81 A First-in-Human Study of a Selective ERBB2 Inhibitor, CGT4255, in Patients Who Have Advanced Solid Tumors With ERBB2 Genetic Alterations or HER2 Overexpression

Background

ERBB2-activating alterations and HER2 overexpression are present in a range of cancers, including breast cancer. Current ERBB2-directed therapies are limited in their ability to penetrate the central nervous system (CNS), which is an important and common site of disease for many solid tumors with ERBB2 alterations. Thus, there is an unmet medical need for a CNS-penetrant, selective ERBB2 inhibitor that covers wild-type and mutant ERBB2, which may benefit patients with HER2-positive breast cancer with brain metastases. CGT4255 is an investigational, oral, ATP-competitive, covalent ERBB2 inhibitor, with potency against clinically relevant gene alterations and wild-type ERBB2 that spares EGFR wild-type, which may avoid EGFR-mediated toxicities, such as rash, mucositis, and paronychia. With evidence of high CNS penetration and in vitro and in vivo activity against ERBB2-activating alterations, nonclinical data support initiation of the first-in-human (FIH) study of CGT4255 in adults with advanced solid tumors harboring ERBB2-activating alterations or HER2 overexpression.

Methods

This open-label, multi-center, dose escalation and dose expansion phase 1/1b study will evaluate safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of CGT4255 in patients with unresectable, locally advanced, or metastatic solid tumors harboring ERBB2-activating alterations or HER2 overexpression. The study will consist of 3 parts: Part A (dose escalation in ERBB2-altered advanced solid tumors), Part B (signal seeking and dose optimization in ERBB2-mutated NSCLC), and Part C (signal seeking in ERBB2-mutated or HER2-positive breast cancer with brain metastases with or without leptomeningeal disease). In Part A, CGT4255 will be administered in 21-day cycles to patients (N = ~50) at a starting dose of 300 mg once daily, and dose escalation will be determined using a Bayesian optimal interval design with backfill. The primary objective of Part A is to determine the maximum tolerated or evaluated doses of CGT4255 to be carried forward to parts B and C through assessment of adverse events. Secondary objectives include evaluation of pharmacokinetics and antitumor activity (assessed by overall objective response rate and disease control rate). Part C will then evaluate the antitumor activity of CGT4255, specifically in ERBB2-mutated or HER2-positive breast cancer with CNS metastases, as assessed by overall objective response rate. Secondary objectives include characterization of overall treatment effect, safety/tolerability, activity against CNS metastatic disease per RANO brain metastases criteria, and pharmacokinetics of CGT4255 in this population.

Status

This study of CGT4255 is open for enrollment at select sites in the US.