Phase I Study of HSK40118 in NSCLC Patients With EGFR Mutation

This is a phase I, open-label, dose-escalation and expansion study to evaluate the safety, tolerability, PK and PD of HSK40118 when given orally in patients with active EGFR mutation locally advanced or metastatic non-small cell lung cancer (NSCLC).

The study will contain two phase: Phase Ia is dose escalation phase and Phase Ib is dose expansion phase.

Phase Ia will contain two part: Dose Escalation Part(Part A) and Extension Part(Part B). Part A based on the "3+3" design for dose escalation and safety evaluation requirements. Patient cohorts at selected doses may be extended to further investigate the tolerability, PK and PD of HSK40118. The number of patients to be enrolled will be up to 10 subjects in each Part B cohort. Approximately 30-70 subjects will be enrolled in Phase Ia.

Phase Ib no less than 130 subjects will be enrolled in each expansion cohort, cohort A will be enrolled 30-50 subjects, cohort B will be enrolled no less than 100 subjects.

Eligibility Criteria:
Inclusion Criteria:

1. Age ≥ 18 years, Male and female patients, at time of signing informed consent form (ICF).
2. ECOG=0-1, with no deterioration in 2 weeks before first dose of HSK40118.
3. Histological or cytological confirmed diagnosis of unresectable locally advanced or metastatic NSCLC.
4. Patients will provide blood or tumor sample according to their own willingness.
5. Patients in Phase Ia and Ib will fulfill the different criteria of the following:

   Phase Ia(Part A): Previous treatment with at least one EGFR-TKI, including 1st, 2nd and 3rd-generation EGFR-TKI; Phase Ia(Part B)/Phase Ib: Previous treatment with 3rd-generation EGFR-TKI.
6. tumour lesions/lymph nodes: Phase Ia(Part A): Patients should have at least one assessable tumour lesions/malignant lymph nodes; Phase Ia(Part B) /Phase Ib: Patients should have at least one measurable tumour lesions/malignant lymph nodes.
7. Life expectancy ≥ 3 months.
8. Adequate hematologic and organ function per protocol.
9. Women of childbearing potential (WOCBP) and fertile males with WOCBP partners must use highly effective contraception per protocol throughout and after 90 days of the last dose of the study.

Exclusion Criteria:

1. malignant tumor within 5 years, with the exception of cutaneous squamous cell carcinoma, cervical carcinoma in situ, papillary thyroid carcinoma, or other tumors with low malignancy.
2. Unstable spinal cord compression or brain metastases per protocol.
3. Uncontrollable pleural effusion, ascites, or pericardial effusion per protocol.
4. Prior treatment with 4th-generation EGFR-TKIs(TKI for 3th-generation resistance).
5. Treatment with any of the following:

   Prior treatment with an EGFR-TKI or other small-molecule anti-tumor drug within 7 days or approximately 5 × t1/2 prior to the first dose of HSK40118, whichever is shorter; Prior treatment with chemotherapy, palliative radiotherapy, or Herbal therapy within 2 weeks or approximately 5 × t1/2 prior to the first dose of HSK40118, whichever is shorter; Prior treatment with radiotherapy, immunotherapy/biotherapy therapy, or other pharmaceutical clinical trial within 4 weeks or approximately 5 × t1/2 prior to the first dose of HSK40118, whichever is shorter.
6. Treatment with inhibitors for P-glycoprotein (P-gp) within 7 days prior to the first dose of HSK40118.
7. 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, dermal toxicity, and other toxicity considering no safety risks by investigator.
8. Any disease which would cause chronic diarrhea, eg. Crohn's disease, or irritable bowel syndrome.
9. Any disease which would preclude drug absorption, metabolism or pharmacokinetics, eg. active peptic ulcer or chronic gastroesophageal reflux disease.
10. Any severe disease of respiratory system, eg. interstitial lung disease, radiation pneumonitis, drug-induced pneumonitis, or uncontrolled asthma.
11. Patient who have clinically significant or uncontrolled cardiac disease, include: QTc interval ≥ 450(male)/470(female) msec; any clinically significant arrhythmia; left ventricular ejection fraction \< 50%; myocardial infarction, unstable angina, or class III/IV cardiac failure by the NYHA that occurred within 6 months prior to the first dose of HSK40118.
12. Any thromboembolic events within 6 months prior to the first dose of HSK40118; any familial or aquired thrombophilia.
13. Active bleeding at screening, history of visceral hemorrhage within 3 months prior to the first dose of HSK40118, or visceral bleeding tendency within 6 months prior to the first dose of HSK40118.
14. Patient who is undergoing, or receiving long-term(\> 6 months) anticoagulant/antiplatelet therapy; receiving drugs affecting coagulation function 1 week prior to the first dose of HSK40118.
15. INR, APTT \> 1.5xULN, or any bleeding tendency or coagulopathy at screening.
16. Uncontroled hypertension(systolic pressure ≥160mmHg, or diastolic pressure ≥100mmHg).
17. Any unstable systemic disease, eg. severe metabolic disease: liver cirrhosis, renal failure, or uremia.
18. Any disease of the eyes \> CTCAE v5.0 Grade 1.
19. Autologous transplantation surgery within 3 months prior to the first dose of HSK40118; Allogeneic transplantation, or stem-cell Transplant surgery within 6 months prior to the first dose of HSK40118; Major surgery or significant traumatic injury occurring within 4 weeks prior to the first dose of HSK40118.
20. Patients with HIV, HBV or HCV infection.
21. Patients with active syphilis infection.
22. Patients who have an uncontroled systematic infection, eg. fungal, bacterial, or virus infection.
23. Patients who would interfere with cooperation or outcome-assessment of the trial.
24. Allergic to any HSK40118 active constituent or ingredients.
25. (Child-bearing period women only)Patients testing positive for pregnancy, or during lactation.
26. Any other circumstances that would, in the investigator's judgment, prevent the subject's participation in the clinical study due to safety concerns or compliance with clinical study procedures.