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

Phase 1

Recruiting

• Conditions: Locally Advanced Solid Tumor
• Interventions: Drug: TNG462; Drug: Pembrolizumab

• Registration Number: NCT05732831
• Lead Sponsor: Tango Therapeutics, Inc.

Brief Summary

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 225 participants.

Detailed Description

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 administered as a single agent and in combination with pembrolizumab in patients with confirmed MTAP-deleted solid tumors. In Phase 2, 6 expansion arms defined by confirmed MTAP-deleted tumor types will enroll in parallel at the RP2D(s) of TNG462 and in combination. In both parts of the study participants who tolerate the drug may continue treatment until disease progression.

Study Timeline

• Study First Submitted: 2023-01-30
• Study First Submitted QC: 2023-02-07
• Study First Posted: 2023-02-17
• Study Start: 2023-05-26
• Status Verified: 2025-05
• Last Update Submitted: 2025-05-05
• Last Update Posted: 2025-05-06
• Primary Completion: 2026-05
• Study Completion: 2026-09

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 225

Inclusion Criteria

1. Age: ≥18 years-of-age at the time of signature of the main study ICF
2. Performance status: ECOG Performance Score of 0 to 1
3. Confirmed histologic or cytologic diagnosis of a locally advanced, metastatic, and/or unresectable solid tumor
4. Prior standard therapy, as available
5. 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.
6. Adequate organ function/reserve per local labs
7. Adequate liver function per local labs
8. Adequate renal function per local labs
9. Negative serum pregnancy test result at screening
10. Written informed consent must be obtained according to local guidelines

Exclusion Criteria

1. Known allergies, hypersensitivity, or intolerance to TNG462, or its excipients or to pembrolizumab in the combination treatment arms

2. Uncontrolled intercurrent illness that will limit compliance with the study requirements

3. Active infection requiring systemic therapy

4. Currently participating in or has planned participation in a study of another investigational agent or device

5. Impairment of GI function or disease that may significantly alter the absorption of oral TNG462

6. Active prior or concurrent malignancy.

7. Central nervous system metastases associated with progressive neurological symptoms

8. Current active liver disease from any cause

9. Known to be HIV positive, unless all of the following criteria are met:

   1. CD4+ count ≥300/μL
   2. Undetectable viral load
   3. Receiving highly active antiretroviral therapy

10. Clinically relevant cardiovascular disease

11. A female patient who is pregnant or lactating

12. Patient is unwilling or unable to comply with the scheduled visits, drug administration plan, laboratory tests, biopsy, or other study procedures and study restrictions

13. 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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Dose Expansion in Mesothelioma	TNG462	Participants with MTAP-deleted mesothelioma will receive TNG462 at the identified RP2D(s)
Dose Escalation	TNG462	Participants with MTAP-deleted solid tumors (excluding primary CNS) will receive escalating doses of TNG462 single agent and in combination with pembrolizumab to estimate the MTD
Dose Escalation	Pembrolizumab	Participants with MTAP-deleted solid tumors (excluding primary CNS) will receive escalating doses of TNG462 single agent and in combination with pembrolizumab to estimate the MTD
Dose Expansion in NSCLC	TNG462	Participants with MTAP-deleted NSCLC (squamous and non squamous) will receive TNG462 at the identified RP2D(s)
Dose Expansion in Pancreatic Ductal Adenocarcinoma	TNG462	Participants with MTAP-deleted pancreatic ductal adenocarcinoma will receive TNG462 at the identified RP2D(s)
Dose Expansion in Sarcoma	TNG462	Participants with MTAP-deleted sarcoma (soft tissue or bone) will receive TNG462 at the identified RP2D(s)
Dose Expansion in Solid Tumors	TNG462	Participants with other MTAP-deleted solid tumors will receive TNG462 at the identified RP2D(s)
Dose Expansion in NSCLC in Combination with Pembrolizumab	TNG462	Participants NSCLC (squamous and non squamous) MTAP-deleted solid tumors will receive TNG462 at the identified RP2D(s)
Dose Expansion in NSCLC in Combination with Pembrolizumab	Pembrolizumab	Participants NSCLC (squamous and non squamous) MTAP-deleted solid tumors will receive TNG462 at the identified RP2D(s)

