ETX-19477 for Cancer

(ERADIC8 Trial)

Recruiting at 4 trial locations

Overseen By 858 Therapeutics, Inc.

Age: 18+

Sex: Any

Trial Phase: Phase 1

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

48 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a two-part, open-label, multicenter, dose escalation and dose expansion study designed to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PDx), and anti- tumor activity of ETX-19477, a novel reversible small molecule inhibitor of PARG.

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.

What data supports the effectiveness of the drug ETX-19477 for cancer?

Research suggests that endothelin-1 (ET-1), which is related to ETX-19477, plays a role in cancer progression, particularly in prostate cancer. Studies have shown that targeting ET-1 can impact cancer growth, indicating potential effectiveness of ETX-19477 in similar contexts. ^{1 2 3 4 5}

What makes the drug ETX-19477 unique for cancer treatment?

ETX-19477 is unique because it is a novel sulfonamide anticancer agent that disrupts the G1/S phase of the cell cycle, which is different from other anticancer drugs. It has shown distinct antitumor activity in various cancer cell lines and has been found to be effective in causing tumor regression in animal models. ^{6 7 8 9 10}

Research Team

Katherine Bell-McGuinn, MD, PhD

Principal Investigator

858 Therapeutics, Inc.

Eligibility Criteria

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 am 18 years or older.

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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, 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]

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]

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]

References

1. Greece pubmed.ncbi.nlm.nih.gov

Mxi-2 Dependent Regulation of p53 in Prostate Cancer. [2020]

2. United States pubmed.ncbi.nlm.nih.gov

Phase 3, randomized, placebo-controlled study of zibotentan (ZD4054) in patients with castration-resistant prostate cancer metastatic to bone. [2014]

3. Germany pubmed.ncbi.nlm.nih.gov

Association of endothelin-1 gene single-nucleotide polymorphisms and haplotypes with risk of hormone refractory prostate cancer. [2018]

4. England 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). [2020]

5. United States pubmed.ncbi.nlm.nih.gov

Endothelin-1 expression in prostate cancer and high grade prostatic intraepithelial neoplasia. [2022]

6. New Zealand pubmed.ncbi.nlm.nih.gov

ET-743. [2018]

7. Japan 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. [2019]

8. England pubmed.ncbi.nlm.nih.gov

Phase I pharmacokinetic and pharmacogenomic study of E7070 administered once every 21 days. [2016]

9. United States 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. [2018]

10. England pubmed.ncbi.nlm.nih.gov

E7070, a novel sulphonamide agent with potent antitumour activity in vitro and in vivo. [2019]