ETX-19477 for Cancer
(ERADIC8 Trial)
Recruiting in Palo Alto (17 mi)
+4 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: 858 Therapeutics, Inc.
Must not be taking: Corticosteroids, PPIs, Warfarin, others
Disqualifiers: Brain metastases, Cardiac disease, Infections, others
No Placebo Group
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.
12345What 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.
678910Eligibility 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.
+3 more
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.
+9 more
Trial 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
Participant Groups
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.
2Treatment groups
Experimental Treatment
Group I: Phase 1 Part 2: Monotherapy Dose ExpansionExperimental Treatment1 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 EscalationExperimental Treatment1 Intervention
Participants will be assigned to a dose level.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
START Center for Cancer Care - Mountain RegionSalt Lake City, UT
Yale Cancer CenterNew Haven, CT
MD Anderson Cancer CenterHouston, TX
Memorial Sloan Kettering Cancer CenterNew York, NY
More Trial Locations
Loading ...
Who Is Running the Clinical Trial?
858 Therapeutics, Inc.Lead Sponsor
References
Mxi-2 Dependent Regulation of p53 in Prostate Cancer. [2020]Endothelin-1 (ET-1) is overexpressed in many types of cancer, inhibiting the release of the microRNA 15a (miR-15a) and inducing the production of Mxi-2. Our aim was to identify a molecular complex regulating p53 activity in prostate cancer (PCa).
Phase 3, randomized, placebo-controlled study of zibotentan (ZD4054) in patients with castration-resistant prostate cancer metastatic to bone. [2014]Endothelin-1 and the endothelin A (ET(A) ) receptor have been implicated in prostate cancer progression in bone. This study aimed to determine whether the specific ET(A) receptor antagonist, zibotentan, prolonged overall survival (OS) in patients with castration-resistant prostate cancer and bone metastases who were pain-free or mildly symptomatic for pain.
Association of endothelin-1 gene single-nucleotide polymorphisms and haplotypes with risk of hormone refractory prostate cancer. [2018]Androgen deprivation is often the treatment of choice for patients with a new diagnosis of metastatic or locally advanced prostate cancer (CaP). However, most CaP patients showing a first response to androgen deprivation will progress to a hormone refractory phase of the disease (HRPC) with a much poorer prognosis. Accumulating evidence suggests that endothelin-1 (ET-1) plays an important role in CaP progression. Singlenucleotide polymorphisms (SNPs) of the ET-1 gene reportedly have been associated with cancer progression and chemoresistance. In the present study, we explored the association of SNPs and haplotypes of the ET-1 gene with the risk of HRPC. We genotyped three SNPs (rs1800541, rs2070699 and rs5370) in the ET-1 gene in a case-control study; 234 CaP patients who developed HRPC within six years after androgen deprivation therapy was used as HRPC cases, and 234 age- and primary therapy-matched CaP patients who had not developed HRPC within six years after androgen deprivation therapy were used as non-HRPC controls. Our results revealed that the G allele at rs1800541 and the G allele at rs2070699 were respectively associated with reduced and increased risk of HRPC at borderline statistical significance (p=0.047 and p=0.058, respectively). With adjustment for potential confounders including body mass index, initial Gleason score at diagnosis of CaP, and post-treatment nadir serum PSA level, we found that rs1800541-rs2070699 TG haplotype was significantly associated with increased risk of HRPC (p=0.033; adjusted OR, 2.10; 95% CI, 1.37-5.04). In conclusion, this study provides the first evidence that a 2-SNP haplotype of the ET-1 gene is associated with increased risk of HRPC, which adds new insights into early identification of CaP patients who are likely to develop HRPC in a later stage of the disease.
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]To evaluate the safety and efficacy of the novel raltitrexed/oxaliplatin combination (TOMOX) as first-line chemotherapy for patients with advanced colorectal cancer.
Endothelin-1 expression in prostate cancer and high grade prostatic intraepithelial neoplasia. [2022]To investigate the prognostic value of endothelin-1 (ET-1), a vasoconstrictor involved in differentiation and growth of cancer, in prostate cancer.
ET-743. [2018]ET-743 is a novel antineoplastic DNA-binding agent derived from the marine tunicate Ecteinascidia turbinata. It has significant cytotoxic activity against soft tissue sarcomas (STS). It also has in vitro activity against melanoma, breast, ovarian, colon, renal, non-small cell lung and prostate carcinomas. The drug has unique mechanism of action which includes in vitro inhibition of transcription-dependent nucleotide excision repair pathways and inhibition of cell cycle progression leading to p53-independent apoptosis. It also selectively inhibits transcriptional activation of multidrug-resistance (MDR1) gene in human sarcoma cells in vivo. The efficacy of ET-743 has been investigated in patients with advanced STS in three multicentre phase II clinical trials. Patients receiving ET-743 as second- or third-line treatment had partial tumour response rates of 6 to 8%. Patients receiving ET-743 as first-line chemotherapy had a partial response rate of 18%. Forty-two to 50% of all patients in these trials achieved stable disease. All responses were durable up to 14 months. A pooled analysis of the three multicentre phase II trials showed the following: median overall survival time of 10.2 months, 1-year survival rate of 40% and 6-month progression-free rate of 27.2%. ET-743 is generally well tolerated. The most common adverse events in clinical trials were non-cumulative haematological and hepatic toxicities. Transient and reversible elevation of hepatic transaminases, nausea, vomiting and asthenia were common but seldom severe and never treatment-limiting. Mucositis, alopecia and cardiac or neurotoxicities were not observed.
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]DX-8951 is a novel water-soluble derivative of camptothecin. We evaluated the effects of DX-8951 on the growth of several pancreatic tumor cell lines in vitro and in vivo. In vitro cytotoxic activity of DX-8951 against SUIT-2 and KP-1N cells, as indicated by IC50 value, was several times more potent than that of SN-38, an active metabolite of CPT-11, and dozens of times more potent than that of SK&F104864 (topotecan). DX-8951 also showed the greatest cytotoxicity against CPT-11-resistant variants, SUIT-2/CPT-11 and KP-1N/CPT-11 cells, and the cross-resistance of these cells to DX-8951 was lower than that to SN-38 and SK&F104864. Topoisomerase I inhibitory activity of DX-8951 was about three-fold stronger than that of SN-38, as measured in crude nuclear extract obtained from SUIT-2 cells. DX-8951 induced DNA fragmentation, a specific feature of apoptosis, in SUIT-2 cells more effectively than SN-38. DX-8951 exhibited potent antitumor effects against SUIT-2 in a solid tumor model and in a liver metastasis model, in which tumor cells were xenografted subcutaneously and intrasplenically, respectively, into nude mice. The in vivo effects were closely similar to or somewhat superior to those of CPT-11. DX-8951 also showed significant antitumor effects against SUIT-2/CPT-11 solid tumors, against which CPT-11 had no effect. These results suggest that, on the basis of its strong antitumor activity and effectiveness against CPT-11-resistant tumors, DX-8951 may be a useful therapeutic agent in the treatment of human cancer. The potent cytotoxicity of DX-8951 may result from strong inhibition of topoisomerase I, which may then trigger apoptotic cell death.
