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

This is a randomized, double-blind, placebo-controlled, multi-center Phase II clinical trial to evaluate the efficacy and safety of Fruquintinib plus best supportive care in patients with advanced non-squamous non-small cell lung cancer who failed to second-line standard chemotherapy.

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.

Eligibility Criteria:
Inclusion Criteria:

1. Fully understand the study and sign the informed consent form voluntarily;
2. Histologically and/or cytologically diagnosed with local advanced and/or metastatic stage IIIB/IV non-squamous NSCLC;
3. 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;
4. Aged 18-75 years (inclusive);
5. Body weight ≥40 kg;
6. Evident measurable lesion(s) (according to RECIST1.1);
7. ECOG Performance Status 0-1;
8. Expected survival \>12 weeks

Exclusion Criteria:

1. 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;
2. Previous therapy with VEGF/VEGFR inhibitors;
3. Unrecovered from toxicity caused by previous anti-cancer treatment (CTCAE \>grade 1), or not completely recovered from previous surgery;
4. Previous active brain metastasis (without radiotherapy previously, or symptoms stable \< 4 weeks, or with clinical symptoms, or with medication to control symptoms);
5. Other malignancies except basal cell carcinoma or cervical carcinoma in situ in the past 5 years;
6. Uncontrolled clinical active infection, e.g. acute pneumonia and active hepatitis B;
7. Dysphagia or known drug malabsorption;
8. 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;
9. Have evidence or a history of thrombosis or bleeding tendency, regardless of seriousness;
10. Stroke and/or transient ischemic attack within 12 months prior to enrollment;
11. 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);
12. Uncontrolled hypertension, systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg with medication; or heart failure NYHA classification ≥ grade 2;
13. Heart function evaluation: left ventricular ejection fraction \<50% (echocardiography);
14. Acute myocardial infarction, severe/unstable angina or coronary bypass surgery within 6 months prior to enrollment; history of arterial thrombosis or deep venous thrombosis;
15. Skin wound, surgical site, wound site, severe mucosal ulcer or fracture without complete healing;
16. Female subjects who are pregnant or lactating or of child bearing potential with positive pregnancy test result before the first dose;
17. Patients with child bearing potential who or whose sexual partners are not willing to take contraceptive measures;
18. Any clinical or laboratory abnormalities unfit to participate in this clinical trial according to the investigator's judgment;
19. Serious psychological or psychiatric disorders which may affect subject compliance in this clinical study;
20. Allergy to Fruquintinib and/or excipient contained in trial drugs.