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

Accent Therapeutics

Status and phase: Enrolling; Phase 1

Conditions: Endometrial Cancer; Rectal Adenocarcinoma; Advanced Solid Tumors; Colon Cancer; Breast Cancer Recurrent; Colorectal Cancer Metastatic

Treatments: Drug: ATX-559

Study type: Interventional

Funder types: Industry

Identifiers

NCT06625515

ATX-559-001

Details and patient eligibility

About

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.

Full 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.

Enrollment: 100 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion 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 exclusion criteria as defined in the study protocol

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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100 participants in 3 patient groups

Dose escalation

Experimental group

Description:

Subjects will be enrolled at various doses or schedules of ATX-559 to identify the RP2D

Treatment:

Drug: ATX-559

Dose Expansion: MSI-H/dMMR solid tumors

Experimental group

Treatment:

Drug: ATX-559

Dose Expansion: BRCA1- or BRCA2-deficient HER2-negative breast cancer

Experimental group

Treatment:

Drug: ATX-559