Phase I pharmacokinetic and pharmacogenomic study of E7070 administered once every 21 days. [2016]E7070 is a novel sulfonamide anticancer agent that disrupts the G1/S phase of the cell cycle. The objectives of this phase I study of E7070 were to estimate the maximal tolerated dose (MTD), to determine the recommended dose for phase II, and to clarify the pharmacokinetic profile of E7070 and its relation to polymorphisms of CYP2C9 (*2, *3) and CYP2C19 (*2, *3) in Japanese patients. Patients received 1-2-h i.v. infusions of E7070 (400, 600, 700, 800 or 900 mg/m2) on day 1 of a 21-day cycle. Twenty-one patients received between one and eight cycles of E7070. The dose-limiting toxicities (DLT) comprised leukopenia, neutropenia, thrombocytopenia, elevation of aspartate aminotransferase, colitis, and ileus. The mean area under the plasma concentration-time curve (AUC) for successive dose levels increased in a non-dose-proportional manner. Two patients were heterozygous for the CYP2C9 mutation. For CYP2C19, eight patients were wild type and the remainder had heterozygous (n = 8) or homozygous mutations (n = 5). Regarding the CYP2C19 genotype, the AUC of patients with mutant alleles were higher than those of patients with wild type at a dose of 600 mg/m2 or more. The severity of toxic effects, such as myelosuppression, seemed to depend on the AUC. No partial responses were observed. One patient treated at a dose of 700 mg/m2 experienced a maximum tumor volume reduction of 22.5%. The MTD was estimated to be 900 mg/m2. A dose of 800 mg/m2 is recommended for further phase II studies. The pharmacokinetic/pharmacodynamic properties of E7070 seemed to be influenced by CYP2C19 genotype. The observed safety profile and preliminary evidence of antitumor activity warrant further investigation of this drug in monotherapy or in combination chemotherapy.
Ecteinascidin 743 induces protein-linked DNA breaks in human colon carcinoma HCT116 cells and is cytotoxic independently of topoisomerase I expression. [2018]Ecteinascidin 743 (Et743; NSC 648766) is a potent antitumor agent presently in clinical trials. Et743 selectively alkylates guanine N2 from the minor groove of duplex DNA and bends the DNA toward the major groove. This differentiates Et743 from other DNA-alkylating agents presently in the clinic. To date, the cellular effects of Et743 have not been elucidated. Recently, Et743 DNA adducts have been found to suppress gene expression selectively and to induce topoisomerase I (top1) cleavage complexes in vitro and top1-DNA complexes in cell culture. In the present study, we characterized the DNA damage and the cell cycle response induced by Et743 in human colon carcinoma HCT116 cells. Alkaline elution experiments demonstrated that micromolar concentrations of Et743 produced comparable frequencies of DNA-protein cross-links and DNA single-strand breaks. The single-strand breaks were protein-cross-linked and were not associated with detectable DNA double-strand breaks. By contrast with camptothecin, these lesions persisted for several hours after drug removal and were not formed at 4 degrees C. Et743 treatment induced transient p53 elevation, dose-dependent cell cycle accumulation in G2-M and in G1- and S-phase, and inhibition of DNA synthesis. The sensitivity of camptothecin-resistant mouse leukemia P388/ CPT45 cells, which fail to express detectable top1, was similar to the sensitivity of wild-type P388 cells, suggesting that top1 is not a critical target for the antiproliferative activity of Et743.
E7070, a novel sulphonamide agent with potent antitumour activity in vitro and in vivo. [2019]E7070 (N-(3-Chloro-7-indolyl)-1,4-benzenedisulphonamide) was selected from our sulphonamide compound collections via antitumour screening and flow cytometric analysis. Following treatment with E7070, the cell cycle progression of P388 murine leukaemia cells was disturbed in the G1 phase. The cell-killing effect on human colon cancer HCT116 cells was found to be time-dependent. In the panel of 42 human tumour cell lines, E7070 showed an antitumour spectrum that was distinct from those of other anticancer drugs used in clinic. Animal tests using human tumour xenograft models demonstrated that E7070 could cause not only tumour growth suppression, but also tumour regression in three of five colorectal and two of two lung cancers. In the HCT116 xenograft model, E7070 was shown to be superior to 5-FU, MMC and CPT-11 (irinotecan). Furthermore, complete regression of advanced LX-1 tumours was observed in 80% of E7070-treated mice. All of these observations have promoted this drug to clinical evaluation.