A Study of PARG Inhibitor ETX-19477 in Patients With Advanced Solid Malignancies

Overview

Sponsor-declared trial summary

Key facts

Sponsor

858 Therapeutics Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Decision date (initial)

2025-04-02

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

858 Therapeutics Inc.

External identifiers

EU CT number

2024-518326-32-00

WHO UTN

U1111-1314-9851

ClinicalTrials.gov

NCT06395519

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Pharmacokinetic, Safety

Phase 1:
- To determine the maximum tolerated dose (MTD) and/or RD of ETX-19477
- To characterize the safety and tolerability of ETX-19477
Phase 2a:
-To assess the anti-tumor activity of ETX-19477 using RECIST v1.1

Secondary objectives 5

1. Phase 1: - To characterize the PK profile of ETX-19477
2. Phase 1: -To assess the preliminary anti-tumor activity of ETX-19477 using RECIST v1.1
3. Phase 2a: To determine the OD of ETX19477
4. Phase 2a: -To further characterize the safety and tolerability of ETX-19477
5. Phase 2a: -To assess additional measures of ETX-19477 anti-tumor activity

Conditions and MedDRA coding

Patients with advanced solid malignancies that have progressed following standard therapy

Regulatory references

Scientific advice from competent authorities

Food And Drug Administration

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. 1.) Males and females of age ≥18 years at the time of signing the informed consent document.
2. 10.) All adverse events resulting from prior cancer therapies must have resolved to NCI CTCAE v5.0 Grade ≤1 or pre-therapy baseline with the exception of alopecia or ≤ Grade 2 neuropathy (except for laboratory parameters outlined below).
3. 11.) Adequate hematological, renal, and hepatic function: a) ANC ≥1.5×109/L (no GCSF within 14 days of study enrollment) b) Platelet count ≥100×109/L (no platelet transfusions within 7 days of study enrollment) c) Hemoglobin ≥10.0 g/dL (no RBC transfusions within 14 days of study enrollment) d) Albumin >3.0 g/dL e) ALT ≤3×ULN (if liver metastases are present, ≤5.0×ULN) f) AST ≤3×ULN (if liver metastases are present, ≤5.0×ULN) g) Total bilirubin ≤1.5×ULN (patients with known Gilbert’s Syndrome may enroll with 2.5×ULN provided the direct bilirubin is ≤1.5 mg/dL) h) Calculated estimated glomerular filtration rate of ≥50 mL/minute/1.73m2 by CKD-EPI equation i) PT and/or INR and PTT or aPTT ≤1.5×ULN
4. 12.) No investigational agent within 3 weeks or 5 half-lives (whichever is shorter; minimum of 2 weeks) prior to first dose of study drug
5. 13.) Female patients of childbearing potential must agree to use highly effective contraception or abstinence during the period of therapy and in the following 90 days after discontinuation of study treatment. Male patients must be surgically sterile or abstinent or both the male and their female partners of childbearing potential must agree to use highly effective contraception with supplementary barrier method (male condom) during the period of therapy and in the following 90 days after discontinuation of study treatment.
6. 14.) Able to swallow an oral medication.
7. 15.) Willing and able to adhere to the study visit schedule and other protocol requirements.
8. 2.) Able to understand and voluntarily sign an informed consent document prior to any study-related assessments/procedures.
9. 3.) Histologically or cytologically confirmed advanced (incurable recurrent, unresectable, or metastatic) solid cancer, excluding primary CNS tumors.
10. 4.) Progression on or after or intolerance to most recent systemic therapy. Prior treatment in the recurrent/metastatic setting; patients must have received approved standard therapy that is available to the patient that is known to confer clinical benefit, unless this therapy is contraindicated, intolerable to the patient, or is declined by the patient. The reason for treatment decline must be clearly documented in the medical record and Sponsor Medical Monitor approval obtained.
11. 6.) Measurable disease per RECIST v1.1.
12. 7.) ECOG performance status 0–1.
13. 8.) Life expectancy of at least 3 months.
14. 9.) Willing to provide a pretreatment tumor sample (either an archival sample or a sample obtained by pretreatment biopsy [preferably from a progressing lesion and preferably obtained during or after disease progression on last regimen received]). Patients without available archival tissue and/or where biopsy is not considered safe and/or medically feasible may be enrolled with approval of the Sponsor Medical Monitor.

