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

Sponsor

Tango Therapeutics, Inc. (Industry)

Overall Status

Not yet recruiting

CT.gov ID

NCT06065059

Collaborator

(none)

140

Enrollment

Arms

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer Ovarian Cancer Pancreas Cancer Prostate Cancer BRCA1 Mutation BRCA-Mutated Ovarian Carcinoma BRCA-Associated Breast Carcinoma HRD Positive Advanced Ovarian Cancer	Drug: TNG348 Drug: Olaparib	Phase 1/Phase 2

Detailed Description

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

140 participants

Allocation:

Non-Randomized

Intervention Model:

Sequential Assignment

Intervention Model Description:

Phase 1 Dose Escalation and Phase 2 Dose ExpansionPhase 1 Dose Escalation and Phase 2 Dose Expansion

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Anticipated Study Start Date :

Dec 1, 2023

Anticipated Primary Completion Date :

Dec 1, 2025

Anticipated Study Completion Date :

Jun 1, 2026

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

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

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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