Study Of Comparing SAF-189s With Crizotinib In First Line ALK-Positive Advanced and Metastatic NSCLC

Inclusion criteria

• Sufficiently understand the study and are willing to sign the informed consent form (ICF);
• Male or female patients ≥ 18；
• Histologically or cytologically confirmed diagnosis of local advanced (Stage IIIB/IIIC) or metastatic (Stage IV) NSCLC;
• ALK-positive as assessed by the Ventana immunohistochemistry (IHC) test. Sufficient tumor tissue available to perform ALK IHC is required. Ventana IHC testing will be performed at the designated central laboratory;
• Measurable disease by response evaluation criteria in solid tumors (RECIST) version 1.1 (v1.1) prior to the administration of study treatment; Lesions that have received radiation therapy cannot be considered as target lesions unless there is confirmed progression of the lesion after radiation therapy;
• Participants with no prior systemic treatment for local advanced (Stage IIIB/IIIC not amenable for multimodality treatment) or metastatic (Stage IV) NSCLC;
• Eastern cooperative oncology group performance status (ECOG PS) of 0-2;
• Life expectancy of at least 12 weeks;
• Adequate organ and bone marrow function as documented by:Hematologic function: absolute neutrophil count (ANC) ≥1.5 × 10^9/L; hemoglobin≥ 90 g/L; Platelet count ≥ 100 × 109/L;Serum total bilirubin ≤ 1.5 × ULN (if the patient has Gilbert's syndrome, ≤ 3 × ULN and direct bilirubin ≤ 1.5 × ULN);Aspartate aminotransferase (AST) and alanine transaminase (ALT) ≤ 2.5 × ULN (≤ 5 × ULN for patient with liver metastases);Creatinine clearance (CrCL) ≥ 50 mL/min (calculated by Cockcroft-Gault equation)；Baseline QTc ≤470 ms corrected by Fridericia fomula;Baseline LVEF≥50%;
• For all females of childbearing potential (FCBP), a negative serum pregnancy test result must be obtained within 7 days prior to starting study treatment, and agree to use a highly effective method of contraception, during the treatment period and for 3 months following the last dose of study drug.For men whose partners are fertile women, agreement to remain abstinent or use a condom plus an additional contraceptive method during the treatment period and for at least 3 months after the last dose of study drug. Abstinence is acceptable only if it is in line with the preferred and usual lifestyle of the participant. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception. This protocol defines a FCBP as a sexually mature woman who:1）has not undergone a hysterectomy or bilateral oophorectomy；2）has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out child-bearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).

Exclusion criteria

• Has had prior anti-cancer treatment with biological drugs, or other investigational agents within 28 days; or received chemotherapy, TKI or targeted therapies within 14 days prior to enrollment; or based on the last administration within 5 half-life of the drug (whichever is shorter);
• Patients with central nervous system (CNS) metastases requiring: 1）clinical local intervention such as surgical excision, radiotherapy or other therapies (known brain metastasis or other CNS metastasis that is either asymptomatic or symptomatic but requiring no local interventions may qualify for the study per the investigator); 2）patients requiring systemic treatment with corticosteroids and >10 mg/day prednisone or equivalent; 3）requiring antiepileptic drug sustained treatment;
• Spinal cord meatstasis with potential risk of or symptomic spinal cord compression;
• National cancer institute common terminology criteria for adverse events (NCI CTCAE) (version 5.0) Grade 2 or higher toxicities due to any prior therapy (e.g., chemotherapy, surgery or radiotherapy) (excluding alopecia)
• Patient has uncontrolled diabetes and intervented by insulin (patient with fasting blood glucose levels <9.8 mmol/L under stable oral hypoglycemic medications allowed to be enrolled);
• Has a history of acute pancreatitis within 1 year before enrollment, ;
• Patients have history of interstitial lung disease, drug-induced interstitial lung disease or induced by radiation therapy and requring hormone therapy, or still receiving medication or other clinical intervention, or currently having active pulmonary interstitial lesions;
• The patients had uncontrollable amounts of pleural effusion, ascites, and pericardial effusion.
• Patients with inability to swallow or with active digestive system disease or underwent major GI surgery, which remarkably affect oral administration or absorption of study drug (e.g., ulcerative diseases, uncontrolled nausea and vomiting, diarrhea, malabsorption syndrome, and small bowel resection);
• History of hypersensitivity to any of the additives in the SAF-189s and drug formulation;
• History of hypersensitivity to any of the additives in the crizotinib and drug formulation;
• Patients with clinically significant active bacterial, fungal or viral infections, including hepatitis B virus surface antigen-positive and hepatitis B virus DNA over 2000 IU/mL, positive for hepatitis C virus (HCV) antibody test; confirmed human immunodeficiency virus (HIV) infection, and those who are unwilling to undergo HIV testing; hepatitis B carriers are allowed to be enrolled;
• Patients have other malignant tumor history in 3 years or with other malignant tumors simultaneously (excluding curatively treated in situ carcinoma of cervix cancer, non-melanoma skin basal cell carcinoma, thyroid carcinoma in situ, and any cured tumor which is considered to have no impact in progression-free survival (PFS) or overall survival (OS) for the current NSCLC);
• Patients with cardiac function impairment or clinically significant heart diseases, including congestive heart-failure New York Heart Association (NYHA) III or above, arrhythmias (including but not limited to complete left bundle branch Atrioventricular block complete and atrioventricular block second degree), conduction abnormality requiring medication, severe coronary artery disease, heart valve disease or myocardiopathy or uncontrolled hypertension;
• Patients who received major surgery within 3 weeks before enrollment or have not adequately recovered from prior surgery. Major surgery is defined as Grade 3 or 4 surgery per Management Measures for Clinical Application of Medical Technology implemented on May 1st, 2009 in China;
• Patients who have been received one of the following treatments: 1）strongly inhibits or induces of CYP3A4, repaglinide (cytochrome [CYP]2C8 sensitive substrate) and drugs metabolized via CYP3A4 enzyme within 1 week before enrollment; 2）medicines which are known to cause QT prolongation or torsade de pointes;3）coumarin anticoagulants within 1 week before enrollment (low molecular weight heparin is permitted);4）illegal drugs;
• Pregnant or lactating: any subjects who experience pregnancy during the trial need to withdraw from the study.
• Any other clinically significant disease or condition, or acute or chronic medical conditions (such as uncontrolled diabetes), or mental condition or abnormal lab test, that investigator assesses that maybe increase the risk of participating or affect the interpretation of research reslults.