Overview
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.
Description
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.
Eligibility
Key Inclusion Criteria:
- 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
Key Exclusion Criteria:
- 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