Comparing Tunlametinib Capsules and Combination Chemotherapy in Advanced NRAS-mutant Melanoma

Inclusion criteria

• ≥ 18 years of age.
• Patients with unresectable stage III or metastatic IV melanoma confirmed by histology or cytology.
• History of immunotherapy failure or could not tolerate immunotherapy
• NRAS mutation at baseline;.
• There is at least one lesion that can be evaluated as target lesions according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1).
• Eastern cooperative oncology group (ECOG) performance status of grade 0-1.
• Life expectancy \> 3 months.
• No major surgery (excluding baseline tumor biopsy) or major trauma occurred at least 4weeks prior to investigational drug administration.
• Left ventricular ejection fraction (LVEF) ≥ 50% within 7 days before dosing according to echocardiographic findings.
• Key laboratory tests must be conducted within 7 days before dosing and meet the inclusion criteria:
• Able to understand and voluntarily sign the Informed Consent Form.
• Patients must be willing and able to complete the study procedure and follow-up examination.

Exclusion criteria

• Exclusion Criteria:
• Having the following treatment before receiving the study drug: ① received chemotherapy, targeted therapy or other study drug treatment within 4 weeks before the first administration or within 5 half lives of the drug (whichever is longer); ② received immunotherapy and biological therapy within 4 weeks before the first administration; ③ received traditional Chinese medicines with anti-tumor activities approved by National Medical Products Administration (NMPA) within 2 weeks before the first administration.;
• The toxic reactions of previous anti-tumor treatment have not been recovered;
• Current use of other anti-cancer drugs.
• Subjects with symptomatic or untreated brain metastasis, meningeal metastasis or spinal cord compression except for subjects with asymptomatic brain metastasis;
• History of any of the following within 6 months of screening: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass grafting, symptomatic congestive heart failure, severe heart arrhythmia requiring medication, uncontrolled hypertension, cerebrovascular accident, or transient ischemic attack, diabetic ketoacidosis, deep vein thrombosis, or symptomatic pulmonary embolism.
• ECG Corrected Q-T interval formula (QTcB) ≥ 480 msec (adjusted by Bazett's formula) during screening, or a history of congenital long QT syndrome.
• History or current evidence of retinal diseases;
• Previous or current neuromuscular diseases related to CK elevation;
• Previous or current interstitial lung disease or interstitial pneumonitis;
• Uncontrolled concomitant diseases or infectious diseases.
• Bleeding symptoms of grade 3 as defined by the National Cancer Institute General Terminology Standard for Adverse Events (NCI CTCAE V5.0) within the 4 weeks prior to study initiation.
• Inability to swallow the capsule, refractory nausea and vomiting, malabsorption, external biliary diversion, or any small intestinal resection that would preclude adequate absorption of the study drug.
• Patients who are receiving and cannot discontinue regimen-prohibited intravenous or oral drugs that affect CYP isoenzymes (strong inducers and strong inhibitors of CYP2C9) at least 1 week prior to initiation of study treatment and during the study period.
• Patients with a history of malignancy within the past 5 years;
• Human immunodeficiency virus (HIV) antibody positive; syphilis antibody (anti-TP) positive; Hepatitis C virus (HCV) antibody positive and HCV RNA positive; HBsAg positive and HBV DNA positive.
• Patients who have been previously treated with MEK inhibitors.
• Patients with known hypersensitivity to investigational drug, proposed chemotherapy or their analogues.
• History of allogeneic bone marrow transplantation or organ transplantation.
• Serum pregnancy test results are positive for premenopausal female patients;
• Other severe, acute, or chronic clinical or psychiatric disorders or laboratory abnormalities that may increase the risk and interfere with the study results in the opinion of investigator.