Study to Evaluate the Safety, Tolerability & Efficacy of TNG462 in Combination in PDAC & NSCLC Patients

Official title

A Phase 1/2, Multicenter, Open-Label Study to Evaluate Safety, Tolerability & Antitumor Activity of TNG462 in Combination With Other Agents in Patients With Pancreatic Cancer With MTAP Loss and Pancreatic or Non-Small Cell Lung Cancer With MTAP Loss & RAS Mutation

Overview

TNG462-C102 is a Phase 1/2, open-label, multicenter study designed to determine the safety, tolerability, PK, PD, and preliminary antineoplastic activity of oral TNG462 in combination with RMC-6236, RMC-9805, mFOLFIRINOX or gemcitabine/nab-paclitaxel. The study comprises a dose escalation phase and a dose expansion phase.

Detailed description

TNG462-C102 is a Phase 1/2, open-label, multicenter study designed to determine the safety, tolerability, PK, PD, and preliminary antineoplastic activity of oral TNG462 in combination with RMC-6236, RMC-9805, mFOLFIRINOX or gemcitabine/nab-paclitaxel.

For the RAS inhibitor arms, the study will be conducted in patients with MTAP loss and RAS mutant metastatic pancreatic adenocarcinoma (PDAC) or locally advanced or metastatic non-small cell lung cancer (NSCLC). For the chemotherapy specific arms, the study will be conducted in patients with MTAP loss locally advanced or metastatic PDAC. The entire study (all arms) will be conducted in 2 parts: Phase 1 (dose escalation) and Phase 2 (dose expansion).

Individual Arms in the dose expansion phase may open once the MTD and/or RD(s) has been determined for the corresponding combination in the dose escalation phase of the study.

Interventions

• Drug TNG462
  MTA cooperative PRMT5 inhibitor
• Drug RMC-9805
  RAS(ON) G12D selective covalent inhibitor
• Drug RMC-6236
  RAS(ON) multi-selective inhibitor
• Drug mFOLFIRINOX
  Chemotherapy
• Drug gemcitabine/nab-paclitaxel
  Chemotherapy

Primary outcome measures

• Phase 1: Maximum Tolerated Dose [Time frame: 21 days]
• Phase 1: Maximum Tolerated Dose [Time frame: 28 days]
• Phase 2: Combination Anti-neoplastic Activity [Time frame: 12 weeks]

Secondary outcome measures (9)

• Phase 1: Combination Anti-neoplastic Activity [Time frame: 12 weeks]
• Phase 1 and 2: Tmax of TNG462 and in Combination [Time frame: 21 days]
• Phase 1 and 2: Tmax of TNG462 and in Combination [Time frame: 28 days]
• Phase 1 and 2: Cmax of TNG462 and in Combination [Time frame: 21 days]
• Phase 1 and 2: Cmax of TNG462 and in Combination [Time frame: 28 days]
• Phase 1 and 2: AUC of TNG462 and in Combination [Time frame: 21 days]
• Phase 1 and 2: AUC of TNG462 and in Combination [Time frame: 28 days]
• Phase 1 and 2 Adverse Event Profile [Time frame: 21 days]
• Phase 1 and 2 Adverse Event Profile [Time frame: 28 days]

Eligibility criteria

Inclusion criteria

• Is ≥18 years of age at the time of signature of the main study ICF.
• Has an ECOG PS of 0 or 1.
• Has a tumor with loss of MTAP protein or bi-allelic deletion of the MTAP gene
• Arms A and B only: Has a tumor with a RAS mutation
• Pathologically documented metastatic PDAC or locally advanced, recurrent or metastatic NSCLC
• Has received prior standard therapy
• Arms A and B only: Must not have received prior RAS-targeted therapy
• Has evidence of measurable disease based on RECIST v1.1.
• Adequate organ function
• Must be able to swallow tablets.
• Negative pregnancy test at screening
• Written informed consent must be obtained according to local guidelines

Exclusion criteria

• Has received prior treatment with a PRMT5 inhibitor, or MAT2A inhibitor
• Arms A and B only: Prior enrollment in any phase 3 clinical trial of RMC-6236 or RMC-9805
• Known allergy, hypersensitivity or intolerance to TNG462 (all arms), RMC-6236 Arm A), RMC-9805 (Arm B), mFOLFIRINOX (Arm C), gemcitabine/nab-paclitaxel (Arm D) or their excipients
• Has uncontrolled intercurrent illness that will limit compliance with the study requirements.
• Has an active infection requiring systemic therapy.
• Is currently participating in or has planned concurrent participation in a study of another investigational agent or device.
• Has impairment of GI function or disease that may significantly alter the absorption of the oral medications
• Has known or suspected active or untreated CNS metastases associated with progressive neurological symptoms
• Has current active liver disease from any cause
• Is known to be HIV positive, unless all the following criteria are met:

• CD4+ count ≥300/µL.
• Undetectable viral load.
• Receiving highly active antiretroviral therapy
• Has clinically relevant cardiovascular disease
• History of or presence of active interstitial lung disease
• Is a female patient who is pregnant or lactating
• Is unwilling or unable to comply with the scheduled visits, study treatment administration plan, laboratory tests or other study procedures and study restrictions.
• 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 ability to assess 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 · 18 centers

• Mayo Clinic Scottsdale — Scottsdale
• Sarah Cannon Research Institute Denver — Denver
• Georgetown University Medical Center — Washington D.C.
• Mayo Clinic Jacksonville — Jacksonville
• Northwestern Memorial Hospital — Chicago
• University of Indiana — Indianapolis
• University of Iowa Health Care — Iowa City
• Massachusetts General Hospital — Boston
• … and 10 more centers

Identifiers

NCT: NCT06922591 · TNG462-C102

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