Safety and Tolerability of TNG462 in Patients With MTAP-deleted Solid Tumors

Study Overview
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Brief Summary
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This is a first in human study in patients with advanced or metastatic solid tumors known to have an MTAP deletion. The first part of the study is an open-label, dose escalation and the second part is an open label dose expansion in specific MTAP-deleted tumor types. The study drug, TNG462, is a selective PRMT5 inhibitor administered orally. The study is planned to treat up to 159 participants.

Detailed Description
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This is a Phase 1/2 multi-center, open label study in solid tumor patients who have a confirmed homozygous MTAP deletion in their tumor. The Phase 1 portion is a dose escalation study of oral TNG462 in patients with confirmed MTAP-deleted solid tumors. In Phase 2, 5 expansion arms defined by confirmed MTAP-deleted tumor types will enroll in parallel at the RP2D of TNG462. In both parts of the study participants who tolerate the drug may continue treatment until disease progression.

Official Title
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A Phase 1/2, Multi-Center, Open-Label Study to Evaluate the Safety, Tolerability, and Preliminary Anti-tumor Activity of TNG462 in Patients With MTAP-deleted Advanced or Metastatic Solid Tumors

Conditions
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Locally Advanced Solid Tumor

Intervention / Treatment
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* Drug: TNG462


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age: ≥18 years-of-age at the time of signature of the main study ICF Performance status: ECOG Performance Score of 0 to 1 Confirmed histologic or cytologic diagnosis of a locally advanced, metastatic, and/or unresectable solid tumor Prior standard therapy, as available Documented bi-allelic (homozygous) deletion of MTAP in a tumor detected by next- generation sequencing or absence of MTAP protein in a tumor detected by IHC. Adequate organ function/reserve per local labs Adequate liver function per local labs Adequate renal 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 TNG462 or its excipients Uncontrolled intercurrent illness that will limit compliance with the study requirements Active infection requiring systemic therapy 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 oral TNG462 Active prior or concurrent malignancy. Central nervous system metastases associated with progressive neurological symptoms Current active liver disease from any cause Known to be HIV positive, unless all of the following criteria are met: CD4+ count ≥300/μL Undetectable viral load Receiving highly active antiretroviral therapy Clinically relevant cardiovascular disease A female patient who is pregnant or lactating Patient is unwilling or unable to comply with the scheduled visits, drug administration plan, laboratory tests, biopsy, or other study procedures and study restrictions Patient has a prior or ongoing clinically significant illness, medical condition, surgical history, physical finding, or laboratory abnormality that, in the investigator's opinion, may affect the safety of the patient or impair the assessment of study results

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 (sequential) followed by phase 2 dose expansion in 5 arms (parallel)
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation<br>Participants with MTAP-deleted solid tumors will receive escalating doses of TNG462 to estimate the MTD | Drug: TNG462<br>* TNG462, a selective PRMT5 inhibitor, will be administered orally<br>|
| Experimental: Dose Expansion in NSCLC<br>Participants with MTAP-deleted NSCLC (squamous and non squamous) will receive TNG462 at the identified RP2D | Drug: TNG462<br>* TNG462, a selective PRMT5 inhibitor, will be administered orally<br>|
| Experimental: Dose Expansion in Mesothelioma<br>Participants with MTAP-deleted mesothelioma will receive TNG462 at the identified RP2D | Drug: TNG462<br>* TNG462, a selective PRMT5 inhibitor, will be administered orally<br>|
| Experimental: Dose Expansion in Cholangiocarcinoma<br>Participants with MTAP-deleted cholangiocarcinoma will receive TNG462 at the identified RP2D | Drug: TNG462<br>* TNG462, a selective PRMT5 inhibitor, will be administered orally<br>|
| Experimental: Dose Expansion in MPNST<br>Participants with MTAP-deleted malignant peripheral nerve sheath tumor (MPNST) will receive TNG462 at the identified RP2D | Drug: TNG462<br>* TNG462, a selective PRMT5 inhibitor, will be administered orally<br>|
| Experimental: Dose Expansion in solid tumors<br>Participants with MTAP-deleted solid tumors will receive TNG462 at the identified RP2D | Drug: TNG462<br>* TNG462, a selective PRMT5 inhibitor, will be administered orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1 Maximum Tolerated Dose | To determine the maximum tolerated dose (MTD) of TNG462 | 28 days | 
| Phase 1 Dosing Schedule | To determine the dosing schedule of TNG462 | 28 days | 
| Phase 2 Anti-neoplastic Activity | To assess anti-neoplastic activity of TNG462 in patients with MTAP-deleted advanced solid tumors by RECIST v1.1 | 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1 Anti-neoplastic Activity | To assess preliminary evidence of anti-neoplastic activity of TNG462 in patients with MTAP-deleted advanced solid tumors by RECIST v1.1 | 16 weeks | 
| Phase 1 and 2 Adverse Event Profile | To describe the safety and tolerability profile of TNG462 by frequency and severity of AEs | 28 days | 
| Phase 1 and 2 Concentration versus Time Curve | Measure the area under the plasma concentration versus time curve (AUC) | 16 days | 
| Phase 1 and 2 Time to Achieve Maximal Plasma Concentration | Measure the time to achieve maximal plasma concentration (Tmax) | 16 days | 
| Phase 1 and 2 Maximum Observed Plasma Concentration | Measure the maximum observed plasma concentration (Cmax) | 16 days | 
| Phase 1 and 2 Terminal Elimination Half-life | Determine the terminal elimination half-life (t1/2) | 16 days | 
| Phase 1 and 2 Total Plasma Clearance | Determine the apparent total plasma clearance when dosed orally (CL/F) | 16 days | 
| Phase 1 and 2 Volume of Distribution | Determine the apparent volume of distribution when dosed orally (Vz/F) | 16 days | 
| Phase 1 and 2 SDMA Levels | SDMA levels in tumor tissue will be assessed pre-treatment and post treatment with TNG462 | 28 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PRMT5, MTAP deletion, cholangiocarcinoma, NSCLC, mesothelioma, MPNST, Tango, pancreatic