A Phase I Study of FCN-411 in Advanced Non-small Cell Lung Cancer Chinese Patients With EGFR Positive Mutation

Inclusion Criteria:

1. Age 18 years and older.
2. Histological or cytological confirmed diagnosed advanced or metastatic NSCLC.
3. 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 ins) and T790M status by biopsy sample or optical microscopy.
4. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG).
5. Have a life expectancy of at least 12 weeks.
6. Have measurable disease based on RECIST v1.1. Note: previously irradiated not chosen, unless disease progression after irradiation.
7. Adequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values:

   1. Neutrophils (absolute value) ≥ 1.5×10\^9/L;
   2. Hemoglobin ≥ 90 g/L;
   3. Platelet ≥ 90×10\^9/L;
   4. Serum total bilirubin ≤ 1.5× ULN（for Patients with Gilbert Syndrome, total bilirubin ≤ 3×ULN and bilirubin ≤ 1.5×ULN should be permitted）
   5. Aspartate aminotransferase、alanine aminotransferase ≤ 2.5×ULN; for patients with hepatic metastases, AST、ALT ≤ 5×ULN;
   6. Creatinine \< 1.5×ULN creatinine clearance rate≥ 45 mL/min (Cockcroft Gault for calculating)
8. Female subjects have a negative urine or serum pregnancy.

Exclusion Criteria:

1. Treatment with any of the following:

   1. Treatment with an EGFR TKI within 14 days or about 5 half-lives, whichever is the longer, of the first dose of study drug;
   2. Any cytotoxic chemotherapy, investigational agents or anticancer drugs for the treatment from a previous treatment regimen within 14 days of the first dose of study treatment;
   3. Major surgery within 4 weeks of the first dose of study treatment;
   4. Systemic irradiation including whole brain irradiation;
   5. Previously treated by EGFR-TKI for T790M (for example Osimertinib).
2. P-glycoprotein inducers (for example Rifampicin) or inhibitors (for example ritonavir) are required during the study.
3. Any unresolved toxicities from prior therapy greater than CTCAE grade 1 at the time of starting study treatment with the exception of alopecia and grade 2, prior platinum-therapy related neuropathy.
4. Meningeal metastases or CNS metastasis received intervention or malignancy related epilepsy; brain metastases without symptom are eligible.
5. Any serious or uncontrolled systemic disease, including but not limited to:

   1. Uncontrolled hypertension;
   2. Active hemorrhage;
   3. Active infections including hepatitis B, or hepatitis C;
   4. Human immunodeficiency virus positive;
   5. Child Pugh C;
   6. Bullous or exfoliative skin diseases;
   7. Severe malnutrition;
   8. History of keratitis or ulcerative keratitis or dry eye;
   9. Uncontrolled large amount of third interstitial fluid retention;
   10. Other serious diseases or mental disorders or laboratory abnormalities.
6. Cardiac function and disease are consistent with the following:

   1. QTc\> 470 milliseconds from 3 electrocardiograms (ECGs);
   2. Any clinically important abnormalities in rhythm;
   3. Any factors that increase the risk of QTc prolongation;
   4. Congestive heart failure ≥ grade 3 by New York Heart Association (NYHA);
7. Previous history with interstitial lung disease、drug-induced interstitial lung disease or radiation pneumonitis require hormone therapy, or other active interstitial lung diseases required treatments.
8. Lung function met one of the following criteria:

   1. Oxygen saturation ≤ 88%;
   2. The first second forced expiratory volume\< 50% of the predicted value;
   3. Diffusion capacity for CO \< 50% of the predicted value.
9. Dysphagia, or active digestive system diseases or medical conditions potentially affect FCN-411 absorption.
10. Hypersensitivity to FCN-411 or similar compounds or excipients.
11. Pregnant or lactating women.