Ningetinib (CT053PTSA) Plus Gefitinib in Stage IIIB or IV NSCLC Patients With EGFR Mutation and T790M Negative

This study is being carried out in two parts, part 1 and part 2.

Part 1: This is the dose-escalation part. The primary purpose of the part 1 portion is to determine the dose limiting toxicity (DLT) and maximum tolerated dose (MTD), and recommend the appropriate doses of CT053PTSA in combination with gefitinib for further studies.

Part 2: This is the expansion part. The part 2 portion of this study will continue to evaluate the safety and efficacy of the combination of CT053PTSA and gefitinib , at the appropriate doses recommended in Part 1, in patients with EGFR mutation, T790M negative NSCLC.

Inclusion criteria

• Histologically or cytologically confirmed Stage IIIB or IV NSCLC
• Resistance to EGFR TKI (1st, 2nd or 3rd generation)
• Histological or cytological evidence of EGFR mutation and T790M negative after progression on last EGFR TKI therapy
• c-Met GCN ≥ 6 or cluster amplification is required if participant is resistant to1st or 2nd generation EGFR-TKI ;c-MET GCN statue is not required, If participant is resistant to3rd generation EGFR-TKI （osimertinib）；
• Measurable disease according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1)
• Toxicity recovered to NCI CTCAE v.4.03 Grade ≤1 from previous treatments (except alopecia)
• ECOG performance status (PS) 0 or 1
• Life expectancy of ≥ 12 weeks
• Adequate organ function

Exclusion criteria

• Prior treatments

• Chemotherapy, targeted therapy (except EGFR TKI), immunotherapy, radiotherapy, or major surgery within 4 weeks prior to study treatment
• Nitrosourea and mitomycin chemotherapy within 6 weeks prior to study treatment
• EGFR TKI treatment within 2 weeks prior to study treatment
• Had received live vaccine within 4 weeks prior to study treatment
• Had received any investigational agent from other clinical study within 4 weeks prior to study treatment or are currently participating in other clinical trials
• Previous treatment with any other c-MET inhibitor or Axl inhibitor (eg, crizotinib, cabozantinib, volitinib, INC280)
• Symptomatic, untreated or unstable central nervous system metastases
• Spinal cord compression, carcinomatous meningitis or leptomeningeal diseaseonly (patient are only permitted if treated, asymptomatic and stable for at least 4 weeks prior to start of study treatment)
• Interstitial pneumonia or radiation pneumonitis
• Uncontrolled hypertension that require more than two anti-hypertensive agents to control, or systolic blood pressure (BP) >140mmHg or diastolic BP >90 mmHg before the first administration (BP is the mean blood pressure of two measures that 1 hours interval or above)
• Doppler ultrasound evaluation：Left ventricular ejection fraction < 50%
• Grade ≥ 2 of arrhythmia (assessed by NCI CTCAE 4.03), or symptomatic bradycardia, or male with QTCF > 450 ms or female with QTCF > 470 ms, or patients with a history of torsion or congenital QT prolonged syndrome long QT syndrome
• Certain factors that would preclude adequate absorption of CT053PTSA and gefitinib (eg. unable to swallow, chronic diarrhea, intestinal obstruction)
• Significant hemoptysis within 2 months prior to enrollment, or a daily hemoptysis volume is 2.5 ml or above
• Patients with evidence of bleeding tendency, including the following cases: gastrointestinal bleeding, hemorrhagic gastric ulcer, fecal occult blood ++ and above; or melena or hematemesis within 2 months; or visceral bleeding that may occur considered by investigator
• History of immunodeficiency, or other acquired or congenital immunodeficiency, or history of organ transplantation
• Any disease of the following bellowed within 12 months prior to administration: Myocardial infarction, severe angina, or unstable angina, coronary or peripheral artery bypass graft, congestive heart failure, or cerebrovascular events (including transient ischemic attack)
• Pulmonary embolism within 6 months prior to administration
• Active infection of hepatitis B, or infection of HIV
• Other malignancies within 5 years prior to enrollment, with the exception of carcinoma in situ of the cervix, basal or squamous cell skin cancer
• History of thyroid dysfunction, and the thyroid function cannot be maintained at the normal range with drugs.
• Serious electrolyte imbalance in the investigator's judgment
• Pregnant or lactating woman
• Any other reason the investigator considers the patient is not suitable to participate in the study