Safety and Tolerability of TNG456 Alone and in Combination With Abemaciclib in Patients With Solid Tumors With MTAP Loss

A Phase 1/2, Multicenter, Open-Label Study to Evaluate the Safety, Tolerability, and Preliminary Antitumor Activity of TNG456 Monotherapy and in Combination With Abemaciclib in Patients With Solid Tumors With MTAP Loss

This is a first in human study of TNG456 alone and in combination with abemaciclib in patients with advanced or metastatic solid tumors known to have an MTAP loss. The first part of the study is an open-label, dose escalation and the second part is an open label dose expansion in specific solid tumor types with a confirmed MTAP loss. The study drug, TNG456, is a selective PRMT5 inhibitor administered orally. The study is planned to treat up to 191 participants.

Study Overview

• Status: Recruiting
• Conditions: Lung Cancer; Solid Tumor; Brain Tumor; Non Small Cell Lung Cancer; Glioma, Malignant; Non-Small Cell Adenocarcinoma; Glioma Glioblastoma Multiforme
• Intervention / Treatment: Drug: TNG456; Drug: abemaciclib

Detailed Description

This is a Phase 1/2 multi-center, open label study in solid tumor patients who have a confirmed MTAP loss in their tumor. The Phase 1 portion is a dose escalation study of oral TNG456 administered as a single agent and in combination with oral abemaciclib in solid tumor patients with confirmed MTAP loss. In the Phase 2 expansion part of the study, 6 arms defined by confirmed tumor types will enroll in parallel at the RP2D(s) of TNG456 and in combination. In both parts of the study participants who tolerate the drug may continue treatment until disease progression.

• Study Type: Interventional
• Enrollment (Estimated): 191
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Tab Cooney, MD; Phone Number: (857) 320-4899; Email: clinicaltrials@tangotx.com

Study Locations

• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85259-5452
      • Recruiting
      • Mayo Clinic Scottsdale
      • Principal Investigator: Mitesh Borad, MD
  • California
    • Irvine, California, United States, 92686
      • Recruiting
      • University of California, Irvine
      • Principal Investigator: Cathleen Park, MD
    • Los Angeles, California, United States, 90995
      • Recruiting
      • University of California Los Angeles
      • Principal Investigator: Timothy Cloughesy, MD
    • San Francisco, California, United States, 94143-2202
      • Recruiting
      • University of California at San Francisco
      • Principal Investigator: Nicolas Butowski, MD
  • District of Columbia
    • Washington D.C., District of Columbia, United States, 20016
      • Recruiting
      • Sibley Memorial Hospital
      • Principal Investigator: Solmaz Sahebjam, MD
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Recruiting
      • Mayo Clinic Jacksonville
      • Principal Investigator: Hani Babiker, MD
  • Illinois
    • Chicago, Illinois, United States, 60611-2908
      • Recruiting
      • Northwestern Memorial Hospital
      • Principal Investigator: Ditte Primdahl, MD
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Recruiting
      • Dana Farber Cancer Institute
      • Principal Investigator: Jia Luo, MD
  • Minnesota
    • Rochester, Minnesota, United States, 55905-0001
      • Recruiting
      • Mayo Clinic Cancer Center
      • Principal Investigator: Kaushal Parikh, MD
  • New York
    • New York, New York, United States, 10016
      • Recruiting
      • NYU Langone Health
      • Principal Investigator: Salman Punekar, MD
    • New York, New York, United States, 11065
      • Recruiting
      • Memorial Sloan Kettering Cancer Center
      • Principal Investigator: Lauren Schaff, MD
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Recruiting
      • Ohio State University Comprehensive Cancer Center
      • Principal Investigator: Dwight Owen, MD
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • MD Anderson Cancer Center
      • Principal Investigator: Jordi Rodon, MD
  • Utah
    • Salt Lake City, Utah, United States, 84112-5500
      • Recruiting
      • University of Utah, Huntsman Cancer Institute
      • Principal Investigator: Howard Coleman, MD
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Recruiting
      • NEXT Virginia
      • Principal Investigator: Alexander Spira, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Has a tumor with a confirmed MTAP loss
• Is ≥18 years of age at the time of signature of the main study ICF
• Has had progression or an inadequate response to or is intolerant of the approved standard of care therapy, no standard of care therapy exists, or the investigator has determined that treatment with the standard of care therapy is not appropriate.
• Is able to swallow tablets
• Adequate Organ function/reserve per local labs
• Negative serum pregnancy test result at screening
• Has an ECOG performance status score of 0 to 1
• Has measurable disease based on RECIST v1.1 or a confirmed glioblastoma (IDH-wildtype) with radiographic evidence of disease progression or recurrence defined by RANO 2.0.
• Has an ECOG performance score of 0 to 1 or for GBM has a Karnofsky performance status score ≥70.

