Trial Title:
A Study of PARG Inhibitor ETX-19477 in Patients With Advanced Solid Malignancies
NCT ID:
NCT06395519
Condition:
Advanced or Metastatic Solid Tumors
Breast Cancer
Ovarian Cancer
Prostate Cancer
Epithelial Ovarian Cancer
BRCA2 Mutation
ER+ Breast Cancer
Castrate Resistant Prostate Cancer
BRCA1 Mutation
BRCA Mutation
Endometrial Cancer
Colorectal Cancer
Gastric Cancer
Conditions: Official terms:
Breast Neoplasms
Prostatic Neoplasms
Ovarian Neoplasms
Carcinoma, Ovarian Epithelial
Endometrial Neoplasms
Conditions: Keywords:
PARG Inhibitor
Study type:
Interventional
Study phase:
Phase 1
Overall status:
Recruiting
Study design:
Allocation:
Non-Randomized
Intervention model:
Sequential Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
ETX-19477
Description:
Oral medication taken daily
Arm group label:
Phase 1 Part 1: Monotherapy Dose Escalation
Arm group label:
Phase 1 Part 2: Monotherapy Dose Expansion
Summary:
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.
Detailed description:
A hallmark of many cancer cells is replication stress, which is characterized by the
slowing or stalling of replication forks during the DNA replication process, leading to
the accumulation of damaged DNA. The cellular response to replication stress is the
activation of cell-cycle checkpoints and the DNA damage response (DDR) pathway to arrest
the cell cycle and promote repair of the damaged DNA.
Poly (ADP) ribose glycohydrolase (PARG) plays a critical role in DDR with genetic
depletion or inhibition by reference compounds resulting in increased numbers of
single-strand breaks (SSBs) and double-strand breaks (DSBs) and reduced kinetics of break
repair. In addition, under conditions of replication stress in cancer cells, PARG
depletion or inhibition has been shown to inhibit proliferation and arrest cells in the S
or G2 phase of the cell cycle and/or induce apoptosis alone or in combination with DNA
damaging agents or replication stress inducers. The replication stress response
represents a cancer-specific vulnerability, which can be targeted by PARG small molecule
inhibition.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- Males and females of age ≥ 18 years at the time of signing the informed consent
document.
- Histologically or cytologically confirmed advanced (incurable recurrent,
unresectable, or metastatic) solid cancer, excluding primary central nervous system
(CNS) tumors.
- Any solid tumor malignancy, excluding primary CNS tumors, with progression on or
after or intolerance to most recent systemic therapy. Preferential enrollment
consideration will be made for patients with known BRCA2 mutations resulting in loss
of function.
- 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.
- No investigational agent within 3 weeks or 5 half-lives (whichever is shorter;
minimum of 2 weeks) prior to first dose of study drug.
- Life expectancy of at least 3 months.
Exclusion Criteria:
- 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.
- Definitive radiotherapy within 6 weeks and palliative radiation within 2 weeks prior
to the first dose of study drug.
- Symptomatic untreated or progressing brain metastases. Stable, treated brain
metastases are allowed if no evidence of radiologic or clinical progression or
increasing corticosteroid use for at least 4 weeks.
- Impairment of gastrointestinal (GI) function or GI disease that may significantly
alter the absorption of ETX-19477 and no history of bowel obstruction within 6
months prior to enrollment.
- Known symptomatic and radiologically progressing or leptomeningeal disease (LMD). If
LMD has been reported radiographically on baseline magnetic resonance imaging (MRI),
but is not suspected clinically by the Investigator, the patient must be free of
neurological symptoms of LMD.
- Resting ECG with QT interval calculated using the Fridericia's formula (QTcF) >470
msec on 2 or more timepoints within a 24-hour period, or history or family history
of congenital long QT syndrome.
- 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.
- 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.
- 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).
- 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.
- Patients receiving proton pump inhibitors (PPIs), strong cytochrome P450 (CYP)3A
inhibitors and inducers, or P-glycoprotein (P-gp) inhibitors. Patients should not
receive PPIs within 7 days prior to first dose of study drug. Strong CYP3A inducers
or inhibitors or strong P-gp inhibitors should not be given within 6 half-lives
prior to first dose of study drug.
- Patients currently treated with therapeutic doses of warfarin sodium (Coumadin®) or
any other coumarin-derivative anticoagulants
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Yale Cancer Center
Address:
City:
New Haven
Zip:
06510
Country:
United States
Status:
Not yet recruiting
Facility:
Name:
Memorial Sloan Kettering Cancer Center
Address:
City:
New York
Zip:
10065
Country:
United States
Status:
Not yet recruiting
Facility:
Name:
MD Anderson Cancer Center
Address:
City:
Houston
Zip:
77030
Country:
United States
Status:
Recruiting
Facility:
Name:
START Center for Cancer Care - Mountain Region
Address:
City:
Salt Lake City
Zip:
84112
Country:
United States
Status:
Recruiting
Facility:
Name:
Virginia Cancer Specialists
Address:
City:
Fairfax
Zip:
22031
Country:
United States
Status:
Recruiting
Start date:
May 13, 2024
Completion date:
December 2026
Lead sponsor:
Agency:
858 Therapeutics, Inc.
Agency class:
Industry
Source:
858 Therapeutics, Inc.
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06395519