Primary Outcome Measures

Name	Time	Method
Phase 1 Maximum Tolerated Dose	28 days and 21 days	To determine the maximum tolerated dose (MTD) of TNG462 when administered as a single agent and in combination with pembrolizumab
Phase 1 Dosing Schedule	28 days	To determine the dosing schedule of TNG462
Phase 2 Anti-neoplastic Activity	16 weeks and 18 weeks	To assess anti-neoplastic activity of TNG462 administered single agent and in combination with pembrolizumab in patients with MTAP-deleted advanced solid tumors by RECIST v1.1, iRECIST or mRECIST v1.1

Secondary Outcome Measures

Name	Time	Method
Phase 1 Anti-neoplastic Activity	16 weeks	To assess preliminary evidence of anti-neoplastic activity of TNG462 as a single agent and when administered in combination with pembrolizumab in patients with MTAP-deleted advanced solid tumors by RECIST v1.1, iRECIST or mRECIST v1.1
Phase 1 and 2 Adverse Event Profile	28 days and 21 days	To describe the safety and tolerability profile of TNG462 by frequency and severity of AEs
Phase 1 and 2 Volume of Distribution	16 days	Determine the apparent volume of distribution when dosed orally (Vz/F)
Phase 1 and 2 Concentration versus Time Curve	16 days	Measure the area under the plasma concentration versus time curve (AUC)
Phase 1 and 2 Time to Achieve Maximal Plasma Concentration	16 days	Measure the time to achieve maximal plasma concentration (Tmax)
Phase 1 and 2 Maximum Observed Plasma Concentration	16 days	Measure the maximum observed plasma concentration (Cmax)
Phase 1 and 2 Terminal Elimination Half-life	16 days	Determine the terminal elimination half-life (t1/2)
Phase 1 and 2 SDMA Levels	28 days	SDMA levels in tumor tissue will be assessed pre-treatment and post treatment with TNG462
Phase 1 and 2 Total Plasma Clearance	16 days	Determine the apparent total plasma clearance when dosed orally (CL/F)

Trial Locations

Locations (25)

Institut de Cancerologie de l'Ouest - Hôpital Saint Herblain - PPDS; 🇫🇷 Saint-Herblain, France

Stanford University; 🇺🇸 Palo Alto, California, United States

Grand Valley Oncology; 🇺🇸 Grand Junction, Colorado, United States

Sylvester Comprehensive Cancer Center; 🇺🇸 Miami, Florida, United States

University Chicago Medicine; 🇺🇸 Chicago, Illinois, United States

Carle Cancer Center; 🇺🇸 Urbana, Illinois, United States

Midwestern Regional Medical Center, City of Hope Chicago; 🇺🇸 Zion, Illinois, United States

Massachusetts General Hospital; 🇺🇸 Boston, Massachusetts, United States

Dana Farber Cancer Institute; 🇺🇸 Boston, Massachusetts, United States

Henry Ford Cancer Center; 🇺🇸 Detroit, Michigan, United States

New York University Langone Health; 🇺🇸 New York, New York, United States

Sarah Cannon Tennessee Oncology; 🇺🇸 Nashville, Tennessee, United States

The University of Texas MD Anderson Cancer Center; 🇺🇸 Houston, Texas, United States

Huntsman Cancer Institute, University of Utah; 🇺🇸 Salt Lake City, Utah, United States

Next Oncology Virginia; 🇺🇸 Fairfax, Virginia, United States

CHU de Brest; 🇫🇷 Brest, France

Centre Berard Leon; 🇫🇷 Lyon, France

Institute Gustav Roussy; 🇫🇷 Villejuif, France

Vall d'Hebron Barcelona Hospital; 🇪🇸 Barcelona, Catalonia, Spain

Hospital HM Nou Delfos; 🇪🇸 Barcelona, Spain

ICO l'Hospitalet - Hospital Duran i Reynals; 🇪🇸 Barcelona, Spain

Hospital Universitario Fundacion Jimenez Diaz; 🇪🇸 Madrid, Spain

Hospital de Sanchinarro; 🇪🇸 Madrid, Spain

Hospital Universitario Virgen de la Victoria; 🇪🇸 Málaga, Spain

Hospital Universitario Virgen del Rocio; 🇪🇸 Sevilla, Spain