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

Exclusion Criteria

• •1. 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;
• •2. 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);
• •3. 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;
• •4. 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;
• •5. Patients with interstitial lung disease or interstitial pneumonia, including clinically significant radiation pneumonitis (i.e. affecting daily living activities or requiring intervention treatment);
• •6. 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);
• •7. History of allogeneic bone marrow transplantation or organ transplantation;
• •8. 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;
• •9. Irreversible electrolyte abnormalities (hypokalemia, hypomagnesemia, hypocalcemia detected by blood biochemistry);
• •10. 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);
• •11. 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;
• •12. Within 4 weeks prior to the first use of medication, the occurrence of Grade 3 bleeding symptoms as defined in the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI CTCAE v5.0);
• •13. Patients with a history of other malignant tumors within the past 5 years, except for those who have been completely cured of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, and cervical carcinoma in situ, and/or any malignant tumor patients who have been cured without disease or have had no disease for at least 5 consecutive years;
• •14. Individuals who are known to be allergic to any component of the investigational drug;
• •15. Have a clear history of neurological or mental disorders, including epilepsy and dementia;
• •16. Central nervous system (CNS) metastasis;
• •17. Prior to drug administration, all relevant anti-tumor treatment toxicity reactions (excluding hair loss, skin pigmentation, grade 1 chemotherapy related peripheral neurotoxicity, grade 2 toxicity caused by immune checkpoint inhibitors such as elevated blood glucose or hypothyroidism) did not recover to ≤ grade 1 levels (as determined by NCI CTCAE v5.0);
• •18. Uncontrolled concomitant diseases, including but not limited to severe diabetes (fasting blood glucose\>250 mg/dl or 13.9 mmol/L), or other serious diseases requiring systemic treatment;
• •19. Vaccination with live or attenuated vaccine within 4 weeks prior to the first dose (note: if enrolled, subjects must not receive live vaccine during the study treatment period and within 30 days after the last dose of the study drug);
• •20. For premenopausal female subjects (postmenopausal female patients must have been menopausal for at least 12 months to be considered infertile), the pregnancy test result is positive; During the study period and at least 30 days after the last administration of the study drug, reproductive age subjects (including male subjects' reproductive age female spouses) who are expected to become pregnant, breastfeed, or unwilling to use effective contraceptive measures;
• •21. Patients who are known to be allergic to the components of the investigational drug or its analogues;
• •22. Patients who are receiving intravenous or oral medications that affect CYP isoenzymes (strong inducers and inhibitors of CYP2C9 and CYP3A4) and cannot discontinue the protocol at least one week before starting study treatment and during the study period; I am currently taking drugs with a narrow therapeutic window that are metabolized by CYP1A2;
• •23. Inability to swallow capsules or intractable nausea and vomiting, malabsorption, extracorporeal bile diversion, or any significant small bowel resection that may hinder the full absorption of the study drug;
• •24. Other situations that researchers consider unsuitable for inclusion. If accompanied by family or social factors, it may affect the safety of the subjects or the collection of data and samples.