A Study to Evaluate Safety and Efficacy of HS-10296 as First-Line Treatment in Patients
Condition: Non Small Cell Lung Cancer
MeSH terms: Carcinoma, Non-Small-Cell Lung
Intervention: HS-10296; Gefitinib
Intervention description: Drug: HS-10296 110 mg/55 mg + placebo The initial dose of HS-10296 110 mg once daily can be reduced to 55 mg once daily under specific circumstances. A cycle of treatment is defined as 21 days of once daily treatment. Number of Cycles: as long as patients are continuing to show clinical benefit, as judged by the Investigator, and in the absence of discontinuation criteria.; Drug: Gefitinib 250 mg + placebo The initial dose of Gefitinib 250 mg once daily cannot be reduced. A cycle of treatment is defined as 21 days of once daily treatment. Number of cycles: as long as patients are continuing to show clinical benefit, as judged by the Investigator, and in the absence of discontinuation criteria.
Intervention MeSH terms: Gefitinib
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 429.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

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

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.

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        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.

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