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

Official title

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

Overview

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.

Interventions

• Drug TNG462
  TNG462, a selective PRMT5 inhibitor, will be administered orally
• Drug Pembrolizumab
  An anti PD-1 antibody, will be administered intravenously

Primary outcome measures

• Phase 1 Maximum Tolerated Dose [Time frame: 28 days and 21 days]
• Phase 1 Dosing Schedule [Time frame: 28 days]
• Phase 2 Anti-neoplastic Activity [Time frame: 16 weeks and 18 weeks]

Secondary outcome measures (9)

• Phase 1 Anti-neoplastic Activity [Time frame: 16 weeks]
• Phase 1 and 2 Adverse Event Profile [Time frame: 28 days and 21 days]
• Phase 1 and 2 Concentration versus Time Curve [Time frame: 16 days]
• Phase 1 and 2 Time to Achieve Maximal Plasma Concentration [Time frame: 16 days]
• Phase 1 and 2 Maximum Observed Plasma Concentration [Time frame: 16 days]
• Phase 1 and 2 Terminal Elimination Half-life [Time frame: 16 days]
• Phase 1 and 2 Total Plasma Clearance [Time frame: 16 days]
• Phase 1 and 2 Volume of Distribution [Time frame: 16 days]
• Phase 1 and 2 SDMA Levels [Time frame: 28 days]

Eligibility criteria

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 or to pembrolizumab in the combination treatment arms
• 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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 15 centers

• Stanford University — Palo Alto
• Grand Valley Oncology — Grand Junction
• Florida Cancer Specialists & Research Institute — Lake Mary
• Sylvester Comprehensive Cancer Center — Miami
• University Chicago Medicine — Chicago
• Carle Cancer Center — Urbana
• Midwestern Regional Medical Center, City of Hope Chicago — Zion
• Massachusetts General Hospital — Boston
• … and 7 more centers

Spain · 7 centers

• Vall d'Hebron Barcelona Hospital — Barcelona
• Hospital HM Nou Delfos — Barcelona
• ICO l'Hospitalet - Hospital Duran i Reynals — Barcelona
• Hospital Universitario Fundacion Jimenez Diaz — Madrid
• Hospital de Sanchinarro — Madrid
• Hospital Universitario Virgen de la Victoria — Málaga
• Hospital Universitario Virgen del Rocio — Seville

France · 4 centers

• CHU de Brest — Brest
• Centre Berard Leon — Lyon
• Institut de Cancerologie de l'Ouest - Hôpital Saint Herblain - PPDS — Saint-Herblain
• Institute Gustav Roussy — Villejuif

Identifiers

NCT: NCT05732831 · TNG462-C101

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