First-in-Human Study of ATX-559, an Oral Inhibitor of DHX9, in Patients With Advanced or Metastatic Solid Tumors, and Molecularly Defined Cancers

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

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.

Study Overview

• Status: Terminated
• Conditions: Advanced Solid Tumors; Endometrial Cancer; Colon Cancer; Colorectal Cancer Metastatic; Breast Cancer Recurrent; Rectal Adenocarcinoma
• Intervention / Treatment: Drug: ATX-559

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.

• Study Type: Interventional
• Enrollment (Actual): 17
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Cancer Center - Anschutz Medical Campus,
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Stephenson Cancer Center at OU Medicine
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • SCRI Oncology Partners
  • Texas
    • Houston, Texas, United States, 77030
      • The University of Texas MD Anderson Cancer Center
    • San Antonio, Texas, United States, 78229
      • NEXT Oncology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dose escalation; Subjects will be enrolled at various doses or schedules of ATX-559 to identify the RP2D	Drug: ATX-559; DHX9 tablets will be taken orally
Experimental: Dose Expansion: MSI-H/dMMR solid tumors	Drug: ATX-559; DHX9 tablets will be taken orally
Experimental: Dose Expansion: BRCA1- or BRCA2-deficient HER2-negative breast cancer	Drug: ATX-559; DHX9 tablets will be taken orally

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recommended phase 2 dose (RP2D) and/or maximum tolerated dose (MTD) of ATX-559	Identification of a tolerable and safe dose for expansion cohorts based on dose limiting toxicities	12 months
Safety and tolerability of ATX-559	Incidence of adverse events graded according to CTCAE v5.0	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Preliminary evidence of antitumor activity	Objective response rate based on RECIST v1.1	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

Collaborators and Investigators

• Sponsor: Accent Therapeutics

Study record dates

Study Major Dates

• Study Start (Actual): October 11, 2024
• Primary Completion (Actual): January 9, 2026
• Study Completion (Actual): January 9, 2026

Study Registration Dates

• First Submitted: September 23, 2024
• First Submitted That Met QC Criteria: October 1, 2024
• First Posted (Actual): October 3, 2024

Study Record Updates

• Last Update Posted (Actual): February 24, 2026
• Last Update Submitted That Met QC Criteria: February 22, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: BRCA1 mutation; BRCA2 mutation; microsatellite instability; dMMR; MSI-high/dMMR tumors; DHX9; deficient mismatch repair
• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Pathologic Processes; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Intestinal Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colorectal Neoplasms; Intestinal Neoplasms; Rectal Diseases; Uterine Diseases; Genital Diseases, Female; Colonic Diseases; Genital Neoplasms, Female; Uterine Neoplasms; Genomic Instability; Pathological Conditions, Signs and Symptoms; Rectal Neoplasms; Colonic Neoplasms; Endometrial Neoplasms; Microsatellite Instability
• Other Study ID Numbers: ATX-559-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No