A Clinical Trial of Fruquintinib in Patients With Advanced Non-small Cell Lung Cancer

Approximately 90 subjects will be randomized to Fruquintinib plus best supportive care or placebo plus best supportive care at a 2:1 ratio.

Randomization will be stratified by EGFR (epidermal growth factor receptor) gene status: mutant vs. wild type vs. unknown.

All subjects will receive Fruquintinib/placebo for consecutive 3 weeks, followed by one-week rest. A treatment cycle consists of 4 weeks. Tumor assessment will be performed every 4 weeks in the first 3 cycles, and every 8 weeks since the 4th cycle, until disease progression. Further treatment and survival follow-up after progression will be recorded.

Inclusion criteria

• Fully understand the study and sign the informed consent form voluntarily;
• Histologically and/or cytologically diagnosed with local advanced and/or metastatic stage IIIB/IV non-squamous NSCLC;
• Previously failed to two chemotherapy regimens(treatment failure is defined as disease progression or intolerable toxicity), patients with positive EGFR mutation permitted to treated by EGFR-TKI previously; patients with EGFR wild type or unknown whether or not treated by EGFR-TKI previously;
• Aged 18-75 years (inclusive);
• Body weight ≥40 kg;
• Evident measurable lesion(s) (according to RECIST1.1);
• ECOG Performance Status 0-1;
• Expected survival >12 weeks

Exclusion criteria

• Treatment in another clinical trials in the past 3 weeks; or treatment with systemic anti-tumor chemotherapy, radiotherapy or biotherapy within 3 weeks prior to administration of the study drug;
• Previous therapy with VEGF/VEGFR inhibitors;
• Unrecovered from toxicity caused by previous anti-cancer treatment (CTCAE >grade 1), or not completely recovered from previous surgery;
• Previous active brain metastasis (without radiotherapy previously, or symptoms stable < 4 weeks, or with clinical symptoms, or with medication to control symptoms);
• Other malignancies except basal cell carcinoma or cervical carcinoma in situ in the past 5 years;
• Uncontrolled clinical active infection, e.g. acute pneumonia and active hepatitis B;
• Dysphagia or known drug malabsorption;
• Present active duodenal ulcer, ulcerative colitis, intestinal obstruction and other gastrointestinal diseases or other conditions that may lead to gastrointestinal bleeding or perforation according to the investigators' judgment; or with a history of intestinal perforation or intestinal fistula;
• Have evidence or a history of thrombosis or bleeding tendency, regardless of seriousness;
• Stroke and/or transient ischemic attack within 12 months prior to enrollment;
• Appropriate organ function. Patients with any of the following conditions will be excluded:

• Absolute neutrophil count (ANC) <1.5×109/L, platelet <100×109/L or hemoglobin <9 g/dL within 1 week prior to enrollment;
• Serum total bilirubin >1.5 upper limit of normal (ULN), alanine transaminase and aspartate transferase >1.5×ULN; ALT and AST > 3×ULN in patients with liver metastasis;
• Electrolyte abnormality of clinical significance;
• Blood creatinine >ULN and creatinine clearance <60 ml/min;
• Urine protein 2+ or above, or 24 h urine protein quantification ≥1.0 g/24 h;
• Activated partial thromboplastin time (APTT) or/and INR and prothrombin time (PT) >1.5×ULN (according to reference range in each clinical study center);
• Uncontrolled hypertension, systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg with medication; or heart failure NYHA classification ≥ grade 2;
• Heart function evaluation: left ventricular ejection fraction <50% (echocardiography);
• Acute myocardial infarction, severe/unstable angina or coronary bypass surgery within 6 months prior to enrollment; history of arterial thrombosis or deep venous thrombosis;
• Skin wound, surgical site, wound site, severe mucosal ulcer or fracture without complete healing;
• Female subjects who are pregnant or lactating or of child bearing potential with positive pregnancy test result before the first dose;
• Patients with child bearing potential who or whose sexual partners are not willing to take contraceptive measures;
• Any clinical or laboratory abnormalities unfit to participate in this clinical trial according to the investigator's judgment;
• Serious psychological or psychiatric disorders which may affect subject compliance in this clinical study;
• Allergy to Fruquintinib and/or excipient contained in trial drugs.