BRCA1 Mutation, BRCA-Associated Breast Carcinoma, BRCA-Mutated Ovarian Carcinoma, Breast Cancer, HRD Positive Advanced Ovarian Cancer, Ovarian Cancer, Pancreas Cancer, Prostate Cancer
Conditions
Keywords
BRCA mutant, HRD positive, solid tumors, USP1, TNG348
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.
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.
Interventions
DRUGTNG348
Ubiquitin Specific Peptidase 1 (USP1) inhibitor
DRUGOlaparib
PARP inhibitor
Sponsors
Tango Therapeutics, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Phase 1 Dose Escalation and Phase 2 Dose Expansion
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| Characterize the plasma PK profile | 16 days | To determine the Cmax of TNG348 |
| 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 |
| 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 |
| 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 |
| 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 |
Countries
United States
Outcome results
None listed