Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Digestive System Diseases

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Gland and Hormone Related Diseases

Rare Diseases

Breast Neoplasms

Stomach Neoplasms

Prostatic Neoplasms

Ovarian Neoplasms

Carcinoma, Ovarian Epithelial

Carcinoma

Endometrial Neoplasms

Breast Diseases

Skin Diseases

Genital Neoplasms, Male

Urogenital Neoplasms

Genital Diseases

Genital Diseases, Male

Urogenital Diseases

Prostatic Diseases

Male Urogenital Diseases

Endocrine Gland Neoplasms

Ovarian Diseases

Adnexal Diseases

Genital Diseases, Female

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Genital Neoplasms, Female

Endocrine System Diseases

Gonadal Disorders

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Uterine Neoplasms

Uterine Diseases

Stomach Cancer

Ovarian Cancer

Ovarian Epithelial Cancer

Participants will be assigned to a dose level.

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

ETX-19477

858 Therapeutics, Inc.

Katherine Bell-McGuinn, MD, PhD

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.

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.

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

Frequency of dose-limiting toxicities (DLTs), frequency and severity of AEs, including abnormal ECG parameters, and serious adverse events (SAEs)

Maximum Plasma Concentration \[Cmax\] for single (Cycle 1 Day 1) dose and at steady state (Cycle 2 Day 1) with trough levels at the beginning of the next cycle (Cycle 3 Day 1).

Time of Maximum Blood Concentration (tmax) for single dose and at steady state with trough levels at the beginning of the next cycle.

Elimination half-life (t1/2) for single dose and at steady state with trough levels at the beginning of the next cycle.

Area Under the Blood Concentration-Time Curve (AUC0-t, AUC0-inf), Clearance (CL), Volume of Distribution (Vd) of ETX-19477

Objective response rate (ORR) assessed using RECIST criteria v1.1

Duration of response (DOR) assessed using RECIST criteria v1.1

Disease control rate (DCR) assessed using RECIST criteria v1.1

Spots Global Cancer Trial Database for parg inhibitor