Exclusion Criteria:

• A female patient is who is pregnant or breastfeeding
• Has impaired GI function or disease that may significantly alter the absorption of oral study treatment(s)
• Has an active infection requiring systemic therapy
• Has received prior treatment with a PRMT5 inhibitor or a MAT2A inhibitor
• Patients in the expansion receiving the combination therapy that have received prior treatment with a CDK4/6 inhibitor
• Clinically relevant cardiovascular disease
• Has a prior or ongoing clinically significant illness may affect the safety of the patient, impair the assessment of study results or compliance with the protocol

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

7

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Single Agent and Combination Dose Escalation; Solid tumor participants with confirmed MTAP loss will receive escalating doses of TNG456 single agent and in combination with abemaciclib to estimate the MTD	Drug: TNG456; A selective PRMT5 inhibitor; Drug: abemaciclib; A kinase inhibitor; Other Names: Verzenio
Experimental: NSCLC Single Agent Dose Expansion; NSCLC (squamous and non squamous) participants with confirmed MTAP loss will receive TNG456 at the identified RP2D(s)	Drug: TNG456; A selective PRMT5 inhibitor
Experimental: GBM Single Agent Dose Expansion; GBM participants with confirmed MTAP loss will receive TNG456 at the identified RP2D(s)	Drug: TNG456; A selective PRMT5 inhibitor
Experimental: Tumor Agnostic Single Agent Dose Expansion; Patients with specific solid tumor types that have a confirmed MTAP loss will receive TNG456 at the identified RP2D(s)	Drug: TNG456; A selective PRMT5 inhibitor
Experimental: NSCLC Combination Expansion; NSCLC (squamous and non-squamous) participants with confirmed MTAP loss will receive TNG456 at the identified RP2D(s) with abemaciclib	Drug: TNG456; A selective PRMT5 inhibitor; Drug: abemaciclib; A kinase inhibitor; Other Names: Verzenio
Experimental: GBM Combination Expansion; GBM participants with confirmed MTAP loss will receive TNG456 at the identified RP2D(s) with abemaciclib	Drug: TNG456; A selective PRMT5 inhibitor; Drug: abemaciclib; A kinase inhibitor; Other Names: Verzenio
Experimental: Tumor Agnostic Combination Expansion; Participants with specific tumor types with confirmed MTAP loss will receive TNG456 at the identified RP2D(s) with abemaciclib	Drug: TNG456; A selective PRMT5 inhibitor; Drug: abemaciclib; A kinase inhibitor; Other Names: Verzenio

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1 Maximum Tolerated Dose	To determine the MTD, recommended dose(s) (RD), and dosing schedule of TNG456 monotherapy and in combination with abemaciclib	21 days
Phase 2 Anti-neoplastic Activity Single Agent	To assess the antitumor activity of TNG456 in patients with advanced or metastatic solid tumors with MTAP loss by RECIST or modified RANO criteria	18 weeks
Phase 2 Anti-neoplastic Activity Combination Treatment	To assess the antitumor activity of TNG456 in combination with abemaciclib in patients with advanced or metastatic tumors with MTAP loss by RECIST or modified RANO criteria	18 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Anti-neoplastic Activity Single Agent	To assess preliminary evidence of antitumor activity of TNG456 in patients with advanced solid tumors with MTAP loss by RECIST or modified RANO criteria	18 weeks
Phase 1 and 2 Adverse Event Profile	To describe the safety and tolerability profile of TNG456 as a monotherapy and in combination with abemaciclib	21 days

Collaborators and Investigators

• Sponsor: Tango Therapeutics, Inc.
• Collaborators: Eli Lilly and Company
• Investigators: Study Director: Tab Cooney, MD, Tango Therapeutics, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): March 24, 2025
• Primary Completion (Estimated): March 31, 2027
• Study Completion (Estimated): September 30, 2027

Study Registration Dates

• First Submitted: January 24, 2025
• First Submitted That Met QC Criteria: January 30, 2025
• First Posted (Actual): February 5, 2025

Study Record Updates

• Last Update Posted (Actual): April 13, 2026
• Last Update Submitted That Met QC Criteria: April 10, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: CDK 4/6; abemaciclib; Tango; PRMT5 inhibitor; MTAP
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms by Site; Neoplasms; Respiratory Tract Diseases; Neoplasms by Histologic Type; Lung Diseases; Neoplasms, Glandular and Epithelial; Respiratory Tract Neoplasms; Thoracic Neoplasms; Astrocytoma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Nervous System Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Central Nervous System Neoplasms; Lung Neoplasms; Glioblastoma; Glioma; Carcinoma, Non-Small-Cell Lung; Brain Neoplasms; abemaciclib
• Other Study ID Numbers: TNG456-C101

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No