Exclusion criteria 15

1. 1.)  Receiving continuous corticosteroids at prednisone-equivalent dose of >10 mg/day. Chronic systemic corticosteroid therapy for physiologic replacement (≤10 mg/day of prednisone equivalents) and the use of non-systemic corticosteroids (e.g., inhaled, topical, intra-nasal, intra-articular, or ophthalmic) are permitted.
2. 10.) Acute or chronic uncontrolled renal disease, pancreatitis, or liver disease (with exception of patients with Gilbert’s Syndrome, asymptomatic gallstones, liver metastases, or stable chronic liver disease per Investigator assessment).
3. 11.) Known other previous/current malignancy requiring treatment within ≤2 years except for limited disease treated with curative intent, such as carcinoma in situ, squamous or basal cell skin carcinoma, or superficial bladder carcinoma and not requiring ongoing chemotherapy.
4. 12.) Pregnant or breastfeeding. Patients with elevated human chorionic gonadotropin due to underlying malignancy may be eligible if confirmed not to be pregnant.
5. 14.) Patients currently treated with therapeutic doses of warfarin sodium (Coumadin®) or any other coumarin-derivative anticoagulants
6. 15.) Any other prior or ongoing significant medical condition, physical finding, laboratory abnormality, psychiatric illness, or social situation that, in the opinion of the Investigator or Medical Monitor, could impact safety or compliance with study requirements or confounds the ability to interpret data.
7. 2.) Definitive radiotherapy within 6 weeks and palliative radiation within 2 weeks prior to the first dose of study drug. If previously irradiated, lesions must have demonstrated clear-cut progression prior to being eligible for evaluation as target lesions.
8. 3.) Major surgery (excluding placement of vascular access) ≤28 days of the first dose of study drug.
9. 4.) Symptomatic untreated or progressing brain metastases. Stable, treated brain metastases are allowed if no evidence of radiologic or clinical progression or corticosteroid use for at least 4 weeks.
10. 5.) Impairment of GI function or GI disease that may significantly alter the absorption of ETX 19477. No history of bowel obstruction within 6 months and/or peritoneal fluid drainage within 8 weeks prior to the first dose of study drug.
11. 6.) Known symptomatic and radiologically progressing or LMD. If LMD has been reported radiographically on baseline MRI, but is not suspected clinically by the Investigator, the patient must be free of neurological symptoms of LMD.
12. 7.) Resting ECG with QTcF >470 msec on 2 or more timepoints within a 24-hour period, or history or family history of congenital long QT syndrome
13. 8.) History of myocardial infarction or unstable angina within 6 months prior to enrollment, or clinically significant cardiac disease, such as ventricular arrhythmia requiring therapy, uncontrolled hypertension, clinically significant uncontrolled arrhythmias, or any history of symptomatic congestive heart failure.
14. 9.) Known active or chronic infection (viral, bacterial, or fungal), including tuberculosis, hepatitis B, hepatitis C, or AIDS-related illness. Controlled infections, including HIV and “cured” hepatitis C (no active fever, no evidence of systemic inflammatory response syndrome) that are stable with undetectable viral load on antiviral treatment are not exclusionary.
15. 16.) Phase 2a tumor profile exclusions: a) High-grade serious ovarian cancer b) ER+ breast cancer

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Phase 1: - Frequency of dose-limiting toxicities (DLTs) - Frequency and severity of AEs, including abnormal ECG parameters, and serious adverse events (SAEs)
2. Phase 2a: Objective response rate

Secondary endpoints 5

1. Phase 1: -Plasma concentrations of ETX-19477 as a function of time post-dosing -PK parameters for single (first) dose and multiple doses
2. Phase 1: - Objective response rate (ORR) - Duration of response (DOR) - Disease control rate (DCR) - Progression-free survival (PFS)
3. Phase 2a: To compare two (or more) dose levels of ETX-19477 with respect to efficacy (ORR, DOR, DCR, PFS), safety, and tolerability in order to select the optimal dose and schedule for Phase 3 development in accordance with FDA's Project Optimus initiative.
4. Phase 2a: - Frequency and severity of AEs and SAEs, dose modifications.
5. Phase 2a: - Duration of response (DOR) - Disease control rate (DCR) - Progression-free survival (PFS)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

858 Therapeutics Inc.

Sponsor organisation

858 Therapeutics Inc.

Address

3115 Merryfield Row Suite 110

City

San Diego

Postcode

92121-1174

Country

United States

Scientific contact point

Organisation

858 Therapeutics Inc.

Contact name

Joseph Leveque

Public contact point

Organisation

858 Therapeutics Inc.

Contact name

Daniel McCormick

Third parties 3

Locations

3 EU/EEA countries · 13 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 22 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications