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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Breast Cancer, Ovarian Cancer, Pancreas Cancer, Prostate Cancer, BRCA1 Mutation, BRCA-Mutated Ovarian Carcinoma, BRCA-Associated Breast Carcinoma, HRD Positive Advanced Ovarian Cancer

Intervention / Treatment
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* Drug: TNG348
* Drug: Olaparib


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Phase 1 Dose Escalation and Phase 2 Dose Expansion
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single Agent Dose Escalation<br>Participants with BRCA 1/2 mutant or HRD+ solid tumors will receive escalating doses of TNG348 to estimate the MTD | Drug: TNG348<br>* Ubiquitin Specific Peptidase 1 (USP1) inhibitor<br>|
| Experimental: Combination Dose Escalation<br>Participants with BRCA 1/2 mutant or HRD+ solid tumors will receive escalating doses of TNG348 in combination with olaparib to estimate the MTD | Drug: TNG348<br>* Ubiquitin Specific Peptidase 1 (USP1) inhibitor<br>Drug: Olaparib<br>* PARP inhibitor<br>* Other names: Lynparza;|
| Experimental: Single agent dose expansion in breast cancer<br>Participants with BRCA 1/2 mutant breast cancer will receive TNG348 at the identified RP2D | Drug: TNG348<br>* Ubiquitin Specific Peptidase 1 (USP1) inhibitor<br>|
| Experimental: Single agent dose expansion in ovarian cancer<br>Participants with BRCA 1/2 mutant ovarian cancer will receive TNG348 at the identified RP2D | Drug: TNG348<br>* Ubiquitin Specific Peptidase 1 (USP1) inhibitor<br>|
| Experimental: Combination therapy dose expansion in breast cancer<br>Participants with BRCA 1/2 mutant breast cancer will receive TNG348 in combination with olaparib at the identified RP2D | Drug: TNG348<br>* Ubiquitin Specific Peptidase 1 (USP1) inhibitor<br>Drug: Olaparib<br>* PARP inhibitor<br>* Other names: Lynparza;|
| Experimental: Combination therapy dose expansion in ovarian cancer<br>Participants with BRCA 1/2 mutant ovarian cancer will receive TNG348 in combination with olaparib at the identified RP2D | Drug: TNG348<br>* Ubiquitin Specific Peptidase 1 (USP1) inhibitor<br>Drug: Olaparib<br>* PARP inhibitor<br>* Other names: Lynparza;|
| Experimental: Combination therapy dose expansion in pancreatic or prostate cancer<br>Participants with BRCA 1/2 mutant pancreatic or prostate cancer will receive TNG348 in combination with olaparib at the identified RP2D | Drug: TNG348<br>* Ubiquitin Specific Peptidase 1 (USP1) inhibitor<br>Drug: Olaparib<br>* PARP inhibitor<br>* Other names: Lynparza;|
| Experimental: Combination therapy dose expansion in HRD+ advanced or metastatic solid tumors<br>Participants with HRD+ advanced or metastatic solid tumors will receive TNG348 in combination with olaparib at the identified RP2D | Drug: TNG348<br>* Ubiquitin Specific Peptidase 1 (USP1) inhibitor<br>Drug: Olaparib<br>* PARP inhibitor<br>* Other names: Lynparza;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine dosing for TNG348 alone and in combination (Phase 1 only) | • To determine the MTD, RP2D(s), and dosing schedule of TNG348 single agent and in combination with olaparib | 21 days | 
| Measure anti-tumor activity using RECIST 1.1 (Phase 2 only) | To assess the antitumor activity of TNG348 single agent and in combination using RECIST 1.1 per investigator assessment | 56 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measure anti-tumor activity using RECIST 1.1 (Phase 1 only) | To assess the antitumor activity of TNG348 single agent and in combination using RECIST 1.1 per investigator assessment | 56 days | 
| Characterize the safety and tolerability profile | Measure frequency, severity, timing, and relationship to study treatment of any AEs, SAEs, and changes in safety laboratory tests | 21 days | 
| Characterize the plasma PK profile | To determine the Cmax of TNG348 | 16 days | 
| Characterize the plasma PK profile | To determine the Tmax | 16 days | 
| Characterize the plasma PK profile | To determine the AUC0-t and AUC0-∞ of TNG348 | 16 days | 
| Characterize the plasma PK profile | To determine the half-life of TNG348 | 16 days | 
| Characterize olaparib concentrations when administered with TNG348 | To characterize the pre treatment and trough concentration levels of olaparib when administered in combination with TNG348 | 16 days | 
| Assess changes in levels of ubPCNA in response to TNG348 as single agent or in combination | Measure ubPCNA in tumor tissue and blood, on study treatment relative to pre-treatment | 22 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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BRCA mutant, HRD positive, solid tumors, USP1, TNG348