Phase II Trial of Tunlametinib in NRAS-Mutant Advanced Thyroid Cancer

NCT06970353 | Recruiting Phase 2

• 1 other identifier: IIT-085-TC-002
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

This phase II trial evaluates Tunlametinib (MEK inhibitor) ± PD-1 in NRAS-mutant advanced thyroid cancer. Key Objectives: Assess efficacy (ORR by RECIST v1.1) Evaluate safety profiles Study Design: Single-arm, single-center 4 cohorts based on:

• Histology (differentiated vs. poorly/undifferentiated)
• Prior therapy status Treatment:
• Cohorts 1-2: Tunlametinib monotherapy (12mg BID)
• Cohorts 3-4: Tunlametinib + PD-1 (commercially available) Key Procedures: Screening: NRAS testing + full staging (CT/MRI/PET) Monitoring: q3-week labs, q9-week imaging Follow-up: 30-day safety visit + q3-month survival tracking Endpoints: Primary: ORR Secondary: Safety (CTCAE), PFS, DoR Unique Aspects: First study targeting NRAS in thyroid cancer with MEK+PD-1 Includes rare aggressive subtypes (poorly/undifferentiated)

Conditions

Radioactive Iodine-refractory, Differentiated Thyroid Cancer With NRAS Mutation; Advanced PDTC or ATC With NRAS Mutation

Keywords

NRAS mutant; Locally advanced thyroid cancer; Thyroid cancer; Metastatic thyroid cancer

Outcome Measures

Primary Outcomes (1)

• Objective Response Rate

  Complete remission rate and partial remission rate

  up to approximately 3-5 years

Secondary Outcomes (5)

• Disease Control Rate

  up to approximately 3-5 years

• Duration of Response

  up to approximately 3-5 years

• Time to Response

  up to approximately 3-5 years

• Progression-free Survival

  up to approximately 3-5 years

• Overall Survival

  up to approximately 3-5 years

Study Arms (1)

Locally advanced or metastatic thyroid cancer with NRAS mutation

EXPERIMENTAL

Progressive locally advanced or metastatic radioactive iodine refractory NRAS mutant thyroid cancer

Drug: Tunlametinib; Drug: Tunlametinib+PD-1 mAb

Interventions

Tunlametinib DRUG

Locally advanced or metastatic radioactive iodine refractory NRAS mutant differentiated thyroid cancer

Locally advanced or metastatic thyroid cancer with NRAS mutation

Tunlametinib+PD-1 mAb DRUG

Locally advanced or metastatic NRAS mutant poor-differentiated, undifferentiated thyroid cancer

Locally advanced or metastatic thyroid cancer with NRAS mutation

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients voluntarily join this study and sign an informed consent form;
• Age: ≥ 18 years old, male or female not limited;
• For locally advanced or recurrent/metastatic thyroid cancer diagnosed by histology and unable to undergo curative surgery, one of the following requirements must be met:
• Iodine refractory thyroid cancer;
• Differentiated thyroid cancer not suitable for iodine therapy;
• High grade, poorly differentiated or poorly differentiated thyroid cancer;
• Undifferentiated thyroid carcinoma;
• Have undergone NGS testing (at our hospital or an external hospital), and be able to find that the test report or medical history has recorded a positive result for NRAS mutation in the gene test.
• ECOG score 0-2 points; According to RECIST v1.1 evaluation, there is at least one assessable lesion;
• \. Expected survival\>12 weeks; 8. The main organ function and bone marrow function are normal.
• Blood routine: Hemoglobin ≥ 90 g/L (no blood transfusion within 14 days); Absolute neutrophil count ≥ 1.5 × 109/L; platelet count ≥ 100 × 109/L;
• Liver function: Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) are ≤ 2.5 times the upper limit of normal (ULN). If there is liver metastasis, ALT and AST are ≤ 5 times ULN, and ALP is ≤ 6 times ULN; Total bilirubin ≤ 1.5 × ULN; Albumin ≥ 30 g/L;
• Renal function: serum creatinine ≤ 1.5 × ULN or creatinine clearance rate calculated by Cockroft Gault formula\>60 mL/min;
• Cardiac function: Echocardiography shows a left ventricular ejection fraction (LVEF) of ≥ 55%; ECG QTcF ≤ 480ms; Creatine kinase (CK) ≤ 1 × ULN, troponin/hypersensitive troponin ≤ 1 × ULN;
• Coagulation function: International normalized ratio of prothrombin time (INR) ≤ 1.5 × ULN; Activated partial thromboplastin time (APTT) ≤ 1.5 × ULN; 9. Women of childbearing age must undergo a pregnancy test (serum or urine) with a negative result within 14 days before enrollment, and voluntarily use appropriate contraception methods during the observation period and within 3 months after the last administration of the study drug; For males, surgical sterilization or consent to use appropriate contraception methods during the observation period and within 3 months after the last administration of the study drug should be used.

