Advanced Solid Tumors, Breast Cancer Recurrent, Colon Cancer, Colorectal Cancer Metastatic, Endometrial Cancer, Rectal Adenocarcinoma
Conditions
Keywords
MSI-high/dMMR tumors, BRCA1 mutation, BRCA2 mutation, DHX9, dMMR, deficient mismatch repair, microsatellite instability
Brief summary
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.
Detailed 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.
Interventions
DRUGATX-559
DHX9 tablets will be taken orally
Sponsors
Accent Therapeutics
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Recommended phase 2 dose (RP2D) and/or maximum tolerated dose (MTD) of ATX-559 | 12 months | Identification of a tolerable and safe dose for expansion cohorts based on dose limiting toxicities |
| Safety and tolerability of ATX-559 | 12 months | Incidence of adverse events graded according to CTCAE v5.0 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Preliminary evidence of antitumor activity | 12 months | Objective response rate based on RECIST v1.1 |
| 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 | — |
Countries
United States
Outcome results
None listed