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

Phase 1

Recruiting

• Conditions: Advanced Solid Tumors; Breast Cancer Recurrent; Colorectal Cancer Metastatic; Colon Cancer; Rectal Adenocarcinoma; Endometrial Cancer
• Interventions: Drug: ATX-559

• Registration Number: NCT06625515
• Lead Sponsor: Accent Therapeutics

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.

Study Timeline

• Study First Submitted: 2024-09-23
• Study First Submitted QC: 2024-10-01
• Study First Posted: 2024-10-03
• Study Start: 2024-10-11
• Status Verified: 2024-12
• Last Update Submitted: 2024-12-30
• Last Update Posted: 2024-12-31
• Primary Completion: 2026-10
• Study Completion: 2027-02

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 100

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Dose escalation	ATX-559	Subjects will be enrolled at various doses or schedules of ATX-559 to identify the RP2D
Dose Expansion: MSI-H/dMMR solid tumors	ATX-559	-
Dose Expansion: BRCA1- or BRCA2-deficient HER2-negative breast cancer	ATX-559	-

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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

Trial Locations

Locations (2)

SCRI Oncology Partners; 🇺🇸 Nashville, Tennessee, United States

NEXT Oncology; 🇺🇸 San Antonio, Texas, United States