Phase I Study of SPH1188-11 in NSCLC (SPH1188-11)

Inclusion Criteria:

1. 18-70years old, male or female.
2. Histological or cytological confirmation diagnosis of Non Small Cell Lung Cancer(NSCLC),Stage IIIBorIV, previous treatment with 1st EGFR-TKI, and/or previous chemotherapy. Regardless of EGFR mutation status.
3. At least one measurable disease according to RECIST 1.1.
4. Life expectancy of at least 3 months.
5. Eastern Cooperative Oncology Group (ECOG) performance score 0 or 1.
6. Females should be using adequate contraceptive measures from the time of screening until 3 months after discontinuing study treatment, should not be breast feeding and must have a negative pregnancy test 7days prior to start of dosing. Males should be willing to use barrier contraception during the trial and 3 months after discontinuing study treatment.
7. Provision of signed and dated, written informed consent prior to any study specific procedures, sampling and analyses.

Exclusion Criteria:

1. Treatment with an EGFR-TKI(eg, erlotinib, gefitinib, icotinib) within 7 days or approximately 5x half-life of study entry.
2. Previous treatment with 2nd EGFR-TKI or 3rd EGFR-TKI(eg, afatinib, osimertinib).
3. Any cytotoxic chemotherapy or anticancer drugs within 4 weeks of the first dose of study treatment.
4. Major surgery(excluding placement of vascular access) within 4 weeks of the first dose of study treatment.
5. Radiotherapy within 4 weeks of the first dose of study treatment.
6. Patients currently receiving(or unable to stop use at least 1 week prior to receiving the first dose) medications or herbal supplements known to be potent inhibitors of CYP3A4/CYP2D6, and/or potent inducers of CYP3A4/CYP2D6.

7. Laboratory values within 7 days of the first dose of study treatment:

   • Absolute neutrophil count<1.5×10^9/L
   • Platelet count <100×10^9/L
   • Haemoglobin<90 g/L
   • Alanine aminotransferase>2.5 times the upper limit of normal(ULN) if no demonstrable liver metastases or >5 times ULN in the presence of liver metastases.
   • Aspartate aminotransferase>2.5 times ULN if no demonstrable liver metastases or >5 times ULN in the presence of liver metastases.
   • Total bilirubin>1.5 times ULN if no liver metastases or >3 times ULN in the presence of documented Gilbert's Syndrome(unconjugated hyperbilirubinaemia) or liver metastases.
   • Creatinine>1.5 times ULN concurrent with creatinine clearance <50ml/min(measured or calculated by Cockcroft and Gault equation); confirmation of creatinine clearance is only required when creatinine is>1.5 times ULN.
8. Any unresolved toxicities from prior therapy greater than Common Terminology Criteria for Adverse Events(CTCAE) grade 1 at the time of starting study treatment (except alopecia and prior platinum-therapy related neuropathy)
9. Spinal cord compression or brain metastases unless asymptomatic, stable and not requiring steroids for at least 4 weeks prior to start of study treatment.
10. Any evidence of severe or uncontrolled systemic diseases, including active bleeding, active infection including hepatitis B(HBsAg+ and HBV-DNA+), hepatitis C and human immunodeficiency virus(HIV).
11. Cardiac criteria: QTc>480msec. LVEF<50%. Any clinically important abnormalities in rhythm, any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, congenital long QT syndrome, family in first degree relatives or any concomitant medication known to prolong the QT interval.
12. Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease.
13. Idiopathic pulmonary fibrosis.
14. Chronic gastrointestinal diseases, characterized by diarrhea.
15. Inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of SPH1188-11.
16. History of Keratitis, ulcerative keratitis, severe xerophthalmia.
17. Previous or concomitant malignancies at other sites, except effectively treated nonmelanoma skin cancers, carcinoma in situ of the cervix, ductal carcinoma in situ or effectively treated malignancy that has been in remission for more than 5 years and is considered to be cured.
18. History of neurological or mental disorders, including epilepsy or dementia.
19. Allergy to the test drug or any excipient of the product.
20. Participate in other drug clinical trials within 4 weeks of the first dose of study treatment.
21. Receiving any other anti-tumor therapy.
22. Women who are breast feeding or pregnant.
23. Judgment by the investigator that the patient should not participate in the study.