Study to Evaluate TNG348 Alone and With a PARP Inhibitor in Patients With BRCA 1/2 Mutant or HRD+ Solid Tumors

Phase 1/2, Multi-Center, Open-Label Study to Evaluate the Safety, Tolerability, and Preliminary Antitumor Activity of TNG348 Single Agent and in Combination With a PARP Inhibitor in Patients With BRCA 1/2 Mutant or Other HRD+ Solid Tumors

The goal of this interventional clinical trial is to learn about TNG348, a ubiquitin specific peptidase 1 (USP1) inhibitor, alone and in combination with olaparib in patients with BRCA 1/2 mutant or HRD+ solid tumors.

The main question[s] it aims to answer are:

• to evaluate the safety and tolerability of single agent and combination therapy
• to determine the recommended dose for Phase 2 of single agent and combination therapy
• to determine the pharmacokinetics of TNG348 as a single agent and in combination therapy
• to evaluate the initial antineoplastic activity as a single agent and in combination therapy

Participants will receive study treatment until they experience an undesirable side effect, their disease progresses or until they withdraw consent.

This is a first-in-human Phase 1/2, open-label, multi-center, dose-escalation and expansion study designed to determine the maximum-tolerated dose (MTD) and recommended Phase 2 dose(s) (RP2D) and evaluate the safety, tolerability, and preliminary antitumor activity of TNG348 single agent and in combination with olaparib in participants with BRCA1/2 mutant or other HRD+ advanced or metastatic solid tumors.

In Phase 1 (dose escalation), the single agent component will explore escalating oral doses of TNG348 administered alone and in combination with olaparib.

Participants in Phase 2 (dose expansion) will be dosed at the RP2D(s) determined from Phase 1 based on safety and tolerability demonstrated, along with the available PK data and studied during Phase 1, as applicable.

In the Phase 2 portion of the study, both single agent and combination therapy may be evaluated to assess an early signal of clinical benefit, as well as for confirmation of safety and tolerability.

Inclusion Criteria:

• Is ≥18 years of age at the time of signature of the main study ICF.
• Has ECOG performance status of 0 or 1.
• Has advanced or metastatic solid tumor with measurable disease based on RECIST v1.1.
• All participants must have documented BRCA 1/2 mutant or other HRD+ in solid tumor, which is identified through a validated sequencing test
• Adequate organ and bone marrow function per local labs
• Negative serum pregnancy test result at screening
• Written informed consent must be obtained according to local guidelines

Exclusion Criteria:

• Known allergies, hypersensitivity, or intolerance to TNG348, olaparib or its excipients
• Uncontrolled intercurrent illness that will limit compliance with the study requirements
• Currently participating in or has planned participation in a study of another investigational agent or device
• Impairment of GI function or disease that may significantly alter the absorption of study drug
• Active prior or concurrent malignancy.
• Central nervous system metastases associated with progressive neurological symptoms
• Participant with MDS
• Clinically relevant cardiovascular disease
• Participant with known active or chronic infection
• A female patient who is pregnant or lactating