmacodynamic activity of ATX-559 in blood over time via measurement of circBRIP1 RNA levels(12 months)
- Maximum observed plasma concentration of ATX-559 (Cmax)(12 months)
- Calculated time to reach maximum observed plasma concentration (Tmax)(12 months)
- Calculated area under the plasma concentration-time curve of ATX-559 (AUC0-t)(12 months)