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ETX-19477

ETX-19477 is a promising new drug currently being studied for patients with advanced solid tumors. This novel treatment works as a PARG inhibitor (Poly ADP-ribose glycohydrolase inhibitor), targeting a specific vulnerability in cancer cells related to DNA damage repair. The ongoing clinical trial is designed to evaluate how safe and effective ETX-19477 is for patients whose cancer has progressed after standard treatments. The study focuses on various types of cancer including breast, ovarian, prostate, endometrial, colorectal, and gastric cancers, with special attention to patients with certain genetic mutations like BRCA1 and BRCA2.

Table of Contents

What is ETX-19477?

ETX-19477 is a new medication being studied for the treatment of advanced solid tumors. It is classified as a PARG inhibitor, which means it blocks an enzyme called Poly (ADP) ribose glycohydrolase (PARG). This medication is currently in clinical trials to evaluate how safe it is, how well it’s tolerated by patients, and whether it shows promising anti-cancer activity.[1]

Specifically, ETX-19477 is described as a novel reversible small molecule inhibitor of PARG. The term “reversible” means that the drug’s effects can be undone when the medication is stopped, and “small molecule” refers to the size of the drug, which allows it to potentially reach targets inside cells more easily.[1]

How ETX-19477 Works

Cancer cells often experience what scientists call replication stress. This is a condition where the process of copying DNA (which happens when cells divide) is slowed down or stalled, leading to damaged DNA accumulating in the cells. Normally, cells have mechanisms to repair this damage through a process called the DNA damage response (DDR).[1]

The enzyme PARG plays an important role in this DNA repair process. When PARG is blocked (as ETX-19477 is designed to do), cancer cells accumulate more DNA damage in the form of single-strand breaks (SSBs) and double-strand breaks (DSBs). The cancer cells also have more difficulty repairing this damage.[1]

When PARG is inhibited in cancer cells that are already experiencing replication stress, research has shown that these cells may:

  • Stop multiplying
  • Get stuck in certain phases of the cell division cycle (S or G2 phase)
  • Undergo apoptosis (programmed cell death)

This effect can happen when PARG inhibitors are used alone or combined with other drugs that damage DNA or increase replication stress.[1]

The research suggests that the replication stress response represents a vulnerability specific to cancer cells, which can be targeted by medications that inhibit PARG, like ETX-19477.[1]

Conditions ETX-19477 May Treat

ETX-19477 is being studied for several types of advanced or metastatic solid tumors. Metastatic means that the cancer has spread from where it started to other parts of the body. Based on the clinical trial information, the following cancer types are included:[1]

  • Breast Cancer – specifically ER+ (estrogen receptor positive) breast cancer, which is a type of breast cancer that grows in response to the hormone estrogen
  • Ovarian Cancer – including epithelial ovarian cancer, which starts in the cells that cover the surface of the ovary
  • Prostate Cancer – specifically castrate-resistant prostate cancer, an advanced form that continues to grow even when the level of testosterone is reduced to very low levels
  • Endometrial Cancer – cancer that begins in the lining of the uterus (womb)
  • Colorectal Cancer – cancer that starts in the colon or rectum
  • Gastric Cancer – cancer that begins in the stomach

The trial also specifically mentions patients with BRCA mutations (BRCA1, BRCA2). These are genetic mutations that affect the body’s ability to repair DNA damage and are associated with increased risk of certain cancers, particularly breast and ovarian cancers.[1]

Current Clinical Trial Design

The clinical trial for ETX-19477 (identified as NCT06395519) is designed as a two-part study:[1]

Part 1: Dose Escalation

In this first phase, researchers are trying to find the right dose of ETX-19477. Participants are assigned to different dose levels to determine:

  • The maximum tolerated dose (MTD) – the highest dose that doesn’t cause unacceptable side effects
  • The recommended Phase 2 dose (RP2D) – the dose that will be used in future larger studies

Part 2: Dose Expansion

Once the appropriate dose is determined in Part 1, more participants will receive ETX-19477 at this dose level. This helps researchers collect more data about the safety and effectiveness of the drug at the chosen dose.[1]

This is an open-label study, which means both the researchers and participants know which treatment is being given. It is also multicenter, meaning it’s being conducted at multiple hospitals or research centers.[1]

Safety Monitoring and Outcomes

A primary goal of the trial is to assess the safety and tolerability of ETX-19477. Researchers are monitoring:[1]

  • Dose-limiting toxicities (DLTs) – side effects that are severe enough to prevent increasing the dose further
  • Adverse events (AEs) – any unfavorable and unintended sign, symptom, or disease that develops during treatment
  • ECG parameters – measurements of heart electrical activity to detect any cardiac effects
  • Serious adverse events (SAEs) – adverse events that result in hospitalization, disability, or are life-threatening

How Effectiveness is Being Measured

The trial is assessing several ways to measure whether ETX-19477 is effective against cancer:[1]

  1. Objective response rate (ORR) – the percentage of patients whose cancer shrinks or disappears after treatment
  2. Duration of response (DOR) – how long the response (cancer remaining smaller or gone) lasts
  3. Disease control rate (DCR) – the percentage of patients whose disease is controlled (stays the same, shrinks, or disappears)

These measurements are being assessed using standardized criteria called RECIST v1.1 (Response Evaluation Criteria in Solid Tumors), which is a set of rules used to determine whether tumors are responding to treatment.[1]

The trial is also studying how ETX-19477 behaves in the body through:

  • Pharmacokinetics (PK) – how the drug moves through the body, including:
    • Maximum plasma concentration (Cmax) – the highest level of drug in the blood
    • Time to maximum concentration (tmax) – how long it takes to reach the highest level
    • Elimination half-life (t1/2) – how long it takes for half of the drug to be eliminated from the body
    • Area Under the Curve (AUC) – a measure of the total exposure to the drug over time
    • Clearance (CL) – how quickly the drug is removed from the body
    • Volume of Distribution (Vd) – how widely the drug is distributed throughout the body
  • Pharmacodynamics (PDx) – the effects of the drug on the body

How ETX-19477 is Administered

ETX-19477 is an oral medication, which means it is taken by mouth. According to the trial information, it is taken daily. This oral administration may be more convenient for patients compared to treatments that need to be given by injection or infusion.[1]

Study Aspect Details
Drug Name ETX-19477
Drug Type PARG (Poly ADP-ribose glycohydrolase) inhibitor
Administration Oral medication taken daily
Study Design Two-part, open-label, multicenter, dose escalation and dose expansion study
Target Conditions Advanced or metastatic solid tumors, including breast cancer (ER+), ovarian cancer, prostate cancer (castrate resistant), endometrial cancer, colorectal cancer, gastric cancer
Genetic Focus Includes patients with BRCA1 and BRCA2 mutations
Primary Outcomes Safety, tolerability, maximum tolerated dose (MTD), recommended Phase 2 dose (RP2D)
Secondary Outcomes Pharmacokinetic profile (Cmax, tmax, t1/2, AUC), anti-tumor activity (objective response rate, duration of response, disease control rate)
Mechanism of Action Targets cancer-specific vulnerability by inhibiting DNA damage repair in cells with replication stress
Clinical Trial Identifier NCT06395519

FAQ

  • What is ETX-19477 and how does it work? ETX-19477 is a novel reversible small molecule inhibitor of PARG (Poly ADP-ribose glycohydrolase). This enzyme plays a critical role in DNA damage response. By inhibiting PARG, ETX-19477 can increase the number of DNA breaks in cancer cells and reduce their ability to repair this damage. This targets a cancer-specific vulnerability related to replication stress, potentially stopping cancer cells from dividing and causing them to die.
  • What types of cancer is ETX-19477 being tested for? ETX-19477 is being tested for multiple types of advanced or metastatic solid tumors. The specific cancer types mentioned in the clinical trial include breast cancer (particularly ER+ breast cancer), ovarian cancer (including epithelial ovarian cancer), prostate cancer (specifically castrate-resistant prostate cancer), endometrial cancer, colorectal cancer, and gastric cancer. The trial also has a focus on patients with BRCA1 and BRCA2 mutations.
  • How is the ETX-19477 clinical trial structured? The clinical trial is structured in two parts: Part 1 is a monotherapy dose escalation phase where different dose levels are tested to determine safety and the maximum tolerated dose. Part 2 is a monotherapy dose expansion phase where, after deciding on an appropriate dose from Part 1, more participants are given the treatment to further evaluate its effectiveness and safety. The trial is open-label (meaning patients know which treatment they're receiving) and multicenter (conducted at multiple medical facilities).
  • How is ETX-19477 administered to patients? ETX-19477 is administered as an oral medication that patients take daily. This means it comes in pill or capsule form that can be swallowed, making it more convenient than treatments that require intravenous administration or hospital visits for each dose.
  • What outcomes are researchers measuring in this trial? Researchers are measuring several outcomes: 1) Safety and tolerability, including side effects and serious adverse events; 2) Pharmacokinetics (how the drug moves through the body), including maximum concentration, time to reach maximum concentration, and how long the drug stays in the body; 3) Anti-tumor activity, measured by objective response rate (how many tumors shrink), duration of response (how long tumors stay smaller), and disease control rate (how many patients have stable disease or better).

