A Study of TY-9591 in Advanced Non-small Cell Lung Cancer(NSCLC) Patients With EGFR Positive Mutation

• To define the maximum tolerated dose(MTD) and the recommended phase 2 dose (RP2D)
• To investigate the pharmacokinetic profile of TY-9591 and its metabolites after single then multiple doses of TY-9591 administered orally once daily
• To evaluate the anti-cancer activity of TY-9591 in NSCLC patients with EGFR mutation(ORR、PFS、DoR、DCR、and CBR)

Inclusion criteria

• 18-75years old, male or female.
• Histological or cytological confirmation diagnosis of NSCLC
• At least one measurable lesion according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1.
• Life expectancy of at least 3 months.
• Eastern Cooperative Oncology Group (ECOG) performance score 0 or 1.
• Documentation of disease progression while on previous continuous treatment with first-line EGFR TKI; patients must have confirmation of tumor EGFR activating mutations (exon 19 del, or exon 21 ) and T790M mutation status
• Adequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values:

a.Neutrophils (absolute value) ≥ 1.5×10^9/L; b.Hemoglobin ≥ 90 g/L; c.Platelet ≥ 80×10^9/L; d.Serum total bilirubin ≤ 1.5× ULN（for Patients with Gilbert Syndrome, total bilirubin ≤ 3×ULN and bilirubin ≤ 1.5×ULN should be permitted） f. Aspartate aminotransferase(AST)、alanine aminotransferase(ALT) ≤ 2.5×ULN; for patients with hepatic metastases, AST、ALT ≤ 5×ULN; g. International standardized ratio (INR) < 1.5, and activated partial prothrombin time (APTT) < 1.5×ULN;

• Female subjects have a negative urine or serum pregnancy.
• Provision of signed and dated, written informed consent prior to any study specific procedures, sampling and analyses.

Exclusion criteria

• Treatment with any of the following:

• Treatment with an EGFR TKI within 14 days or about 5x half-life, whichever is the longer, of the first dose of study drug;
• Any cytotoxic chemotherapy, investigational agents or anticancer drugs for the treatment from a previous treatment regimen within 4 weeks of the first dose of study treatment;
• Major surgery within 4 weeks of the first dose of study treatment;
• Radiotherapy with a limited field of radiation within 1 week of the first dose of study treatment, with the exception of patients receiving radiation to more than 30% of the bone marrow or with a wide field of radiation that had to be completed within 4 weeks of the first dose of study treatment;
• Previously treated by other third-generation epidermal growth factor receptor tyrosine kinase inhibitor(EGFR-TKI) for T790M (for example Osimertinib).
• Patients currently receiving (or at least within 1 week prior to receiving the first dose )medications or herbal supplements known to be potent inhibitors or inducers of cytochrome P450 isoenzyme (CYP)3A4.
• Any unresolved toxicities from prior therapy greater than Common Terminology Criteria for Adverse Events (CTCAE) grade 1 at the time of starting study treatment with the exception of alopecia and grade 2, prior platinum-therapy related neuropathy.
• Spinal cord compression or brain metastases unless asymptomatic.
• Dysphagia, or active digestive system diseases or previous significant bowel resection or medical conditions potentially affect TY-9591 absorption.
• Cardiac function and disease are consistent with the following:

• Corrected QT interval(QTc)> 470 milliseconds from 3 electrocardiograms (ECGs);
• Any clinically important abnormalities in rhythm;
• Any factors that increase the risk of QTc prolongation;
• Left ventricular ejection fraction (LVEF) <50%;
• Active human immunodeficiency virus (HIV), syphilis, hepatitis c virus (HCV) or hepatitis b virus (HBV) infection, with the exception of asymptomatic chronic hepatitis b or hepatitis c carriers.

7 .Previous history of interstitial lung disease(ILD)、drug-induced ILD or radiation pneumonitis require steroid treatment, or any evidence of clinically active ILD diseases.

• Previous allogeneic bone marrow transplant. 9. Hypersensitivity to TY-9591 or similar compounds or excipients. 10.Pregnant or lactating women.