A Study to Evaluate Safety and Efficacy of HS-10296 as First-Line Treatment in Patients

This is a randomized, controlled, double-blind, multicenter, phase III clinical study.

This is a randomized, controlled, double-blind, multicenter, phase III clinical trial, evaluating the efficacy and safety of HS-10296 compared to gefitinib in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor sensitizing mutations (EGFRm+) who have not received systemic therapy. Patients are randomly assigned to an HS-10296 treatment group or a gefitinib treatment group at a ratio of 1:1 and receive a once-daily oral dose of HS-10296 or gefitinib, in order to compare the efficacy and safety of the two different treatment regimens.

Eligibility Criteria:
Inclusion Criteria: Inclusion Criteria:

Any patient who meets all of the following inclusion criteria will qualify for entry into the study:

1. Provision of informed consent prior to any study specific procedures, sampling and analyses.
2. Male or female, age at least 18 years.
3. Pathologically confirmed locally advanced or metastatic NSCLC (e.g. this may occur systemic recurrence after prior surgery for early stage disease or patients may be newly diagnosed with stage IIIB/IV disease). Patients must be treatment-naïve for locally advanced or metastatic NSCLC. Prior adjuvant and neo-adjuvant therapy is permitted (chemotherapy, radiotherapy, investigational agents) provided all other entry criteria are satisfied.
4. The tumour harbours one of the 2 common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19del, L858R), either or in combination with other EGFR mutations assessed by central testing using tumour tissue sample or blood sample.
5. A WHO performance status equal to 0-1 with no deterioration over the previous 2 weeks and a minimum life expectancy of 12 weeks.
6. At least 1 lesion that has not previously been irradiated, that has not been chosen for biopsy during the study screening period, and that can be accurately measured at Baseline as ≥ 10 mm in the longest diameter (except lymph nodes, which must have short axis ≥ 15mm) with computerized tomography (CT) or magnetic resonance imaging (MRI), whichever is suitable for accurately repeated measurements. If only one measurable lesion exists, it is acceptable to be used (as a target lesion) as long as it has not been previously irradiated and baseline tumour assessment scans are done at least 14days afar the screening biopsy is performed.
7. Females should be using adequate contraceptive measures throughout the study; should not be breastfeeding at the time of screening, during the study and until 3 months after completion of the study; and must have a negative pregnancy test prior to start of dosing if of childbearing potential or must have evidence of non-childbearing potential by fulfilling 1 of the following criteria at Screening:

   1. Postmenopausal defined as age more than 50 years and amenorrheic for at least 12 months following cessation of all exogenous hormonal treatments.
   2. Women under 50 years old would be considered postmenopausal if they have been amenorrheic for 12 months or more, following cessation of exogenous hormonal treatments, and with luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels in the postmenopausal range for the laboratory.
   3. Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy, or bilateral salpingectomy, but not by tubal ligation.
8. Male patients should be willing to use barrier contraception (i.e., condoms).
9. For inclusion in study, patient must provide a written informed consent.

   -

Exclusion Criteria: Exclusion Criteria:

Any patient who meets any of the following exclusion criteria will not qualify for entry into the study:

1. Treatment with any of the following:

   1. Prior treatment with systemic anti-cancer therapy for locally advancer or metastatic NSCLC including chemotherapy, biologic therapy, immunotherapy, or any investigational drug.
   2. Prior treatment with an EGFR TKI.
   3. Major surgery (excluding placement of vascular access) within 4 weeks of the first dose of study drug.
   4. Radiotherapy with a limited field of radiation for palliation within 4 week of the first dose of study drug, with the exception of patients receiving radiation to \> 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of study drug.
   5. Medications that are predominantly CYP3A4 strong inhibitors or inducers or sensitive substrates of CYP3A4 with a narrow therapeutic range within 7 days of the first dose of study drug.
2. Any concurrent and/or other active malignancy that has required treatment within 2 years of first dose of study drug.
3. 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.
4. Spinal cord compression or brain metastases unless asymptomatic, stable, and not requiring steroids for at least 2 weeks prior to start of study treatment.
5. Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension or active bleeding diatheses, which, in the Investigator's opinion, makes it undesirable for the patient to participate in the trial OR which would jeopardize compliance with the protocol such as active infection. Screening for chronic conditions is not required.
6. Refractory nausea, vomiting, or chronic gastrointestinal diseases, inability to swallow the study drug, or previous significant bowel resection that would preclude adequate absorption of HS 10296.
7. Any of the following cardiac criteria:

   1. Mean resting corrected QT interval (QTc) \> 470 ms obtained from 3 electrocardiograms (ECGs), using the screening clinic's ECG machine and Fridericia's formula for QT interval correction (QTcF).
   2. Any clinically important abnormalities in rhythm, conduction, or morphology of the resting ECG (e.g., complete left bundle branch block, third-degree heart block, second-degree heart block, PR interval \> 250 ms).
   3. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events, such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval.
   4. Left ventricular ejection fraction (LVEF) ≤ 40%.
8. Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis that required steroid treatment, or any evidence of clinically active interstitial lung disease.
9. Inadequate bone marrow reserve or organ function, as demonstrated by any of the following laboratory values:

   1. Absolute neutrophil count (ANC) \<1.5×109 / L
   2. Platelet count \<100×109 / L
   3. Hemoglobin \<90 g/L（\<9 g/dL）
   4. Alanine aminotransferase \> 2.5 × upper limit of normal (ULN) if no demonstrable liver metastases or \> 5 × ULN in the presence of liver metastases.
   5. Aspartate aminotransferase (AST) \> 2.5 × ULN if no demonstrable liver metastases or \> 5 × ULN in the presence of liver metastases.
   6. Total bilirubin (TBL) \> 1.5 × ULN if no liver metastases or \> 3 × ULN in the presence of documented Gilbert's Syndrome (unconjugated hyperbilirubinemia) or liver metastases.
   7. Creatinine \> 1.5 × ULN concurrent with creatinine clearance \< 50 mL/min (measured or calculated by the Cockcroft-Gault equation); confirmation of creatinine clearance is only required when creatinine is \> 1.5 × ULN.
10. Women who are breastfeeding or have a positive urine or serum pregnancy test at the Screening Visit.
11. History of hypersensitivity to any active or inactive ingredient of HS 10296 or to drugs with a similar chemical structure or class to HS 10296.
12. Judgment by the Investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions, and requirements.
13. Any severe and uncontrolled ocular disease that may, in the ophthalmologist's opinion, present a specific risk to the patient's safety.
14. Any disease or condition that, in the opinion of the Investigator, would compromise the safety of the patient or interfere with study assessments.

    -