Clinical trial NCT06625515: First-in-Human Study of ATX-559, an Oral Inhibitor of DHX9, in Patients With Advanced or Metastatic Solid Tumors, and Molecularly Defined Cancers
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Advanced Solid Tumors
Breast Cancer Recurrent
Colorectal Cancer Metastatic
Colon Cancer
Rectal Adenocarcinoma
Endometrial Cancer
Keywords: MSI-high/dMMR tumors
BRCA1 mutation
BRCA2 mutation
DHX9
dMMR
deficient mismatch repair
microsatellite instability
Lead sponsor: Accent Therapeutics
Sponsor class: INDUSTRY
First posted: 2024-10-03
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

Eligibility 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

Primary outcomes:
measure: Recommended phase 2 dose (RP2D) and/or maximum tolerated dose (MTD) of ATX-559
timeFrame: 12 months
measure: Safety and tolerability of ATX-559
timeFrame: 12 months
Secondary outcomes:
measure: Preliminary evidence of antitumor activity
timeFrame: 12 months
measure: Pharmacodynamic activity of ATX-559 in blood over time via measurement of circBRIP1 RNA levels
timeFrame: 12 months
measure: Maximum observed plasma concentration of ATX-559 (Cmax)
timeFrame: 12 months
measure: Calculated time to reach maximum observed plasma concentration (Tmax)
timeFrame: 12 months
measure: Calculated area under the plasma concentration-time curve of ATX-559 (AUC0-t)
timeFrame: 12 months
Other outcomes:
Locations:
city: Oklahoma City
country: United States
facility: Stephenson Cancer Center at OU Medicine
state: Oklahoma
city: Nashville
country: United States
facility: SCRI Oncology Partners
state: Tennessee
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center
state: Texas
city: San Antonio
country: United States
facility: NEXT Oncology
state: Texas
Study officials:
References: