ETX-19477 for Cancer

(ERADIC8 Trial)

Recruiting at 12 trial locations

Overseen By 858 Therapeutics, Inc.

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: 858 Therapeutics, Inc.

Must not be taking: Corticosteroids, PPIs, Warfarin, others

Disqualifiers: Brain metastases, Cardiac disease, Infections, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

120 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment called ETX-19477, aimed at combating advanced solid cancers that have not responded to other treatments. The study assesses the safety of this drug, how the body processes it, and its ability to slow or stop tumor growth. The trial consists of two parts: the first part determines the right dose, and the second part tests that dose in more participants. It is suitable for adults with solid tumors, particularly those whose cancers have stopped responding to standard treatments and who have a BRCA2 gene mutation. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new therapy.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications, such as proton pump inhibitors, strong CYP3A inhibitors and inducers, and P-glycoprotein inhibitors, before starting the study drug. You should also not be on therapeutic doses of warfarin or other coumarin-derivative anticoagulants. Please consult with the trial team for specific guidance on your current medications.

Is there any evidence suggesting that ETX-19477 is likely to be safe for humans?

Research has shown that ETX-19477, a new cancer treatment, is under study to assess its safety for people. ETX-19477 blocks a protein called PARG, which aids cancer cell growth. In lab tests, this treatment effectively stopped cancer cells from spreading.

The current study tests different doses of ETX-19477 to find one that is both effective and safe. As an early-phase trial, the main goal is to identify the best dose that patients can tolerate without serious side effects. Early trials like this often have less safety information compared to later trials. While lab results are promising, safety data in humans is still being collected.

Prospective participants should know that joining this trial is an important step in understanding the safety of ETX-19477 for cancer treatment. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Most treatments for cancer, like chemotherapy and radiation, work by broadly attacking rapidly dividing cells, which can harm healthy cells too. But ETX-19477 is unique because it targets specific cancer cell pathways, potentially reducing side effects and improving effectiveness. Researchers are particularly excited because this new mechanism of action could offer a more precise attack on cancer cells, making it a promising alternative to the current standard of care.

What evidence suggests that ETX-19477 might be an effective treatment for cancer?

Research has shown that ETX-19477, a new cancer treatment under study in this trial, delivers promising results. Early lab studies demonstrated strong effects against cancer by targeting weaknesses in cancer cell reproduction, potentially stopping their growth. ETX-19477 targets a specific protein essential for cancer cells, which could enhance the treatment's precision and effectiveness. Early evidence suggests it might provide a new option for treating cancers unresponsive to standard treatments. Participants in this trial will receive ETX-19477 at different dose levels to evaluate its safety and effectiveness. ^{1 2 3 4 6}

Who Is on the Research Team?

Daniel McCormick

Principal Investigator

858 Therapeutics, Inc.

Are You a Good Fit for This Trial?

This trial is for adults with advanced solid tumors, including specific cancers like breast, ovarian, prostate, colorectal and stomach cancer. Participants must have a BRCA1 or BRCA2 mutation. Details on who can't join are not provided.

Inclusion Criteria

Life expectancy of at least 3 months

I have a BRCA2 mutation that affects its function.

I haven't taken any experimental drugs within the last 3 weeks.

Exclusion Criteria

Resting ECG with QT interval calculated using the Fridericia's formula (QTcF) >470 msec on 2 or more timepoints within a 24-hour period

I am currently taking warfarin or similar blood thinners.

I do not have any active infections like TB, hepatitis B, C, or AIDS.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Monotherapy Dose Escalation

Participants will be assigned to a dose level to evaluate safety, tolerability, and pharmacokinetics of ETX-19477

6 months

Monotherapy Dose Expansion

After a dose is decided in Part 1, participants will be assigned to a dose level to further assess safety and anti-tumor activity

2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

3-6 months

What Are the Treatments Tested in This Trial?

Interventions

• ETX-19477

Trial Overview The study tests ETX-19477 in two parts: first to find the right dose (dose escalation) and then to see its effects at that dose (dose expansion). It's an open-label trial so everyone knows they're getting the drug.

How Is the Trial Designed?

Group I: Phase 1 Part 2: Monotherapy Dose Expansion Experimental Treatment 1 Intervention

After a dose is decided in Part 1, participants entering part 2 will be assigned to a dose level.

Group II: Phase 1 Part 1: Monotherapy Dose Escalation Experimental Treatment 1 Intervention

Participants will be assigned to a dose level.

Who Is Running the Clinical Trial?

858 Therapeutics, Inc.

Lead Sponsor

Trials

1

Recruited

50+

Published Research Related to This Trial

Ecteinascidin 743 (Et743) is a unique antitumor agent that selectively binds to DNA, causing specific types of damage, such as DNA-protein cross-links and single-strand breaks, without producing detectable double-strand breaks.

In human colon carcinoma cells, Et743 induces a cell cycle response characterized by p53 elevation and accumulation in various phases, indicating its potential effectiveness in inhibiting cancer cell proliferation, even in cells resistant to other treatments like camptothecin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ecteinascidin 743 induces protein-linked DNA breaks in human colon carcinoma HCT116 cells and is cytotoxic independently of topoisomerase I expression. Takebayashi, Y., Goldwasser, F., Urasaki, Y., et al.[2018]

The raltitrexed/oxaliplatin combination (TOMOX) demonstrated a 50% overall response rate in 58 patients with advanced colorectal cancer, indicating its efficacy as a first-line chemotherapy treatment.

The treatment was generally well tolerated, with manageable side effects; the most common severe toxicity was grade III/IV neutropenia in 17% of patients, and no toxic deaths were reported, suggesting a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Raltitrexed plus oxaliplatin (TOMOX) as first-line chemotherapy for metastatic colorectal cancer. A phase II study of the Italian Group for the Study of Gastrointestinal Tract Carcinomas (GISCAD). Cascinu, S., Graziano, F., Ferraù, F., et al.[2020]

Endothelin-1 (ET-1) is overexpressed in prostate cancer compared to benign tissue and high-grade prostatic intraepithelial neoplasia (HGPIN), indicating its potential role in cancer progression.

Stronger ET-1 expression is associated with a shorter recurrence-free survival in prostate cancer patients, suggesting that it could serve as a prognostic marker for predicting biochemical recurrence after radical prostatectomy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Endothelin-1 expression in prostate cancer and high grade prostatic intraepithelial neoplasia. Rosenblatt, R., Valdman, A., Cheng, L., et al.[2022]

In a study involving 594 patients with castration-resistant prostate cancer and bone metastases, zibotentan did not significantly improve overall survival compared to placebo, with median survival times of 24.5 months versus 22.5 months, respectively.

While zibotentan was generally well-tolerated, it was associated with higher rates of peripheral edema and cardiac failure events compared to placebo, indicating a need for careful monitoring of these side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 3, randomized, placebo-controlled study of zibotentan (ZD4054) in patients with castration-resistant prostate cancer metastatic to bone. Nelson, JB., Fizazi, K., Miller, K., et al.[2014]

A study involving 468 prostate cancer patients found that specific genetic variations (SNPs) in the endothelin-1 (ET-1) gene are linked to the risk of developing hormone refractory prostate cancer (HRPC) after androgen deprivation therapy.

The rs1800541-rs2070699 haplotype was significantly associated with an increased risk of HRPC, suggesting that genetic testing for these SNPs could help identify patients at higher risk for disease progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association of endothelin-1 gene single-nucleotide polymorphisms and haplotypes with risk of hormone refractory prostate cancer. Xu, D., Wang, X., Lou, Y.[2018]

ET-743, derived from a marine organism, shows significant cytotoxic activity against soft tissue sarcomas and has a unique mechanism of action that includes inhibiting DNA repair pathways and promoting apoptosis, making it a promising treatment option.

In clinical trials, ET-743 demonstrated a partial response rate of 18% in first-line treatment for advanced soft tissue sarcomas, with a median overall survival of 10.2 months and generally well-tolerated side effects, primarily mild and reversible.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ET-743. Cvetkovic, RS., Figgitt, DP., Plosker, GL.[2018]

DX-8951, a new derivative of camptothecin, demonstrated significantly stronger cytotoxic effects against pancreatic tumor cell lines compared to SN-38 and topotecan, especially in CPT-11-resistant variants, indicating its potential as a more effective treatment option.

In animal models, DX-8951 showed potent antitumor effects against solid tumors and liver metastases, outperforming CPT-11 in resistant cases, suggesting it could be a valuable therapeutic agent for treating human cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor effect of DX-8951, a novel camptothecin analog, on human pancreatic tumor cells and their CPT-11-resistant variants cultured in vitro and xenografted into nude mice. Takiguchi, S., Kumazawa, E., Shimazoe, T., et al.[2019]

E7070 has shown a unique antitumor effect in a variety of human cancer cell lines, particularly disrupting the cell cycle in leukemia cells and demonstrating time-dependent cell-killing effects in colon cancer cells.

In animal studies, E7070 not only suppressed tumor growth but also caused complete regression in 80% of advanced lung cancer tumors, outperforming standard treatments like 5-FU and irinotecan, which supports its advancement to clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

E7070, a novel sulphonamide agent with potent antitumour activity in vitro and in vivo. Ozawa, Y., Sugi, NH., Nagasu, T., et al.[2019]

E7070, a new anticancer drug, was found to have a maximum tolerated dose (MTD) of 900 mg/m2, with a recommended dose of 800 mg/m2 for future studies, indicating its potential safety for patients.

The study revealed that the drug's effectiveness and side effects, such as myelosuppression, were influenced by the patients' CYP2C19 genetic variations, suggesting that genetic testing may help tailor treatment for better outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I pharmacokinetic and pharmacogenomic study of E7070 administered once every 21 days. Yamada, Y., Yamamoto, N., Shimoyama, T., et al.[2016]

Endothelin-1 (ET-1) is linked to the regulation of p53 activity in prostate cancer, as it inhibits the release of microRNA 15a (miR-15a) and promotes Mxi-2 production, which is associated with cancer aggressiveness.

A molecular complex involving Argonaut 2 (Ago2), Mxi-2, and microRNA 1285 (miR-1285) was identified, with Mxi-2 levels correlating with prostate cancer aggressiveness, suggesting it could serve as a non-invasive marker for diagnosis and progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mxi-2 Dependent Regulation of p53 in Prostate Cancer. KÖditz, B., Fries, JWU., GÖbel, H., et al.[2020]

Citations

1. aacrjournals.org aacrjournals.org/cancerres/article/84/6_Supplement/2083/736581/Abstract-2083-Discovery-of-ETX-19477-a-novel-and

Discovery of ETX-19477, a novel and selective PARG inhibitor ... Preclinical data show ETX-19477 demonstrates potent and specific anti-proliferative effects by exposing underlying existing replication ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT06395519

NCT06395519 | A Study of PARG Inhibitor ETX-19477 in ... This is a two-part, open-label, multicenter, dose escalation and dose expansion study designed to evaluate the safety, tolerability, pharmacokinetics (PK), ...

3. clinicaltrials.eu clinicaltrials.eu/inn/etx-19477/

ETX-19477: A PARG Inhibitor for Advanced Solid Tumors 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 ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12123320/

Prospects for PARG inhibitors in cancer therapy - PMC By exploiting the inherent vulnerability of cancer cells to replication stress, ETX-19477 has been shown to have effective and specific antiproliferative ...

5. mayo.edu mayo.edu/research/clinical-trials/cls-20579584

A Study Of PARG Inhibitor ETX-19477 In Patients With ... The purpose of this study is designed to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PDx), and anti-tumor activity of ETX-19477.

6. fredhutch.org fredhutch.org/en/research/clinical-trials/trial-details.fh_trial_id_15330.a-study-of-parg-inhibitor-etx-19477-in-patients-with-advanced-solid-malignancies-eradic8.html

A Study of PARG Inhibitor ETX-19477 in Patients With ... This is a two-part, open-label, multicenter, dose escalation and dose expansion study designed to evaluate the safety, tolerability, ...