Ongoing Clinical Trials on ETX-19477

  • Study of ETX-19477 for Patients with Advanced Solid Tumors After Standard Treatment

    Not yet recruiting

    1 1
    Investigated diseases:
    Investigated drugs:
    France Italy Spain

Glossary

  • PARG (Poly ADP-ribose glycohydrolase): An enzyme that plays a critical role in DNA damage response in cells. It helps remove certain chemical modifications that are added to proteins during DNA repair processes.
  • Replication stress: A condition in cells where the process of DNA replication (copying) is slowed or stalled, leading to accumulation of damaged DNA. This is common in many cancer cells and represents a potential vulnerability that can be targeted by treatments.
  • DNA damage response (DDR): A network of cellular pathways that detect, signal, and repair DNA damage. Cancer cells often have defects in these pathways, which can make them more vulnerable to certain treatments.
  • Single-strand breaks (SSBs): Damage to DNA where only one of the two strands in the DNA double helix is broken. These are less severe than double-strand breaks but still need to be repaired by the cell.
  • Double-strand breaks (DSBs): Damage to DNA where both strands of the DNA double helix are broken. These are more difficult for cells to repair and can lead to cell death if not fixed properly.
  • Apoptosis: A form of programmed cell death that occurs in multicellular organisms. It's a controlled process where cells essentially commit suicide when they are damaged or no longer needed.
  • Maximum tolerated dose (MTD): The highest dose of a drug that does not cause unacceptable side effects. Finding this dose is often a key goal of early-phase clinical trials.
  • RP2D (Recommended Phase 2 Dose): The dose of a drug that is recommended for use in Phase 2 clinical trials, based on safety and preliminary effectiveness data from Phase 1 trials.
  • Dose-limiting toxicities (DLTs): Side effects that are severe enough to prevent increasing the dose of a drug in a clinical trial.
  • Pharmacokinetics (PK): The study of how drugs move through the body, including how they are absorbed, distributed, metabolized, and eliminated.
  • Pharmacodynamics (PDx): The study of how drugs affect the body, including their mechanism of action and the relationship between drug concentration and effect.
  • RECIST v1.1: Response Evaluation Criteria In Solid Tumors version 1.1. This is a standardized set of rules used to determine if tumors are responding to treatment, staying the same, or growing.
  • Objective response rate (ORR): The percentage of patients whose cancer shrinks or disappears after treatment.
  • Duration of response (DOR): The length of time that a tumor continues to respond to treatment without growing or spreading.
  • Disease control rate (DCR): The percentage of patients who have achieved stable disease or better (partial or complete response) after treatment.
  • Advanced or Metastatic Solid Tumors: Solid cancers (as opposed to blood cancers) that have either grown extensively at their original site (advanced) or have spread to other parts of the body (metastatic).
  • BRCA1 and BRCA2 Mutations: Genetic changes in the BRCA1 or BRCA2 genes that increase risk for certain cancers, particularly breast and ovarian cancers. These mutations also affect how tumors respond to certain treatments.
  • ER+ Breast Cancer: Breast cancer that tests positive for estrogen receptors, meaning the cancer cells grow in response to the hormone estrogen.
  • Castrate Resistant Prostate Cancer: Prostate cancer that continues to grow even when the level of testosterone in the body is reduced to very low levels.

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