You may not qualify if:

• Within 4 weeks before the first medication, major surgery (excluding biopsy and outpatient minor surgery, such as placement of vascular access) or severe trauma occurred;
• There are clinical symptoms of third interstitial fluid accumulation that cannot be controlled by drainage or other methods (such as a large amount of pleural fluid or ascites);
• Cardiovascular and cerebrovascular diseases with impaired heart function or significant clinical significance, including but not limited to any of the following:
• Within 6 months prior to the start of treatment, acute coronary syndrome occurred, including acute myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty, and stent implantation;
• Symptomatic congestive heart failure (NYHA classification ≥ II); Evidence of clinically significant arrhythmia and/or conduction abnormalities within 6 months prior to the start of treatment or at present;
• Poor control of hypertension (systolic blood pressure ≥ 140 and/or diastolic blood pressure ≥ 90 mmHg under medication control); Abnormal cardiac valve morphology (≥ grade 2) recorded by echocardiography, Note: Patients with grade 1 abnormal valve morphology (such as mild regurgitation/stenosis) are allowed to be enrolled, but patients with moderate valve thickening are prohibited from being enrolled;
• History of congenital long QT syndrome; Or those who take drugs known to prolong the QT interval and cannot guarantee discontinuation during the study period;
• Previous or screening retinal diseases, such as retinal vein occlusion (RVO), retinal artery occlusion, retinal vasculitis, diabetes retinopathy, hypertensive retinopathy, retinal telangiectasia (Costs disease), retinal pigment epithelial detachment (RPED), etc; Risk factors for RVO during screening (such as uncontrolled glaucoma or high intraocular pressure, history of high viscosity or hypercoagulability syndrome); Retinal diseases such as RPED;
• Patients with interstitial lung disease or interstitial pneumonia, including clinically significant radiation pneumonitis (i.e. affecting daily living activities or requiring intervention treatment);
• Positive for human immunodeficiency virus (HIV) antibodies, syphilis antibodies (Anti TP), hepatitis C virus (HCV) antibodies and HCV RNA, hepatitis B virus surface antigen (HBsAg) and HBV DNA (HBsAg positivity requires further testing for HBV DNA, HBV DNA ≥ 200 IU/ml, or ≥ 103 copies/ml);
• History of allogeneic bone marrow transplantation or organ transplantation;
• There are uncontrollable active infectious diseases (such as intravenous drip of antibiotics, antifungal or antiviral drugs) within 2 weeks before the first administration, or fever of unknown cause\>38.5 ° C occurs during screening/before the first administration;
• Irreversible electrolyte abnormalities (hypokalemia, hypomagnesemia, hypocalcemia detected by blood biochemistry);
• Neuromuscular diseases related to CK elevation in the past or present (such as inflammatory myopathy, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy, rhabdomyolysis syndrome);
• Arterial/venous thrombotic events that occur within 6 months prior to the first use of medication, such as cerebrovascular accidents (including temporary ischemic attacks, cerebral hemorrhage, cerebral infarction), deep vein thrombosis, and pulmonary embolism;

Sponsors & Collaborators

• Fudan University: lead

Study Sites (1)

Fudan University Shanghai Cancer Center

Shanghai, Shanghai Municipality, 200032, China

RECRUITING

MeSH Terms

Conditions

Thyroid Neoplasms

Condition Hierarchy (Ancestors)

Endocrine Gland Neoplasms; Neoplasms by Site; Neoplasms; Head and Neck Neoplasms; Endocrine System Diseases; Thyroid Diseases

Study Officials

• Yu-Long Wang, M.D

  Fudan University

  PRINCIPAL INVESTIGATOR

• Qing-Hai Ji, M.D

  Fudan University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Dongmei Ji, M.D

CONTACT

021-64175590; jidongmei2000@hotmail.com

Yu-Long Wang, M.D

CONTACT

021-64175590; yulongwang@fudan.edu.cn

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associated Professor

Study Record Dates

• First Submitted: May 6, 2025
• First Posted: May 14, 2025
• Study Start: May 27, 2025
• Primary Completion (Estimated): December 30, 2026
• Study Completion (Estimated): December 30, 2031
• Last Updated: August 7, 2025

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)